Clinical and genomic epidemiology of mcr-9-carrying carbapenem-resistant Enterobacterales isolates in Metropolitan Atlanta, 2012-2017 (preprint)
Babiker A , Bower C , Lutgring JD , Howard-Anderson J , Ansari U , McAllister G , Adamczyk M , Breaker E , Satola SW , Jacob JT , Woodworth MH . medRxiv 2021 2021.10.13.21264308 Colistin is a last-resort antibiotic for multidrug-resistant gram-negative infections. Recently, the ninth allele of the mobile colistin resistance (mcr) gene family, designated mcr-9, was reported. However, its clinical and public health significance remains unclear. We queried genomes of carbapenem-resistant Enterobacterales (CRE) for mcr-9 from a convenience sample of clinical isolates collected between 2012-2017 through the Georgia Emerging Infections Program, a population- and laboratory-based surveillance program. Isolates underwent phenotypic characterization and whole genome sequencing. Phenotypic characteristics, genomic features, and clinical outcomes of mcr-9 positive and negative CRE cases were then compared. Among 235 sequenced CRE genomes, thirteen (6%) were found to harbor mcr-9, all of which were Enterobacter cloacae complex. The median MIC, rates of heteroresistance and inducible resistance to colistin were similar between mcr-9 positive and negative isolates. However, rates of resistance were higher among mcr-9 positive isolates across most antibiotic classes. All cases had significant healthcare exposures. The 90-day mortality was similarly high in both mcr-9 positive (31%) and negative (7%) CRE cases. Nucleotide identity and phylogenetic analysis did not reveal geo-temporal clustering. mcr-9 positive isolates had a significantly higher number of median [range] AMR genes (16 [4-22] vs. 6 [2-15]; p <0.001) compared to mcr-9 negative isolates. Pan genome tests confirmed a significant association of mcr-9 detection with mobile genetic element and heavy metal resistance genes. Overall, the presence of mcr-9 was not associated with significant changes in colistin resistance or clinical outcomes but continued genomic surveillance to monitor for emergence of AMR genes is warranted.Competing Interest StatementThe authors have declared no competing interest.Funding StatementEIP Surveillance of the Multi-site Gram-Negative Surveillance Initiative (MuGSI) was funded through the Centers for Disease Control and Preventions Emerging Infections Program [U50CK000485].Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Georgia EIP surveillance activities are reviewed and approved by the Emory University Institutional Review Board.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors |
Protocol for a sequential, prospective meta-analysis to describe coronavirus disease 2019 (COVID-19) in the pregnancy and postpartum periods (preprint)
Smith ER , Oakley E , He S , Zavala R , Ferguson K , Miller L , Grandner GW , Abejirinde IO , Afshar Y , Ahmadzia H , Aldrovandi G , Akelo V , Tippett Barr BA , Bevilacqua E , Brandt JS , Broutet N , Fernández Buhigas I , Carrillo J , Clifton R , Conry J , Cosmi E , Delgado-López C , Divakar H , Driscoll AJ , Favre G , Flaherman V , Gale C , Gil MM , Godwin C , Gottlieb S , Hernandez Bellolio O , Kara E , Khagayi S , Kim CR , Knight M , Kotloff K , Lanzone A , Le Doare K , Lees C , Litman E , Lokken EM , Laurita Longo V , Magee LA , Martinez-Portilla RJ , McClure E , Metz TD , Money D , Mullins E , Nachega JB , Panchaud A , Playle R , Poon LC , Raiten D , Regan L , Rukundo G , Sanin-Blair J , Temmerman M , Thorson A , Thwin S , Tolosa JE , Townson J , Valencia-Prado M , Visentin S , von Dadelszen P , Adams Waldorf K , Whitehead C , Yang H , Thorlund K , Tielsch JM . medRxiv 2022 2020.11.08.20228056 We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis.Competing Interest StatementClare Whitehead declares a a relationship with the following entities, Ferring Pharmaceuticals COVID19 Investigational, Grant, NHMRC Fellowship (salary support). Alice Panchaud declares the following research grants to institution: H2020-Grant (Consortium member of Innovative medicine initiative call 13 topic 9) (ConcePTION), Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead (CONSIGN: Study on impact of COVID-19 infection and medicines in pregnancy), Safety monitoring of COVID-19 vaccines in the EU Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3) 4. Federal Office of Public Health (207000 CHF). (The COVI-Preg registry). Edward Mullins declares a relationship with the following entities National Institute for Health Research (Project grant for PAN COVID study) Deborah Money declares a relationship with the following entities, Canadian Institutes of Health Research (payments to my institution only), Public Health Agency of Canada (payments to my institution only), BC Womens Foundation (payments to my institution only) and is a Member of the COVID-19 Immunity Task Force sponsored by the Canadian government. Torri D. Metz declares a relationship with the following entities, Pfizer (site Principal Investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to me), NICHD (subcommittee Chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study), and Society for Maternal-Fetal Medicine (board member). Erica Lokken declares a relationship with the following entity, US NIH (paid institution). Karen L. Kotloff declares a relationship with the following entity, Bill and Melinda Gates Foundation. Siran He declares a relationship with the following entity, Bill and Melinda Gates Foundtion (payments made to my institution). Valerie Flaherman declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments to my institution), Yellow Chair Foundati n (payments to my institution), Robert Woods Johnson Foundation (payments to my institution), CDC Foundation, California Health Care Foundation (payments to my institution), Tara Health Foundation (payments to my institution), UCSF Womens Health Center of Excellence (payments to my institution) and California Department of Health Care Services (payments made to my institution). Jose Sanin-Blair declares a relationship with the following entity, Ferring Pharmaceuticals which give a grant ($10,000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology Yalda Afshar declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments made to my institution), CDC Foundation (payments made to my institution), Robert Woods Johnson Foundation (payments made to my institution), and UCLA Deans Office COVID-19 research (payments made to my institution). Rebecca Cliffton declares a relationship with the following entity, NIH HD36801 (MFMU Network DCC).Clinical TrialPROSPERO ID: 188955Funding StatementFunded by the Bill & Melinda Gates Foundation grant to Emily Smith (INV-022057) at George Washington University and a grant to Emily Smith via a grant from the Bill & Melinda Gates Foundation to Stephanie Gaw (INV-017035) at University of California San Francisco.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This is a protocol paper and thus exempt from ethical approval. Ultimately, the meta-analysis study is exempt from human research ethics approval as the study authors will be synthesizing de-identified or aggregate data.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThis is a protocol paper and there is no related data to share. |
A Remote Household-Based Approach to Influenza Self-Testing and Antiviral Treatment (preprint)
Heimonen J , McCulloch DJ , O'Hanlon J , Kim AE , Emanuels A , Wilcox N , Brandstetter E , Stewart M , McCune D , Fry S , Parsons S , Hughes JP , Jackson ML , Uyeki TM , Boeckh M , Starita LM , Bedford T , Englund JA , Chu HY . medRxiv 2021 2021.02.01.21250973 Background Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery.Methods We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter.Results 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test was 72.7% and 96.2%, respectively. There were 8 home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset.Conclusions We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.Summary In this pilot study, 481 individuals self-monitored for respiratory symptoms. Of 58 home tests, 12 were influenza-positive. There were 8 baloxavir home deliveries within 48 hours of illness onset. A home-based approach to influenza diagnosis and treatment could be feasible.Competing Interest StatementH.Y.C. has received research support from GlaxoSmithKline, Novavax, and Sanofi Pasteur; J.A.E. has received research support from AstraZeneca, GlaxoSmithKine, Merck, and Pfizer and served as a consultant for Sanofi Pasteur and Meissa Vaccines. M.L.J. has received research support from Sanofi Pasteur. M.B. receives research support and serves as a consultant for Ansun Biopharma, Gilead Sciences, Janssen, and Vir Biotechnology; and serves as a consultant to GlaxoSmithKline, ReViral, ADMA, Pulmocdie and ModernaClinical TrialNCT04141930Funding StatementThe Seattle Flu Study is funded by Gates Ventures. The funder was not involved in the design of the study, does not have any ownership over the management and conduct of the study, the data, or the rights to publish.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Washington Institutional Review Board (STUDY00008200)All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and code used for analyses may be available upon request. |
Risk factors for illness severity among pregnant women with confirmed SARS-CoV-2 infection – Surveillance for Emerging Threats to Mothers and Babies Network, 20 state, local, and territorial health departments, March 29, 2020 -January 8, 2021 (preprint)
Galang RR , Newton SM , Woodworth KR , Griffin I , Oduyebo T , Sancken CL , Olsen EO , Aveni K , Wingate H , Shephard H , Fussman C , Alaali ZS , Silcox K , Siebman S , Halai UA , Lopez CD , Lush M , Sokale A , Barton J , Chaudhary I , Patrick PH , Schlosser L , Reynolds B , Gaarenstroom N , Chicchelly S , Read JS , de Wilde L , Mbotha D , Azziz-Baumgartner E , Hall AJ , Tong VT , Ellington S , Gilboa SM . medRxiv 2021 2021.02.27.21252169 Background Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness compared with nonpregnant women. Data to assess risk factors for illness severity among pregnant women with COVID-19 are limited. This study aimed to determine risk factors associated with COVID-19 illness severity among pregnant women with SARS-CoV-2 infection.Methods Pregnant women with SARS-CoV-2 infection confirmed by molecular testing were reported during March 29, 2020–January 8, 2021 through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET). Criteria for illness severity (asymptomatic, mild, moderate-to-severe, or critical) were adapted from National Institutes of Health and World Health Organization criteria. Crude and adjusted risk ratios for moderate-to-severe or critical COVID-19 illness were calculated for selected demographic and clinical characteristics.Results Among 5,963 pregnant women with SARS-CoV-2 infection, moderate-to-severe or critical COVID-19 illness was associated with age 30–39 years, Black/Non-Hispanic race/ethnicity, healthcare occupation, pre-pregnancy obesity, chronic lung disease, chronic hypertension, cardiovascular disease, and pregestational diabetes mellitus. Risk of moderate-to-severe or critical illness increased with the number of underlying medical or pregnancy-related conditions.Conclusions Pregnant women with moderate-to-severe or critical COVID-19 illness were more likely to be older and have underlying medical conditions compared to pregnant women with asymptomatic infection or mild COVID-19 illness. This information might help pregnant women understand their risk for moderate-to-severe or critical COVID-19 illness and inform targeted public health messaging.Summary Among pregnant women with COVID-19, older age and underlying medical conditions were risk factors for increased illness severity. These findings can be used to inform pregnant women about their risk for severe COVID-19 illness and public health messaging.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialThis activity was reviewed by CDC, determined to be a non-research, public health surveillance activity, and was conducted consistent with applicable federal law and CDC policy.Clinical Protocols https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643898/ Funding StatementThis study was performed as regular work of the Centers for Disease Control and Prevention. This work is supported by the Epidemiology and Laboratory Capacity for Prevention and Control of Emerging Infectious Diseases (ELC) Cooperative Agreement (ELC CK19-1904) and through contractual mechanisms, including the Local Health Department Initiative.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by the human subjects advisor of the U.S. Centers for Disease Control and Prevention (CDC), National Center on Birth Defects and Developmental Disorders and was determined to be non-research, public health surveillance and exempt from IRB review. This activity was conducted consistent with applicable federal law and CDC policy. (Department of Health and Human Services - 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq. Available from: https://www.hhs.gov/ohrp/sites/default/files/ohrp/policy/ohrpregulations.pdf.)All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, p ease provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThese data are collected under relevant provisions of the Public Health Service Act and are protected at CDC by an Assurance of Confidentiality (Section 308(d) of the Public Health Service Act, 42 U.S.C. section 242 m(d)) (https://www.cdc.gov/od/science/integrity/confidentiality/), which prohibits use or disclosure of any identifiable or potentially identifiable information collected under the Assurance for purposes other than those set out in the Assurance. Publicly available aggregated data are available: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/special-populations/birth-data-on-covid-19.html. Requests for access will be considered on a case by case basis, and inquiries should be directed to setnet@cdc.gov |
SARS-CoV-2 susceptibility of cell lines and substrates commonly used in diagnosis and isolation of influenza and other viruses (preprint)
Wang L , Fan X , Bonenfant G , Cui D , Hossain J , Jiang N , Larson G , Currier M , Liddell J , Wilson M , Tamin A , Harcourt J , Ciomperlik-Patton J , Pang H , Dybdahl-Sissoko N , Campagnoli R , Shi PY , Barnes J , Thornburg NJ , Wentworth DE , Zhou B . bioRxiv 2021 2021.01.04.425336 Coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses is inevitable as the COVID-19 pandemic continues. This study aimed to evaluate cell lines commonly used in virus diagnosis and isolation for their susceptibility to SARS-CoV-2. While multiple kidney cell lines from monkeys were susceptible and permissive to SARS-CoV-2, many cell types derived from human, dog, mink, cat, mouse, or chicken were not. Analysis of MDCK cells, which are most commonly used for surveillance and study of influenza viruses, demonstrated that they were insusceptible to SARS-CoV-2 and that the cellular barrier to productive infection was due to low expression level of the angiotensin converting enzyme 2 (ACE2) receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by over-expression of canine ACE2 in trans. Moreover, SARS-CoV-2 cell tropism did not appear to be affected by a D614G mutation in the spike protein.Competing Interest StatementThe authors have declared no competing interest. |
Trade-offs between individual and ensemble forecasts of an emerging infectious disease (preprint)
Oidtman RJ , Omodei E , Kraemer MUG , Castañeda-Orjuela CA , Cruz-Rivera E , Misnaza-Castrillón S , Cifuentes MP , Rincon LE , Cañon V , Alarcon P , España G , Huber JH , Hill SC , Barker CM , Johansson MA , Manore CA , Reiner RC Jr , Rodriguez-Barraquer I , Siraj AS , Frias-Martinez E , García-Herranz M , Perkins TA . medRxiv 2021 2021.02.25.21252363 When new pathogens emerge, numerous questions arise about their future spread, some of which can be addressed with probabilistic forecasts. The many uncertainties about the epidemiology of emerging pathogens can make it difficult to choose among model structures and assumptions, however. To assess the potential for uncertainties about emerging pathogens to affect forecasts of their spread, we evaluated the performance of a suite of 16 forecasting models in the context of the 2015-2016 Zika epidemic in Colombia. Each model featured a different combination of assumptions about the role of human mobility in driving transmission, spatiotemporal variation in transmission potential, and the number of times the virus was introduced. All models used the same core transmission model and the same iterative data assimilation algorithm to generate forecasts. By assessing forecast performance through time using logarithmic scoring with ensemble weighting, we found that which model assumptions had the most ensemble weight changed through time. In particular, spatially coupled models had higher ensemble weights in the early and late phases of the epidemic, whereas non-spatial models had higher ensemble weights at the peak of the epidemic. We compared forecast performance of the equally-weighted ensemble model to each individual model and identified a trade-off whereby certain individual models outperformed the ensemble model early in the epidemic but the ensemble model outperformed all individual models on average. On balance, our results suggest that suites of models that span uncertainty across alternative assumptions are necessary to obtain robust forecasts in the context of emerging infectious diseases.Competing Interest StatementThe authors have declared no competing interest.Funding StatementRJO acknowledges support from an Eck Institute for Global Health Fellowship, GLOBES grant, Arthur J. Schmitt Fellowship, and the UNICEF Office of Innovation. MUGK is supported by The Branco Weiss Fellowship - Society in Science, administered by the ETH Zurich and acknowledges funding from the Oxford Martin School and the European Union Horizon 2020 project MOOD (\#874850). SCH is supported by the Wellcome Trust (220414/Z/20/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:No IRB approvals were necessary.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe mobile phone data set used in this study is proprietary and subject to strict privacy regulations. The access to this data set was granted after reaching a non-disclosure agreement with the proprietor, who anonymized and aggregated the original data before giving access to the authors. The mobile phone is available on request after negotiation of a non-disclosure agreement with the company. The contact person is Enrique Frias-Martinez (efm{at}tid.es). Epidemiological, meteorological, and demographic data are available from Siraj et al.2018 and additionally available on https://github.com/roidtman/eid_ensemble_forecasting. https://www.github.com/roidtman/eid_ensemble_forecasting |
Two-Month Follow-up of Persons with SARS-CoV-2 Infection—Zambia, September 2020 (preprint)
Zulu JE , Banda D , Hines JZ , Luchembe M , Sivile S , Siwingwa M , Kampamba D , Zyambo KD , Chirwa R , Chirwa L , Malambo W , Barradas D , Sinyange N , Agolory S , Mulenga LB , Fwoloshi S . medRxiv 2021 2021.06.15.21258964 Background COVID-19 is often characterized by an acute upper respiratory tract infection. However, information on longer-term clinical sequelae following acute COVID-19 is emerging. We followed a group of persons with COVID-19 in Zambia at two months to assess persistent symptoms.Methods In September 2020, we re-contacted participants from SARS-CoV-2 prevalence studies conducted in Zambia in July 2020 whose PCR tests were positive. Participants with valid contact information were interviewed using a structured questionnaire that captured demographics, pre-existing conditions, and types and duration of symptoms. We describe the frequency and duration of reported symptoms and used chi-square tests to explore variability of symptoms by age group, gender, and underlying conditions.Results Of 302 participants, 155 (51%) reported one or more acute COVID-19-related symptoms in July 2020. Cough (50%), rhinorrhoea (36%) and headache (34%) were the most frequently reported symptoms proximal to diagnosis. The median symptom duration was 7 days (IQR: 3-9 days). At a median follow up of 54 days (IQR: 46-59 day), 27 (17%) symptomatic participants had not yet returned to their pre-COVID-19 health status. These participants most commonly reported cough (37%), headache (26%) and chest pain (22%). Age, sex, and pre-existing health conditions were not associated with persistent symptoms.Conclusion A notable percentage of persons with SARS-CoV-2 infection in July still had symptoms nearly two months after their diagnosis. Zambia is implementing ‘post-acute COVID-19 clinics’ to care for patients with prolonged symptoms of COVID-19, to address their needs and better understand how the disease will impact the population over time.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by the US Centres for Disease Control and PreventionAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The University of Zambia Biomedical Research Ethics Committee Ridgeway Campus, P.O. Box 50110 Lusaka, Zambia E-mail: unzarec{at}zamtel.zmAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data referred to in this manuscript is available for viewing and verification |
Unrecognized introductions of SARS-CoV-2 into the state of Georgia shaped the early epidemic (preprint)
Babiker A , Martin MA , Marvil C , Bellman S , Petit Iii RA , Bradley HL , Stittleburg VD , Ingersoll J , Kraft CS , Read TD , Waggoner JJ , Koelle K , Piantadosi A . medRxiv 2021 2021.09.19.21262615 In early 2020, as SARS-CoV-2 diagnostic and surveillance responses ramped up, attention focused primarily on returning international travelers. Here, we build on existing studies characterizing early patterns of SARS-CoV-2 spread within the U.S. by analyzing detailed clinical, molecular, and viral genomic data from the state of Georgia through March 2020. We find evidence for multiple early introductions into Georgia, despite relatively sparse sampling. Most sampled sequences likely stemmed from a single introduction from Asia at least two weeks prior to the state’s first detected infection. Our analysis of sequences from domestic travelers demonstrates widespread circulation of closely-related viruses in multiple U.S. states by the end of March 2020. Our findings indicate that the early attention directed towards identifying SARS-CoV-2 in returning international travelers may have led to a failure to recognize locally circulating infections for several weeks, and points towards a critical need for rapid and broadly-targeted surveillance efforts in the future.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was supported by the CDC contract 75D30121C10084 under BAA ERR 20-15-2997 the Pediatric Research Alliance Center for Childhood Infections and Vaccines and Childrens Healthcare of Atlanta and the Emory WHSC COVID-19 Urgent Research Engagement (CURE) Center made possible by generous philanthropic support from the O. Wayne Rollins Foundation and the William Randolph Hearst Foundation. AP is supported by NIH K08 AI139348. The Yerkes NHP Genomics Core is supported in part by NIH P51 OD011132 and sequence data was acquired on an Illumina NovaSeq6000 funded by NIH S10 OD 026799. Sample collection was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Emory University institutional review boardAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesPublicly-available SARS-CoV-2 sequences from Georgia were generously contributed by Mayo Clinic Laboratories, Quest Diagnostics, and the U.S. Air Force School of Aerospace Medicine. We gratefully acknowledge the authors from the originating laboratories responsible for obtaining the specimens, as well as the submitting laboratories where the genome data were generated and shared via GISAID, on which this research is based (Supplementary Table 10). All Submitters of data may be contacted directly via www.gisaid.org.All the data will be publicly released upon publication. |
Use of U.S. Blood Donors for National Serosurveillance of SARS-CoV-2 Antibodies: Basis for an Expanded National Donor Serosurveillance Program (preprint)
Stone M , Di Germanio C , Wright DJ , Sulaeman H , Dave H , Fink RV , Notari EP , Green V , Strauss D , Kessler D , Destree M , Saa P , Williamson PC , Simmons G , Stramer SL , Opsomer J , Jones JM , Kleinman S , Busch MP . medRxiv 2021 2021.05.01.21255576 Introduction The REDS-IV-P Epidemiology, Surveillance and Preparedness of the Novel SARS-CoV-2 Epidemic (RESPONSE) seroprevalence study conducted monthly cross-sectional testing for SARS-CoV-2 antibodies on blood donors in six U.S. metropolitan regions to estimate the extent of SARS-COV-2 infections over time.Study Design/Methods During March-August 2020, approximately ≥1,000 serum specimens were collected monthly from each region and tested for SARS-CoV-2 antibodies using a well-validated algorithm. Regional seroprevalence estimates were weighted based on demographic differences with the general population. Seroprevalence was compared with reported COVID-19 case rates over time.Results/Findings For all regions, seroprevalence was <1.0% in March 2020. New York experienced the biggest increase (peak seroprevalence, 15.8 % in May). All other regions experienced modest increases in seroprevalence(1-2% in May-June to 2-4% in July-August). Seroprevalence was higher in younger, non-Hispanic Black, and Hispanic donors. Temporal increases in donor seroprevalence correlated with reported case rates in each region. In August, 1.3-5.6 estimated cumulative infections (based on seroprevalence data) per COVID-19 case reported to CDC.Conclusion Increases in seroprevalence were found in all regions, with the largest increase in New York. Seroprevalence was higher in non-Hispanic Black and Hispanic blood donors than in non-Hispanic White blood donors. SARS-CoV-2 antibody testing of blood donor samples can be used to estimate the seroprevalence in the general population by region and demographic group. The methods derived from the RESPONSE seroprevalence study served as the basis for expanding SARS-CoV-2 seroprevalence surveillance to all 50 states and Puerto Rico.Summary SARS-CoV-2 serosurveillance data from blood donors in 6 US regions were used to estimate population weighted seroprevalence. Seroprevelance rates were higher in case rates. The study was expanded to a national donor serosurveillance program.Disclaimer The content is solely the responsibility of the authors and does not represent the policy of the National Institutes of Health or the Department of Health and Human Services. Any specific brandnames included in this manuscript are for identification purposes only and are not intended to represent an endorsement by CDC. The findings and conclusions in this report are those of the authorsand do not necessarily represent the official position of the Centers of Disease Control and Prevention.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe authors were supported by research contracts from the National Heart, Lung, and Blood Institute (NHLBI Contracts HHSN 75N92019D00032 and HHSN 75N92019D00033) as well as with funding support from the National Institute of Allergies and Infectious Diseases (NIAID), NIH.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was reviewed by the UCSF Committee for Human Research and determined to meet the definition of research as defined in 46.102(l) but did not involve human subjects based on anonymization of data and routine consent for blood donation testing that includes use of residual samples for research purposes (as defined in 46.103(e)(1) consistent with applicable federal law and CDC policy (45 C.F.R. part 46; 21 C.F.R. part 56; 42 U.S.C. p241(d), 5 U.S.C. p552a, 44 U.S.C. p3501)).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a pros ective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data is not being made publicly available for privacy reasons related to federal regulations but a limited dataset may be made available upon request after formal review by NHLBI and CDC's privacy office before release. |
Utilization of Whole Genome Sequencing to Understand SARS-CoV-2 Transmission Dynamics in Long-Term Care Facilities, Correctional Facilities and Meat Processing Plants in Minnesota, March – June 2020 (preprint)
Lehnertz NB , Wang X , Garfin J , Taylor J , Zipprich J , VonBank B , Martin K , Eikmeier D , Medus C , Wiedinmyer B , Bernu C , Plumb M , Pung K , Honein MA , Carter R , MacCannell D , Smith KE , Como-Sabetti K , Ehresmann K , Danila R , Lynfield R . medRxiv 2021 2020.12.30.20248277 Congregate settings and high-density workplaces have endured a disproportionate impact from COVID-19. In order to provide further understanding of the transmission patterns of SARS-CoV-2 in these settings, whole genome sequencing (WGS) was performed on samples obtained from 8 selected outbreaks in Minnesota from March – June, 2020. WGS and phylogenetic analysis was conducted on 319 samples, constituting 14.4% of the 2,222 total SARS-CoV-2-positive individuals associated with these outbreaks. Among the sequenced specimens, three LTCFs and both correctional facilities had spread associated with a single genetic sequence. A fourth LTCF had outbreak cases associated with two distinct sequences. In contrast, cases associated with outbreaks in the two meat processing plants represented multiple SARS-CoV-2 sequences. These results suggest that a single introduction of SARS-CoV-2 into a facility can result in a widespread outbreak, and early identification and cohorting of cases, along with continued vigilance with infection prevention and control measures is imperative.Competing Interest StatementThe authors have declared no competing interest.Funding StatementStudy was supported by the ELC Cares grant from CDC.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The manuscript was reviewed in accordance with standard CDC protocol, in which the approved CDC chain of command in the COVID 19 response division reviewed the manuscript and determined that it was non-research, public health response. As such, it was determined by CDC review to be exempt from further institutional review board evaluation. In summary, this manuscript and activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (see e.g., 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C 552a; 44 U.S.C. 351 et seq.).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThere is no referred data. |
Laboratory Study of Physical Barrier Efficiency for Worker Protection against SARS-CoV-2 while Standing or Sitting (preprint)
Bartels J , Estill CF , Chen IC , Neu D . medRxiv 2021 2021.07.26.21261146 Transparent barriers were installed as a response to the SARS-COV-2 pandemic in many customer-facing industries. Transparent barriers are an engineering control that are utilized to intercept air traveling between customers to workers. Information on the effectiveness of these barriers against aerosols is limited. In this study, a cough simulator was used to represent a cough from a customer. Two optical particle counters were used (one on each side of the barrier, labeled reference and worker) to determine the number of particles that migrated around a transparent barrier. Nine barrier sizes and a no barrier configuration were tested with six replicates each. Tests of these 10 configurations were conducted for both sitting and standing scenarios to represent configurations common to nail salons and grocery stores, respectively. Barrier efficiency was calculated using a ratio of the particle count results (reference/worker). Barriers had better efficiency when they were 9 to 39 cm (3.5 to 15.5”) above cough height and at least 91 cm (36”) wide, 92% and 93% respectively. Barriers that were 91 cm (36”) above table height for both scenarios blocked 71% or more of the particles between 0.35–0.725 µm and 68% for particles between 1 to 3 µm. A barrier that blocked an initial cough was effective at reducing particle counts. While the width of barriers was not as significant as height in determining barrier efficiency it was important that a barrier be placed where interactions between customers and workers are most frequent.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis research was funded by the CDC. NIOSH is a part of the CDCAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:NIOSH Institutional Review BoardAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll the data that has been tabulated in the manuscript can be provided in a more accessible format. |
Methods for Estimation of SARS-CoV-2 Seroprevalence and Reported COVID-19 Cases in U.S. Children, August 2020—May 2021 (preprint)
Couture A , Lyons BC , Mehrotra ML , Sosa L , Ezike N , Ahmed FS , Brown CM , Yendell S , Azzam IA , Katić BJ , Cope A , Dickerson K , Stone J , Traxler LB , Dunn JR , Davis LB , Reed C , Clarke KEN , Flannery B , Charles MD . medRxiv 2021 2021.09.26.21263756 Background and Objectives Case-based surveillance of pediatric COVID-19 cases underestimates the prevalence of SARS-CoV-2 infections among children and adolescents. Our objectives were to: 1) estimate monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years and 2) calculate ratios of SARS-CoV-2 infections to reported COVID-19 cases among children and adolescents in 14 U.S. states.Methods Using data from commercial laboratory seroprevalence surveys, we estimated monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years from August 2020 through May 2021. Seroprevalence estimates were based on SARS-CoV-2 anti-nucleocapsid immunoassays from February to May 2021. We compared estimated numbers of children infected with SARS-CoV-2 by May 2021 to cumulative incidence of confirmed and probable COVID-19 cases from case-based surveillance, and calculated infection: case ratios by state and type of anti-SARS-CoV-2 nucleocapsid immunoassay used for seroprevalence testing.Results Analyses included 67,321 serum specimens tested for SARS-CoV-2 antibodies among children in 14 U.S. states. Estimated ratios of SARS-CoV-2 infections to reported confirmed and probable COVID-19 cases among children and adolescents varied by state and type of immunoassay, ranging from 0.8-13.3 in May 2021.Conclusions Through May 2021, the majority of children in selected states did not have detectable SARS-CoV-2 nucleocapsid antibodies. Case-based surveillance underestimated the number of children infected with SARS-CoV-2, however the predicted extent of the underestimate varied by state, immunoassay, and over time. Continued monitoring of pediatric SARS-CoV-2 antibody seroprevalence should inform prevention and vaccination strategies.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFunding for this work was supported by CDC (Atlanta, Georgia).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by Centers for Disease Control and Prevention and determined to be consistent with non human participant research activity. Informed consent was waived, as data were deidentified. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDeidentified individual participant data will not be made available.CDCCenters of Disease Control and PreventionMIS-CMultisystem inflammatory syndrome in childrenEUAEmergency Use AuthorizationFDAU.S. Food and Drug AdministrationACIPAdvisory Committee on Immunizations PracticesNNucleocapsidSSpikeIgImmunoglobulinCIConfidence intervals |
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome (preprint)
Sulaiman I , Chung M , Angel L , Koralov S , Wu B , Yeung S , Krolikowski K , Li Y , Duerr R , Schluger R , Thannickal S , Koide A , Rafeq S , Barnett C , Postelnicu R , Wang C , Banakis S , Perez-Perez L , Jour G , Shen G , Meyn P , Carpenito J , Liu X , Ji K , Collazo D , Labarbiera A , Amoroso N , Brosnahan S , Mukherjee V , Kaufman D , Bakker J , Lubinsky A , Pradhan D , Sterman D , Heguy A , Uyeki T , Clemente J , de Wit E , Schmidt AM , Shopsin B , Desvignes L , Wang C , Li H , Zhang B , Forst C , Koide S , Stapleford K , Khanna K , Ghedin E , Weiden M , Segal L . Res Sq 2021 Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized. |
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome (preprint)
Sulaiman I , Chung M , Angel L , Tsay JJ , Wu BG , Yeung ST , Krolikowski K , Li Y , Duerr R , Schluger R , Thannickal SA , Koide A , Rafeq S , Barnett C , Postelnicu R , Wang C , Banakis S , Perez-Perez L , Jour G , Shen G , Meyn P , Carpenito J , Liu X , Ji K , Collazo D , Labarbiera A , Amoroso N , Brosnahan S , Mukherjee V , Kaufman D , Bakker J , Lubinsky A , Pradhan D , Sterman DH , Weiden M , Hegu A , Evans L , Uyeki TM , Clemente JC , De Wit E , Schmidt AM , Shopsin B , Desvignes L , Wang C , Li H , Zhang B , Forst CV , Koide S , Stapleford KA , Khanna KM , Ghedin E , Segal LN . medRxiv 2021 Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized. |
Mitigating outbreaks in congregate settings by decreasing the size of the susceptible population (preprint)
Blumberg S , Lu P , Hoover CM , Lloyd-Smith JO , Kwan AT , Sears D , Bertozzi SM , Worden L . medRxiv 2021 While many transmission models have been developed for community spread of respiratory pathogens, less attention has been given to modeling the interdependence of disease introduction and spread seen in congregate settings, such as prisons or nursing homes. As demonstrated by the explosive outbreaks of COVID-19 seen in congregate settings, the need for effective outbreak prevention and mitigation strategies for these settings is critical. Here we consider how interventions that decrease the size of the susceptible populations, such as vaccination or depopulation, impact the expected number of infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a branching process, while spread between residents is modeled via a compartmental model. Control is modeled as a proportional decrease in both the number of susceptible residents and the reproduction number. We find that vaccination or depopulation can have a greater than linear effect on anticipated infections. For example, assuming a reproduction number of 3.0 for density-dependent COVID-19 transmission, we find that reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. We highlight the California state prison system as an example for how these findings provide a quantitative framework for implementing infection control in congregate settings. Additional applications of our modeling framework include optimizing the distribution of residents into independent residential units, and comparison of preemptive versus reactive vaccination strategies. |
Modeling effectiveness of testing strategies to prevent COVID-19 in nursing homes —United States, 2020 (preprint)
See I , Paul P , Slayton RB , Steele MK , Stuckey MJ , Duca L , Srinivasan A , Stone N , Jernigan JA , Reddy SC . medRxiv 2021 2020.12.18.20248255 Background SARS-CoV-2 outbreaks in nursing homes can be large with high case fatality. Identifying asymptomatic individuals early through serial testing is recommended to control COVID-19 in nursing homes, both in response to an outbreak (“outbreak testing” of residents and healthcare personnel) and in facilities without outbreaks (“non-outbreak testing” of healthcare personnel). The effectiveness of outbreak testing and isolation with or without non-outbreak testing was evaluated.Methods Using published SARS-CoV-2 transmission parameters, the fraction of SARS-CoV-2 transmissions prevented through serial testing (weekly, every three days, or daily) and isolation of asymptomatic persons compared to symptom-based testing and isolation was evaluated through mathematical modeling using a Reed-Frost model to estimate the percentage of cases prevented (i.e., “effectiveness”) through either outbreak testing alone or outbreak plus non-outbreak testing. The potential effect of simultaneous decreases (by 10%) in the effectiveness of isolating infected individuals when instituting testing strategies was also evaluated.Results Modeling suggests that outbreak testing could prevent 54% (weekly testing with 48-hour test turnaround) to 92% (daily testing with immediate results and 50% relative sensitivity) of SARS-CoV-2 infections. Adding non-outbreak testing could prevent up to an additional 8% of SARS-CoV-2 infections (depending on test frequency and turnaround time). However, added benefits of non-outbreak testing were mostly negated if accompanied by decreases in infection control practice.Conclusions When combined with high-quality infection control practices, outbreak testing could be an effective approach to preventing COVID-19 in nursing homes, particularly if optimized through increased test frequency and use of tests with rapid turnaround.Summary Mathematical modeling evaluated the effectiveness of serially testing asymptomatic persons in a nursing home in response to a SARS-CoV-2 outbreak with or without serial testing of asymptomatic staff in the absence of known SARS-CoV-2 infections.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received. All work was conducted as part of government duties.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (see e.g., 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C 552a; 44 U.S.C. 351 et seq.).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData provided in supplemental materials or publicly available through links in the manuscript. https://github.com/cdcepi/Nursing-home-SARS-CoV-2-testing-model/ |
Performance of Repeat BinaxNOW SARS-CoV-2 Antigen Testing in a Community Setting, Wisconsin, November-December 2020 (preprint)
Shah MM , Salvatore PP , Ford L , Kamitani E , Whaley MJ , Mitchell K , Currie DW , Morgan CN , Segaloff HE , Lecher S , Somers T , Van Dyke ME , Bigouette JP , Delaney A , DaSilva J , O'Hegarty M , Boyle-Estheimer L , Abdirizak F , Karpathy SE , Meece J , Ivanic L , Goffard K , Gieryn D , Sterkel A , Bateman A , Kahrs J , Langolf K , Zochert T , Knight NW , Hsu CH , Kirking HL , Tate JE . medRxiv 2021 2021.04.05.21254834 Repeating the BinaxNOW antigen test for SARS-CoV-2 by two groups of readers within 30 minutes resulted in high concordance (98.9%) in 2,110 encounters. BinaxNOW test sensitivity was 77.2% (258/334) compared to real-time reverse transcription-polymerase chain reaction. Repeating antigen testing on the same day did not significantly improve test sensitivity while specificity remained high.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. See e.g., 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C. 552a; 44 U.S.C. 3501 et seq.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will be made available upon reasonable request. |
Population analysis of Vibrio cholerae in aquatic reservoirs reveals a novel sister species (Vibrio paracholerae sp. nov.) with a history of association with human infections (preprint)
Islam MT , Nasreen T , Kirchberger P , Liang KYH , Orata FD , Johura FT , Im MS , Tarr CL , Alam M , Boucher YF . bioRxiv 2021 2021.05.05.442690 Most efforts to understand the biology of Vibrio cholerae have focused on a single group, the pandemic-generating lineage harbouring the strains responsible for all known cholera pandemics. Consequently, little is known about the diversity of this species in its native aquatic environment. To understand the differences in the V. cholerae populations inhabiting in regions with varying history of cholera cases and how that might influence the abundance of pandemic strains, a comparative analysis of population composition was performed. Little overlap was found in lineage compositions between those in Dhaka (cholera endemic) located in the Ganges delta, and of Falmouth (no known history of cholera), a small coastal town on the US East Coast. The most striking difference was the presence of a group of related lineages at high abundance in Dhaka which was completely absent from Falmouth. Phylogenomic analysis revealed that these lineages form a cluster at the base of the phylogeny of V. cholerae species, sufficiently differentiated genetically and phenotypically to form a novel species. Strains from this species have been anecdotally isolated from around the world and were isolated as early as 1916 from a British soldier in Egypt suffering from choleraic diarrhoea. In 1935 Gardner and Venkatraman unofficially referred to a member of this group as Vibrio paracholerae. In recognition of this earlier designation, we propose the name Vibrio paracholerae, sp. nov. for this bacterium. Genomic analysis suggests a link with human populations for this novel species and substantial interaction with its better-known sister species.Importance Cholera continues to remain a major public health threat around the globe. Understanding the ecology, evolution and environmental adaptation of the causative agent Vibrio cholerae and tracking the emergence of novel lineages with pathogenic potential are essential to combat the problem. In this study, we investigated the population dynamics of Vibrio cholerae in an inland locality which is known as endemic for cholera and compared with that of a cholera free coastal location. We found the consistent presence of the pandemic generating V. cholerae in cholera-endemic Dhaka and an exclusive presence of a lineage phylogenetically distinct from other V. cholerae. Our study suggests that this lineage represents a novel species having pathogenic potential and a human link to its environmental abundance. The possible association with human population, co-existence and interaction with toxigenic V. cholerae in the natural environment make this potential human pathogen an important subject for future studies.Competing Interest StatementThe authors have declared no competing interest. |
Efficacy of universal masking for source control and personal protection from simulated cough and exhaled aerosols in a room (preprint)
Lindsley WG , Beezhold DH , Coyle J , Derk RC , Blachere FM , Boots T , Reynolds JS , McKinney WG , Sinsel E , Noti JD . medRxiv 2021 2021.04.21.21255880 Face masks reduce the spread of infectious respiratory diseases such as COVID-19 by blocking aerosols produced during coughs and exhalations (“source control”). Masks also slow and deflect cough and exhalation airflows, which changes the dispersion of aerosols. Factors such as the directions in which people are facing (orientation) and separation distance also affect aerosol dispersion. However, it is not clear how masking, orientation, and distance interact. We placed a respiratory aerosol simulator (“source”) and a breathing simulator (“recipient”) in a 3 m x 3 m chamber and measured aerosol concentrations for different combinations of masking, orientation, and separation distance. When the simulators were front-to-front during coughing, masks reduced the 15-minute mean aerosol concentration at the recipient by 92% at 0.9 and 1.8 m separation. When the simulators were side-by-side, masks reduced the concentration by 81% at 0.9 m and 78% at 1.8 m. During breathing, masks reduced the aerosol concentration by 66% when front-to-front and 76% when side-by-side at 0.9 m. Similar results were seen at 1.8 m. When the simulators were unmasked, changing the orientations from front-to-front to side-by-side reduced the cough aerosol concentration by 59% at 0.9 m and 60% at 1.8 m. When both simulators were masked, changing the orientations did not significantly change the concentration at either distance during coughing or breathing. Increasing the distance between the simulators from 0.9 m to 1.8 m during coughing reduced the aerosol concentration by 25% when no masks were worn but had little effect when both simulators were masked. During breathing, when neither simulator was masked, increasing the separation reduced the concentration by 13%, which approached significance, while the change was not significant when both source and recipient were masked. Our results show that universal masking reduces exposure to respiratory aerosol particles regardless of the orientation and separation distance between the source and recipient.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialRegistration not requiredFunding StatementThis work was supported by the US Centers for Disease Control and Prevention (CDC).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:IRB approval was not required for this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesExperimental data is available upon request. |
Estimates of cases and hospitalizations averted by COVID-19 case investigation and contact tracing in 14 health jurisdictions in the United States (preprint)
Jeon S , Rainisch G , Lash RR , Moonan PK , Oeltmann JE , Greening BJr , Adhikari BB , Meltzer MI . medRxiv 2021 2021.05.27.21257931 Context The implementation of case investigation and contact tracing (CICT) for controlling COVID-19 (caused by SARS-Cov-2 virus) has proven challenging due to varying levels of public acceptance and initially constrained resources, especially enough trained staff. Evaluating the impacts of CICT will aid efforts to improve such programs.Objectives Estimate the number of COVID-19 cases and hospitalizations averted by CICT and identify CICT processes that could improve overall effectiveness.Design We used data on proportion of cases interviewed, contacts notified or monitored, and days from testing to contact notification from 14 jurisdictions to model the impact of CICT on cumulative cases counts and hospitalizations over a 60-day period. Using the Centers for Disease Control and Prevention (CDC)’s COVIDTracer tool, we estimated a range of impacts by assuming either contacts would quarantine only if monitored or would do so upon notification of potential exposure. We also varied the observed program metrics to assess their relative influence.Results Performance by jurisdictions varied widely. Jurisdictions isolated between 12 and 86% of cases (including contacts which became cases) within 6 to 10 days after exposure-and-infection. We estimated that CICT-related reductions in transmission ranged from 0.4% to 32%. For every 100 cases prevented by nonpharmaceutical interventions, CICT averted between 4 and 97 additional cases. Reducing time to case isolation by one day increased averted case estimates by up to 15 percentage points. Increasing the proportion of cases interviewed or contacts notified by 20 percentage points each resulted in at most 3 or 6 percentage point improvements in averted cases.Conclusions We estimated that case investigation and contact tracing reduced the number of COVID-19 cases and hospitalizations among all jurisdictions studied. Reducing time to isolation produced the greatest improvements in impact of CICT.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was performed as part of the official duties of all participants in support of the US CDC's COVID-19 Response.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData is available upon request |
Estimating COVID-19 Hospitalizations in the United States with surveillance data using a Bayesian Hierarchical model (preprint)
Couture A , Iuliano D , Chang H , Patel N , Gilmer M , Steele M , Havers F , Whitaker M , Reed C . medRxiv 2021 2021.10.14.21264992 Introduction In the United States, COVID-19 is a nationally notifiable disease, cases and hospitalizations are reported to the CDC by states. Identifying and reporting every case from every facility in the United States may not be feasible in the long term. Creating sustainable methods for estimating burden of COVID-19 from established sentinel surveillance systems is becoming more important. We aimed to provide a method leveraging surveillance data to create a long-term solution to estimate monthly rates of hospitalizations for COVID-19.Methods We estimated monthly hospitalization rates for COVID-19 from May 2020 through April 2021 for the 50 states using surveillance data from COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) and a Bayesian hierarchical model for extrapolation. We created a model for six age groups (0-17, 18-49, 50-64, 65-74, 75-84, and ≥85 years), separately. We identified covariates from multiple data sources that varied by age, state, and/or month, and performed covariate selection for each age group based on two methods, Least Absolute Shrinkage and Selection Operator (LASSO) and Spike and Slab selection methods. We validated our method by checking sensitivity of model estimates to covariate selection and model extrapolation as well as comparing our results to external data.Results We estimated 3,569,500 (90% Credible Interval:3,238,000 – 3,934,700) hospitalizations for a cumulative incidence of 1,089.8 (988.6 – 1,201.3) hospitalizations per 100,000 population with COVID-19 in the United States from May 2020 through April 2021. Cumulative incidence varied from 352 – 1,821per 100,000 between states. The age group with the highest cumulative incidence was aged ≥85 years (5,583.1; 5,061.0 – 6,157.5). The monthly hospitalization rate was highest in December (183.8; 154.5 – 218.0). Our monthly estimates by state showed variations in magnitudes of peak rates, number of peaks and timing of peaks between states.Conclusions Our novel approach to estimate COVID-19 hospitalizations has potential to provide sustainable estimates for monitoring COVID-19 burden, as well as a flexible framework leveraging surveillance data.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFunding for this work was supported by CDC (Atlanta, Georgia). The authors received no financial support for the research, authorship, or publication of these data.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will not be made available online.BRFSSBehavioral Risk Factor Surveillance SystemCDCCenters for Disease Control and PreventionCKDchronic kidney diseaseCOPDchronic obstructive pulmonary diseaseCOVID-19Coronavirus Disease 2019COVID-NETCoronavirus Disease 2019-Associated Hospitalization Surveillance NetworkCrICredible IntervalFluSurv-NETInfluenza Hospitalization Surveillance NetworkHHSDepartment of Health and Human ServicesICUintensive care unitLASSO east Absolute Shrinkage and Selection OperatorMCMCMarkov chain Monte CarloNCHSNational Center for Health StatisticsNNDSSNational Notifiable Disease Surveillance SystemNVSSNational Vital Statistics SystemSARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2 |
Estimating the contribution of HIV-infected adults to household pneumococcal transmission in South Africa, 2016-2018: A hidden Markov modelling study (preprint)
Thindwa D , Wolter N , Pinsent A , Carrim M , Ojal J , Tempia S , Moyes J , McMorrow M , Kleynhans J , Gottberg AV , French N , Cohen C , Flasche S . medRxiv 2021 2021.05.21.21257622 Human immunodeficiency virus (HIV) infected adults are at a higher risk of pneumococcal colonisation and disease, even while receiving antiretroviral therapy (ART). To help evaluate potential indirect effects of vaccination of HIV-infected adults, we assessed whether HIV-infected adults disproportionately contribute to household transmission of pneumococci. We constructed a hidden Markov model to capture the dynamics of pneumococcal carriage acquisition and clearance observed during a longitudinal household-based nasopharyngeal swabbing study, while accounting for sample misclassifications. Households were followed-up twice weekly for 10 months for nasopharyngeal carriage detection via real-time PCR. We estimated the effect of participant’s age, HIV status, presence of a HIV-infected adult within the household and other covariates on pneumococcal acquisition and clearance probabilities. Of 1,684 individuals enrolled, 279 (16.6%) were younger children (<5 years-old) of whom 4 (1.5%) were HIV-infected and 726 (43.1%) were adults (≥18 years-old) of whom 214 (30.4%) were HIV-infected, most (173, 81.2%) with high CD4+ count. The observed range of pneumococcal carriage prevalence across visits was substantially higher in younger children (56.9-80.5%) than older children (5-17 years-old) (31.7-50.0%) or adults (11.5-23.5%). We estimate that 14.4% (95% Confidence Interval [CI]: 13.7-15.0) of pneumococcal-negative swabs were false negatives. Daily carriage acquisition probabilities among HIV-uninfected younger children were similar in households with and without HIV-infected adults (hazard ratio: 0.95, 95%CI: 0.91-1.01). Longer average carriage duration (11.4 days, 95%CI: 10.2-12.8 vs 6.0 days, 95%CI: 5.6 - 6.3) and higher median carriage density (622 genome equivalents per millilitre, 95%CI: 507-714 vs 389, 95%CI: 311.1-435.5) were estimated in HIV-infected vs HIV-uninfected adults. The use of ART and antibiotics substantially reduced carriage duration in all age groups, and acquisition rates increased with household size. Although South African HIV-infected adults on ART have longer carriage duration and density than their HIV-uninfected counterparts, they show similar patterns of pneumococcal acquisition and onward transmission.Author summary We assessed the contribution of HIV-infected adults to household pneumococcal transmission by applying a hidden Markov model to pneumococcal cohort data comprising 115,595 nasopharyngeal samples from 1,684 individuals in rural and urban settings in South Africa. We estimated 14.4% of sample misclassifications (false negatives), representing 85.6% sensitivity of a test that was used to detect pneumococcus. Pneumococcal carriage prevalence and acquisition rates, and average duration were usually higher in younger or older children than adults. The use of ART and antibiotics reduced the average carriage duration across all age and HIV groups, and carriage acquisition risks increased in larger household sizes. Despite the longer average carriage duration and higher median carriage density in HIV-infected than HIV-uninfected adults, we found similar carriage acquisition and onward transmission risks in the dual groups. These findings suggest that vaccinating HIV-infected adults on ART with PCV would reduce their risk for pneumococcal disease but may add little to the indirect protection against carriage of the rest of the population.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02519803Clinical Protocols https://www.medrxiv.org/content/10.1101/2021.01.06.21249313v1.full.pdf Funding StatementThis research was commissioned by the National Institute for Health Research (NIHR) Global Health Research Unit on Mucosal Pathogens under the UK Government. PHIRST study was funded by a cooperative agreement with the United States Centers for Disease Control and Prevention (grant number 1U01IP001048) (https://www.cdc.gov) and the Bill and Melinda Gates Foundation (Grant number: OPP1164778) (https://www.gatesfoundation.org). DT, OJ are supported by th National Institute for Health Research (NIHR) Global Health Research Unit on Mucosal Pathogens (MPRU) using UK aid from the UK Government (16/136/46) (https://www.mpru.org). AP is supported by the Bill and Melinda Gates Foundation (https://www.gatesfoundation.org). SF is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z) (https://wellcome.org). CC and AvG receive grant support through their institution from Sanofi Pasteur (https://www.sanofi.com/en). The funders had no involvement in the study design; collection, analysis and interpretation of data; writing of the report; or decision to submit the article for publication.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The longitudinal pneumococcal carriage data described in this study were obtained from consenting South African children and adults as part of the PHIRST study. The use of data was granted by the University of Witwatersrand, Human Research Ethics Committee (HREC) and the Protocol Review Committee (PRC) under approval 150808, the US CDC Institutional Review Board relied on the local review (6840), and the London School of Hygiene and Tropical Medicine Observational Research Ethics Committee under approval 17902.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData cannot be shared publicly because of confidentiality. Data are available from the National Institute of Communicable Disease (NICD) if authorised by Institutional Data Access / Ethics Committee (contact via Professor Cherly Cohen, cherylc@nicd.ac.za) for researchers who meet the criteria for access to confidential data. The code underlying the results presented in the study are available from GitHub through the following link (https://github.com/deusthindwa/hmm.pneumococcus.hiv.south-africa) or contact Deus Thindwa through email: deus.thindwa@gmail.com |
Evaluation of Different Types of Face Masks to Limit the Spread of SARS-CoV-2 – A Modeling Study (preprint)
Gurbaxani BM , Hill AN , Paul P , Prasad PV , Slayton RB . medRxiv 2021 2021.04.21.21255889 We updated a published mathematical model of SARS-CoV-2 transmission with laboratory-derived source and wearer protection efficacy estimates for a variety of face masks to estimate their impact on COVID-19 incidence and related mortality in the United States. When used at already-observed population rates of 80% for those ≥65 years and 60% for those <65 years, face masks are associated with 69% (cloth) to 78% (medical procedure mask) reductions in cumulative COVID-19 infections and 82% (cloth) to 87% (medical procedure mask) reductions in related deaths over a 6-month timeline in the model, assuming a basic reproductive number of 2.5. If cloth or medical procedure masks’ source control and wearer protection efficacies are boosted about 30% each to 84% and 60% by cloth over medical procedure masking, fitters, or braces, the COVID-19 basic reproductive number of 2.5 could be reduced to an effective reproductive number ≤ 1.0, and from 6.0 to 2.3 for a variant of concern similar to delta (B.1.617.2).Article Summary Line Adapting a published SARS-CoV-2 transmission model together with updated, laboratory-derived source control and wearer protection efficacy estimates for a variety of face coverings as well as N95 respirators, we demonstrate that community masking as currently practiced has likely reduced cases and deaths and that this benefit can be increased with wider adoption of better performing masks.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialThis is an epidemiological modeling study, not a clinical trialFunding StatementNo external funding was received.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:No IRB was needed as this is an epidemiological modeling study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data/parameters used in the models are reported in the manuscript. Code is available upon request. |
Face mask fit modifications that improve source control performance (preprint)
Blachere FM , Lemons AR , Coyle JP , Derk RC , Lindsley WG , Beezhold DH , Woodfork K , Duling MG , Boutin B , Boots T , Harris JR , Nurkiewicz T , Noti JD . medRxiv 2021 2021.09.16.21263642 BACKGROUND During the COVID-19 pandemic, face masks are used as source control devices to reduce the expulsion of respiratory aerosols from infected people. Modifications such as mask braces, earloop straps, knotting and tucking, and double masking have been proposed to improve mask fit. However, the data on source control are limited.METHODS The effectiveness of mask fit modifications was determined by conducting fit tests on human subjects and simulator manikins and by performing simulated coughs and exhalations using a source control measurement system.RESULTS Medical masks without modification blocked ≥56% of cough aerosols and ≥42% of exhaled aerosols. Modifying fit by crossing the earloops or placing a bracket under the mask did not increase performance, while using earloop toggles, an earloop strap, and knotting and tucking the mask increased performance. The most effective modifications for improving source control performance were double masking and using a mask brace. Placing a cloth mask over a medical mask blocked ≥85% of cough aerosols and ≥91% of exhaled aerosols. Placing a brace over a medical mask blocked ≥95% of cough aerosols and ≥99% of exhaled aerosols.CONCLUSION Fit modifications can greatly improve the performance of face masks as source control devices for respiratory aerosols.Competing Interest StatementThe authors have declared no competing interest.Funding StatementResearch was supported by the following sources: Centers for Disease Control and Prevention, National Institutes of Health R01 ES015022 (TRN) and WV-CTSI U54 GM104942-05.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:WVU Protocol #: 2009119037All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData is available from research personnel upon request. |
Feasibility, Acceptability, and Barriers to Implementing Select Non-Pharmaceutical Interventions to Reduce the Transmission of Pandemic Influenza - United States, 2019 (preprint)
Ahmed F , Qualls N , Kowalczyk S , Randolph Cunningham S , Zviedrite N , Uzicanin A . medRxiv 2021 2021.09.22.21263963 Objective To assess feasibility and acceptability of implementing non-pharmaceutical interventions (NPIs) reserved for influenza pandemics (voluntary home quarantine; use of face masks by ill persons; childcare facility closures; school closures; and social distancing at schools, workplaces, and mass gatherings), and the availability and usefulness of influenza surveillance data for triggering implementation of NPIs.Methods Public health officials in all 50 states, Washington, DC, and 8 territories, and a stratified, random sample of 822 local health departments (LHDs) were surveyed in 2019.Results The response rates for the states/territories and LHDs were 75% (44/59) and 25% (206/822), respectively. About two-thirds to three-fourths of the state/territorial respondents stated that the feasibility and acceptability of implementing the NPIs were high, except for K-12 school closures lasting up to 6 weeks or 6 months. The LHD respondents also indicated that feasibility and acceptability were lowest for prolonged school closures. Compared to LHD respondents in suburban or urban areas, those in rural areas expressed lower feasibility and acceptability. Availability of influenza surveillance data in near real-time was lowest for influenza-like illness and influenza cases in schools.Conclusions The findings can provide insights regarding the implementation of NPIs during the Corona Virus Disease 2019 (COVID-19) pandemic.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialThis is not a clinical trialFunding StatementCenters for Disease Control and PreventionAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Human Subjects Advisor, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, made the following determination: "Project does not meet the definition of research under 45 CFR 46.102(d). IRB review is not required." As the purpose of the project is to conduct a feasibility evaluation of a programmatic activity, it is consistent with non-research public health program evaluation, per CDC guidelines. The project is not designed to contribute to generalizable knowledge.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData can be shared upon request. |
Global emergence and dissemination of Neisseria gonorrhoeae ST-9363 isolates with reduced susceptibility to azithromycin (preprint)
Joseph SJ , Thomas Iv JC , Schmerer MW , Cartee J , St Cyr S , Schlanger K , Kersh EN , Raphael BH , Gernert KM . bioRxiv 2021 2021.08.05.455198 Neisseria gonorrhoeae multi-locus sequence type (ST) 9363 genogroup isolates have been associated with reduced azithromycin susceptibility (AZMrs) and show evidence of clonal expansion in the U.S. Here we analyze a global collection of ST-9363 genogroup genomes to shed light on the emergence and dissemination of this strain. The global population structure of ST-9363 genogroup falls into three lineages: Basal, European, and North American; with 32 clades within all lineages. Although, ST-9363 genogroup is inferred to have originated from Asia in the mid-19th century; we estimate the three modern lineages emerged from Europe in the late 1970s to early 1980s. The European lineage appears to have emerged and expanded from around 1986 to 1998, spreading into North America and Oceania in the mid-2000s with multiple introductions, along with multiple secondary reintroductions into Europe. Our results suggest two separate acquisition events of mosaic mtrR and mtrR promoter alleles: first during 2009-2011 and again during the 2012-2013 time, facilitating the clonal expansion of this genogroup with AZMrs in the U.S. By tracking phylodynamic evolutionary trajectories of clades that share distinct demography as well as population-based genomic statistics, we demonstrate how recombination and selective pressures in the mtrCDE efflux operon granted a fitness advantage to establish ST-9363 as a successful gonococcal lineage in the U.S. and elsewhere. Although it is difficult to pinpoint the exact timing and emergence of this young genogroup, it remains critically important to continue monitoring it, as it could acquire additional resistance markers.Competing Interest StatementThe authors have declared no competing interest. |
Investigation and public health response to a COVID-19 outbreak in a rural resort community — Blaine County, Idaho, 2020 (preprint)
Dunne EM , Maxwell T , Dawson-Skuza C , Burns M , Ball C , Turner K , Hahn CG , Bowyer M , Carter KK , Hudson L . medRxiv 2021 2021.02.09.21251216 Blaine County, Idaho, a rural area with a renowned resort, experienced an outbreak of novel coronavirus disease (COVID-19). We undertook an epidemiologic investigation to describe the outbreak and guide public health action. Confirmed cases of COVID-19 were identified from reports of SARS-CoV-2-positive laboratory test results to South Central Public Health District.Information on symptoms, hospitalization, recent travel, healthcare worker status, and close contacts was obtained by medical record review and patient interviews. Viral sequence analysis was conducted on a subset of available specimens. During March 13–April 10, 2020, a total of 451 COVID-19 cases occurred among Blaine County residents (1,959 cases per 100,000 population). An additional 37 cases occurred in out-of-state residents. Among the 451 COVID-19 patients, the median age was 51 years (Interquartile range [IQR]: 37–63), 52 (11.5%) were hospitalized, and 5 (1.1%) died. The median duration between specimen collection and a positive laboratory result was 9 days (IQR: 4–10). Forty-four (9.8%) patients reported recent travel. Healthcare workers comprised 56 (12.4%) cases; 33 of whom worked at the only hospital in the county, leading to a 15-day disruption of hospital services. Of 562 close contacts monitored by public health authorities, 22 (3.9%) had laboratory-confirmed COVID-19 and an additional 29 (5.2%) experienced compatible symptoms. Sequencing results from 34 Idaho specimens supported epidemiologic findings indicating travel as a source of SARS-CoV-2, and identified multiple lineages among hospital workers. Community mitigation strategies included school and resort closure, stay-at-home orders, and restrictions on incoming travelers. COVID-19 outbreaks in rural communities can disrupt health services. Lack of local laboratory capacity led to long turnaround times for COVID-19 test results. Rural communities frequented by tourists should consider implementing restrictions on incoming travelers among other mitigation strategies to reduce COVID-19 transmission.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:COVID-19 is a reportable disease under Idaho Department of Health and Welfare Rules, IDAPA 16.02.10. Case investigation, data collection, and analysis were conducted for public health purposes. This project was reviewed by the Center for Surveillance, Epidemiology, and Laboratory Services Human Subjects Contact at the Centers for Disease Control and Prevention (CDC). The project was determined to meet the requirements of public health surveillance covered by the U.S. Department of Health and Human Services Policy for the Protection of Human Research Subjects as defined in 45 CFR 46.102, and the decision was made that this project was nonresearch and did not require ethical review by the CDC Human Research Protection Office. Ethical approval was waived and informed consent was not required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesSARS-CoV-2 sequence data have be n uploaded to the GISAID database, with accession numbers provided in S1 Table. Data on the estimated proportion of Blaine County residents staying at home are available at https://docs.safegraph.com/docs/social-distancing-metrics. Census block group data are available at https://data.census.gov/cedsci/. De-identified patient data are not publicly available for legal and ethical reasons. These data were collected as part of reportable disease surveillance under Idaho law, and not for research purposes. Due to the rural setting and relatively small population, there is a risk of reidentification of some patients included in the data set. De-identified data can be requested from the Idaho Division of Public Health by contacting the Bureau of Communicable Diseases Epidemiology Section at Epimail{at}dhw.Idaho.gov. https://www.gisaid.org/ |
Attitudes toward COVID-19 illness and COVID-19 vaccination among pregnant women: a cross-sectional multicenter study during August-December 2020 (preprint)
Battarbee AN , Stockwell MS , Varner M , Newes-Adeyi G , Daugherty M , Gyamfi-Bannerman C , Tita AT , Vorwaller K , Vargas C , Subramaniam A , Reichle L , Galang RR , Powers E , Lucca-Susana M , Parks M , Chen TJ , Razzaghi H , Dawood FS . medRxiv 2021 2021.03.26.21254402 Objective Evaluate pregnant women’s attitudes toward COVID-19 illness and vaccination and identify factors associated with vaccine acceptability.Study Design Cross-sectional survey among pregnant women enrolled in a prospective COVID-19 cohort study in Salt Lake City, UT, Birmingham, AL, and New York, NY, August 9– December 10, 2020. Women were eligible if they were 18-50 years old and <28 weeks of gestation. Upon enrollment, women completed surveys regarding concerns about COVID-19 illness and likelihood of getting COVID-19 vaccine if one were available during pregnancy. Vaccine acceptability was defined as a response of “very likely” or “somewhat likely” on a 4-point Likert scale. Factors associated with vaccine acceptability were assessed with multivariable logistic regression.Results Of 939 pregnant women eligible for the main cohort study, 915 (97%) consented to participate. Among these 915 women, 39% self-identified as White, 23% Black, 33% Hispanic, and 4% Other. Sixty-two percent received an influenza vaccine last season. Seventy-two percent worried about getting sick with COVID-19. If they were to get sick, 92% worried about harm to their pregnancy and 80% about harm to themselves. Only 41% reported they would get a vaccine. Of women who were unlikely to get vaccinated, the most frequently cited concern was vaccine safety for their pregnancy (82%). Non-Hispanic Black and Hispanic women had lower odds of accepting a vaccine compared with non-Hispanic White women (adjusted odds ratios (aOR) 0.4, 95%CI 0.2–0.6 for both). Receipt of influenza vaccine during the previous season was associated with higher odds of vaccine acceptability (aOR 2.1, 95%CI 1.5-3.0).Conclusion Although most pregnant women worried about COVID-19 illness, <50% were willing to get vaccinated during pregnancy. Racial and ethnic disparities in plans to accept COVID-19 vaccine highlight the need to prioritize strategies to address perceived barriers among groups at high risk for COVID-19.Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; author CGB has an unrestricted grant from SMFM/AMAG to study prematurity.Funding StatementFunding: This study was funded by the US Centers for Disease Control and Prevention through Contract # 75D30120C08150 with Abt Associates.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Centralized Institutional Review Board approval was obtained (IRB-AAAT1906), and informed consent was obtained from all participants. The Columbia University Medical Center IRB served as the centralized IRB for this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will automatically be sequestered by site. |
Characterizing the countrywide epidemic spread of influenza A(H1N1)pdm09 virus in Kenya between 2009 and 2018 (preprint)
Owuor DC , de Laurent ZR , Kikwai GK , Mayieka LM , Ochieng M , Müller NF , Otieno NA , Emukule GO , Hunsperger EA , Garten R , Barnes JR , Chaves SS , Nokes DJ , Agoti CN . medRxiv 2021 2021.03.30.21254587 Background The spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data is lacking.Methods We isolated, sequenced, and analyzed 383 influenza A(H1N1)pdm09 viral genomes isolated from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods.Results The transmission dynamics of influenza A(H1N1)pdm09 virus in Kenya was characterized by: (i) multiple virus introductions into Kenya over the study period, although these were remarkably few, with only a few of those introductions instigating seasonal epidemics that then established local transmission clusters; (ii) persistence of transmission clusters over several epidemic seasons across the country; (iii) seasonal fluctuations in effective reproduction number (Re) associated with lower number of infections and seasonal fluctuations in relative genetic diversity after an initial rapid increase during the early pandemic phase, which broadly corresponded to epidemic peaks in the northern and southern hemispheres; (iv) high virus genetic diversity with greater frequency of seasonal fluctuations in 2009-11 and 2018 and low virus genetic diversity with relatively weaker seasonal fluctuations in 2012-17; and (v) virus migration from multiple geographical regions to multiple geographical destinations in Kenya.Conclusion Considerable influenza virus diversity circulates within Africa, as demonstrated in this report, including virus lineages that are unique to the region, which may be capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied low-to-middle income tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses in humans and to inform vaccination strategies within these regions.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFunding: The authors D.C.O. and C.N.A. were supported by the Initiative to Develop African Research Leaders (IDeAL) through the DELTAS Africa Initiative [DEL-15-003]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)'s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [107769/Z/10/Z] and the UK government. The study was also part funded by a Wellcome Trust grant [1029745] and the USA CDC grant [GH002133]. N.F.M. is supported by the Swiss National Science Foundation (PZEZP3_191891). This paper is published with the permission of the Director of KEMRI.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Kenya Medical Research Institute (KEMRI) and KEMRI-Wellcome Trust Research Programme Scientific and Ethics Review Unit (SERU), which is mandated to provide ethical approval for research work conducted in Kenya, provided ethical approval for the studies which collected and archived the samples used in these studies. These were approved under the following Scientific Steering Committee (SSC) approvals: 1. SSC No. 1899, SSC No. 2558 and SSC No. 2692; 2. KEMRI-Wellcome Trust Research Programme SSC No. 1055 and SSC No. 1433.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as Clini alTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll generated sequence data were deposited in the Global Initiative on Sharing All Influenza Data (GISAID). https://github.com/DCollinsOwuor/H1N1pdm09_Kenya_Phylodynamics/tree/main/Data/. |
Clinical Trends Among U.S. Adults Hospitalized with COVID-19, March-December 2020 (preprint)
Garg S , Patel K , Pham H , Whitaker M , O'Halloran A , Milucky J , Anglin O , Kirley PD , Reingold A , Kawasaki B , Herlihy R , Yousey-Hindes K , Maslar A , Anderson EJ , Openo KP , Weigel A , Teno K , Ryan PA , Monroe ML , Reeg L , Kim S , Como-Sabetti K , Bye E , Shrum Davis S , Eisenberg N , Muse A , Barney G , Bennett NM , Felsen CB , Billing L , Shiltz J , Sutton M , Abdullah N , Talbot HK , Schaffner W , Hill M , Chatelain R , Wortham J , Taylor C , Hall A , Fry AM , Kim L , Havers FP . medRxiv 2021 2021.04.21.21255473 Background The COVID-19 pandemic has caused substantial morbidity and mortality.Objectives To describe monthly demographic and clinical trends among adults hospitalized with COVID-19.Design Pooled cross-sectional.Setting 99 counties within 14 states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET).Patients U.S. adults (aged ≥18 years) hospitalized with laboratory-confirmed COVID-19 during March 1-December 31, 2020.Measurements Monthly trends in weighted percentages of interventions and outcomes including length of stay (LOS), intensive care unit admissions (ICU), invasive mechanical ventilation (IMV), vasopressor use and in-hospital death (death). Monthly hospitalization, ICU and death rates per 100,000 population.Results Among 116,743 hospitalized adults, median age was 62 years. Among 18,508 sampled adults, median LOS decreased from 6.4 (March) to 4.6 days (December). Remdesivir and systemic corticosteroid use increased from 1.7% and 18.9% (March) to 53.8% and 74.2% (December), respectively. Frequency of ICU decreased from 37.8% (March) to 20.5% (December). IMV (27.8% to 8.7%), vasopressors (22.7% to 8.8%) and deaths (13.9% to 8.7%) decreased from March to October; however, percentages of these interventions and outcomes remained stable or increased in November and December. Percentage of deaths significantly decreased over time for non-Hispanic White patients (p-value <0.01) but not non-Hispanic Black or Hispanic patients. Rates of hospitalization (105.3 per 100,000), ICU (20.2) and death (11.7) were highest during December.Limitations COVID-NET covers approximately 10% of the U.S. population; findings may not be generalizable to the entire country.Conclusions After initial improvement during April-October 2020, trends in interventions and outcomes worsened during November-December, corresponding with the 3rd peak of the U.S. pandemic. These data provide a longitudinal assessment of trends in COVID-19-associated outcomes prior to widespread COVID-19 vaccine implementation.Competing Interest StatementDr. Evan Anderson reports grants from Pfizer, grants from Merck, grants from PaxVax, grants from Micron, grants from Sanofi-Pasteur, grants from Janssen, grants from MedImmune, grants from GSK, personal fees from Sanofi-Pasteur, personal fees from Pfizer, personal fees from Medscape, personal fees from Kentucky Bioprocessing, Inc, personal fees from Sanofi-Pasteur, outside the submitted work. Dr. William Schaffner reports personal fees from VBI Vaccines, outside the submitted work. Funding StatementThis work was supported by the Centers of Disease Control and Prevention through an Emerging Infections Program cooperative agreement (grant CK17-1701) and through a Council of State and Territorial Epidemiologists cooperative agreement (grant NU38OT000297-02-00).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. Sites participating in COVID-NET obtained approval from their respective state and local Institutional Review Boards, as applicable.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting check ist(s) and other pertinent material as supplementary files, if applicable.YesPublicly available data referred to in this analysis can be found at: https://gis.cdc.gov/grasp/covidnet/covid19_3.html https://gis.cdc.gov/grasp/covidnet/covid19_3.html |
Cohort Profile: a Prospective Household cohort study of Influenza, Respiratory Syncytial virus, and other respiratory pathogens community burden and Transmission dynamics in South Africa (PHIRST), 2016-2018 (preprint)
Cohen C , McMorrow ML , Martinson NA , Kahn K , Treurnicht FK , Moyes J , Mkhencele T , Hellferscee O , Lebina L , Moroe M , Motlhaoleng K , Gómez-Olivé FX , Wagner R , Tollman S , Wafawanaka F , Ngobeni S , Kleynhans J , Mathunjwa A , Buys A , Maake L , Wolter N , Carrim M , Piketh S , Language B , Mathee A , von Gottberg A , Tempia S . medRxiv 2021 2021.01.06.21249313 Purpose The PHIRST study (Prospective Household cohort study of Influenza, Respiratory Syncytial virus, and other respiratory pathogens community burden and Transmission dynamics in South Africa) aimed to estimate the community burden of influenza and respiratory syncytial virus (RSV) including the incidence of infection, symptomatic fraction, and disease severity, and to assess household transmission. We further aimed to estimate the impact of HIV infection and age on disease burden and transmission, and to assess the burden of Bordetella pertussis and Streptococcus pneumoniae.Participants We enrolled 1684 individuals in 327 randomly selected households in two sites (rural Agincourt subdistrict, Mpumalanga Province and urban Jouberton Township, North West Province) over 3 consecutive influenza and RSV seasons. A new cohort of households was enrolled each year. Eligible households included those with >2 household members where ≥80% of household members provided consent (and assent for children aged 7-17 years). Enrolled household members were sampled with nasopharyngeal swabs twice weekly during the RSV and influenza seasons of the year of enrolment. Serology samples were collected at enrolment and before and after the influenza season annually.Findings to date There were 122,113 potential individual follow-up visits over the 3 years, and participants were interviewed for 105,783 (87%) of these. Out of 105,683 nasopharyngeal swabs from follow-up visits, 1,258 (1%), 1,026 (1%), 273 (<1%), 38,829 (37%) tested positive on PCR for influenza viruses, respiratory syncytial virus, pertussis and pneumococcus respectively.Future plans Future planned analyses include analysis of influenza serology results and RSV burden and transmission. Households enrolled in the PHIRST study during 2016-2018 were eligible for inclusion in a study of SARS-CoV-2 transmission initiated in July 2020. This study uses similar testing frequency and household selection methods to assess the community burden of SARS-CoV-2 infection and the role of asymptomatic infection in virus transmission.Registration Clinical trials.gov NCT02519803Strengths and limitations of this studyPHIRST was conducted in urban and rural African settings with high HIV prevalence, allowing assessment of the effect of HIV on community burden and transmission dynamics of respiratory pathogens.Households were selected randomly to provide a representative sample of the community. Twice weekly sampling from each cohort of individuals for 6-10 months irrespective of symptoms allows estimation of community burden, household secondary infection risk, and serial interval including asymptomatic or paucisymptomatic episodes.Polymerase chain reaction testing of >100,000 nasopharyngeal swab samples for multiple pathogens (influenza, respiratory syncytial virus, pertussis and Streptoccocus pneumonia) allows detailed examination of disease burden and transmission and pathogen interactionsPHIRST was not powered to assess severe outcomes (i.e. hospitalisation and death).We only examined four pathogens, but other micro-organisms may be important. Samples have been stored which could allow us to implement broader multi-pathogen testing in the future.Competing Interest StatementCheryl Cohen has received research grants awarded to her institution from Sanofi Pasteur, US Centers for Disease Control and Prevention. Cheryl Cohen has had costs for travel to a meeting supported by Parexel. Maimuna Carrim was awarded the Robert Austrian Research Award in Pneumococcal Vaccinology sponsored by Pfizer. Neil Martinson has a research grant awarded to his institution by Pfizer South Africa. Anne von Gottberg has received research grants awarded to her institution from Sanofi Pasteur, Pfizer and US Centers for Disease Control and Prevention.Clinical TrialNCT02519803Funding StatementThe study was funded through a cooperative agreement with the United States Centers for Disease Control and Prevention (CDC) (grant number 1U01IP001048). Testing for RSV and pneumococcus was supported by the Bill and Melin a Gates Foundation (Grant number: OPP1164778). Testing for B. pertussis was supported by Sanofi Pasteur (Grant number: PER00059). The Agincourt Health and Socio-Demographic Surveillance System is a node of the South African Population Research Infrastructure Network (SAPRIN) and is supported by the National Department of Science and Innovation, the Medical Research Council and the University of the Witwatersrand, South Africa, and the Wellcome Trust, UK (grants 058893/Z/99/A; 069683/Z/02/Z; 085477/Z/08/Z; 085477/B/08/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of the Witwatersrand Human Research Ethics CommitteeAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesPrimary study results for influenza as well as a description of the quality of housing at the two sites have been prepared and submitted to international peer-reviewed journals. Analysis of the data for other pathogens is planned to be completed by December 2021. Additional modelling and serologic studies will be concluded within 3 years and primary de-identified data should be publicly available no later than November 2023. The investigators welcome enquiries about possible collaborations and access to the data set. Investigators interested in more details about this study, or in accessing these resources, should contact the principle investigator, Prof Cheryl Cohen, at NICD (cherylc{at}nicd.ac.za). |
COVID-19 case definitions, diagnostic testing criteria, and surveillance across the pandemic’s 25 highest burden countries (preprint)
Suthar AB , Schubert S , Garon J , Couture A , Brown AM , Charania S . medRxiv 2021 2021.05.11.21257047 Objective We compared suspect, probable, and confirmed case definitions, as well as diagnostic testing criteria, used in the COVID-19 pandemic’s 25 highest burden countries to aid interpretation of global and national surveillance data.Methods We identified the COVID-19 pandemic’s 25 countries with the highest disease burden based on the number of cumulative reported cases to the World Health Organization (WHO) as of 1 October 2020. We searched official websites of these countries for suspect, probable, and confirmed case definitions. Given that confirmation of COVID-19 usually requires diagnostic testing, we also searched for diagnostic testing eligibility criteria in these countries. Extracted case definitions and testing criteria were managed in a database and analyzed in Microsoft Excel.Findings We identified suspect, probable, and confirmed case definitions in 96%, 64%, and 100% of countries, respectively. Testing criteria were identified in 100% of countries. 56% of identified countries followed WHO recommendations for using a combination of clinical and epidemiological criteria as part of the suspect case definition. 75% of identified countries followed WHO recommendations on using clinical, epidemiological, and diagnostic criteria for probable cases. 72% of countries followed WHO recommendations on using PCR testing for confirming a case of COVID-19. Finally, 64% of countries used testing eligibility criteria at least as permissive as WHO.Conclusion There is marked heterogeneity in who is eligible for testing in countries and how countries define a case of COVID-19. This affects the ability to compare burden, transmission, and response impact estimates derived from case surveillance data across countries.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNoneAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Not applicableAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are available in the manuscript body and appendices. |
A Decision Analytics Model to Optimize Investment in Interventions Targeting the HIV PrEP Cascade of Care (preprint)
Jenness SM , Knowlton G , Smith DK , Marcus JL , Anderson EJ , Siegler AJ , Jones J , Sullivan PS , Enns E . medRxiv 2021 2020.12.10.20247270 Objectives Gaps between recommended and actual levels of HIV preexposure prophylaxis (PrEP) use remain among men who have sex with men (MSM). Interventions can address these gaps, but it is unknown how public health initiatives should invest prevention funds into these interventions to maximize their population impact.Design We used a stochastic network-based HIV transmission model for MSM in the Atlanta area paired with an economic budget optimization model.Methods The model simulated MSM participating in up to three real-world PrEP cascade interventions designed to improve initiation, adherence, or persistence. The primary outcome was infections averted over 10 years. The budget optimization model identified the investment combination under different budgets that maximized this outcome given intervention costs from a payer perspective.Results From the base 15% PrEP coverage level, the three interventions could increase coverage to 27%, resulting in 12.3% of infections averted over 10 years. Uptake of each intervention was interdependent: maximal use of the adherence and persistence interventions depended on new PrEP users generated by the initiation intervention. As the budget increased, optimal investment involved a mixture of the initiation and persistence interventions, but not the adherence intervention. If adherence intervention costs were halved, the optimal investment was roughly equal across interventions.Conclusions Investments into the PrEP cascade through initiatives should account for the interactions of the interventions as they are collectively deployed. Given current intervention efficacy estimates, the total population impact of each intervention may be improved with greater total budgets or reduced intervention costs.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by Centers for Disease Control and Prevention cooperative agreement number U38 PS004646 and National Institutes of Health grant R01 AI138783. Dr. Marcus is supported in part by National Institutes of Health grant K01 AI122853.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Emory University Institutional Review Board approved the study protocols for the primary empirical data collection yielding model parameters for the current study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe model code and parameters are all open and availability at the Github repository linked below. https://github.com/EpiModel/PrEP-Optimize |
Description of a University COVID-19 Outbreak and Interventions to Disrupt Transmission, Wisconsin, August – October 2020 (preprint)
Currie DW , Moreno GK , Delahoy MJ , Pray IW , Jovaag A , Braun KM , Cole D , Shechter T , Fajardo GC , Griggs C , Yandell BS , Goldstein S , Bushman D , Segaloff HE , Kelly GP , Pitts C , Lee C , Grande KM , Kita-Yarbro A , Grogan B , Mader S , Baggott J , Bateman AC , Westergaard RP , Tate JE , Friedrich TC , Kirking HL , O'Connor DH , Killerby ME . medRxiv 2021 2021.05.07.21256834 University settings have demonstrated potential for COVID-19 outbreaks, as they can combine congregate living, substantial social activity, and a young population predisposed to mild illness. Using genomic and epidemiologic data, we describe a COVID-19 outbreak at the University of Wisconsin (UW)–Madison. During August – October 2020, 3,485 students tested positive, including 856/6,162 students living in residence halls. Case counts began rising during move-in week for on-campus students (August 25-31, 2020), then rose rapidly during September 1-11, 2020. UW-Madison initiated multiple prevention efforts, including quarantining two residence halls; a subsequent decline in cases was observed. Genomic surveillance of cases from Dane County, where UW-Madison is located, did not find evidence of transmission from a large cluster of cases in the two residence halls quarantined during the outbreak. Coordinated implementation of prevention measures can effectively reduce SARS-CoV-2 spread in university settings and may limit spillover to the community surrounding the university.Competing Interest StatementThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention.Clinical TrialN/A.Funding StatementG.K.M. is supported by an NLM training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). This work was funded in part by the U.S. Centers for Disease Control and Prevention Contract #75D30120C09870: Defining the Role of College Students in SARS-CoV-2 Spread in the Upper Midwest.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:A waiver of HIPAA Authorization was obtained by the Western Institutional Review Board (WIRB #1-1290953-1) to obtain the clinical specimens for whole genome sequencing. This analysis was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. These activities were determined to be non-research public health surveillance by the Institutional Review Board at UW-Madison.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll sequencing data is available on www.gisaid.org. Scripts for sequence data analysis is available at https://github.com/gagekmoreno/SARS-CoV-2-at-UW_Madison. https://github.com/gagekmoreno/SARS-CoV-2-at-UW_Madison |
Reducing travel-related SARS-CoV-2 transmission with layered mitigation measures: Symptom monitoring, quarantine, and testing (preprint)
Johansson MA , Wolford H , Paul P , Diaz PS , Chen TH , Brown CM , Cetron MS , Alvarado-Ramy F . medRxiv 2020 2020.11.23.20237412 Balancing the control of SARS-CoV-2 transmission with the resumption of travel is a global priority. Current recommendations include mitigation measures before, during, and after travel. Pre- and post-travel strategies including symptom monitoring, testing, and quarantine can be combined in multiple ways considering different trade-offs in feasibility, adherence, effectiveness, cost and adverse consequences. Here we use a mathematical model to analyze the expected effectiveness of symptom monitoring, testing, and quarantine under different estimates of the infectious period, test-positivity relative to time of infection, and test sensitivity to reduce the risk of transmission from infected travelers during and after travel. If infection occurs 0-7 days prior to travel, immediate isolation following symptom onset prior to or during travel reduces risk of transmission while traveling by 26-30%. Pre-departure testing can further reduce risk if testing is close to the time of departure. For example, testing on the day of departure can reduce risk while traveling by 37-61%. For transmission risk after travel with infection time up to 7 days prior to arrival at the destination, isolation based on symptom monitoring reduced introduction risk at the destination by 42-56%. A 14-day quarantine after arrival, without symptom monitoring or testing, can reduce risk by 97-100% on its own. However, a shorter quarantine of 7 days combined with symptom monitoring and a test on day 3-4 after arrival is also effective (95-99%) at reducing introduction risk and is less burdensome, which may improve adherence. To reduce the risk of introduction without quarantine, optimal test timing after arrival is close to the time of arrival; with effective quarantine after arrival, testing a few days later optimizes sensitivity to detect those infected immediately before or while traveling. These measures can complement recommendations such as social distancing, using masks, and hand hygiene, to further reduce risk during and after travel.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding supported this research.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Centers for Disease Control and PreventionAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesOnly publicly available data informed this research. |
Risk Factors for COVID-19-associated hospitalization: COVID-19-Associated Hospitalization Surveillance Network and Behavioral Risk Factor Surveillance System (preprint)
Ko JY , Danielson ML , Town M , Derado G , Greenlund KJ , Daily Kirley P , Alden NB , Yousey-Hindes K , Anderson EJ , Ryan PA , Kim S , Lynfield R , Torres SM , Barney GR , Bennett NM , Sutton M , Talbot HK , Hill M , Hall AJ , Fry AM , Garg S , Kim L . medRxiv 2020 2020.07.27.20161810 Background Identification of risk factors for COVID-19-associated hospitalization is needed to guide prevention and clinical care.Objective To examine if age, sex, race/ethnicity, and underlying medical conditions is independently associated with COVID-19-associated hospitalizations.Design Cross-sectional.Setting 70 counties within 12 states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET) and a population-based sample of non-hospitalized adults residing in the COVID-NET catchment area from the Behavioral Risk Factor Surveillance System.Participants U.S. community-dwelling adults (≥18 years) with laboratory-confirmed COVID-19-associated hospitalizations, March 1- June 23, 2020.Measurements Adjusted rate ratios (aRR) of hospitalization by age, sex, race/ethnicity and underlying medical conditions (hypertension, coronary artery disease, history of stroke, diabetes, obesity [BMI ≥30 kg/m2], severe obesity [BMI≥40 kg/m2], chronic kidney disease, asthma, and chronic obstructive pulmonary disease).Results Our sample included 5,416 adults with COVID-19-associated hospitalizations. Adults with (versus without) severe obesity (aRR:4.4; 95%CI: 3.4, 5.7), chronic kidney disease (aRR:4.0; 95%CI: 3.0, 5.2), diabetes (aRR:3.2; 95%CI: 2.5, 4.1), obesity (aRR:2.9; 95%CI: 2.3, 3.5), hypertension (aRR:2.8; 95%CI: 2.3, 3.4), and asthma (aRR:1.4; 95%CI: 1.1, 1.7) had higher rates of hospitalization, after adjusting for age, sex, and race/ethnicity. In models adjusting for the presence of an individual underlying medical condition, higher hospitalization rates were observed for adults ≥65 years, 45-64 years (versus 18-44 years), males (versus females), and non-Hispanic black and other race/ethnicities (versus non-Hispanic whites).Limitations Interim analysis limited to hospitalizations with underlying medical condition data.Conclusion Our findings elucidate groups with higher hospitalization risk that may benefit from targeted preventive and therapeutic interventions.Competing Interest StatementDr. Anderson reports personal fees from AbbVie, personal fees from Pfizer, grants from Pfizer, grants from Merck, grants from Micron, grants from Paxvax, grants from Sanofi Pasteur, grants from Novavax, grants from MedImmune, grants from Regeneron, grants from GSK, outside the submitted work. Mr. Henderson, Ms. Kim, Ms. George, and Ms. Hill report grants from Council of State and Territorial Epidemiologists (CSTE), during the conduct of the study. Dr. Lynfield reports grants from CDC- Emerging Infections Program, during the conduct of the study; and Royalties from a book on infectious disease surveillance and compensation for AAP Red Book (Report from Committee on Infectious Disease) donated to Minnesota Dept of Health. Dr. Schaffner reports grants from CDC, during the conduct of the study; personal fees from VBI Vaccines, outside the submitted work. Dr. Talbot reports other from Seqirus, outside the submitted work.Funding StatementThis work was supported by the Centers of Disease Control and Prevention through an Emerging Infections Program cooperative agreement (grant CK17-1701) and through a Council of State and Territorial Epidemiologists cooperative agreement (grant NU38OT000297-02-00).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This analysis was exempt from CDC's Institutional Review Board, as it was considered part of public health surveillance and emergency response. Participating sites obtained approval for the COVID-NET surveillance protocol from their respective state and local IRBs, as required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved regi try, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData is not publically available at this time. |
Risk of fomite-mediated transmission of SARS-CoV-2 in child daycares, schools, and offices: a modeling study (preprint)
Kraay ANM , Hayashi MAL , Berendes DM , Sobolik JS , Leon JS , Lopman BA . medRxiv 2020 2020.08.10.20171629 SARS-CoV-2 can persist on surfaces, suggesting that surface-based transmission might be important for this pathogen. We find that fomites may be a substantial source of risk, particularly in schools and child daycares. Combining surface cleaning and decontamination with strategies to reduce pathogen shedding on surfaces can help mitigate this risk.Competing Interest StatementDr. Lopman reports grants and personal fees from Takeda Pharmaceuticals, personal fees from World Health Organization, outside the submitted work.Funding StatementThis research was funded by the National Institutes of Health (to A.N.M.K. and B.A.L., grant supplement to R01GM124280; to J.S.S., grant 2T32ES012870-16), the National Institute of Food and Agriculture at the U.S. Department of Agriculture (J.S.L. and B.A.L, grant 2018-07410; J.S.S., grant 2020-67034-31728).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The research study does not include primary data on human subjects and is therefore exempt from IRB approval.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data used in the manuscript are taken from published studies cited in the text. |
The Seattle Flu Study: a multi-arm community-based prospective study protocol for assessing influenza prevalence, transmission, and genomic epidemiology (preprint)
Chu HY , Boeckh M , Englund JA , Famulare M , Lutz B , Nickerson DA , Rieder M , Starita LM , Shendure J , Bedford T , Adler A , Brandstetter E , Frazer CD , Han PD , Gulati RK , Hadfield J , Jackson M , Kiavand A , Kimball LE , Lacombe K , Logue JK , Lyon VR , Newman KL , Sibley TR , Zigman Suchsland M , Wolf C . medRxiv 2020 2020.03.02.20029595 Introduction Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterize, and potentially contain new and emerging influenza strains at a population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.Methods and Analysis Starting in the 2018-19 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses, and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modeling platforms are in development to characterize the regional spread of influenza and other respiratory pathogens.Ethics and Dissemination The study was approved by the University of Washington’s Institutional Review Board. Results will be disseminated through talks at conferences, peer-reviewed publications, and on the study website (www.seattleflu.org).Strengths and limitations of this study- Large-scale multiple-arm study of respiratory illness characterization with collection of samples from individuals in the community as well as in ambulatory care and hospital settings- Integration of sociodemographic, clinical, and geospatial data on a regional level- Multiplex molecular testing for multiple viral and bacterial pathogens and whole genome sequencing of influenza for detailed molecular epidemiologic characterization and transmission mapping- Geographically and socioeconomically diverse sampling of community-based acute respiratory illnessesCompeting Interest StatementAmanda Adler, Elisabeth Brandstetter, Michael Famulare, Chris D. Frazar, Peter D. Han, Reena K. Gulati, James Hadfield, Michael L. Jackson, Anahita Kiavand, Louise E. Kimball, Kirsten Lacombe, Jennifer Logue, Victoria Lyon, Kira L. Newman, Thomas R. Sibley, Jay Shendure, Lea Starita, Monica L. Zigman Suchsland, and Caitlin Wolf declare no competing interests. Helen Y Chu receives research support from Sanofi, Cepheid, and Genentech/Roche and is a consultant for Merck. Janet Englund receives research support to her institution from Astrazeneca, GlaxoSmithKline, Merck, and Novavax and is a consultant for Sanofi Pasteur and Meissa Vaccines.Funding StatementThe Seattle Flu Study is funded through the Brotman Baty Institute. The funder was not involved in the design of the study, does not have any ownership over the management and conduct of the study, the data, or the rights to publishAuthor DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable YesThe data will be accessed only by authorized individuals on the study team. Access to deidentified, aggregated data and analysis code will be publicly available on the study web page (www.seattleflu.org). http://www.seattleflu.org |
Seroprevalence of antibodies against Chlamydia trachomatis and enteropathogens and distance to the nearest water source among young children in the Amhara Region of Ethiopia (preprint)
Aiemjoy K , Aragie S , Wittberg DM , Tadesse Z , Callahan EK , Gwyn S , Martin D , Keenan JD , Arnold BF . medRxiv 2020 2020.04.16.20060996 Background The transmission of trachoma, caused by repeat infections with Chlamydia trachomatis, and many enteropathogens are linked to water quantity. We hypothesized that children living further from a water source would have higher exposure to C. trachomatis and enteric pathogens as determined by antibody responses.Methods We used a multiplex bead assay to measure IgG antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in eluted dried blood spots collected from 2267 children ages 1–9 years in 40 communities in rural Ethiopia in 2016. Linear distance from the child’s house to the nearest water source was calculated. We derived seroprevalence cutoffs using external negative control populations, if available, or by fitting finite mixture models. We used targeted maximum likelihood estimation to estimate differences in seroprevalence according to distance to the nearest water source.Results Seroprevalence among 1–9-year-olds was 43% for C. trachomatis, 28% for S. enterica, 70% for E. histolytica, 54% for G. intestinalis, 96% for C. jejuni, 76% for ETEC and 94% for C. parvum. Seroprevalence increased with age for all pathogens. Median distance to the nearest water source was 473 meters (IQR 268, 719). Children living furthest from a water source had a 12% (95% CI: 2.6, 21.6) higher seroprevalence of S. enterica and a 12.7% (95% CI: 2.9, 22.6) higher seroprevalence of G. intestinalis compared to children living nearest.Conclusion Seroprevalence for C. trachomatis and enteropathogens was high, with marked increases for most enteropathogens in the first two years of life. Children living further from a water source had higher seroprevalence of S. enterica and G. intestinalis indicating that improving access to water in the Ethiopia’s Amhara region may reduce exposure to these enteropathogens in young children.AUTHOR SUMMARY Trachoma, and infection of the eye caused by the bacteria Chlamydia trachomatis, and many diarrhea-causing infections are associated with access to water for washing hands and faces. Measuring these different pathogens in a population is challenging and rarely are multiple infections measured at the same time. Here, we used an integrated approach to simultaneously measure antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae among young children residing in rural Ethiopia. We found that the seroprevalence of all pathogens increased with age and that seropositivity to more than one pathogen was common. Children living further from a water source were more likely to be exposed to S. enterica and G. intestinalis. Integrated sero-surveillance is a promising avenue to explore the complexities of multi-pathogen exposure as well as to investigate the relationship water, sanitation and hygiene related exposures disease transmission.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by the National Institutes of Health, National Eye Institute (NEI U10 EY016214)Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in adva ce).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAssociated data will be available on OSF upon publication |
Seroprevalence of Antibodies to SARS-CoV-2 in Six Sites in the United States, March 23-May 3, 2020 (preprint)
Havers FP , Reed C , Lim T , Montgomery JM , Klena JD , Hall AJ , Fry AM , Cannon DL , Chiang CF , Gibbons A , Krapiunaya I , Morales-Betoulle M , Roguski K , Rasheed MAU , Freeman B , Lester S , Mills L , Carroll DS , Owen SM , Johnson JA , Semenova V , Schiffer J , Thornburg NJ , Blackmore C , Blog D , Dunn A , Lindquist S , Pritchard S , Sosa L , Turabelidze G , Wiesman J , Williams RW . medRxiv 2020 2020.06.25.20140384 Importance Reported cases of SARS-CoV-2 infection likely underestimate the prevalence of infection in affected communities. Large-scale seroprevalence studies provide better estimates of the proportion of the population previously infected.Objective To estimate prevalence of SARS-CoV-2 antibodies in convenience samples from several geographic sites in the United States.Design Serologic testing of convenience samples using residual sera obtained for routine clinical testing by two commercial laboratory companies.Setting Connecticut (CT), south Florida (FL), Missouri (MO), New York City metro region (NYC), Utah (UT), and Washington State’s (WA) Puget Sound region.Participants Persons of all ages with serum collected during intervals from March 23 through May 3, 2020.Exposure SARS-CoV-2 virus infection.Main outcomes and measures We estimated the presence of antibodies to SARS-CoV-2 spike protein using an ELISA assay. We standardized estimates to the site populations by age and sex. Estimates were adjusted for test performance characteristics (96.0% sensitivity and 99.3% specificity). We estimated the number of infections in each site by extrapolating seroprevalence to site populations. We compared estimated infections to number of reported COVID-19 cases as of last specimen collection date.Results We tested sera from 11,933 persons. Adjusted estimates of the proportion of persons seroreactive to the SARS-CoV-2 spike protein ranged from 1.13% (95% confidence interval [CI] 0.70-1.94) in WA to 6.93% (95% CI 5.02-8.92) in NYC (collected March 23-April 1). For sites with later collection dates, estimates ranged from 1.85% (95% CI 1.00-3.23, collected April 6-10) for FL to 4.94% (95% CI 3.61-6.52) for CT (April 26-May 3). The estimated number of infections ranged from 6 to 24 times the number of reported cases in each site.Conclusions and relevance Our seroprevalence estimates suggest that for five of six U.S. sites, from late March to early May 2020, >10 times more SARS-CoV-2 infections occurred than the number of reported cases. Seroprevalence and under-ascertainment varied by site and specimen collection period. Most specimens from each site had no evidence of antibody to SARS-CoV-2. Tracking population seroprevalence serially, in a variety of specific geographic sites, will inform models of transmission dynamics and guide future community-wide public health measures.Question What proportion of persons in six U.S. sites had detectable antibodies to SARS-CoV-2, March 23-May 3, 2020?Findings We tested 11,933 residual clinical specimens. We estimate that from 1.1% of persons in the Puget Sound to 6.9% in New York City (collected March 23-April 1) had detectable antibodies. Estimates ranged from 1.9% in south Florida to 4.9% in Connecticut with specimens collected during intervals from April 6-May 3. Six to 24 times more infections were estimated per site with seroprevalence than with case report data.Meaning For most sites, evidence suggests >10 times more SARS-CoV-2 infections occurred than reported cases. Most persons in each site likely had no detectable SARS-CoV-2 antibodies.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This protocol underwent review by CDC human subjects research officials, who determined that the testing represented non-research activity in the setting of a public health response to the COVID-19 pandemic.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any su h study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesA limited dataset will be made publicly available at a later time. |
Seroprevalence of SARS-CoV-2 Antibodies in Seattle, Washington—October 2019–April 2020 (preprint)
McCulloch DJ , Jackson ML , Hughes JP , Lester S , Mills L , Freeman B , Rasheed MAU , Thornburg NJ , Chu HY . medRxiv 2020 2020.12.07.20244103 Estimating prevalence of SARS-CoV-2 antibodies is important to determine disease burden. We tested residual samples from 763 Seattle-area adults for SARS-CoV-2 antibodies. Prevalence rose from 0% to 1.2% between October 2019–April 2020, suggesting a small percentage of this metropolitan-area cohort had been infected with SARS-CoV-2 at that time.Competing Interest StatementHelen Y. Chu receives research support from Cepheid and is a consultant for Merck, Pfizer, the Bill and Melinda Gates Foundation, and Ellume. Michael L. Jackson receives research funding from Sanofi Pasteur. Denise J. McCulloch, James P. Hughes, Sandra Lester, Lisa Mills, Brandi Freeman, Mohammad Ata Ut Rasheed, and Natalie J. Thornburg, declare no competing interests.Funding StatementThis work was supported by the University of Washington Department of Medicine Scholars Award to Helen Chu.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Washington IRBAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data analyzed during the current study are available from the corresponding author on reasonable request. |
Use of Public Data to Describe COVID-19 Contact Tracing in China during January 20–February 29, 2020 (preprint)
Dirlikov E , Zhou S , Han L , Li Z , Hao L , Millman AJ , Marston B . medRxiv 2020 2020.12.04.20243972 Objective Although contact tracing is generally not used to control influenza pandemics, China and several countries in the Western Pacific Region employed contact tracing as part of COVID-19 response activities. To improve understanding on the use of contact tracing for COVID-19 emergency public health response activities, we describe reported COVID-19 contacts traced and quarantined in China and a proxy for number of reported contacts traced per reported case.Methods We abstracted publicly available online aggregate data reported from China’s National Health Commission and provincial health commissions’ COVID-19 daily situational reports for January 20–February 29, 2020. The number of new contacts traced by report date was computed as the difference between total contacts traced on consecutive reports. A proxy for the number of contacts traced per case was computed as the number of new contacts traced divided by the number of new cases.Results During January 20–February 29, 2020, China reported 80,968 new COVID-19 cases (Hubei Province = 67,608 [83%]), and 659,899 contacts traced (Hubei Province = 265,617 [40%]). Non-Hubei provinces reported more contacts traced per case than Hubei Province; this difference increased over time.Discussion Along with other NPI used in China, contact tracing likely contributed to reducing SARS-CoV-2 transmission by quarantining a large number of potentially infected contacts. Despite reporting only 15% of total cases, non-Hubei provinces had 1.5 times more reported contacts traced compared to Hubei Province. Contract tracing may have been more complete in areas and periods with lower case counts.Competing Interest StatementThe authors have declared no competing interest.Funding StatementData collection and analysis were conducted as part of COVID-19 emergency response. No external funds were used.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was determined to be non-research, public health emergency response, consistent with applicable U.S. federal law and CDC policy.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData were compiled from Provincial-Level Health Commission Websites Containing Publicly Available Reported Data on COVID-19 National Health Commission http://weekly.chinacdc.cn/news/TrackingtheEpidemic.htm Anhui http://wjw.ah.gov.cn/ Beijing http://wjw.beijing.gov.cn/xwzx_20031/xwfb/ Chongqing http://wsjkw.cq.gov.cn/ Fujian http://wjw.fujian.gov.cn/ Gansu http://wsjk.gansu.gov.cn/ Guangdong http://wsjkw.gd.gov.cn/zwyw_yqxx/index.html Guangxi http://wsjkw.gxzf.gov.cn/gzdt/bt/ Guizhou http://www.gzhfpc.gov.cn/ Hainan http://wst.hainan.gov.cn/swjw/index.html Hebei http://wsjkw.hebei.gov.cn/ Heilongjiang http://wsjkw.hlj.gov.cn/ Henan http://www.hnwsjsw.gov.cn/ Hubei http://wjw.hubei.gov.cn/fbjd/dtyw/ Hunan http://wjw.hunan.gov.cn/ Inner Mongolia http://wjw.nmg.gov.cn/ Jiangsu http://wjw.jiangsu.gov.cn/ Jiangxi http://hc.jiangxi.gov.cn/ Jilin http://wsjkw.jl.gov.cn/ Liaoning http://wsjk.ln.gov.cn/ Ningxia http://wsjkw.nx.gov.cn/ Qinghai https://wsjkw.qinghai.gov.cn/ Shaanxi http://sx jw.shaanxi.gov.cn/ Shandong http://wsjkw.shandong.gov.cn Shanghai http://wsjkw.sh.gov.cn/xwfb/index.html Shanxi http://wjw.shanxi.gov.cn/ Sichuan http://wsjkw.sc.gov.cn/scwsjkw/szyw/tygl.shtml Tianjin http://wsjs.tj.gov.cn/ Tibet http://wjw.xizang.gov.cn Xinjiang http://xjhfpc.gov.cn Yunnan http://ynswsjkw.yn.gov.cn/wjwWebsite/web/index Zhejiang http://www.zjwjw.gov.cn/col/col1202101/index.html |
Loss of Taste and Smell as Distinguishing Symptoms of COVID-19 (preprint)
Dawson P , Rabold EM , Laws RL , Conners EE , Gharpure R , Yin S , Buono SA , Dasu T , Bhattacharyya S , Westergaard RP , Pray IW , Ye D , Nabity SA , Tate JE , Kirking HL . medRxiv 2020 2020.05.13.20101006 Olfactory and taste dysfunctions have emerged as symptoms of COVID-19. Among individuals with COVID-19 enrolled in a household study, loss of taste and/or smell was the fourth most commonly reported symptom (26/42; 62%), and among household contacts, it had the highest positive predictive value (83%; 95% CI: 55–95%) for COVID-19. These findings support consideration of loss of taste and/or smell in possible case identification and testing prioritization for COVID-19.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData presented in the current study may be available from the corresponding author on request. |
Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment (preprint)
Nguyen-Van-Tam JS , Killingley B , Enstone J , Hewitt M , Pantelic J , Grantham ML , Bueno de Mesquita PJ , Lambkin-Williams R , Gilbert A , Mann A , Forni J , Noakes CJ , Levine MZ , Berman L , Lindstrom S , Cauchemez S , Bischoff W , Tellier R , Milton DK . medRxiv 2020 2019.12.13.19014381 Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer ‘Donors’ (n=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). ‘Recipients’ randomized to Intervention (IR, n=40) or Control (CR, n=35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p=0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.Author summary Understanding the relative importance of influenza modes of transmission informs strategic use of preventive measures to reduce influenza risk in high-risk settings such as hospitals and is important for pandemic preparedness. Given the increasing evidence from epidemiological modelling, exhaled viral aerosol, and aerobiological survival studies supporting a role for airborne transmission and the potential benefit of respirators (and other precautions designed to prevent inhalation of aerosols) versus surgical masks (mainly effective for reducing exposure to large droplets) to protect healthcare workers, more studies are needed to evaluate the extent of risk posed airborne versus contact and large droplet spray transmission modes. New human challenge-transmission studies should be carefully designed to overcome limitations encountered in the current study. The low secondary attack rate reported herein also suggests that the current challenge-transmission model may no longer be a more promising approach to resolving questions about transmission modes than community-based studies employing environmental monitoring and newer, state-of-the-art deep sequencing-based molecular epidemiological methods.Competing Interest StatementJSN-V-T and BK declare previous consultancy fees from H-Vivo plc, unrelated to the current work. JSN-V-T is currently seconded to the Department of Health and Social Care (DHSC), England; the views expressed in this paper are not necessarily those of DHSC. RLW, AG and AM are employees of H-Vivo plc each of whom hold shares and /or share options in the company.Clinical TrialNCT01710111Funding StatementThis work was supported by U.S. CDC, Cooperative Agreement: Grant Number 1U01P000497-01. The views expressed in this paper are those of the authors and do not necessarily represent the official position of the funding agency.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData required for reproduction of analyses is available upon request. Scripts and other documentati n to reproduce analyses are available at Digital Repositories at the University of Maryland (13) and https://gitlab.com/jacobbueno/emit_quarantine_main. http://drum.lib.umd.edu/handle/1903/25315 |
Modeling an Integrated HIV Prevention and Care Continuum to Achieve the Ending the HIV Epidemic Goals (preprint)
Jenness SM , Johnson JA , Hoover KW , Smith DK , Delaney KP . medRxiv 2020 2020.03.02.20030254 Objective We sought to evaluate which combinations of HIV prevention and care activities would have the greatest impact towards reaching the US Ending the HIV Epidemic (EHE) plan goals of reducing HIV incidence at least 75% by 2025 and 90% by 2030.Design A stochastic HIV transmission model for men who have sex with men (MSM), calibrated to local surveillance estimates in the Atlanta area, a focal EHE target jurisdiction.Methods Model scenarios varied HIV screening rates relative to current levels, under different assumptions of how HIV-negative MSM would be linked to PrEP initiation, and also considered improvements to HIV care linkage and retention for those screening positive.Results A 10-fold relative increase in HIV screening rates (to approximately biannual screening for black and Hispanic MSM and quarterly for white MSM) would lead to 43% of infections averted if integrated with PrEP initiation. Improvements to HIV care retention would avert 41% of infections if retention rates were improved 10-fold. If both screening and retention were jointly improved 10-fold, up to 74% of cumulative infections would be averted. Under this scenario, it would take 4 years to meet the 75% EHE goal and 12 years to meet the 90% goal for MSM in Atlanta.Conclusions Interventions to improve HIV screening linked with PrEP for those screening negative, and HIV care retention would have a substantial impact on HIV prevention. However, additional interventions may be necessary to reach the EHE goal of a 90% reduction in incidence for Atlanta MSM by 2030.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by Centers for Disease Control and Prevention cooperative agreement number U38 PS004646 and National Institutes of Health grants R21 MH112449 and R01 AI138783.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesModel data and analysis scripts are available on our Github repository linked below. https://github.com/EpiModel/CombPrev |
Outbreak of COVID-19 and Interventions in One of the Largest Jails in the United States — Cook County, IL, 2020 (preprint)
Zawitz C , Welbel S , Ghinai I , Mennella C , Levin R , Samala U , Smith MB , Gubser J , Jones B , Varela K , Kirbiyik U , Rafinski J , Fitzgerald A , Orris P , Bahls A , Black SR , Binder AM , Armstrong PA . medRxiv 2020 2020.07.12.20148494 Background Correctional and detention facilities are disproportionately affected by COVID-19 due to shared space, contact between staff and detained persons, and movement within facilities of detained persons, many with pre-existing medical conditions. On March 18, 2020, Cook County Jail, one of the United States’ largest, identified its first suspected case of COVID-19 in a detained person.Methods This analysis includes SARS-CoV-2 cases confirmed by molecular detection among detained persons and Cook County Sheriff’s Office staff. We examined occurrence of symptomatic cases in each building and proportions of asymptomatic detained persons testing positive. We describe timing of interventions including social distancing, mask use, and expanded testing and show outbreak trajectory in the jail versus contemporaneous case counts in Chicago.Results During March 1–April 30, 907 symptomatic and asymptomatic cases of SARS-CoV-2 infection were detected among detained persons (n = 628) and staff (n = 279), with nine deaths. Symptomatic cases occurred in all housing divisions; in 9/13 buildings, staff cases occurred first. Among asymptomatic detained persons in quarantine, 23.6% tested positive. Visitation stopped March 15, programmatic activities were suspended March 23, cells were converted into single occupancy beginning March 26, and universal masking was implemented for staff (April 2) and detained persons (April 13). Cases at the jail declined while cases in Chicago increased.Conclusion Aggressive intervention strategies coupled with widespread diagnostic testing of detained and staff populations can limit introduction and mitigate transmission of SARS-CoV-2 infection in correctional and detention facilities.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received for the execution of this study or manuscript preparation.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was reviewed by Centers for Disease Control and Prevention, Chicago Department of Public Health, Cook County Health, and Cook County Sheriff's Office institutional review boards or the equivalent entity and deemed not to be research involving human subjects and public health response.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData were provided by the Cook County Sheriff's Office, Chicago Department of Public Health, Cermak Health Services, and Cook County Health. Access to data submitted into the Illinois' National Electronic Disease Surveillance System was provided by Chicago Department of Public Health. Data represent protected health information (PHI), and cannot be made available in raw form. Results are presented in aggregate in this manuscript. Authors had access to data. |
Prevalence of Nonsuppressed Viral Load and Associated Factors Among Adults Receiving Antiretroviral Therapy in Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe (2015-2017): Results from Population-Based Nationally-Representative Surveys (preprint)
Haas AD , Radin E , Hakim AJ , Jahn A , Philip NM , Jonnalagadda S , Saito S , Low A , Patel H , Schwitters AM , Rogers JH , Frederix K , Kim E , Bello G , Williams DB , Parekh B , Sachathep K , Barradas DT , Kalua T , Birhanu S , Musuka G , Mugurungi O , Tippett Barr BA , Sleeman K , Mulenga LB , Thin K , Ao TT , Brown K , Voetsch AC , Justman JE . medRxiv 2020 2020.07.13.20152553 Introduction The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a target of ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) to have viral load suppression (VLS). We examined factors associated with nonsuppressed viral Load (NVL).Methods We included PLHIV receiving ART aged 15–59 years from Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe. Blood samples from PLHIV were analyzed for HIV RNA and recent exposure to antiretroviral drugs (ARVs). Outcomes were NVL (viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL), and receiving second-line ART. We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART.Results The prevalence of NVL was 11.2%: 8.2% experienced VF, and 3.0% interrupted ART. Younger age, male gender, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married, and residing in Zimbabwe, Lesotho, or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female gender, shorter ART duration, higher CD4 count, and alcohol use were associated with higher odds for interrupted ART and lower odds for VF. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART.Conclusions Countries are approaching UNAIDS VLS targets for adults. Treatment support for people initiating ART with asymptomatic HIV infection, scale-up of viral load monitoring, and optimized ART regimens may further reduce NVL prevalence.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFunding: This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of grant number U2GGH001226. ADH was supported by a Swiss National Science Foundation (SNF) Early Postdoc Mobility Fellowship (grant number: P2BEP3_178602). Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Eswatini Scientific and Ethics Committee, the National Health Science Research Committee Malawi, the National Health Research Ethics Committee Lesotho, the National Health Research Ethics Committee Lesotho, the Tropical Diseases Research Centre Ethics Review Committee, Zambia, the Medical Research Council of Zimbabwe, and the Institutional Review Boards at the Centers for Disease Control and Prevention (CDC; Atlanta, GA) and Columbia University Medical Center (New York, NY) approved the PHIA surveys.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesPublic datasets for Eswatini, Malawi, and Zambia are available. Public datasets for Lesotho and Zimbabwe will be made available soon. For more information see: https://phia-data.icap.columbia.edu/ https://phia-data.icap.columbia.edu/ |
Probabilistic reconstruction of measles transmission clusters from routinely collected surveillance data (preprint)
Robert A , Kucharski AJ , Gastanaduy PA , Paul P , Funk S . medRxiv 2020 2020.02.13.20020891 Pockets of susceptibility resulting from spatial or social heterogeneity in vaccine coverage can drive measles outbreaks, as cases imported into such pockets are likely to cause further transmission and lead to large transmission clusters. Characterising the dynamics of transmission is essential for identifying which individuals and regions might be most at risk.As data from detailed contact tracing investigations are not available in many settings, we developed a R package called o2geosocial to reconstruct the transmission clusters and the importation status of the cases from their age, location, genotype, and onset date.We compared our inferred cluster size distributions to 737 transmission clusters identified through detailed contact-tracing in the United States between 2001 and 2016. We were able to reconstruct the importation status of the cases and found good agreement between the inferred and reference clusters. The results were improved when the contact-tracing investigations were used to set the importation status before running the model.Spatial heterogeneity in vaccine coverage is difficult to measure directly. Our approach was able to highlight areas with potential for local transmission using a minimal number of variables and could be applied to assess the intensity of ongoing transmission in a region.Competing Interest StatementThe authors have declared no competing interest.Funding StatementAR was supported by the Medical Research Council (MR/N013638/1). SF was supported by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (210758/Z/18/Z). AJK was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (206250/Z/17/Z).Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe package we developed is publicly available on Github (https://github.com/alxsrobert/o2geosocial), along with the code used to analyse the data and generate the figures (https://github.com/alxsrobert/datapaperMO). Combinations of variables in the surveillance data used to validate this algorithm may contain sensitive personally identifiable health information which are subject to the Privacy Act and cannot be shared publicly. A toy dataset was attached to the o2geosocial package (in o2geosocial/data). The script analysis_generated_data.R in the datapaperMO repository generates toy datasets with different parameters (distance kernel, number of cases, reproduction numbers..) and can be used to re-run the model and test its performance. https://github.com/alxsrobert/o2geosocial https://github.com/alxsrobert/datapaperMO |
Efficacy of face masks, neck gaiters and face shields for reducing the expulsion of simulated cough-generated aerosols (preprint)
Lindsley WG , Blachere FM , Law BF , Beezhold DH , Noti JD . medRxiv 2020 2020.10.05.20207241 Face masks are recommended to reduce community transmission of SARS-CoV-2. One of the primary benefits of face masks and other coverings is as source control devices to reduce the expulsion of respiratory aerosols during coughing, breathing, and speaking. Face shields and neck gaiters have been proposed as an alternative to face masks, but information about face shields and neck gaiters as source control devices is limited. We used a cough aerosol simulator with a pliable skin headform to propel small aerosol particles (0 to 7 µm) into different face coverings. An N95 respirator blocked 99% of the cough aerosol, a medical grade procedure mask blocked 59%, a 3-ply cotton cloth face mask blocked 51%, and a polyester neck gaiter blocked 47% as a single layer and 60% when folded into a double layer. In contrast, the face shield blocked 2% of the cough aerosol. Our results suggest that face masks and neck gaiters are preferable to face shields as source control devices for cough aerosols.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis research was funded by the National Institute for Occupational Safety and Health (NIOSH), US Centers for Disease Control and Prevention (CDC).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:No IRB approval requiredAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesExperimental data is available upon request. |
Enhanced Contact Investigations for Nine Early Travel-Related Cases of SARS-CoV-2 in the United States (preprint)
Burke RM , Balter S , Barnes E , Barry V , Bartlett K , Beer KD , Benowitz I , Biggs HM , Bruce H , Bryant-Genevier J , Cates J , Chatham-Stephens K , Chea N , Chiou H , Christiansen D , Chu VT , Clark S , Cody SH , Cohen M , Conners EE , Dasari V , Dawson P , DeSalvo T , Donahue M , Dratch A , Duca L , Duchin J , Dyal JW , Feldstein LR , Fenstersheib M , Fischer M , Fisher R , Foo C , Freeman-Ponder B , Fry AM , Gant J , Gautom R , Ghinai I , Gounder P , Grigg CT , Gunzenhauser J , Hall AJ , Han GS , Haupt T , Holshue M , Hunter J , Ibrahim MB , Jacobs MW , Jarashow MC , Joshi K , Kamali T , Kawakami V , Kim M , Kirking HL , Kita-Yarbro A , Klos R , Kobayashi M , Kocharian A , Lang M , Layden J , Leidman E , Lindquist S , Lindstrom S , Link-Gelles R , Marlow M , Mattison CP , McClung N , McPherson TD , Mello L , Midgley CM , Novosad S , Patel MT , Pettrone K , Pillai SK , Pray IW , Reese HE , Rhodes H , Robinson S , Rolfes M , Routh J , Rubin R , Rudman SL , Russell D , Scott S , Shetty V , Smith-Jeffcoat SE , Soda EA , Spitters C , Stierman B , Sunenshine R , Terashita D , Traub E , Vahey GM , Verani JR , Wallace M , Westercamp M , Wortham J , Xie A , Yousaf A , Zahn M . medRxiv 2020 2020.04.27.20081901 Background Coronavirus disease 2019 (COVID-19), the respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China and has since become pandemic. As part of initial response activities in the United States, enhanced contact investigations were conducted to enable early identification and isolation of additional cases and to learn more about risk factors for transmission.Methods Close contacts of nine early travel-related cases in the United States were identified. Close contacts meeting criteria for active monitoring were followed, and selected individuals were targeted for collection of additional exposure details and respiratory samples. Respiratory samples were tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (RT-PCR) at the Centers for Disease Control and Prevention.Results There were 404 close contacts who underwent active monitoring in the response jurisdictions; 338 had at least basic exposure data, of whom 159 had ≥1 set of respiratory samples collected and tested. Across all known close contacts under monitoring, two additional cases were identified; both secondary cases were in spouses of travel-associated case patients. The secondary attack rate among household members, all of whom had ≥1 respiratory sample tested, was 13% (95% CI: 4 – 38%).Conclusions The enhanced contact tracing investigations undertaken around nine early travel-related cases of COVID-19 in the United States identified two cases of secondary transmission, both spouses. Rapid detection and isolation of the travel-associated case patients, enabled by public awareness of COVID-19 among travelers from China, may have mitigated transmission risk among close contacts of these cases.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was sought or received.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData may be available upon reasonable request. |
Impact of non-pharmaceutical interventions for SARS-CoV-2 on norovirus outbreaks: an analysis of outbreaks reported by 9 US States (preprint)
Kraay ANM , Han P , Kambhampati AK , Wikswo ME , Mirza SA , Lopman BA . medRxiv 2020 2020.11.25.20237115 Importance The impact of non-pharmaceutical interventions (NPIs) in response to the SARS-CoV-2 pandemic on incidence of other infectious diseases is still being assessed.Objective To determine if the observed change in reported norovirus outbreaks in the United States was best explained by underreporting, seasonal trends, or reduced exposure due to NPIs. We also aimed to assess if the change in reported norovirus outbreaks varied by setting.Design An ecologic, interrupted time series analysis of norovirus outbreaks from nine states reported to the National Outbreak Reporting System (NORS) from July 2012–July 2020.Setting Surveillance data from Massachusetts, Michigan, Minnesota, Ohio, Oregon, South Carolina, Tennessee, Virginia, and Wisconsin were included in the analysis.Participants 9,226 reports of acute gastroenteritis outbreaks with norovirus as an epidemiologically suspected or laboratory-confirmed etiology were included in the analysis, resulting in more than 8 years of follow up. Outbreak reports from states that participated in NoroSTAT for at least 4 years were included in the analysis (range: 4–8 years).Exposure The main exposure of interest was time period: before (July 2012–February 2020) or after (April 2020–July 2020) the start of NPIs in the United StatesMain outcome The main outcome of interest was monthly rate of reported norovirus outbreaks. As a secondary outcome, we also examined the average outbreak size.Results We found that the decline in norovirus outbreak reports was significant for all 9 states considered (pooled incidence rate ratio (IRR) comparing April 2020-July 2020 vs. all pre-COVID months for each state= 0.14, 95% CI: 0.098, 0.21; P=<0.0001), even after accounting for typical seasonal decline in incidence during the summer months. These patterns were similar across a variety of settings, including nursing homes, child daycares, healthcare settings, and schools. The average outbreak size was also reduced by 61% (95% CI: 56%, 42.7%; P=<0.0001), suggesting that the decline does not reflect a tendency to report only more severe outbreaks due to strained surveillance systems, but instead reflects a decline in incidence.Conclusions and relevance While NPIs implemented during the spring and summer of 2020 were intended to reduce transmission of SARS-CoV-2, these changes also appear to have impacted the incidence of norovirus, a non-respiratory pathogen. These results suggest that NPIs may provide benefit for preventing transmission of other human pathogens, reducing strain to health systems during the continued SARS-CoV-2 pandemic.Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC).Competing Interest StatementBAL reports grants and personal fees from Takeda Pharmaceuticals and personal fees from World Health Organization outside the submitted work.Funding StatementBAL and ANMK were supported by NIH/NIGMS (R01 GM124280, R01 GM 12480-03S1) and NSF (2032084).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval to use the data for the present work was provided by the Norovirus Outbreak Reporting System team upon submitting a formal data request. For the present analysis, data were only provided at the outbreak level and no personally identifiable data were used such that the released data meets federal guidelines for ethical compliance in release of surveillance data, as described in the Public Health Service Act. The original data collection is from public health surveillance and is covered by section 301 of the Public Health Service Act (42 USC 241). As a surveillance activity, the initial data collection is considered not to be research with human subjects based on these guidelines.All necessary patient/participa t consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesNorostat data are publicly available at https://www.cdc.gov/norovirus/reporting/norostat/data-table.html. More detailed Norostat data can be obtained by sending a formal data request to the Centers for Disease Control and Prevention at NORSDashboard@cdc.gov. https://www.cdc.gov/norovirus/reporting/norostat/data-table.html |
Influenza and other respiratory viral infections associated with absence from school among schoolchildren in Pittsburgh, Pennsylvania, USA: a cohort study (preprint)
Read JM , Zimmer S , Vukotich CJr , Schweizer ML , Galloway D , Lingle C , Yearwood G , Calderone P , Noble E , Quadelacy T , Grantz K , Rinaldo C , Gao H , Rainey J , Uzicanin A , Cummings DAT . medRxiv 2020 2020.04.16.20068593 Background Information on the etiology and age-specific burden of respiratory viral infections among school-aged children remains limited.Methods We conducted a cohort study to determine the etiology of ILI (influenza like illness) among 2,519 K–12 students during the 2012–13 influenza season. We obtained nasal swabs from students with ILI-related absences. Generalized linear mixed-effect regressions determined associations of outcomes, including ILI and laboratory-confirmed respiratory virus infection, with school grade and other covariates.Results Overall, 459 swabs were obtained from 552 ILI–related absences. Respiratory viruses were found in 292 (63.6%) samples. Influenza was found in 189 (41.2%) samples. with influenza B found in 134 (70.9%). Rates of influenza B were significantly higher in grades 1 (10.1%, 95% CI 6.8%–14.4%), 2 (9.7%, 6.6%–13.6%), 3 (9.3%, 6.3%–13.2%), and 4 (9.9%, 6.8%–13.8%) than in kindergarteners (3.2%, 1.5%–6.0%). After accounting for grade, sex and self-reported vaccination status, influenza B infection risk was lower among kindergarteners in half-day programs compared to kindergarteners in full-day programs (OR = 0.19; 95% CI 0.08–0.45).Conclusions ILI and influenza infection is concentrated in younger schoolchildren. Reduced infection by respiratory viruses is associated with a truncated school day for kindergarteners, but requires further investigation in other grades and populations.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by Cooperative Agreement number [1U01CK00179] from the US Centers for Disease Control and Prevention (CDC, www.cdc.gov). The findings and conclusions in this study are solely the responsibility of the authors and do not necessarily represent the official position of CDC. JMR acknowledges additional support from the Engineering and Physical Sciences Research Council (EP/N014499/1).Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData for reproduction of major results and figures is made available through the DRYAD archive. |
Interim Analysis of Risk Factors for Severe Outcomes among a Cohort of Hospitalized Adults Identified through the U.S. Coronavirus Disease 2019 (COVID-19)-Associated Hospitalization Surveillance Network (COVID-NET) (preprint)
Kim L , Garg S , O'Halloran A , Whitaker M , Pham H , Anderson EJ , Armistead I , Bennett NM , Billing L , Como-Sabetti K , Hill M , Kim S , Monroe ML , Muse A , Reingold AL , Schaffner W , Sutton M , Talbot HK , Torres SM , Yousey-Hindes K , Holstein R , Cummings C , Brammer L , Hall AJ , Fry AM , Langley GE . medRxiv 2020 2020.05.18.20103390 Background As of May 15, 2020, the United States has reported the greatest number of coronavirus disease 2019 (COVID-19) cases and deaths globally.Objective To describe risk factors for severe outcomes among adults hospitalized with COVID-19.Design Cohort study of patients identified through the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network.Setting 154 acute care hospitals in 74 counties in 13 states.Patients 2491 patients hospitalized with laboratory-confirmed COVID-19 during March 1-May 2, 2020.Measurements Age, sex, race/ethnicity, and underlying medical conditions.Results Ninety-two percent of patients had ≥1 underlying condition; 32% required intensive care unit (ICU) admission; 19% invasive mechanical ventilation; 15% vasopressors; and 17% died during hospitalization. Independent factors associated with ICU admission included ages 50-64, 65-74, 75-84 and ≥85 years versus 18-39 years (adjusted risk ratio (aRR) 1.53, 1.65, 1.84 and 1.43, respectively); male sex (aRR 1.34); obesity (aRR 1.31); immunosuppression (aRR 1.29); and diabetes (aRR 1.13). Independent factors associated with in-hospital mortality included ages 50-64, 65-74, 75-84 and ≥85 years versus 18-39 years (aRR 3.11, 5.77, 7.67 and 10.98, respectively); male sex (aRR 1.30); immunosuppression (aRR 1.39); renal disease (aRR 1.33); chronic lung disease (aRR 1.31); cardiovascular disease (aRR 1.28); neurologic disorders (aRR 1.25); and diabetes (aRR 1.19). Race/ethnicity was not associated with either ICU admission or death.Limitation Data were limited to patients who were discharged or died in-hospital and had complete chart abstractions; patients who were still hospitalized or did not have accessible medical records were excluded.Conclusion In-hospital mortality for COVID-19 increased markedly with increasing age. These data help to characterize persons at highest risk for severe COVID-19-associated outcomes and define target groups for prevention and treatment strategies.Funding Source This work was supported by grant CK17-1701 from the Centers of Disease Control and Prevention through an Emerging Infections Program cooperative agreement and by Cooperative Agreement Number NU38OT000297-02-00 awarded to the Council of State and Territorial Epidemiologists from the Centers for Disease Control and Prevention.Competing Interest StatementH. Keipp Talbot reports personal fees from Seqirus outside the submitted work. William Schaffner reports personal fees from Pfizer and personal fees from Roche Diagnostics outside the submitted work. Evan Anderson reports personal fees from Abbvie and Pfizer outside the submitted work. H. Keipp Talbot reports grants from Sanofi outside the submitted work; Mary Hill reports grants from CSTE, during the conduct of the study; Melissa Sutton reports grants from CDC Emerging Infections Program during the conduct of the study; William Schaffner reports grants from CDC during the conduct of the study. Sue Kim reports grants from CSTE during the conduct of the study. Evan Anderson reports grants from Pfizer, grants from MedImmune, grants from Regeneron, grants from PaxVax, grants from Merck, grants from Novavax, grants from Sanofi-Pasteur, grants from Micron, outside the submitted work. Laurie Billing reports grants from the Council of State and Territorial Epidemiologists (CSTE) and the Centers for Disease Control and Prevention (CDC) during the conduct of the study.Funding StatementThis work was supported by grant CK17-1701 from the Centers of Disease Control and Prevention through an Emerging Infections Program cooperative agreement and by Cooperative Agreement Number NU38OT000297-02-00 awarded to the Council of State and Territorial Epidemiologists from the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that al clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAggregate data is available on CDC’s COVID-NET Interactive website. https://gis.cdc.gov/grasp/COVIDNet/COVID19_3.html https://gis.cdc.gov/grasp/COVIDNet/COVID19_5.html |
Addressing Personal Protective Equipment (PPE) Decontamination: Methylene Blue and Light Inactivates SARS-CoV-2 on N95 Respirators and Masks with Maintenance of Integrity and Fit (preprint)
Lendvay TS , Chen J , Harcourt BH , Scholte FE , Lin YL , Kilinc-Balci FS , Lamb MM , Homdayjanakul K , Cui Y , Price A , Heyne B , Sahni J , Kabra KB , Lin YC , Evans D , Mores CN , Page K , Chu LF , Haubruge E , Thiry E , Ludwig-Begall LF , Wielick C , Clark T , Wagner T , Timm E , Gallagher T , Faris P , Macia N , Mackie CJ , Simmons SM , Reader S , Malott R , Hope K , Davies JM , Tritsch SR , Dams L , Nauwynck H , Willaert JF , De Jaeger S , Liao L , Zhao M , Laperre J , Jolois O , Smit SJ , Patel AN , Mayo M , Parker R , Molloy-Simard V , Lemyre JL , Chu S , Conly JM , Chu MC . medRxiv 2020 2020.12.11.20236919 Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in severe shortages of personal protective equipment (PPE) necessary to protect front-line healthcare personnel. These shortages underscore the urgent need for simple, efficient, and inexpensive methods to decontaminate SARS-CoV-2-exposed PPE enabling safe reuse of masks and respirators. Efficient decontamination must be available not only in low-resourced settings, but also in well-resourced settings affected by PPE shortages. Methylene blue (MB) photochemical treatment, hitherto with many clinical applications including those used to inactivate virus in plasma, presents a novel approach for widely applicable PPE decontamination. Dry heat (DH) treatment is another potential low-cost decontamination method.Methods MB and light (MBL) and DH treatments were used to inactivate coronavirus on respirator and mask material. We tested three N95 filtering facepiece respirators (FFRs), two medical masks (MMs), and one cloth community mask (CM). FFR/MM/CM materials were inoculated with SARS-CoV-2 (a Betacoronavirus), murine hepatitis virus (MHV) (a Betacoronavirus), or porcine respiratory coronavirus (PRCV) (an Alphacoronavirus), and treated with 10 µM MB followed by 50,000 lux of broad-spectrum light or 12,500 lux of red light for 30 minutes, or with 75°C DH for 60 minutes. In parallel, we tested respirator and mask integrity using several standard methods and compared to the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method. Intact FFRs/MMs/CM were subjected to five cycles of decontamination (5CD) to assess integrity using International Standardization Organization (ISO), American Society for Testing and Materials (ASTM) International, National Institute for Occupational Safety and Health (NIOSH), and Occupational Safety and Health Administration (OSHA) test methods.Findings Overall, MBL robustly and consistently inactivated all three coronaviruses with at least a 4-log reduction. DH yielded similar results, with the exception of MHV, which was only reduced by 2-log after treatment. FFR/MM integrity was maintained for 5 cycles of MBL or DH treatment, whereas one FFR failed after 5 cycles of VHP+O3. Baseline performance for the CM was variable, but reduction of integrity was minimal.Interpretation Methylene blue with light and DH treatment decontaminated masks and respirators by inactivating three tested coronaviruses without compromising integrity through 5CD. MBL decontamination of masks is effective, low-cost and does not require specialized equipment, making it applicable in all-resource settings. These attractive features support the utilization and continued development of this novel PPE decontamination method.Competing Interest StatementAuthors Thomas S. Lendvay, James Chen are Co-Founders and equity owners of Singletto, Inc. (Seattle, WA, USA) Authors Yi Cui and Steven Chu are Co-Founders and equity owners of 4C Air, Inc. (Sunnyvale, CA)Funding StatementThis study was funded by Open Philanthropy; Amazon Inc./University of Washington Catalyst Award; University of Liege (Belgium) and the Walloon Region, Belgium; Li Ka Shing Institute; Alberta Health Services; and an Anonymous donor to the University of Washington, Department of Urology.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Stanford University and Alberta Health Services/University of Calgary were exempt from IRB as the human fit testing was considered Quality Improvement. ERB for clinical specimen use: A clinical saliva specimen with a SARS-CoV-2 was provided by Dr. John Conly from Calgary, Alberta with Calgary ERB approval (ID# Pro00099761).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective inte ventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will be freely shared post publication on reasonable request by contacting the corresponding author of the study. |
Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys (preprint)
Grantz KH , Cummings DAT , Zimmer S , Vukotich C , Galloway D , Schweizer ML , Guclu H , Cousins J , Lingle C , Yearwood GMH , Li K , Calderone PA , Noble E , Gao H , Rainey J , Uzicanin A , Read JM . medRxiv 2020 Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission. |
Association Between Birth Region and Time to Tuberculosis Diagnosis After US Entry Among Non–US-Born Persons (preprint)
Talwar A , Li R , Langer AJ . medRxiv 2020 2020.08.02.20160135 Approximately 90% of US tuberculosis (TB) cases among non–US-born persons are attributable to progression of latent TB infection to TB disease. Using survival analysis, we investigated if birthplace is associated with time of progression to TB disease among non–US-born persons. We derived a Cox regression model comparing differences in time to TB diagnosis after US entry among 19 global birth regions, adjusting for sex, birth year, and age at diagnosis. Compared with persons from Western Europe, the adjusted hazard rate of developing TB was significantly higher (p ≤0.05) for persons from all other regions, except North America and Northern Europe, and highest among persons from Middle Africa (adjusted hazard ratio = 7.0; 95% confidence interval: 6.5–7.4). Time to TB diagnosis among non–US-born persons therefore varied by birth region, which represents an important prognostic indicator for progression to TB disease.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNeither the authors nor their institutions at any time received payment or services from a third party for any aspect of the submitted work.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All data were collected as part of routine disease surveillance and were not part of human subjects research requiring institutional review board approval.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data contain information abstracted from the national tuberculosis case report form called the Report of Verified Case of Tuberculosis (RVCT) (OMB No. 0920-0026). These data have been reported voluntarily to CDC by state and local health departments, and are protected under the Assurance of Confidentiality (Sections 306 and 308(d) of the Public Health Service Act, 42 U.S.C. 242k and 242m(d)), which prevents disclosure of any information that could be used to directly or indirectly identify patients. For more information, see the CDC/ATSDR Policy on Releasing and Sharing Data (http://www.cdc.gov/maso/Policy/ReleasingData.pdf). A limited dataset is available at http://wonder.cdc.gov/TB.html. Researchers seeking additional data may apply to analyze National Tuberculosis Surveillance System data at CDC headquarters by contacting the Division of Tuberculosis Elimination (TBinfo{at}cdc.gov). |
Clinical symptoms among ambulatory patients tested for SARS-CoV-2 (preprint)
Chung JR , Kim SS , Jackson ML , Jackson LA , Belongia EA , King JP , Zimmerman RK , Nowalk MP , Martin ET , Monto AS , Gaglani M , Smith ME , Patel M , Flannery B . medRxiv 2020 2020.10.20.20213272 We compared symptoms and characteristics of 4961 ambulatory patients with and without laboratory-confirmed SARS-CoV-2 infection. Findings indicate that clinical symptoms alone would be insufficient to distinguish between COVID-19 and other respiratory infections (e.g., influenza) and/or to evaluate the effects of preventive interventions (e.g., vaccinations).Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: AM reports personal fees from Sanofi Pasteur and from Seqirus outside the submitted work; EB reports grants from CDC during the conduct of the study. EM reports grants from Centers for Disease Control and Prevention during the conduct of the study and personal fees from Pfizer outside the submitted work; LJ reports grants from CDC during the conduct of the study and grants from Novavax outside the submitted work; MG reports grants from Centers for Disease Control and Prevention during the conduct of the study and grants from Centers for Disease Control and Prevention - Abt Associates outside the submitted work; MJ reports grants from Centers for Disease Control during the conduct of the study and grants from Sanofi Pasteur outside the submitted work; MN reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Merck & Co outside the submitted work; RZ reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Sanofi Pasteur outside the submitted work. All other authors have nothing to disclose.Funding StatementThis work was supported through cooperative agreements funded by US Centers for Disease Control and Prevention and, at the University of Pittsburgh, by infrastructure funding by UL1 TR001857 from National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approved or waived by the Centers for Disease Control and Prevention (CDC) IRB with reliance on: 1.University of Michigan IRB (Approved) a. CDC protocol 6238 b. University of Michigan protocol HUM00119183 2. University of Pittsburgh IRB (Approved) a. CDC protocol 6219 b. University of Pittsburgh protocol STUDY19070407 3. Baylor Scott and White Health IRB (Approved) a. CDC protocols 7125 and 7277 b. Baylor Scott and White protocols 160145 and 20-153 4. Kaiser Permanente Washington Research Institute (Waived) 5. Marshfield Clinic Research Institute (Approved) a. CDC protocol 6197 b. Marshfield Clinic Research Institute protocol BEL10511 All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData may be made available in accordance with CDC data availability policy. |
The distribution and spread of susceptible and resistant Neisseria gonorrhoeae across demographic groups in a major metropolitan center (preprint)
Mortimer TD , Pathela P , Crawley A , Rakeman JL , Lin Y , Harris SR , Blank S , Schillinger JA , Grad YH . medRxiv 2020 2020.04.30.20086413 Background Genomic epidemiology studies of gonorrhea in the United States have primarily focused on national surveillance for antibiotic resistance, and patterns of local transmission between demographic groups of resistant and susceptible strains are unknown.Methods We analyzed a convenience sample of genome sequences, antibiotic susceptibility, and patient data from 897 gonococcal isolates cultured at the NYC Public Health Laboratory from NYC Department of Health and Mental Hygiene (DOHMH) Sexual Health Clinic (SHC) patients, primarily in 2012-13. We reconstructed the gonococcal phylogeny, defined transmission clusters using a 10 non-recombinant single nucleotide polymorphism threshold, tested for clustering of demographic groups, and placed NYC isolates in a global phylogenetic context.Results The NYC gonococcal phylogeny reflected global diversity with isolates from 22/23 of the prevalent global lineages (96%). Isolates clustered on the phylogeny by patient sexual behavior (p<0.001) and race/ethnicity (p<0.001).Minimum inhibitory concentrations were higher across antibiotics in isolates from men who have sex with men compared to heterosexuals (p<0.001) and white heterosexuals compared to black heterosexuals (p<0.01). In our dataset, all large transmission clusters (≥10 samples) of N. gonorrhoeae were susceptible to ciprofloxacin, ceftriaxone, and azithromycin and comprised isolates from patients across demographic groups.Conclusions All large transmission clusters were susceptible to gonorrhea therapies, suggesting that resistance to empiric therapy was not a main driver of spread, even as risk for resistance varied across demographic groups. Further study of local transmission networks is needed to identify drivers of transmission.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01 AI132606 and 1 F32 AI145157-01] and the Wellcome Trust [098051].Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesWhole genome sequencing data were deposited in the European Nucleotide Archive (ERA) under study accession PRJEB10016. All additional data and scripts are available at https://github.com/gradlab/GC_NYC. https://www.ebi.ac.uk/ena/data/view/PRJEB10016 https://github.com/gradlab/GC_NYC |
Use of undetectable viral load to improve population-based survey estimates of known HIV-positive status and antiretroviral treatment coverage in Kenya (preprint)
Young PW , Zielinski-Gutierrez E , Wamicwe J , Mukui I , Kim AA , Waruru A , Zeh C , Kretzschmar ME , De Cock KM . medRxiv 2019 19002592 Introduction Underreporting of prior HIV diagnosis and antiretroviral therapy (ART) use based on self-report is well-documented in national surveys. Antiretroviral (ARV) testing has been used to improve survey estimates, by reclassifying respondents with ARVs detected in blood as previously-diagnosed and on ART. Viral load testing, which is more affordable and more routinely available than ARV testing, is also an indicator of ART use. We examined the impact of adjusting estimated knowledge of HIV-positive status and antiretroviral therapy (ART) use based on self-report with biomarkers for antiretroviral (ARV) drug detection and undetectable viral load (UVL).Methods We reclassified HIV-positive participants aged 15-64 years in the 2012 Kenya AIDS Indicator Survey (KAIS) that were unaware of their HIV-positive status by self-report as aware and on ART if either ARVs were detected or viral load was undetectable (<550 copies/mL) on dried blood spots. We compared self-report to adjustments for ARVs measurement, UVL, or both. We calculated measures of accuracy for UVL and UVL & ARV-adjusted versions of knowledge of status and ART use versus ARV-adjusted self-report as a reference standard.Results Among 235 of 648 HIV-positive respondents with UVL, self-reported status was: 65 unaware (28.7%), 25 aware, not on ART (9.9%) and 145 aware, on ART (61.3%). Treatment coverage among all HIV-positive respondents increased from 31.8% for self-report to 42.5% [95% confidence interval (CI) 37.4-47.8] based on ARV detection alone, to 42.8% (95% CI 37.9-47.8) when ARV-adjusted, 46.2% (95% CI 41.3-51.1) when UVL-adjusted and 48.8% (95% CI 43.9-53.8) when adjusted for ARV and UVL. Awareness of positive status increased from 46.9% for self-report to 56.2% (95% CI 50.7-61.6) when ARV-adjusted, 57.5% (95% CI 51.9-63.0) when UVL-adjusted, and 59.8% (95% CI 54.2-65.1) when adjusted for ARV and UVL. Sensitivity and specificity of UVL-adjusted known HIV-positive status were 95.8% and 91.3%, and of UVL-adjusted ART use were 93.0% and 88.8% respectively, versus ARV-adjusted self-report.Conclusions Undetectable viral load may be a useful adjunct or alternative to ARV detection for adjusting knowledge of status and ART use indicators in population-based surveys.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe 2012 Kenya AIDS Indicator Survey has been supported by the President?s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control and Prevention (CDC) under the terms of #PS001805, GH000069, and PS001814. The survey was also funded in part by support from the Global Fund, World Bank, and the Joint United Nations Programme on HIV/AIDS.Author DeclarationsAll relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesAny clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript.Not ApplicableI have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable.YesData for KAIS 2012 are available upon request from NASCOP by emailing head@nascop.or.ke, or from the Kenya National Bureau of Statistics by requesting at http://statistics.knbs.or.ke/nada/index.php |
Immunologic and epidemiologic drivers of norovirus transmission in daycare and school outbreaks (preprint)
Havumaki J , Eisenberg JNS , Mattison CP , Lopman BA , Ortega-Sanchez IR , Hall AJ , Hutton DW , Eisenberg MC . medRxiv 2019 2019.12.19.19015396 Background Norovirus outbreaks are notoriously explosive, with dramatic symptomology and rapid disease spread. Children are particularly vulnerable to infection and drive norovirus transmission due to their high contact rates with each other and the environment. Despite the explosive nature of norovirus outbreaks, attack rates in schools and daycares remain low with the majority of students not reporting symptoms.Methods We explore immunologic and epidemiologic mechanisms that may underlie epidemic norovirus transmission dynamics using a disease transmission model. Towards this end, we compared different model scenarios, including innate resistance and acquired immunity (collectively denoted ‘immunity’), stochastic extinction, and an individual exclusion intervention. We calibrated our model to daycare and school outbreaks from national surveillance data.Results Recreating the low attack rates observed in daycare and school outbreaks required a model with immunity. However, immunity alone resulted in shorter duration outbreaks than what was observed. The addition of individual exclusion (to the immunity model) extended outbreak durations by reducing the amount of time that symptomatic people contribute to transmission. Including both immunity and individual exclusion mechanisms resulted in simulations where both attack rates and outbreak durations were consistent with surveillance data.Conclusions The epidemiology of norovirus outbreaks in daycare and school settings cannot be well described by a simple transmission model in which all individuals start as fully susceptible. Interventions should leverage population immunity and encourage more rigorous individual exclusion to improve venue-level control measures.Competing Interest StatementDr. Lopman reports personal fees from Takeda Pharmaceuticals, CDC Foundation, and Hall Booth Smith, P.C. outside the submitted work.Funding StatementThis Study was funded by the Joint Initiative for Vaccine Economics, Phase 5, a cooperative agreement between the University of Michigan and the Centers for Disease Control and Prevention (U01IP000965). Additionally, this study was funded by the National Institute of General Medical Sciences (U01GM110712). Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe surveillance datasets are available from the Centers for Disease Control and Prevention upon request and application. Computing code available from the corresponding author upon reasonable request. |
Impact of community treatment with ivermectin for the control of scabies on the prevalence of antibodies to Strongyloides stercoralis in children (preprint)
Marks M , Gwyn S , Toloka H , Kositz C , Asugeni J , Asugeni R , Diau J , Kaldor JM , Romani L , Redman-MacLaren M , MacLaren D , Solomon AW , Mabey DCW , Steer AC , Martin D . medRxiv 2019 2019.12.18.19015248 Prevalence of antibodies to Strongyloides stercoralis was measured in 0–12-year-olds using a bead-based immunoassay before and after ivermectin mass drug administration (MDA) for scabies in the Solomon Islands. Seroprevalence was 9.3% before and 5.1% after MDA (p = 0.019), demonstrating collateral benefits of scabies MDA in this setting.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02775617Funding StatementThe study was funded by a Wellcome Trust Clinical PhD fellowship to MM (102807). The US CDC paid the laboratory costs. The funders did not have any role in the design, conduct or analysis of the study.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData available in supplementary material |
Age-specific prevalence of anti-Pgp3 antibodies and severe conjunctival scarring in the Solomon Islands (preprint)
Butcher R , Sokana O , Jack K , Martin DL , Burton MJ , Solomon AW , Mabey DCW , Roberts CH . bioRxiv 2017 141135 Background Trachomatous trichiasis (TT) and ocular Chlamydia trachomatis (Ct) infection in the Solomon Islands are scarce, whereas trachomatous inflammation–follicular (TF) is prevalent.Methods We enrolled 1511 people aged ≥1 year from randomly selected households in 13 villages in which >10% of the population had TF prior to a single round of azithromycin MDA undertaken six months previously. Blood was collected from people of all ages to be screened for anti-Pgp3 antibodies. Photographs were collected from people of all ages for analysis of scarring severity.Results Conjunctival scars were visible in 13.1% of photographs. Mild (p<0.0001) but not severe (p=0.149) scars increased in prevalence with age. Anti-Pgp3 antibody seroprevalence was 18% in 1–9 year olds, increased sharply around the age of sexual debut, and reached 69% in those over 25 years. Anti-Pgp3 seropositivity did not increase significantly between the ages of 1–9 years, and was not associated with scarring in children (p=0.472) or TF in children (p=0.581).Conclusions Signs of trachoma are common in the Solomon Islands but occur frequently in individuals who have no serological evidence of prior ocular infection with Ct. WHO recommendations for directing MDA provision based on signs alone may not be suitable in this context. |
Cause-specific student absenteeism monitoring in K-12 schools for detection of increased influenza activity in the surrounding community - Dane County, Wisconsin, 2014-2020 (preprint)
Temte JL , Barlow S , Goss M , Temte E , Schemmel A , Bell C , Reisdorf E , Shult P , Wedig M , Haupt T , Conway JH , Gangnon R , Uzicanin A . medRxiv 2021 2021.05.26.21257819 Background Schools are primary venues of influenza amplification with secondary spread to communities. We assessed K-12 student absenteeism monitoring as a means for early detection of influenza activity in the community.Materials and Methods Between September 2014 and March 2020, we conducted a prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness–associated (a-ILI) absenteeism within the Oregon School District (OSD), Dane County, Wisconsin. Absenteeism was reported through the electronic student information system. Students were visited at home where pharyngeal specimens were collected for influenza RT-PCR testing. Surveillance of medically-attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining OSD. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis.Findings Influenza was detected in 723 of 2,378 visited students, and in 1,327 of 4,903 MAI patients. Over six influenza seasons, a-ILI was significantly correlated with MAI in the community (r = 0.57; 95% CI: 0.53—0.63) with a one-day lead time and a-I was significantly correlated with MAI in the community (r = 0.49; 0.44-0.54) with a 10-day lead time, while a-TOT performed poorly (r = 0.27; 0.21—0.33), following MAI by six days.Discussion Surveillance using cause-specific absenteeism was feasible and performed well over a study period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can provide early warning of seasonal influenza in time for community mitigation efforts.Competing Interest StatementDr. Jonathan Temte has received financial and material support from Quidel Corporation. Dr. John Tamerius and Quidel Corporation have generously supplied RIDT analyzers and tests.Funding StatementThis study has been supported by CDC through the cooperative agreement # 5U01CK000542-02-00. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All components of this proposed study were reviewed and approved by the Human Subjects Committees of the Education and Social/Behavioral Sciences IRB (initial approval on September 4, 2013) and the University of Wisconsin Health Sciences-IRB (initial approval on December 5, 2013, with additional approvals as the protocol expanded and modified). The study is in full compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA), FERPA, and all other federally mandated human subjects regulations. The US Office of Management and Budget has approved all forms used in this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated and/or analyzed during the current study are not publicly available because the study is ongoing, but may be available from the corresponding author on reasonable request. |
COVID-19-associated school closures and related efforts to sustain education and subsidized meal programs, United States, February 18–June 30, 2020 (preprint)
Zviedrite N , Hodis JD , Jahan F , Gao H , Uzicanin A . medRxiv 2021 2021.03.05.21252848 Pre-emptive school closures are frontline community mitigation measures recommended by CDC for implementation during severe pandemics. This study describes the spatiotemporal patterns of publicly announced school closures implemented in response to the coronavirus disease 2019 (COVID-19) pandemic and assesses how public K-12 districts adjusted their methods of education delivery and provision of subsidized meals. During February 18–June 30, 2020, we used daily systematic media searches to identify publicly announced coronavirus disease 2019 (COVID-19)–related school closures lasting ≥1 day in the United States (US). We also collected statewide school closure policies from state government websites. Data on distance learning and subsidized meal programs were collected from a stratified sample of 600 school districts. The first COVID-19–associated school closure occurred on February 27, 2020 in Washington state. By March 30, 2020, all but one US public school districts were closed, representing the first-ever nearly synchronous nationwide closure of public K-12 schools in the US. Approximately 100,000 public schools were closed for ≥8 weeks because of COVID-19, affecting >50 million K-12 students. Of 600 districts sampled, the vast majority offered distance learning (91.0%) and continued provision of subsidized meal programs (78.8%) during the closures. Despite the sudden and prolonged nature of COVID-19–associated school closures, schools demonstrated flexibility by implementing distance learning and alternate methods to continue subsidized meal programs.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was supported by the United States Centers for Disease Control and Prevention (http://www.cdc.gov/). Several co-authors are or were employees (NZ HG AU) or contractors (FJ) of the US CDC at the time of the study. During the study period, JH was a fellow appointed through the Research Participation Program at the US CDC administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US CDC.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The project underwent ethical review at the Centers for Disease Control and Prevention and was determined not to involve human subjects; it was therefore not subject to institutional review board review requirements.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe authors confirm that all data underlying the findings are fully available without restriction. Data are available from Google (www.google.com), Google News (news.google.com), and the National Center for Education Statistics (nces.ed.gov). The search and linking strategy used for these data sources is detailed within the paper. |
Rapid Evolution of Knockdown Resistance Haplotypes in Response to Pyrethroid Selection in Aedes aegypti (preprint)
Baltzegar J , Vella M , Gunning C , Vasquez G , Astete H , Stell F , Fisher M , Scott TW , Lenhart A , Lloyd AL , Morrison A , Gould F . bioRxiv 2021 2021.04.02.438212 This study describes the evolution of knockdown resistance (kdr) haplotypes in Aedes aegypti in response to pyrethroid insecticide use over the course of 18 years in Iquitos, Peru. Based on the duration and intensiveness of sampling (∼10,000 samples), this is the most thorough study of kdr population genetics in Ae. aegypti to date within a city. We provide evidence for the direct connection between programmatic citywide pyrethroid spraying and the increase in frequency of specific kdr haplotypes by identifying two evolutionary events in the population. The relatively high selection coefficients, even under infrequent insecticide pressure, emphasizes how quickly populations can evolve. The observed rapid increase in frequency of resistance alleles might have been aided by the incomplete dominance of resistance-conferring alleles over corresponding susceptibility alleles. In addition to dramatic temporal shifts, spatial suppression experiments reveal that genetic heterogeneity existed not only at the citywide scale, but also on a very fine scale within the city.Competing Interest StatementThe authors have declared no competing interest. |
Avian influenza A viruses reassort and diversify differently in mallards and mammals (preprint)
Ganti K , Bagga A , DaSilva J , Shepard SS , Barnes JR , Shriner S , Koelle K , Lowen AC . bioRxiv 2021 2021.02.08.430042 Reassortment among co-infecting influenza A viruses (IAVs) is an important source of viral diversity and can facilitate expansion into novel host species. Indeed, reassortment played a key role in the evolution of the last three pandemic IAVs. Observed patterns of reassortment within a coinfected host are likely to be shaped by several factors, including viral load, the extent of viral mixing within the host and the stringency of selection. These factors in turn are expected to vary among the diverse host species that IAV infects. To investigate host differences in IAV reassortment, here we examined reassortment of two distinct avian IAV within their natural host (mallards) and a mammalian model system (guinea pigs). Animals were co-inoculated with A/wildbird/California/187718-36/2008 (H3N8) and A/mallard/Colorado/P66F1-5/2008 (H4N6) viruses. Longitudinal samples were collected from the cloaca of mallards or the nasal tract of guinea pigs and viral genetic exchange was monitored by genotyping clonal isolates from these samples. Relative to those in guinea pigs, viral populations in mallards showed higher frequencies of reassortant genotypes and were characterized by higher genotype richness and diversity. In line with these observations, analysis of pairwise segment combinations revealed lower linkage disequilibrium in mallards as compared to guinea pigs. No clear longitudinal patterns in richness, diversity or linkage disequilibrium were present in either host. Our results reveal mallards to be a highly permissive host for IAV reassortment and suggest that reduced viral mixing limits avian IAV reassortment in a mammalian host.Competing Interest StatementThe authors have declared no competing interest. |
Under pressure: phenotypic divergence and convergence associated with microhabitat adaptations in Triatominae (preprint)
Abad-Franch F , Monteiro FA , Pavan MG , Patterson JS , Bargues MD , Zuriaga MÁ , Aguilar M , Beard CB , Mas-Coma S , Miles MA . bioRxiv 2020 2020.07.28.224535 Background Triatomine bugs, the vectors of Chagas disease, associate with vertebrate hosts in highly diverse ecotopes. When these blood-sucking bugs adapt to new microhabitats, their phenotypes may change. Although understanding phenotypic variation is key to the study of adaptive evolution and central to phenotype-based taxonomy, the drivers of phenotypic change and diversity in triatomines remain poorly understood.Methods/Findings We combined a detailed phenotypic appraisal (including morphology and morphometrics) with mitochondrial cytb and nuclear ITS2 DNA-sequence analyses to study Rhodnius ecuadoriensis populations from across the species’ range. We found three major, naked-eye phenotypic variants. Southern-Andean bugs (SW Ecuador/NW Peru) from house and vertebrate-nest microhabitats are typical, light-colored, small bugs with short heads/wings. Northern-Andean bugs (W Ecuador wet-forest palms) are dark, large bugs with long heads/wings. Finally, northern-lowland bugs (coastal Ecuador dry-forest palms) are light-colored and medium-sized. Wing and (size-free) head shapes are similar across Ecuadorian populations, regardless of habitat or naked-eye phenotype, but distinct in Peruvian bugs. Bayesian phylogenetic and multispecies-coalescent DNA-sequence analyses strongly suggest that Ecuadorian and Peruvian populations are two independently-evolving lineages, with little within-lineage structuring/differentiation.Conclusions We report sharp naked-eye phenotypic divergence of genetically similar Ecuadorian R. ecuadoriensis (house/nest southern-Andean vs. palm-dwelling northern bugs; and palm-dwelling Andean vs. lowland); and sharp naked-eye phenotypic similarity of typical, yet genetically distinct, southern-Andean bugs from house and nest (but not palm) microhabitats (SW Ecuador vs. NW Peru). This remarkable phenotypic diversity within a single nominal species likely stems from microhabitat adaptations possibly involving predator-driven selective pressure (yielding substrate-matching camouflage coloration) and a shift from palm-crown to vertebrate-nest microhabitats (yielding smaller bodies and shorter heads and wings). These findings shed new light on the origins of phenotypic diversity in triatomines, warn against excess reliance on phenotype-based triatomine-bug taxonomy, and confirm the Triatominae as an informative model-system for the study of phenotypic change under ecological pressure.Author summary Triatomine bugs feed on the blood of vertebrates including humans and transmit the parasite that causes Chagas disease. The bugs, of which 150+ species are known, are highly diverse in size, shape, and color. Some species look so similar that they are commonly confused, whereas a few same-species populations look so different that they were thought to be separate species. Despite the crucial role of naked-eye phenotypes in triatomine-bug identification and classification (which are essential for vector control-surveillance), the origins of this variation remain unclear. Here, we describe a striking case of phenotypic divergence, with genetically similar bugs looking very different from one another, and phenotypic convergence, with bugs from two genetically distinct populations (likely on their way to speciation) looking very similar – and all within a single nominal species, Rhodnius ecuadoriensis. Phenotypically divergent populations occupy different ecological regions (wet vs. dry) and microhabitats (palm-crowns vs. vertebrate nests), whereas convergent populations occupy man-made and nest (but not palm) microhabitats. These findings suggest that triatomines can ‘respond’ to ecological novelty by changing their external, naked-eye phenotypes as they adapt to new microhabitats. We therefore warn that phenotypic traits such as overall size or color may confound triatomine-bug species identification and classification. |
Western Kenyan Anopheles gambiae s.s. showing intense permethrin resistance harbor distinct microbiota (preprint)
Omoke D , Kipsum M , Otieno S , Esalimba E , Sheth M , Lenhart A , Njeru EM , Ochomo E , Dada N . bioRxiv 2020 2020.11.12.378760 Background Insecticide resistance poses a growing challenge to malaria vector control in Kenya and around the world. Following evidence of associations between the mosquito microbiota and insecticide resistance, we comparatively characterized the microbiota of An. gambiae s.s. from Tulukuyi village, Bungoma, Kenya, with differing permethrin resistance profiles.Methods Using the CDC bottle bioassay, 133 2-3 day-old, virgin, non-blood fed female F1 progeny of field-caught An. gambiae s.s. were exposed to five times (107.5μg/ml) the discriminating dose of permethrin. Post bioassay, 50 resistant and 50 susceptible mosquitoes were subsequently screened for kdr East and West mutations, and individually processed for microbial analysis using high throughput sequencing targeting the universal bacterial and archaeal 16S rRNA gene.Results 47% of the samples tested (n=133) were resistant, and of the 100 selected for further processing, 99% were positive for kdr East and 1% for kdr West. Overall, 84 bacterial taxa were detected across all mosquito samples, with 36 of these shared between resistant and susceptible mosquitoes. A total of 20 were unique to the resistant mosquitoes and 28 were unique to the susceptible mosquitoes. There were significant differences in bacterial composition between resistant and susceptible individuals (F=2.33, P=0.001), with presence of Sphingobacterium, Lysinibacillus and Streptococcus (all known pyrethroid-degrading taxa), and the radiotolerant Rubrobacter, being significantly associated with resistant mosquitoes. On the other hand, the presence of Myxococcus, was significantly associated with susceptible mosquitoes.Conclusion This is the first report of distinct microbiota in An. gambiae s.s. associated with intense pyrethroid resistance. The findings highlight differentially abundant bacterial taxa between resistant and susceptible mosquitoes, and further suggest a microbe-mediated mechanism of insecticide resistance in mosquitoes. Our results also indicate fixation of the kdr East mutation in this mosquito population, precluding further analysis of its associations with the mosquito microbiota, but presenting the hypothesis that any microbe-mediated mechanism of insecticide resistance would be likely of a metabolic nature. Overall, this study lays initial groundwork for understanding microbe-mediated mechanisms of insecticide resistance in African malaria vectors, and potentially identifying novel microbial markers of insecticide resistance that could supplement existing vector surveillance tools.Competing Interest StatementThe authors have declared no competing interest. |
Insecticide resistance status of Aedes aegypti in Bangladesh (preprint)
Al-Amin HM , Johora FT , Irish SR , Hossainey MRH , Vizcaino L , Paul KK , Khan WA , Haque R , Alam MS , Lenhart A . bioRxiv 2020 2020.07.31.231076 Background Arboviral diseases including dengue and chikungunya are major public health concern in Bangladesh, with unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is control of Aedes aegypti using pyrethroid insecticides. Although chemical control is long-practiced, no comprehensive analysis of Ae. aegypti susceptibility to insecticides has previously been conducted. This study aimed to determine the insecticide resistance status of Ae. aegypti in Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms.Methods Aedes eggs were collected using ovitraps from five districts across the country and in eight neighborhoods of the capital city Dhaka from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3-5-day old F0-F2 non-blood fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410.Results High levels of resistance to permethrin were detected in all Ae. aegypti populations, with mortality ranging from 0 – 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2X) doses of permethrin (5.1 – 44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency of kdr alleles varied across the Dhaka populations, and Leu410 was not detected in any of the tested populations.Conclusions The detection of widespread pyrethroid resistance and multiple mechanisms highlights the urgency for implementing alternate Ae. aegypti control strategies. In addition, implementing routine monitoring of insecticide resistance in Ae. aegypti in Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.Competing Interest StatementThe authors have declared no competing interest.AChEacetylcholine esterase;BIBreteau Index;β-ESTβ esterase;CIconfidence intervals;DDTdichlorodiphenyltrichloroethane;DTNBdithio-bis-2-nitrobenzoic acid;GSTsglutathione S-transferases;HWEHardy-Weinberg equilibrium;IRSindoor residual spraying;IACHEinsensitive acetylcholine esterase;icddr,bInternational Centre for Diarrhoeal Disease Research, Bangladesh;kdrknockdown resistance:LLINslong-lasting insecticidal nets:MFOsmixed-function oxidases;ODoptical density;ROCKRockefeller;CDCU.S. Centers for Disease Control and Prevention;VGSCvoltage-gated sodium channel;WHOWorld Health Organization |
Reduction of exposure to simulated respiratory aerosols using ventilation, physical distancing, and universal masking (preprint)
Coyle JP , Derk RC , Lindsley WG , Boots T , Blachere FM , Reynolds JS , McKinney WG , Sinsel EW , Lemons AR , Beezhold DH , Noti JD . medRxiv 2021 2021.09.16.21263702 To limit community spread of SARS-CoV-2, CDC recommends universal masking indoors, maintaining 1.8 m of physical distancing, adequate ventilation, and avoiding crowded indoor spaces. Several studies have examined the independent influence of each control strategy in mitigating transmission in isolation, yet controls are often implemented concomitantly within an indoor environment. To address the influence of physical distancing, universal masking, and ventilation on very fine respiratory droplets and aerosol particle exposure, a simulator that coughed and exhaled aerosols (the source) and a second breathing simulator (the recipient) were placed in an exposure chamber. When controlling for the other two mitigation strategies, universal masking with 3-ply cotton masks reduced exposure to 0.3–3 µm coughed and exhaled aerosol particles by > 77% compared to unmasked tests, whereas physical distancing (0.9 or 1.8 m) significantly changed exposure to cough but not exhaled aerosols. The effectiveness of ventilation depended upon the respiratory activity, i.e., coughing or breathing, as well as the duration of exposure time. Our results demonstrate that a combination of administrative and engineering controls can reduce personal inhalation exposure to potentially infectious very fine respiratory droplets and aerosol particles within an indoor environment.PRACTICAL IMPLICATIONSUniversal masking provided the most effective strategy in reducing inhalational exposure to simulated aerosols.Physical distancing provided limited reductions in exposure to small aerosol particles.Ventilation promotes air mixing in addition to aerosol removal, thus altering the exposure profile to individuals.A combination of mitigation strategies can effectively reduce exposure to potentially infectious aerosols.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the Centers for Disease Control and Prevention Emergency Operations Center.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Not ApplicableAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. |
Impact of an Urban Sanitation Intervention on Enteric Pathogen Detection in Soils (preprint)
Capone D , Berendes D , Cumming O , Holcomb D , Knee J , Konstantinidis KT , Levy K , Nalá R , Risk BB , Stewart J , Brown J . bioRxiv 2021 2021.04.02.438233 Environmental fecal contamination is common in many low-income cities, contributing to a high burden of enteric infections and associated negative sequelae. To evaluate the impact of a shared onsite sanitation intervention in Maputo, Mozambique on enteric pathogens in the domestic environment, we collected 179 soil samples at shared latrine entrances from intervention (n= 49) and control (n= 51) compounds during baseline (pre-intervention) and after 24 months (post-intervention) as part of the Maputo Sanitation Trial. We tested soils for the presence of nucleic acids associated with 20 enteric pathogens using a multiplex reverse transcription qPCR platform. We detected at least one pathogen-associated target in 91% (163/179) of soils and a median of 3 (IQR=1.5, 5) pathogens. Using a difference-in-difference analysis and adjusting for compound population, visibly wet soil, sun exposure, wealth, temperature, animal presence, and visible feces, we estimate the intervention reduced the probability of ≥1 pathogen detected by 15% (adjusted prevalence ratio, aPR=0.85; 95% CI: 0.70, 1.0) and the total number of pathogens detected by 35% (aPR =0.65; 0.44, 0.95) in soil 24 months following the intervention. These results suggest that the intervention reduced the presence of some fecal contamination in the domestic environment, but pathogen detection remained prevalent 24-months following the introduction of new latrines.Competing Interest StatementThe authors have declared no competing interest. |
Estimating typhoid incidence from community-based serosurveys: A multicohort study in Bangladesh, Nepal, Pakistan and Ghana (preprint)
Aiemjoy K , Seidman JC , Saha S , Munira SJ , Islam Sajib MS , Sium SMA , Sarkar A , Alam N , Zahan FN , Kabir MS , Tamrakar D , Vaidya K , Shrestha R , Shakya J , Katuwal N , Shrestha S , Yousafzai MT , Iqbal J , Dehraj IF , Ladak Y , Maria N , Adnan M , Pervaiz S , Carter AS , Longley AT , Fraser C , Ryan ET , Nodoushani A , Fasano A , Leonard MM , Kenyon V , Bogoch II , Jeon HJ , Haselbeck A , Park SE , Zellweger RM , Marks F , Owusu-Dabo E , Adu-Sarkodie Y , Owusu M , Teunis P , Luby SP , Garrett DO , Qamar FN , Saha SK , Charles RC , Andrews JR . medRxiv 2022 2021.10.20.21265277 Background The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.Methods We collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.Findings The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children <5 years ranged between 58.5 per 100 person-years (95% CI: 42.1 - 81.4) in Dhaka, Bangladesh to 6.6 (95% CI: 4.3-9.9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.Interpretation The approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.Funding This work was supported by the Bill and Melinda Gates Foundation (INV-000572).Evidence before this study Previous studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this study We developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidence Many a -risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by th eBill and Melinda Gates Foundation (grant INV-000572)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Boards in the United States (Centers for Disease Control and Prevention; Stanford University Institutional Review Board), Bangladesh (Bangladesh Institute of Child Health Ethical Review Committee), Nepal (Nepal Health Research Council Ethical Review Board), Pakistan (AKU Ethic Review Committee and Pakistan National Bioethics Committee), Korea (International Vaccine Institute IRB), Belgium (Institute of Tropical Medicine Antwerp Institutional Review Board) and Ghana (Komfo Anokye Teaching Hospital, Committee on Human Research, Publication and Ethics) approved the study forms and protocols.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors |
The Oregon Child Absenteeism Due to Respiratory Disease Study (ORCHARDS): Rationale, Objectives, and Design (preprint)
Temte JL , Barlow S , Goss M , Temte E , Schemmel A , Maerz B , Bell C , Comp L , Arnold M , Breunig K , Clifford S , Reisdorf E , Shult P , Wedig M , Haupt T , Conway J , Gangnon R , Fowlkes A , Uzicanin A . medRxiv 2021 2021.02.01.21250878 Background Influenza viruses pose significant disease burdens through annual seasonal outbreaks and unpredictable pandemics. Existing influenza surveillance programs have relied heavily on reporting of medically attended influenza (MAI). Continuously monitoring cause-specific school absenteeism may identify local acceleration of seasonal influenza activity. The Oregon Child Absenteeism Due to Respiratory Disease Study (ORCHARDS; Oregon, WI) implements daily school-based monitoring of influenza-like illness–specific student absenteeism (a-ILI) in pre-kindergarten through grade 12 schools and assesses this approach for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities.Methods Starting in September 2014, ORCHARDS combined automated reporting of daily absenteeism within 6 schools and home visits to school children with acute respiratory infections (ARI). Demographic, epidemiological, and symptom data are collected along with respiratory specimens. Specimens are tested for influenza and other respiratory viruses. Household members can opt into a supplementary household transmission study. Community comparisons are possible using a pre-existing, long-standing, and highly effective influenza surveillance program, based on MAI at 5 primary care clinics in the same geographical area.Results Over the first 5 years, a-ILI occurred on 6,634 (0.20%) of 3,260,461 student school days. Viral pathogens were detected in 64.5% of the 1,728 children with ARI who received a home visit. Influenza was the most commonly detected virus, noted in 23.3% of ill students. Influenza (p<0.001) and adenovirus (P=0.004) were significantly associated with a-ILI.Conclusion ORCHARDS uses a community-based design to detect influenza trends over multiple seasons and to evaluate the utility of absenteeism for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities. Initial findings suggest the study design is succeeding in collecting appropriate data to achieve study objectives.Competing Interest StatementDr. Jonathan Temte has received financial and material support from Quidel Corporation. Dr. John Tamerius and Quidel Corporation have generously supplied RIDT analyzers and tests.Funding StatementDr. John Tamerius and Quidel Corporation have generously supplied RIDT analyzers and tests. This study has been supported by CDC through the cooperative agreement # 5U01CK000542-02-00. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All components of this proposed study were reviewed and approved by the Human Subjects Committees of the Education Research IRB - Social and Behavioral Sciences IRB (initial approval on September 4, 2013) and the University of Wisconsin Health Sciences-IRB (initial approval on December 5, 2013, with additional approvals as the protocol expanded and modified). The study is in full compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA), FERPA, and all other federally mandated human subjects regulations. The US Office of Management and Budget has approved all forms used in this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a s atement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated and/or analyzed during the current study are not publicly available because the study is ongoing, but may be available from the corresponding author on reasonable request.4k4-year-old pre-kindergartena-Iabsenteeism due to illnessa-ILIabsenteeism due to influenza-like illnessa-TOTall-cause absenteeismARIacute respiratory infectionCDCCenters for Disease Control and PreventionCoVcoefficient of variationFERPAFamily Educational Rights and Privacy ActFluinfluenzaFDAFood and Drug AdministrationHIPPAHealth Insurance Portability and Accountability ActILIinfluenza-like illnessITinformation technologyIRBinstitutional review boardMAImedically attended influenzaNPnasopharyngealORCHARDSOregon Child Absenteeism Due to Respiratory Disease StudyOSDOregon School DistrictOPoropharyngealPCRpolymerase chain reactionRIDTrapid influenza diagnostic testRedCapResearch Electronic Data CaptureRPPrespiratory pathogen panelR/Erhinovirus/enterovirusRPhuman RNAse PSISschool information systemW-IISPWisconsin Influenza Incidence Surveillance ProjectWIRWisconsin Immunization RegistryWSLHWisconsin State Laboratory of HygieneVTMviral transport medium |
Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the US (preprint)
Cramer EY , Ray EL , Lopez VK , Bracher J , Brennen A , Castro Rivadeneira AJ , Gerding A , Gneiting T , House KH , Huang Y , Jayawardena D , Kanji AH , Khandelwal A , Le K , Mühlemann A , Niemi J , Shah A , Stark A , Wang Y , Wattanachit N , Zorn MW , Gu Y , Jain S , Bannur N , Deva A , Kulkarni M , Merugu S , Raval A , Shingi S , Tiwari A , White J , Abernethy NF , Woody S , Dahan M , Fox S , Gaither K , Lachmann M , Meyers LA , Scott JG , Tec M , Srivastava A , George GE , Cegan JC , Dettwiller ID , England WP , Farthing MW , Hunter RH , Lafferty B , Linkov I , Mayo ML , Parno MD , Rowland MA , Trump BD , Zhang-James Y , Chen S , Faraone SV , Hess J , Morley CP , Salekin A , Wang D , Corsetti SM , Baer TM , Eisenberg MC , Falb K , Huang Y , Martin ET , McCauley E , Myers RL , Schwarz T , Sheldon D , Gibson GC , Yu R , Gao L , Ma Y , Wu D , Yan X , Jin X , Wang YX , Chen Y , Guo L , Zhao Y , Gu Q , Chen J , Wang L , Xu P , Zhang W , Zou D , Biegel H , Lega J , McConnell S , Nagraj VP , Guertin SL , Hulme-Lowe C , Turner SD , Shi Y , Ban X , Walraven R , Hong QJ , Kong S , van de Walle A , Turtle JA , Ben-Nun M , Riley S , Riley P , Koyluoglu U , DesRoches D , Forli P , Hamory B , Kyriakides C , Leis H , Milliken J , Moloney M , Morgan J , Nirgudkar N , Ozcan G , Piwonka N , Ravi M , Schrader C , Shakhnovich E , Siegel D , Spatz R , Stiefeling C , Wilkinson B , Wong A , Cavany S , España G , Moore S , Oidtman R , Perkins A , Kraus D , Kraus A , Gao Z , Bian J , Cao W , Lavista Ferres J , Li C , Liu TY , Xie X , Zhang S , Zheng S , Vespignani A , Chinazzi M , Davis JT , Mu K , Pastore YPiontti A , Xiong X , Zheng A , Baek J , Farias V , Georgescu A , Levi R , Sinha D , Wilde J , Perakis G , Bennouna MA , Nze-Ndong D , Singhvi D , Spantidakis I , Thayaparan L , Tsiourvas A , Sarker A , Jadbabaie A , Shah D , Della Penna N , Celi LA , Sundar S , Wolfinger R , Osthus D , Castro L , Fairchild G , Michaud I , Karlen D , Kinsey M , Mullany LC , Rainwater-Lovett K , Shin L , Tallaksen K , Wilson S , Lee EC , Dent J , Grantz KH , Hill AL , Kaminsky J , Kaminsky K , Keegan LT , Lauer SA , Lemaitre JC , Lessler J , Meredith HR , Perez-Saez J , Shah S , Smith CP , Truelove SA , Wills J , Marshall M , Gardner L , Nixon K , Burant JC , Wang L , Gao L , Gu Z , Kim M , Li X , Wang G , Wang Y , Yu S , Reiner RC , Barber R , Gakidou E , Hay SI , Lim S , Murray C , Pigott D , Gurung HL , Baccam P , Stage SA , Suchoski BT , Prakash BA , Adhikari B , Cui J , Rodríguez A , Tabassum A , Xie J , Keskinocak P , Asplund J , Baxter A , Oruc BE , Serban N , Arik SO , Dusenberry M , Epshteyn A , Kanal E , Le LT , Li CL , Pfister T , Sava D , Sinha R , Tsai T , Yoder N , Yoon J , Zhang L , Abbott S , Bosse NI , Funk S , Hellewell J , Meakin SR , Sherratt K , Zhou M , Kalantari R , Yamana TK , Pei S , Shaman J , Li ML , Bertsimas D , Skali Lami O , Soni S , Tazi Bouardi H , Ayer T , Adee M , Chhatwal J , Dalgic OO , Ladd MA , Linas BP , Mueller P , Xiao J , Wang Y , Wang Q , Xie S , Zeng D , Green A , Bien J , Brooks L , Hu AJ , Jahja M , McDonald D , Narasimhan B , Politsch C , Rajanala S , Rumack A , Simon N , Tibshirani RJ , Tibshirani R , Ventura V , Wasserman L , O'Dea EB , Drake JM , Pagano R , Tran QT , Ho LST , Huynh H , Walker JW , Slayton RB , Johansson MA , Biggerstaff M , Reich NG . medRxiv 2021 2021.02.03.21250974 Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. In 2020, the COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized hundreds of thousands of specific predictions from more than 50 different academic, industry, and independent research groups. This manuscript systematically evaluates 23 models that regularly submitted forecasts of reported weekly incident COVID-19 mortality counts in the US at the state and national level. One of these models was a multi-model ensemble that combined all available forecasts each week. The performance of individual models showed high variability across time, geospatial units, and forecast horizons. Half of the models evaluated showed better accuracy than a naïve baseline model. In combining the forecasts from all teams, the ensemble showed the best overall probabilistic accuracy of any model. Forecast accuracy degraded as models made predictions farther into the future, with probabilistic accuracy at a 20-week horizon more than 5 times worse than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.Competing Interest StatementAV, MC, and APP report grants from Metabiota Inc outside the submitted work.Funding StatementFor teams that reported receiving funding for their work, we report the sources and disclosures below. CMU-TimeSeries: CDC Center of Excellence, gifts from Google and Facebook. CU-select: NSF DMS-2027369 and a gift from the Morris-Singer Foundation. COVIDhub: This work has been supported by the US Centers for Disease Control and Prevention (1U01IP001122) and the National Institutes of General Medical Sciences (R35GM119582). The content is solely the responsibility of the authors and does not necessarily represent the official views of CDC, NIGMS or the National Institutes of Health. Johannes Bracher was supported by the Helmholtz Foundation via the SIMCARD Information& Data Science Pilot Project. Tilmann Gneiting gratefully acknowledges support by the Klaus Tschira Foundation. DDS-NBDS: NSF III-1812699. EPIFORECASTS-ENSEMBLE1: Wellcome Trust (210758/Z/18/Z) GT_CHHS-COVID19: William W. George Endowment, Virginia C. and Joseph C. Mello Endowments, NSF DGE-1650044, NSF MRI 1828187, research cyberinfrastructure resources and services provided by the Partnership for an Advanced Computing Environment (PACE) at Georgia Tech, and the following benefactors at Georgia Tech: Andrea Laliberte, Joseph C. Mello, Richard Rick E. & Charlene Zalesky, and Claudia & Paul Raines GT-DeepCOVID: CDC MInD-Healthcare U01CK000531-Supplement. NSF (Expeditions CCF-1918770, CAREER IIS-2028586, RAPID IIS-2027862, Medium IIS-1955883, NRT DGE-1545362), CDC MInD program, ORNL and funds/computing resources from Georgia Tech and GTRI. IHME: This work was supported by the Bill & Melinda Gates Foundation, as well as funding from the state of Washington and the National Science Foundation (award no. FAIN: 2031096). IowaStateLW-STEM: Iowa State University Plant Sciences Institute Scholars Program, NSF DMS-1916204, NSF CCF-1934884, Laurence H. Baker Center for Bioinformatics and Biological Statistics. JHU_IDD-CovidSP: State of California, US Dept of Health and Human Services, US Dept of Homeland Security, US Office of Foreign Disaster Assistance, Johns Hopkins Health System, Office of the Dean at Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University Modeling and Policy Hub, Centers fo Disease Control and Prevention (5U01CK000538-03), University of Utah Immunology, Inflammation, & Infectious Disease Initiative (26798 Seed Grant). LANL-GrowthRate: LANL LDRD 20200700ER. MOBS-GLEAM_COVID: COVID Supplement CDC-HHS-6U01IP001137-01. NotreDame-mobility and NotreDame-FRED: NSF RAPID DEB 2027718 UA-EpiCovDA: NSF RAPID Grant # 2028401. UCSB-ACTS: NSF RAPID IIS 2029626. UCSD-NEU: Google Faculty Award, DARPA W31P4Q-21-C-0014, COVID Supplement CDC-HHS-6U01IP001137-01. UMass-MechBayes: NIGMS R35GM119582, NSF 1749854. UMich-RidgeTfReg: The University of Michigan Physics Department and the University of Michigan Office of Research.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:UMass-Amherst IRBAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data and code referred to in the manuscript are publicly available. https://github.com/reichlab/covid19-forecast-hub/ https://github.com/reichlab/covidEnsembles https://zoltardata.com/project/44 |
Social contact patterns among employees in 3 U.S. companies during early phases of the COVID-19 pandemic, April to June 2020 (preprint)
Kiti MC , Aguolu OG , Liu CY , Mesa AR , Regina R , Willebrand K , Couzens C , Bartelsmeyer T , Nelson KN , Jenness S , Riley S , Melegaro A , Ahmed F , Malik F , Lopman BA , Omer SB . medRxiv 2020 2020.10.14.20212423 Importance Devising control strategies against diseases such as COVID-19 require understanding of contextual social mixing and contact patterns. There has been no standardized multi-site social contact study conducted in workplace settings in the United States that can be used to broadly inform pandemic preparedness policy in these settings.Objective The study aimed to characterize the patterns of social contacts and mixing across workplace environments, including on-site or when teleworking.Design This was a cross-sectional non-probability survey that used standardized social contact diaries to collect data. Employees were requested to record their physical and non-physical contacts in a diary over two consecutive days, documented at the end of each day. Employees from each company were enrolled through email and electronic diaries sent as individual links. Data were collected from April to June 2020.Setting Two multinational consulting companies and one university administrative department, all located in Georgia, USA.Participants Employees opted into the study by accepting the invitation on a link sent via email.Main Outcome The outcome was median number of contacts per person per day. This was stratified by day of data collection, age, sex, race and ethnicity.Results Of 3,835 employees approached, 357 (9.3%) completed the first day of contact diary of which 304 completed both days of contact diary. There was a median of 2 contacts (IQR: 1-4, range: 0-21) per respondent on both day one and two. The majority (55%) of contacts involved conversation only, occurred at home (64%), and cumulatively lasted more than 4 hours (38%). Most contacts were repeated, and within same age groups, though participants aged 30-59 years reported substantial inter-generational mixing with children.Conclusion Participating employees in 3 surveyed workplaces reported few contacts, similar to studies from the UK and China when shelter-in-place orders were in effect during the pandemic. Many contacts were repeated which may limit the spread of infection. Future rounds are planned to assess changes in contact patterns when employees resume work in the office after the lockdown due to COVID-19 pandemic.Competing Interest StatementThe authors have declared no competing interest.Funding StatementCenters for Disease Control and Prevention, Atlanta, Georgia (Comprehensively profiling social mixing patterns in workplace settings to model pandemic influenza transmission; U01-CK000572)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was given by Yale University (IRB number 2000026906).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll de-identified data and code used for analysis are available in Github through the link provided. https://github.com/lopmanlab/corpmix |
Primary case inference in viral outbreaks through analysis of intra-host variant population (preprint)
Gussler JW , Campo DS , Dimitrova Z , Skums P , Khudyakov Y . bioRxiv 2020 2020.09.18.303131 Investigation of outbreaks to identify the primary case is crucial for the interruption and prevention of transmission of infectious diseases. These individuals may have a higher risk of participating in near future transmission events when compared to the other patients in the outbreak, so directing more transmission prevention resources towards these individuals is a priority. Genetic characterization of intra-host viral populations, although highly efficient in the identification of transmission clusters, is not as efficient in routing transmissions during outbreaks, owing to complexity of viral evolution. Here, we present a new computational framework, PYCIVO: primary case inference in viral outbreaks. This framework expands upon our earlier work in development of QUENTIN, which builds a probabilistic disease transmission tree based on simulation of evolution of intra-host hepatitis C virus (HCV) variants between cases involved in direct transmission during an outbreak. PYCIVO improves upon QUENTIN by also implementing a custom heterogeneity index which empowers PYCIVO to make the important ‘No primary case’ prediction. One or more samples, possibly including the primary case, may have not been sampled, and this designation is meant to account for these scenarios. These approaches were validated using a set of 105 sequence samples from 11 distinct HCV transmission clusters identified during outbreak investigations, in which the primary case was epidemiologically verified. Both models can detect the correct primary case in 9 out of 11 transmission clusters (81.8%). However, while QUENTIN issues erroneous predictions on the remaining 2 transmission clusters, PYCIVO issues a null output for these clusters, giving it an effective prediction accuracy of 100%. To further evaluate accuracy of the inference, we created 10 modified transmission clusters in which the primary case had been removed. In this scenario, PYCIVO was able to correctly identify that there was no primary case in 8/10 (80%) of these modified clusters. This model was validated with HCV; however, this approach may be applicable to other microbial pathogens.A version of this software is publicly available at the following url: https://www.github.com/walkergussler/PYCIVO |
Competition is a determinant of multidrug resistant plasmid acquisition in Salmonella (preprint)
Oladeinde A , Abdo Z , Zwirzitz B , Woyda R , Lakin SM , Press MO , Cook K , Cox NA , Thomas JCIV , Looft T , Rothrock MJJr , Zock G , Plumblee Lawrence J , Cudnik D , Ritz C , Aggrey SE . bioRxiv 2021 2021.04.02.438293 Host microbiome homeostasis ensures that gut conditions are unfavorable to an invading pathogen such as Salmonella enterica. Consequently, fostering a “balanced” gut microbiome through the administration of microbes that can competitively exclude pathogens has gained a lot of attention and use in human and animal medicine. However, little is known on how competitive exclusion affects the transfer of antibiotic resistance. To shed more light on this question, we challenged neonatal broiler chicks raised on reused broiler chicken litter – a complex environment comprising of decomposing pine shavings, feces, uric acid, feathers, and feed, with Salmonella Heidelberg (S. Heidelberg), a model pathogen. We show that chicks raised on reused litter carried lower abundance of Salmonella and harbored a more uniform and diverse microbiome comprising of bacterial species that are known to provide colonization resistance towards Salmonella compared to chicks raised on fresh bedding composed of pine shavings. Additionally, these bacterial species were associated with a lower horizontal transfer of multidrug resistance genes to S. Heidelberg. Using in vitro competition experiments, we confirmed that conjugation between S. Heidelberg and E. coli strains from chicks raised on fresh litter resulted in the acquisition of multidrug resistant plasmids. Contrastingly, bacteriophage-mediated recombination between S. Heidelberg and E. coli strains made the acquisition of plasmid-mediated β-lactamase gene (blaCMY-2) possible. Collectively, this study demonstrates that competitive exclusion can reduce the transfer of antibiotic resistance and provides information on the bacterial species that can be explored for their benefits to reduce antibiotic resistance transfer.Importance/Significance Antimicrobial resistance spread is a worldwide health challenge, stemming in large part, from the ability of microorganisms to share their genetic material through horizontal gene transfer. To address this issue, many countries and international organization have adopted a one health approach to curtail the proliferation of antibiotic resistant bacteria. This includes the removal and reduction of antibiotics used in food animal production and the development of alternatives to antibiotics. However, there is still a significant knowledge gap in our understanding of how antimicrobial resistance spreads in the absence of antibiotic selection and the role commensal bacteria play in reducing antibiotic resistance transfer. In this study, we demonstrate that commensal bacteria play a key role in reducing the horizontal transfer of antibiotic resistance to Salmonella and provide the identity and characteristics of the bacterial species that performs this function in broiler chickens. |
Emergence and global spread of Listeria monocytogenes main clinical clonal complex (preprint)
Moura A , Lefrancq N , Leclercq A , Wirth T , Borges V , Gilpin B , Dallman TJ , Frey J , Franz E , Nielsen EM , Thomas J , Pightling A , Howden BP , Tarr CL , Gerner-Smidt P , Cauchemez S , Salje H , Brisse S , Lecuit M . bioRxiv 2020 2020.12.18.423387 Retracing microbial emergence and spread is essential to understanding the evolution and dynamics of pathogens. The bacterial foodborne pathogen Listeria monocytogenes clonal complex 1 (Lm-CC1) is the most prevalent clonal group associated with listeriosis, and is strongly associated with cattle and dairy products. Here we analysed 2,021 Lm-CC1 isolates collected from 40 countries, since the first Lm isolation to the present day, to define its evolutionary history and population dynamics. Our results suggest that Lm-CC1 spread worldwide from North America following the Industrial Revolution through two waves of expansion, coinciding with the transatlantic livestock trade in the second half of the 19th century and the rapid growth of cattle farming in the 20th century. Lm-CC1 then firmly established at a local level, with limited inter-country spread. This study provides an unprecedented insight into Lm-CC1 phylogeography and dynamics and can contribute to effective disease surveillance to reduce the burden of listeriosis.Competing Interest StatementThe authors have declared no competing interest. |
Efficient rescue of a newly classified Ebinur lake orthobunyavirus with GFP reporter and its application in rapid antiviral screening (preprint)
Ren N , Wang F , Zhao L , Wang S , Zhang G , Li J , Zhang B , Bergeron E , Yuan Z , Xia H . bioRxiv 2022 2022.03.25.485793 Orthobunyaviruses have been reported to cause severe diseases in humans or animals, posing a threat to human health and social economy. Ebinur lake virus (EBIV) is a newly classified orthobunyavirus, which needs further intensive study and therapies to cope with its potential infection risk to human and animals. Here, through the reverse genetics system, the recombinant EBIV of wild type (rEBIV/WT) and NP-conjugated-eGFP (rEBIV/eGFP/S) were rescued for the application of the rapid antiviral drug screening. The eGFP fluorescence signal of the rEBIV/eGFP/S was stable in the process of successive passage in BHK-21 cells (over 10 passages) and this recombinant virus could replicate in various cell lines. Compared to the wild type EBIV, the rEBIV/eGFP/S caused the smaller plaques and its peak titers were lower, suggesting attenuation due to the eGFP insertion. Through the high-content screening (HCS) system, ribavirin showed an inhibitory effect on the rEBIV/eGFP/S with an EC50 of 21.91 μM, while favipiravir did not inhibit, even at high concentrations. In addition, five of ninety-six natural compounds had antiviral against EBIV. The robust reverse genetics system for EBIV will facilitate investigation into replication and assembly mechanisms and assist drug and vaccine development.Competing Interest StatementThe authors have declared no competing interest. |
In silico analyses of penicillin binding proteins in Burkholderia pseudomallei uncovers SNPs with utility for phylogeography, species differentiation, and sequence typing (preprint)
Mclaughlin HP , Gulvik CA , Sue D . bioRxiv 2021 2021.10.08.463618 Background Burkholderia pseudomallei causes melioidosis. Sequence typing this pathogen can reveal geographical origin and uncover epidemiological associations. Here, we describe B. pseudomallei genes encoding putative penicillin binding proteins (PBPs) and investigate their utility for determining phylogeography and differentiating closely related species.Methodology & Principal Findings We performed in silico analysis to characterize 10 PBP homologs in B. pseudomallei 1026b. As PBP active site mutations can confer β-lactam resistance in Gram-negative bacteria, PBP sequences in two resistant B. pseudomallei strains were examined for similar alterations. Sequence alignments revealed single amino acid polymorphisms (SAAPs) unique to the multidrug resistant strain Bp1651 in the transpeptidase domains of two PBPs, but not directly within the active sites. Using BLASTn analyses of complete assembled genomes in the NCBI database, we determined genes encoding PBPs were conserved among B. pseudomallei (n=101) and Burkholderia mallei (n=26) strains. Within these genes, single nucleotide polymorphisms (SNPs) useful for predicting geographic origin of B. pseudomallei were uncovered. SNPs unique to B. mallei were also identified. Based on 11 SNPs identified in two genes encoding predicted PBP-3s, a dual-locus sequence typing (DLST) scheme was developed. The robustness of this typing scheme was assessed using 1,523 RefSeq genomes from B. pseudomallei (n=1,442) and B. mallei (n=81) strains, resulting in 32 sequence types (STs). Compared to multi-locus sequence typing (MLST), the DLST scheme demonstrated less resolution to support the continental separation of Australian B. pseudomallei strains. However, several STs were unique to strains originating from a specific country or region. The phylogeography of Western Hemisphere B. pseudomallei strains was more highly resolved by DLST compared to internal transcribed spacer (ITS) typing, and all B. mallei strains formed a single ST.Significance Conserved genes encoding PBPs in B. pseudomallei are useful for strain typing, can enhance predictions of geographic origin, and differentiate strains of closely related Burkholderia species.Author Summary Burkholderia pseudomallei causes the life-threatening disease melioidosis and is considered a biological threat and select agent by the United States government. This soil-dwelling bacterium is commonly found in regions of southeast Asia and northern Australia, but it is also detected in other tropical and sub-tropical areas around the world. With a predicted global burden of 165,000 annual cases and mortality rate that can exceed 40% without prompt and appropriate antibiotic treatment, understanding the epidemiology of melioidosis and mechanisms of antibiotic resistance in B. pseudomallei can benefit public health and safety. Recently, we identified ten conserved genes encoding putative penicillin binding proteins (PBPs) in B. pseudomallei. Here, we examined B. pseudomallei PBP sequences for amino acid mutations that may contribute to β-lactam resistance. We also uncovered nucleotide mutations with utility to predict the geographical origin of B. pseudomallei strains and to differentiate closely related Burkholderia species. Based on 11 informative single nucleotide polymorphisms in two genes each encoding a PBP-3, we developed a simple, targeted dual-locus typing approach.Competing Interest StatementThe authors have declared no competing interest. |
Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project (preprint)
Wilcox E , Harrison SM , Lockhart E , Voelkerding K , Lubin IM , Rehm HL , Kalman L , Funke B . medRxiv 2021 2021.06.09.21258594 Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.Competing Interest StatementThe authors have declared no competing interest.Funding StatementClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: U41HG006834, U41HG009649, U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the following three grants: U24HD093483, U24HD093486, U24HD093487.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study did not involve human subjects and therefore no IRB was required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is included in the figures, tables and supplement included in the manuscript. |
Improving reporting standards for polygenic scores in risk prediction studies (preprint)
Wand H , Lambert SA , Tamburro C , Iacocca MA , O'Sullivan JW , Sillari C , Kullo IJ , Rowley R , Dron JS , Brockman D , Venner E , McCarthy MI , Antoniou AC , Easton DF , Hegele RA , Khera AV , Chatterjee N , Kooperberg C , Edwards K , Vlessis K , Kinnear K , Danesh JN , Parkinson H , Ramos EM , Roberts MC , Ormond KE , Khoury MJ , Janssens Acjw , Goddard KAB , Kraft P , MacArthur JAL , Inouye M , Wojcik GL . medRxiv 2020 2020.04.23.20077099 Polygenic risk scores (PRS), often aggregating the results from genome-wide association studies, can bridge the gap between the initial discovery efforts and clinical applications for disease risk estimation. However, there is remarkable heterogeneity in the reporting of these risk scores. This lack of adherence to reporting standards hinders the translation of PRS into clinical care. The ClinGen Complex Disease Working Group, in a collaboration with the Polygenic Score (PGS) Catalog, have updated the Genetic Risk Prediction (GRIPS) Reporting Statement to the current state of the field and to enable downstream utility. Drawing upon experts in epidemiology, statistics, disease-specific applications, implementation, and policy, this 22-item reporting framework defines the minimal information needed to interpret and evaluate a PRS, especially with respect to any downstream clinical applications. Items span detailed descriptions of the study population (recruitment method, key demographic and clinical characteristics, inclusion/exclusion criteria, and outcome definition), statistical methods for both PRS development and validation, and considerations for potential limitations of the published risk score and downstream clinical utility. Additionally, emphasis has been placed on data availability and transparency to facilitate reproducibility and benchmarking against other PRS, such as deposition in the publicly available PGS Catalog. By providing these criteria in a structured format that builds upon existing standards and ontologies, the use of this framework in publishing PRS will facilitate translation of PRS into clinical care and progress towards defining best practices.Summary In recent years, polygenic risk scores (PRS) have increasingly been used to capture the genome-wide liability underlying many human traits and diseases, hoping to better inform an individual’s genetic risk. However, a lack of adherence to existing reporting standards has hindered the translation of this important tool into clinical and public health practice; in particular, details necessary for benchmarking and reproducibility are underreported. To address this gap, the ClinGen Complex Disease Working Group and Polygenic Score (PGS) Catalog have updated the Genetic Risk Prediction (GRIPS) Reporting Statement into the 22-item Polygenic Risk Score Reporting Statement (PRS-RS). This framework provides the minimal information expected of authors to promote the validity, transparency, and reproducibility of PRS by encouraging authors to detail the study population, statistical methods, and potential clinical utility of a published score. The widespread adoption of this framework will encourage rigorous methodological consideration and facilitate benchmarking to ensure high quality scores are translated into the clinic.Competing Interest StatementMIM is on the advisory panels Pfizer, Novo Nordisk, and Zoe Global; Honoraria: Merck, Pfizer, Novo Nordisk, and Eli Lilly; Research funding: Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. As of June 2019, he is an employee of Genentech with stock and stock options in Roche. No other authors have competing interests to declare.Funding StatementClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: U41HG006834, U41HG009649, U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the following three grants: U24HD093483, U24HD093486, U24HD093487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additionally, the views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number U41HG007823 (EBI-NHGRI GWAS Catalog, PGS Catalog). In addition, we acknowledge funding from the European Molecular Biology Laboratory. Individuals were funded from the following sources: MIM was a Wellcome Investigator and an NIHR Senior Investigator with funding from NIDDK (U01-DK105535); Wellcome (090532, 098381, 106130, 203141, 212259). MI, SAL, and JD were supported by core funding from: the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). SAL is supported by a Canadian Institutes of Health Research postdoctoral fellowship (MFE-171279). JD holds a British Heart Foundation Personal Chair and a National Institute for Health Research Senior Investigator Award. This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesN/A |
Comparative neurotranscriptomics reveal widespread species differences associated with bonding (preprint)
Tripp JA , Berrio A , McGraw LA , Matz MV , Davis JK , Inoue K , Thomas JW , Young LJ , Phelps SM . bioRxiv 2020 2020.12.07.415463 Background Pair bonding with a reproductive partner is rare among mammals but is an important feature of human social behavior. Decades of research on monogamous prairie voles (Microtus ochrogaster), along with comparative studies using the related non-bonding meadow vole (M. pennsylvanicus), have revealed many of the neural and molecular mechanisms necessary for pair-bond formation in that species. However, these studies have largely focused on just a few neuromodulatory systems. To test the hypothesis that neural gene expression differences underlie differential capacities to bond, we performed RNA-sequencing on tissue from three brain regions important for bonding and other social behaviors across bond-forming prairie voles and non-bonding meadow voles. We examined gene expression in the amygdala, hypothalamus, and combined ventral pallidum/nucleus accumbens in virgins and at three time points after mating to understand species differences in gene expression at baseline, in response to mating, and during bond formation.Results We first identified species and brain region as the factors most strongly associated with gene expression in our samples. Next, we found gene categories related to cell structure, translation and metabolism that differed in expression across species in virgins, as well as categories associated with cell structure, synaptic and neuroendocrine signaling, and transcription and translation that varied among the focal regions in our study. Additionally, we identified genes that were differentially expressed across species after mating in each of our regions of interest. These include genes involved in regulating transcription, neuron structure, and synaptic plasticity. Finally, we identified modules of co-regulated genes that were strongly correlated with brain region in both species, and modules that were correlated with post-mating time points in prairie voles but not meadow voles.Conclusions These results reinforce the importance of pre-mating differences that confer the ability to form pair bonds in prairie voles but not promiscuous species such as meadow voles. Gene ontology analysis supports the hypothesis that pair-bond formation involves transcriptional regulation, and changes in neuronal structure. Together, our results expand knowledge of the genes involved in the pair bonding process and open new avenues of research in the molecular mechanisms of bond formation.Competing Interest StatementThe authors have declared no competing interest.AMYAmygdalaAVPArginine-vasopressinFDRFalse discovery rateHTHypothalamusLFCLog (base 2) fold changeMEModule eigengeneMWUMann-Whitney U testOTOxytocinVP/NAcVentral pallidum/nucleus accumbens |
COPLA, a taxonomic classifier of plasmids (preprint)
Redondo-Salvo S , Bartomeus-Peñalver R , Vielva L , Tagg KA , Webb HE , Fernández-López R , de la Cruz F . bioRxiv 2020 2020.12.15.422809 The Plasmid Taxonomic Unit (PTU) concept is an initial step for a natural classification of plasmids. Here we present COPLA, a software for plasmid assignation to existing PTUs. To assess its performance, we used a sample of 1,000 plasmids missing from its current database. Overall, 41% of samples could be assigned an existing PTU (63% within the most abundant order, Enterobacterales), while 4% of samples could help to define new PTUs once COPLA database was updated.Competing Interest StatementThe authors have declared no competing interest. |
Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris (preprint)
Muñoz JF , Welsh RM , Shea T , Batra D , Gade L , Litvintseva AP , Cuomo CA . bioRxiv 2019 754143 Candida auris is an emerging fungal pathogen of rising concern due to its increasing incidence, its ability to cause healthcare-associated outbreaks and antifungal resistance. Genomic analysis revealed that early cases of C. auris that were detected contemporaneously were geographically stratified into four major clades. Clade II, also termed East Asian clade, consists of the initial isolates described from cases of ear infection, is less frequently resistant to antifungal drugs and to date, the isolates from this group have not been associated with outbreaks. Here, we generate nearly complete genomes (“telomere-to-telomere”) of an isolate of this clade and of the more widespread Clade IV. By comparing these to genome assemblies of the other two clades, we find that the Clade II genome appears highly rearranged, with 2 inversions and 9 translocations resulting in a substantially different karyotype. In addition, large subtelomeric regions have been lost from 10 of 14 chromosome ends in the Clade II genomes. We find that shorter telomeres and genome instability might be a consequence of a naturally occurring loss-of-function mutation in DCC1 exclusively found in Clade II isolates, resulting in a hypermutator phenotype. We also determine that deleted subtelomeric regions might be linked to clade-specific adaptation as these regions are enriched in Hyr/Iff-like cell surface proteins, novel candidate cell surface proteins, and an ALS-like adhesin. The presence of these cell surface proteins in the clades responsible for global outbreaks causing invasive infections suggests an explanation for the different phenotypes observed between clades.IMPORTANCE Candida auris was unknown prior to 2009 and since then it has quickly spread around the world, causing outbreaks in healthcare facilities and representing a high fraction of candidemia cases in some regions. The emergence of C. auris is a major concern, since it is often multidrug-resistant, easily spread between patients, and causes invasive infections. While isolates from three global clades cause invasive infections, isolates from Clade II primarily cause ear infections and have not been implicated in outbreaks, though cases of Clade II infections have been reported on different continents. Here, we describe genetic differences between Clade II and Clades I, III and IV, including a loss-of-function mutation in a gene associated with telomere length maintenance and genome stability, and the loss of cell wall proteins involved in adhesion and biofilm formation, that may suggest an explanation for the lower virulence and potential for transmission of Clade II isolates. |
Health and economic outcomes of newborn screening for infantile-onset Pompe disease (preprint)
Richardson JS , Kemper AR , Grosse SD , Lam WKK , Rose AM , Ahmad A , Gebremariam A , Prosser LA . medRxiv 2020 2020.04.28.20080606 Purpose To estimate health and economic outcomes associated with NBS for infantile-onset Pompe disease in the United States.Methods A decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared to clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course.Results Universal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared to clinical detection. The ICER was $408,000/QALY from the health care perspective and $379,000/QALY from a societal perspective. Results were sensitive to the cost of enzyme replacement therapy.Conclusions Newborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFinancial support for this study was provided by a grant from the Agency for Health Care Research and Quality, R01 HS020644. The funding agreement ensured the authors independence in designing the study, interpreting the data, writing, and publishing the report.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Not regulatedAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe manuscript and supplementary materials are designed to provide sufficient information for an interested reader to replicate the analysis. The statistical code is available by request from Dr. Prosser lisapros{at}umich.edu. |
Cost-effectiveness of Dengue Vaccination in Puerto Rico (preprint)
España G , Leidner AJ , Waterman SH , Perkins TA . medRxiv 2020 2020.10.07.20208512 An effective and widely used vaccine could reduce the burden of dengue virus (DENV) around the world. DENV is endemic in Puerto Rico, where the dengue vaccine CYD-TDV is currently under consideration as a control measure. CYD-TDV has demonstrated efficacy in clinical trials in vaccinees who had prior dengue infection. However, in vaccinees who had no prior dengue infection, the vaccine had a modestly elevated risk of hospitalization and severe disease. The WHO therefore recommended a strategy of pre-vaccination screening and vaccination of seropositive persons. To estimate the cost-effectiveness and benefits of this intervention (i.e., screening and vaccination of seropositive persons) in Puerto Rico, we simulated 10 years of the intervention in 9-year-olds using an agent-based model. Across the entire population, we found that 5.5% (4.6%-6.3%) of dengue hospitalizations could be averted. However, we also found that 1.6 (1.3 - 2.1) additional hospitalizations could occur for every 1,000 DENV-naïve children who were vaccinated following a false-positive test results for prior exposure. The ratio of the averted hospitalizations among all vaccinees to additional hospitalizations among DENV-naïve vaccinees was estimated to be 19 (13-24). At a base case cost of vaccination of 382 USD, we found an incremental cost-effectiveness ratio of 122,000 USD per QALY gained. Our estimates can provide information for considerations to introduce the CYD-TDV vaccine in Puerto Rico.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis publication was made possible with partial support from Grant Numbers TL1 TR002531 and UL1 TR002529 (A. Shekhar, PI) from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study does not require ethical guidelines as it's a simulation experimentAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data is publicly available |
Food insecurity and the risk of HIV acquisition: Findings from population-based surveys in six sub-Saharan African countries (2016-2017) (preprint)
Low A , Gummerson E , Schwitters A , Bonifacio R , Teferi M , Mutenda N , Ayton S , Juma J , Ahpoe C , Ginindza C , Patel H , Biraro S , Sachathep K , Hakim AJ , Barradas D , Hassani AS , Kirungi W , Jackson K , Goeke L , Philips N , Mulenga L , Ward J , Hong S , Rutherford G , Findley S . medRxiv 2021 2021.09.27.21263917 Introduction Food insecurity has a bidirectional relationship with HIV infection, with hunger driving compensatory risk behaviors, while infection can increase poverty. We used a laboratory recency assay to estimate the timing of HIV infection vis-à-vis the timing of severe food insecurity (SFI).Methods Data from population-based surveys in Zambia, Eswatini, Lesotho, Uganda, and Tanzania and Namibia were used. We defined SFI as having no food ≥three times in the past month. Recent HIV infection was identified using the HIV-1 LAg avidity assay, with a viral load (>1000 copies/ml) and no detectable antiretrovirals indicating an infection in the past 6 months. Logistic regression was conducted to assess correlates of SFI. Poisson regression was conducted on pooled data, adjusted by country to determine the association of SFI with recent HIV infection and risk behaviors, with effect heterogeneity evaluated for each country. All analyses were done using weighted data.Results Of 112,955 participants aged 15-59, 10.3% lived in households reporting SFI. SFI was most common in urban, woman-headed households. Among women and not men, SFI was associated with a two-fold increase in risk of recent HIV infection (adjusted relative risk [aRR] 2.08, 95% CI 1.09-3.97), with lower risk in high prevalence countries (Eswatini and Lesotho). SFI was associated with transactional sex (aRR 1.28, 95% CI 1.17-1.41), a history of forced sex (aRR 1.36, 95% CI 1.11-1.66), and condom-less sex with a partner of unknown or positive HIV status (aRR 1.08, 95% CI 1.02-1.14) in all women, and intergenerational sex (partner ≥10 years older) in women aged 15-24 (aRR 1.23, 95% CI 1.03-1.46), although this was heterogeneous. Recent receipt of food support was protective (aRR 0.36, 95% CI 0.14-0.88).Conclusion SFI increased risk for HIV acquisition in women by two-fold. Worsening food scarcity due to climactic extremes could imperil HIV epidemic control.What is already knownThe link between food insecurity and the adoption of high-risk sexual behaviors as a coping mechanism has been shown in several settings.HIV infection can also drive food insecurity due to debilitating illness reducing productivity, the costs of treatment diverting money from supplies, and potentially reduced labor migration.Food insecurity has been associated with chronic HIV infection, but it has not been linked with HIV acquisition.What are the new findingsThis study of 112,955 adults across six countries in sub-Saharan Africa provides unique information on the association between acute food insecurity and recent HIV infection in women, as well as the potential behavioral and biological mediators, including community viremia as a measure of infectiousness.The data enabled a comprehensive analysis of factors associated with risk of infection, and how these factors differed by country and gender. Women living in food insecure households had a two-fold higher risk of recent HIV acquisition, and reported higher rates of transactional sex, early sexual debut, forced sex, intergenerational sex and sex without a condom with someone of unknown or positive HIV status. This pattern was not seen in men.This study is also the first to demonstrate a protective association for food support, which was associated with a lower risk of recent HIV infection in women.What do the new findings implyIn light of worsening food insecurity due to climate change and the recent COVID-19 pandemic, our results support further exploration of gender-specific pathways of response to acute food insecurity, particularly how women’s changes in sexual behavior heighten their risk of HIV acquisition.These and other data support the inclusion of food insecurity in HIV risk assessments for women, as well as the exploration of provision of food support to those households at highest risk based on geographic and individual factors.Competing Interest StatementThe authors have declared no competing interest.Clinical Protocols https://phia.icap.columbia.edu/ Funding StatementThis project has been supported by the Presid nt Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of cooperative agreement #U2GGH001226.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The PHIA protocol and data collection tools were approved by national ethics committees for each country, and the institutional review boards at Columbia University Irving Medical Center, the US Centers for Disease Control and Prevention (CDC) and the University of California, San Francisco in the case of Namibia. Due to the inclusion of six countries and the multiple ethical boards involved, we are providing the protocol numbers for the Columbia University Irving Medical Center, which approved all protocols (AAAQ0753, AAAQ7860, AAAQ8408, AAAQ8537, AAAR2051, AAAQ889). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data used in this manuscript are publicly available at https://phia-data.icap.columbia.edu/. https://phia-data.icap.columbia.edu/ |
The Role of Interspecies recombinations in the evolution of antibiotic-resistant pneumococci (preprint)
D'Aeth JC , van der Linden MPG , McGee L , De Lencastre H , Turner P , Song JH , Lo SW , Gladstone RA , Sa-Leao R , Ko KS , Hanage WP , Beall B , Bentley SD , Croucher NJ . bioRxiv 2021 2021.02.22.432219 The evolutionary histories of the antibiotic-resistant Streptococcus pneumoniae lineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1 into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout the S. pneumoniae chromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.Competing Interest StatementNJC has consulted for Antigen Discovery Inc. NJC has received an investigator-initiated award from GlaxoSmithKline. |
Impact of the COVID-19 Pandemic on Antimicrobial Resistance (AMR) Surveillance, Prevention and Control: A Global Survey (preprint)
Tomczyk S , Taylor A , Brown A , de Kraker MEA , Eckmanns T , Alshamrani M , Hendriksen RS , Jacob M , Löfmark S , Perovic O , Shetty N , Sievert D , Smith R , Stelling J , Thakur S , Vietor AC , Eremin S . medRxiv 2021 2021.03.24.21253807 Objectives The COVID-19 pandemic has had a substantial impact on health systems. The WHO Antimicrobial Resistance (AMR) Collaborating Centres Network conducted a survey to assess the effects of COVID-19 on AMR surveillance, prevention and control.Methods From October-December 2020, WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) national focal points completed a questionnaire including Likert-scales and open-ended questions. Data were descriptively analysed, income/regional differences were assessed, and free-text questions were thematically analysed.Results Seventy-three countries across income levels participated. During the COVID-19 pandemic, 67% reported limited ability to work with AMR partnerships; decreases in funding were frequently reported by low- and middle-income countries (LMICs; p<0.01). Reduced availability of nursing, medical and public health staff for AMR was reported by 71%, 69% and 64%, respectively, whereas 67% reported stable cleaning staff availability. The majority (58%) reported reduced reagents/consumables, particularly LMICs (p<0.01). Decreased numbers of cultures, elective procedures, chronically ill admissions and outpatients and increased intensive care unit admissions reported could bias AMR data. Reported overall infection prevention and control (IPC) improvement could decrease AMR rates, whereas increases in selected inappropriate IPC practices and antibiotic prescribing could increase rates. Most did not yet have complete data on changing AMR rates due to COVID-19.Conclusions This was the first survey to explore the global impact of COVID-19 on AMR among GLASS countries. Responses revealed universal patterns but also captured country variability. Although focus is understandably on COVID-19, gains in detecting and controlling AMR, a global health priority, cannot afford to be lost.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by a working group belonging to the WHO AMR Surveillance and Quality Assessment Collaborating Centres Network. It was led by the coordinator of the Network at the Robert Koch Institute in Berlin, Germany, who received funding from the Global Protection Programme (GHPP) at the German Federal Ministry of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The anonymous survey was conducted as part of routine public health work by the WHO Antimicrobial Resistance (AMR) Surveillance and Quality Assessment Collaborating Centres Network. No human subjects, samples or data were involved for this research purpose. As per the policy in Germany, the survey protocol was reviewed and waived by the data protection institutional review board of the Network coordinator at Robert Koch Institute, Berlin, Germany.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe aggregated data is avaiable on a case-by-case basis upon consultation with the WHO AMR Surveillance and Quality Assessment Collaborating Centres Network coordinator (Robert Koch Institute, Berlin, Germany) |
Expected Rates of Select Adverse Events following Immunization for COVID-19 Vaccine Safety Monitoring (preprint)
Abara WE , Gee J , Delorey M , Ye T , Mu Y , Shay DK , Shimabukuro T . medRxiv 2021 2021.08.31.21262919 Background Knowledge of expected rates of potential adverse events of special interest (AESI) that may occur coincidentally following COVID-19 vaccination is essential for vaccine safety surveillance and assessment. We calculated the expected rates of 21 potential AESI following COVID-19 vaccination among vaccinated persons within 1 day, 7 days, and 42 days of vaccination.Methods We used meta-analytic methods to estimate background rates of 21 medical conditions considered potential AESI and calculated expected rates of each potential AESI within 1 day, 7 days, and 42 days of vaccination.Results Background rates of three commonly monitored AESI, Guillain-Barre syndrome (GBS), myopericarditis, and all-cause deaths were 2.0 GBS cases/100,000 person-years, 1.3 myopericarditis cases/100,000 person-years, and 863.8 all-cause deaths/100,000 person-years, respectively. Based on these background rates, if 10,000,000 persons are vaccinated, we would expect 0.5, 3.7, and 22.5 GBS cases; 0.3, 2.4, and 14.3 myopericarditis cases; and 236.5, 1655.5, and 9932.8 all-cause deaths to occur in coincident temporal association (i.e., as a result of background incidence) within 1 day, 7 days, and 42 days of vaccination, respectively.Conclusion Knowledge of expected rates of potential AESI can help contextualize adverse health events associated temporally with immunization, aid in safety signal detection, guide COVID-19 vaccine public health communication, and inform benefit-risk assessments of COVID-19 vaccines.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThere are no funding sources for this study.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This analysis was exempt from CDC Institutional Review Board review.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesWe conducted a meta-analysis using incidence rate data from eligible published studies cited in this paper. |
Imprinted anti-hemagglutinin and anti-neuraminidase antibody responses after childhood infections of A(H1N1) and A(H1N1)pdm09 influenza viruses (preprint)
Daulagala P , Mann BR , Leung K , Lau EHY , Yung L , Lei R , Nizami SIN , Wu JT , Chiu SS , Daniels RS , Wu NC , Wentworth D , Peiris M , Yen HL . bioRxiv 2023 2023.02.01.526741 Immune imprinting is a driver known to shape the anti-hemagglutinin (HA) antibody landscape of individuals born within the same birth cohort. With the HA and neuraminidase (NA) proteins evolving at different rates under immune selection pressures, anti-HA and anti-NA antibody responses since childhood influenza infections have not been evaluated in parallel at the individual level. This is partly due to the limited knowledge of changes in NA antigenicity, as seasonal influenza vaccines have focused on generating neutralising anti-HA antibodies against HA antigenic variants. Here we systematically characterised the NA antigenic variants of seasonal A(H1N1) viruses from 1977 to 1991 and completed the antigenic profile of N1 NAs from 1977 to 2015. We identified that NA proteins of A/USSR/90/77, A/Singapore/06/86, and A/Texas/36/91 were antigenically distinct and mapped N386K as a key determinant of the NA antigenic change from A/USSR/90/77 to A/Singapore/06/86. With comprehensive panels of HA and NA antigenic variants of A(H1N1) and A(H1N1)pdm09 viruses, we determined hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) antibodies from 130 subjects born between 1950-2015. Age-dependent imprinting was observed for both anti-HA and anti-NA antibodies, with the peak HI and NI titers predominantly detected from subjects at 4-12 years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations.IMPORTANCE Seasonal influenza vaccines have aimed to generate neutralizing anti-HA antibodies for protection since licensure. More recently, anti-NA antibodies have been established as an additional correlate of protection. While HA and NA antigenic changes occurred discordantly, the anti-HA and anti-NA antibody profiles have rarely been analysed in parallel at the individual level, due to the limited knowledge on NA antigenic changes. By characterizing NA antigenic changes of A(H1N1) viruses, we determined the anti-HA and anti-NA antibody landscape against antigenically distinct A(H1N1) and A(H1N1)pdm09 viruses using sera of 130 subjects born between 1950-2015. We observed age-dependent imprinting of both anti-HA and anti-NA antibodies against strains circulated during the first decade of life. 67.7% (88/130) and 90% (117/130) of participants developed cross-reactive antibodies to multiple HA and NA antigens at titers ≥1:40. With slower NA antigenic changes and cross-reactive anti-NA antibody responses, including NA protein in influenza vaccine preparation may enhance vaccine efficacy. (150 words) |
A randomized controlled trial of antibody response to 2019-20 cell-based inactivated and egg-based live attenuated influenza vaccines in children and young adults (preprint)
Williams KV , Zhai B , Alcorn JF , Patricia Nowalk M , Levine MZ , Kim SS , Flannery B , Moehling Geffel K , Jaber Merranko A , Nagg JP , Collins M , Susick M , Clarke KS , Zimmerman RK , Martin JM . medRxiv 2021 2021.09.02.21263043 Background Hemagglutination inhibition (HAI) titers to the live-attenuated influenza vaccine (LAIV4) are typically lower than its counterpart egg-based inactivated influenza vaccines (IIV). Similar comparisons have not been made between LAIV4 and the 4-strain, cell-culture inactivated influenza vaccine (ccIIV4). We compared healthy children and young adult HAI titers against the 2019-2020 LAIV4 and ccIIV4.Methods Participants aged 4-21 years were randomized 1:1 to receive ccIIV4 (n =100) or LAIV4 (n=98). Blood was drawn prevaccination and on day 28 (21-35) post vaccination. HAI assays against egg-grown A/H1N1, A/H3N2, both vaccine B strains and cell-grown A/H3N2 antigens were conducted. Outcomes were geometric mean titers (GMT) and geometric mean fold rise (GMFR) in titers.Results GMTs to A/H1N1, A/H3N2 and B/Victoria increased following both ccIIV and LAIV and to B/Yamagata following ccIIV (p<0.05). The GMFR range was 2.4-3.0 times higher for ccIIV4 than for LAIV4 (p<0.001). Within vaccine types, egg-grown A/H3N2 GMTs were higher (p<0.05) than cell-grown GMTs [ccIIV4 day 28: egg=205 (95% CI: 178-237); cell=136 (95% CI:113-165); LAIV4 day 28: egg=96 (95% CI: 83-112); cell=63 (95% CI: 58-74)]. The GMFR to A/H3N2 cell-grown and egg-grown antigens were similar. Pre-vaccination titers inversely predicted GMFR.Conclusion The HAI response to ccIIV4 was greater than LAIV4 in this study of mostly older children, and day 0 HAI titers inversely predicted GMFR for both vaccines. For both vaccines, the A/H3N2 cell-grown antigen levels were lower than egg-grown, but the GMFR for cell-grown and egg-grown did not differ significantly within vaccine type.Clinical Trials No NCT03982069Competing Interest StatementConflict of Interest: RKZ has received funding by Sanofi for an unrelated study. MPN has research funding from Merck & Co., Inc. for an unrelated study. JMM has received funding from Merck, Sharp and Dohme for an unrelated study.Clinical TrialClinical Trials No.: NCT03982069Funding StatementThis work was supported by the Centers for Disease Control and Prevention (CDC) [5U01IP001035] and by National Institutes of Health (NIH) [UL1TR001857], [KL2 TR001856], and/or [TL1 TR001858]. This work represents the views of the authors and not the CDC or NIH. Pennsylvania Statewide Immunization Information System (PA-SIIS) vaccine registry was used to verify vaccination status. These data were supplied in part by the Bureau of Health Statistics & Registries, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. REDCap and the Department of Biomedical Informatics grant support (Clinical and Translational Sciences Institute at the University of Pittsburgh Grant Number UL1-TR-001857). Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Institutional Review Boards at the University of Pittsburgh and the Centers for Disease Control and Prevention (CDC) approved this study. Written informed consent and assent, where appropriate, were obtained from all participants and/or their parents/legal guardians prior to beginning study procedures.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field expla ning why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData can be made available upon request.HAIhemagglutination inhibition assayIIVinactivated influenza vaccineccIIV4cell-culture-based inactivated influenza vaccine quadrivalentLAIV4Egg-based live attenuated influenza vaccine quadrivalentEMRElectronic medical recordRDEReceptor-destroying enzymePBSPhosphate-buffered salineCDCCenters for Disease Control and PreventionFDAFood and Drug AdministrationGMTGeometric mean titersGMFRGeometric mean fold riseACIPAdvisory Committee on Immunization PracticePA-SIISPennsylvania Statewide Immunization Information System |
Safety Monitoring of mRNA Vaccines Administered During the Initial 6 Months of the U.S. COVID-19 Vaccination Program: Reports to Vaccine Adverse Events Reporting System (VAERS) and v-safe (preprint)
Rosenblum HG , Gee J , Liu R , Marquez PL , Zhang B , Strid P , Abara WE , McNeil MM , Myers TR , Hause AM , Su JR , Baer B , Menschik D , Markowitz LE , Shimabukuro TT , Shay DK . medRxiv 2021 2021.10.26.21265261 Background In December 2020, two mRNA-based COVID-19 vaccines were authorized for use in the United States. Vaccine safety was monitored using the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and v-safe, an active surveillance system.Methods VAERS and v-safe data during December 14, 2020—June 14, 2021 were analyzed. VAERS reports were categorized as non-serious, serious, or death; reporting rates were calculated. Rates of reported deaths were compared to expected mortality rates by age. Proportions of v-safe participants reporting local and systemic reactions or health impacts the week following doses 1 and 2 were determined.Findings During the analytic period, 298,792,852 doses of mRNA vaccines were administered in the United States. VAERS processed 340,522 reports; 92·1% were non-serious; 6·6%, serious, non-death; and 1·3%, death. Over half of 7,914,583 v-safe participants self-reported local and systemic reactogenicity, more frequently after dose 2. Injection-site pain, fatigue, and headache were commonly reported during days 0–7 following vaccination. Reactogenicity was reported most frequently one day after vaccination; most reactions were mild. More reports of being unable to work or do normal activities occurred after dose 2 (32·1%) than dose 1 (11·9%); <1% of participants reported seeking medical care after vaccination. Rates of deaths reported to VAERS were lower than expected background rates by age group.Interpretation Safety data from >298 million doses of mRNA COVID-19 vaccine administered in the first 6 months of the U.S. vaccination program show the majority of reported adverse events were mild and short in duration.Competing Interest StatementDisclosures: Ruiling Liu- Stock or stock options, Johnson &Johnson50 shares of stocks Moderna20 shares of stocks & Spouse works for Ethicon|Johnson & Johnson, on surgery robotics Funding StatementThis study did not receive any funding.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Both VAERS and v-safe conduct surveillance as a public health function and are exempt from institutional review board review. This analysis was reviewed by the CDC and conducted in accordance with applicable federal law and CDC policy (See: 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C. 552a; 44 U.S.C. 3501 et seq.). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData produced in the present study are available upon reasonable request to the authors |
Surveillance of COVID-19 vaccination in US nursing homes, December 2020-April 2021 (preprint)
Geller AI , Budnitz DS , Dubendris H , Gharpure R , Soe M , Wu H , Kalayil EJ , Benin AL , Patel SA , Lindley MC , Link-Gelles R . medRxiv 2021 2021.05.14.21257224 Monitoring COVID-19 vaccination coverage among nursing home (NH) residents and staff is important to ensure high coverage and guide patient-safety policies. With the termination of the federal Pharmacy Partnership for Long-Term Care Program, another source of facility-based vaccination data is needed. We compared numbers of COVID-19 vaccinations administered to NH residents and staff reported by pharmacies participating in the temporary federal Pharmacy Partnership for Long-Term Care Program with those reported by NHs participating in new COVID-19 vaccination modules of CDC’s National Healthcare Safety Network (NHSN). Pearson correlation coefficients comparing the number vaccinated between the two approaches were 0.89, 0.96, and 0.97 for residents and 0.74, 0.90, and 0.90 for staff, in the weeks ending January 3, 10, and 17, respectively. Based on subsequent NHSN reporting, vaccination coverage with ≥1 vaccine dose reached 77% for residents and 50% for staff the week ending January 31 and plateaued through April 2021.Three-question summary boxWhat is the current understanding of the subject?Because of high risk of disease, nursing home residents and staff were prioritized for COVID-19 vaccination when doses were limited.What does this report add to the literature?National monitoring of nursing home residents and staff vaccination coverage through the CDC National Healthcare Safety Network (NHSN) correlated with vaccination administration reports from the federal Pharmacy Partnership for Long-Term Care Program in January 2021. NHSN-reported vaccination coverage rates plateaued from February through April 2021.What are the implications for public health practice?NHSN can track COVID-19 vaccination in nursing homes and help guide efforts to increase vaccine uptake in residents and staff.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe authors received no financial support for the research, authorship, and/or publication of this article.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (See e.g., 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. section 241(d); 5 U.S.C. section 552a; 44 U.S.C. section 3501 et seq.).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData supporting the findings of the study are found in the manuscript and/or supplementary files. Any other data can be furnished upon request. |
Theoretical framework for retrospective studies of the effectiveness of SARS-CoV-2 vaccines (preprint)
Lewnard JA , Patel MM , Jewell NP , Verani JR , Kobayashi M , Tenforde MW , Dean NE , Cowling BJ , Lopman BA . medRxiv 2021 2021.01.21.21250258 Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. These are now in planning amid the ongoing rollout of SARS-CoV-2 vaccines globally. While traditional case-control (TCC) and test-negative design (TND) studies feature prominently among strategies used to assess vaccine effectiveness, such studies may encounter important threats to validity. Here we review the theoretical basis for estimation of vaccine direct effects under TCC and TND frameworks, addressing specific natural history parameters of SARS-CoV-2 infection and COVID-19 relevant to these designs. Bias may be introduced by misclassification of cases and controls, particularly when clinical case criteria include common, non-specific indicators of COVID-19. When using diagnostic assays with high analytical sensitivity for SARS-CoV-2 detection, individuals testing positive may be counted as cases even if their symptoms are due to other causes. The TCC may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The TND reduces but may not eliminate this confounding, for instance if individuals who receive vaccination seek care or testing for less-severe infection. These circumstances indicate the two study designs cannot be applied naively to datasets gathered through public health surveillance or administrative sources. We suggest practical strategies to reduce bias in vaccine effectiveness estimates at the study design and analysis stages.Competing Interest StatementJAL has received grants and consulting fees from Pfizer, Inc. unrelated to this research.Funding StatementThis work was supported by grants R01-AI14812701 from the National Institute for Allergy and Infectious Diseases to NPJ and JAL, and R01-AI139761 from the National Institute for Allergy and Infectious Diseases to NED.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThis is a theoretical study without patient data; equations used to generate the figures appear in the manuscript. |
mRNA Vaccine Effectiveness against COVID-19 among Symptomatic Outpatients Aged ≥16 Years in the United States, February – May 2021 (preprint)
Kim SS , Chung JR , Belongia EA , McLean HQ , King JP , Nowalk MP , Zimmerman RK , Balasubramani GK , Martin ET , Monto AS , Lamerato LE , Gaglani M , Smith ME , Dunnigan KM , Jackson ML , Jackson LA , Tenforde MW , Verani JR , Kobayashi M , Schrag S , Patel MM , Flannery B . medRxiv 2021 2021.07.20.21260647 Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.Competing Interest StatementMPN reports grants from Merck & Co. outside the submitted work. RKZ reports grants from Sanofi Pasteur outside the submitted work. GKB reports grants from Merck & Co outside the submitted work and consulting fees from New World Medical, LLC. ETM reports grants from Merck & Co. outside the submitted work and consulting fees from Pfizer. ASM reports consulting fees from Sanofi Pasteur and Seqirus. LEL reports grants from Xcenda, Inc., eMAXHealth, AstraZeneca, Pfizer, Evidera outside the submitted work. MLJ reports grants from Sanofi Pasteur. All other authors report nothing to disclose.Funding StatementThis work was supported by the US Centers for Disease Control and Prevention through cooperative agreements U01IP001034-U01IP001039. At Pittsburgh, the project was also supported by the National Institutes of Health through grant ULTR001857.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Centers for Disease Control and Prevention IRB project determination numbers for included projects: 0900f3eb81c2e791, 0900f3eb81c52dc5; 0900f3eb81c52420, 0900f3eb81bc746b, 6238All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDe-identified dataset can be made available upon request |
Neutralizing Antibody Response to Pseudotype SARS-CoV-2 Differs between mRNA-1273 and BNT162b2 COVID-19 Vaccines and by History of SARS-CoV-2 Infection (preprint)
Tyner HL , Burgess JL , Grant L , Gaglani M , Kuntz JL , Naleway AL , Thornburg NJ , Caban-Martinez AJ , Yoon SK , Herring MK , Beitel SC , Blanton L , Nikolich-Zugich J , Thiese MS , Pleasants JF , Fowlkes AL , Lutrick K , Dunnigan K , Yoo YM , Rose S , Groom H , Meece J , Wesley MG , Schaefer-Solle N , Louzado-Feliciano P , Edwards LJ , Olsho LEW , Thompson MG . medRxiv 2021 2021.10.20.21265171 Background Data on the development of neutralizing antibodies against SARS-CoV-2 after SARS-CoV-2 infection and after vaccination with messenger RNA (mRNA) COVID-19 vaccines are limited.Methods From a prospective cohort of 3,975 adult essential and frontline workers tested weekly from August, 2020 to March, 2021 for SARS-CoV-2 infection by Reverse Transcription- Polymerase Chain Reaction (RT-PCR) assay irrespective of symptoms, 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection population). Serum was collected after infection and each vaccine dose. Serum- neutralizing antibody titers against USA-WA1/2020-spike pseudotype virus were determined by the 50% inhibitory dilution. Geometric mean titers (GMTs) and corresponding fold increases were calculated using t-tests and linear mixed effects models.Results Among 170 unvaccinated participants with SARS-CoV-2 infection, 158 (93%) developed neutralizing antibodies (nAb) with a GMT of 1,003 (95% CI=766-1,315). Among 139 previously uninfected participants, 138 (99%) developed nAb after mRNA vaccine dose-2 with a GMT of 3,257 (95% CI = 2,596-4,052). GMT was higher among those receiving mRNA-1273 vaccine (GMT =4,698, 95%CI= 3,186-6,926) compared to BNT162b2 vaccine (GMT=2,309, 95%CI=1,825-2,919). Among 32 participants with prior SARS-CoV-2 infection, GMT was 21,655 (95%CI=14,766-31,756) after mRNA vaccine dose-1, without further increase after dose- 2.Conclusions A single dose of mRNA vaccine after SARS-CoV-2 infection resulted in the highest observed nAb response. Two doses of mRNA vaccine in previously uninfected participants resulted in higher nAb to SARS-CoV-2 than after one dose of vaccine or SARS- CoV-2 infection alone. Neutralizing antibody response also differed by mRNA vaccine product.Main Point Summary One dose of mRNA COVID-19 vaccine after previous SARS-CoV-2 infection produced the highest neutralizing antibody titers; among those without history of infection, two doses of mRNA vaccine produced the most robust response.Competing Interest StatementAllison Naleway receives research funding from Pfizer and Vir Biotechnology and Jennifer Kuntz receives research funding from Pfizer, Novartis, and Vir Biotechnology for unrelated studies. All other authors: No conflicts. Funding StatementThis work was supported by the Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases [contracts 75D30120R68013 to Marshfield Clinic Research Institute, 75D30120C08379 to the University of Arizona, and 75D30120C08150 to Abt Associates].Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study is governed by Centers for Disease Control and Prevention IRB review board and gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the pres nt work are contained in the manuscript |
Prevention and Attenuation of COVID-19 by BNT162b2 and mRNA-1273 Vaccines (preprint)
Thompson MG , Burgess JL , Naleway AL , Tyner H , Yoon SK , Meece J , Olsho LEW , Caban-Martinez AJ , Fowlkes AL , Lutrick K , Groom HC , Dunnigan K , Odean MJ , Hegmann K , Stefanski E , Edwards LJ , Schaefer-Solle N , Grant L , Ellingson K , Kuntz JL , Zunie T , Thiese MS , Ivacic L , Wesley MG , Mayo Lamberte J , Sun X , Smith ME , Phillips AL , Groover KD , Yoo YM , Gerald J , Brown RT , Herring MK , Joseph G , Beitel S , Morrill TC , Mak J , Rivers P , Poe BP , Lynch B , Zhou Y , Zhang J , Kelleher A , Li Y , Dickerson M , Hanson E , Guenther K , Tong S , Bateman A , Reisdorf E , Barnes J , Azziz-Baumgartner E , Hunt DR , Arvay ML , Kutty P , Fry AM , Gaglani M . medRxiv 2021 2021.06.01.21257987 BACKGROUND Information is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions.METHODS Prospective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14 2020—April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription–polymerase-chain-reaction (RT-PCR). VE was calculated as 100%×(1−hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation.RESULTS SARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially (≥14 days post-dose-1 to 13 days after dose-2) or fully (≥14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status (<14 days after dose-1) were excluded. Adjusted mRNA VE of full vaccination was 91% (95% confidence interval [CI]=76%–97%) against symptomatic or asymptomatic SARS-CoV-2 infection; VE of partial vaccination was 81% (95% CI=64%-90%). Among partially or fully vaccinated participants with SARS-CoV-2 infection, mean viral RNA load (Log10 copies/mL) was 40% lower (95% CI=16%-57%), the risk of self-reported febrile COVID-19 was 58% lower (Risk Ratio=0.42, 95% CI=0.18-0.98), and 2.3 fewer days (95% CI=0.8-3.7) were spent sick in bed compared to unvaccinated infected participants.CONCLUSIONS Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination.Competing Interest StatementAllison L. Naleway reported funding from Pfizer for a meningococcal B vaccine study unrelated to the submitted work. Kurt T. Hegmann serves at the Editor of the American College of Occupational and Environmental Medicine evidence-based practice guidelines. Matthew S. These reported grants and personal fees from Reed Group and the American College of Occupational and Environmental Medicine, outside the submitted work. Other authors have reported no conflicts of interest.Funding StatementFunding provided in whole or in part by federal funds from the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention under contract numbers 75D30120R68013 awarded to Marshfield Clinic Research Laboratory, 75D30120C08379 to University of Arizona, and 75D30120C08150 awarded to Abt Associates, Inc.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was reviewed and approved by the University of Arizona IRB as the single IRB for this studyAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesSummary data will be available once all study objectives are met. |
Effectiveness of COVID-19 Vaccines among Incarcerated People in California State Prisons: A Retrospective Cohort Study (preprint)
Chin ET , Leidner D , Zhang Y , Long E , Prince L , Schrag SJ , Verani JR , Wiegand RE , Alarid-Escudero F , Goldhaber-Fiebert JD , Studdert DM , Andrews JR , Salomon JA . medRxiv 2021 BACKGROUND: Prisons and jails are high-risk settings for COVID-19 transmission, morbidity, and mortality. COVID-19 vaccines may substantially reduce these risks, but evidence is needed of their effectiveness for incarcerated people, who are confined in large, risky congregate settings. METHODS: We conducted a retrospective cohort study to estimate effectiveness of mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), against confirmed SARS-CoV-2 infections among incarcerated people in California prisons from December 22, 2020 through March 1, 2021. The California Department of Corrections and Rehabilitation provided daily data for all prison residents including demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination status, and outcomes. We estimated vaccine effectiveness using multivariable Cox models with time-varying covariates that adjusted for resident characteristics and infection rates across prisons. FINDINGS: Among 60,707 residents in the cohort, 49% received at least one BNT162b2 or mRNA-1273 dose during the study period. Estimated vaccine effectiveness was 74% (95% confidence interval [CI], 64-82%) from day 14 after first dose until receipt of second dose and 97% (95% CI, 88-99%) from day 14 after second dose. Effectiveness was similar among the subset of residents who were medically vulnerable (74% [95% CI, 62-82%] and 92% [95% CI, 74-98%] from 14 days after first and second doses, respectively), as well as among the subset of residents who received the mRNA-1273 vaccine (71% [95% CI, 58-80%] and 96% [95% CI, 67-99%]). CONCLUSIONS: Consistent with results from randomized trials and observational studies in other populations, mRNA vaccines were highly effective in preventing SARS-CoV-2 infections among incarcerated people. Prioritizing incarcerated people for vaccination, redoubling efforts to boost vaccination and continuing other ongoing mitigation practices are essential in preventing COVID-19 in this disproportionately affected population. FUNDING: Horowitz Family Foundation, National Institute on Drug Abuse, Centers for Disease Control and Prevention, National Science Foundation, Open Society Foundation, Advanced Micro Devices. |
Effectiveness of Influenza Vaccines in the HIVE household cohort over 8 years: is there evidence of indirect protection? (preprint)
Malosh RE , Petrie JG , Callear A , Truscon R , Johnson E , Evans R , Bazzi L , Cheng C , Thompson MS , Martin ET , Monto AS . medRxiv 2021 2021.02.16.21251827 Background The evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (i.e. indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort.Methods Using longitudinal data from the HIVE cohort from 2010-11 through 2017-18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households.Results The pooled, direct VE against any influenza was 30.2% (14.0-43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8); and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (−6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccine coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VET was 56.4% (30.1-72.9) in low coverage, 43.2% (19.5-59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households.Conclusion Influenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. While there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the National Institute of Allergy and Infectious Disease (R03AI137658). The HIVE Study was further supported by the Centers for Disease Control and Prevention (U01 IP000170, U01 IP000474) and the National Institute of Allergy and Infectious Diseases (R01 AI097150, R56 AI097150).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The HIVE study is approved by the institutional review board at the University of Michigan Medical School.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data included in this analysis are available from the corresponding author on reasonable request. |
Estimating the number of symptomatic SARS-CoV-2 infections among vaccinated individuals in the United States—January–April, 2021 (preprint)
Kugeler KJ , Williamson J , Curns AT , Healy JM , Nolen LD , Clark TA , Martin SW , Fischer M . medRxiv 2021 2021.08.03.21261442 As of March 2021, three COVID-19 vaccines have been authorized by the U.S. Food and Drug Administration (FDA) for use in the United States. Each has substantial efficacy in preventing COVID-19. However, as efficacy from trials was <100% for all three vaccines, disease in vaccinated people is expected to occur. We created a spreadsheet-based tool to estimate the number of symptomatic vaccine breakthrough infections based on published vaccine efficacy (VE) data, percent of the population that has been fully vaccinated, and average number of COVID-19 cases reported per day. We estimate that approximately 51,000 symptomatic vaccine breakthrough infections (95% CI: ∼48,000–55,000 cases) occurred in the United States during January–April 2021 among >77 million fully vaccinated people, reflecting <0.5% of COVID-19 cases that occurred during that time. With ongoing SARS-CoV-2 transmission and increasing numbers of people vaccinated in the United States, vaccine breakthrough infections will continue to accumulate before population immunity is sufficient to interrupt transmission. Understanding expectations regarding number of vaccine breakthrough infections enables accurate public health messaging to help ensure that the occurrence of such cases does not negatively affect vaccine perceptions, confidence, and uptake.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was conducted consistent with applicable federal policy.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll input data are publicly available |
Identifying and alleviating bias due to differential depletion of susceptible people in post-marketing evaluations of COVID-19 vaccines (preprint)
Kahn R , Schrag SJ , Verani JR , Lipsitch M . medRxiv 2021 2021.07.15.21260595 Recent studies have provided key information about SARS-CoV-2 vaccines’ efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptibles between vaccinated and unvaccinated groups. Here we examine the extent to which biases occur under different scenarios and assess whether serologic testing has the potential to correct this bias. By identifying non-vaccine antibodies, these tests could identify individuals with prior infection. We find in scenarios with high baseline VE, differential depletion of susceptibles creates minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE is lower, the bias for leaky vaccines (that reduce individual probability of infection given contact) is larger and should be corrected by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serologic testing, on this critical variable.Competing Interest StatementDr. Lipsitch reports consulting/honoraria from Bristol Myers Squibb, Sanofi Pasteur, and Merck, as well as a grant through his institution, unrelated to COVID-19, from Pfizer. He has served as an unpaid advisor related to COVID-19 to Pfizer, One Day Sooner, Astra-Zeneca, Janssen, and COVAX (United Biomedical). Dr. Kahn discloses consulting fees from Partners In Health.Funding StatementThis work was supported by the U.S. National Cancer Institute Seronet cooperative agreement U01CA261277. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesCode is available on github. https://github.com/rek160/spurious-waning |
Impact of Diabetes Status on Immunogenicity of Trivalent Inactivated Influenza Vaccine in Older Adults (preprint)
Spencer S , Chung JR , Belongia EA , Sundaram M , Meece J , Coleman LA , Zimmerman RK , Nowalk MP , Moehling Geffel K , Ross T , Carter CE , Shay D , Levine M , Liepkalns J , Kim JH , Sambhara S , Thompson MG , Flannery B . medRxiv 2021 2021.10.04.21264429 Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among individuals with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.Competing Interest StatementKKM, MPN and RZ have received research funds from Merck & Co., Inc and Pfizer, Inc. KKM and RZ have received research funds from Sanofi Pasteur, Inc. LC is currently employed by Novartis. The remaining authors report no conflicts of interest.Funding StatementThis study was supported by cooperative agreements U01 IP000471 and U01 IP000467 from the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of those authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Boards at the University of Pittsburgh and Marshfield Clinic approved this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData are not publicly available at this time. |
Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: a matched cohort study (preprint)
Nakphook S , Patumanond J , Shrestha M , Prasert K , Chittaganpitch M , Mott JA , Praphasiri P . medRxiv 2021 2021.04.07.21255057 Background We compared influenza antibody titers among vaccinated and unvaccinated pregnant and non-pregnant women.Methods During 1st June – 30th September 2018, four groups of cohort participants - vaccinated pregnant, unvaccinated pregnant, vaccinated non-pregnant, and unvaccinated non-pregnant women were selected by matching age, gestational age, and the week of vaccination. Serum antibody titers against each strain of 2018 Southern Hemisphere inactivated trivalent influenza vaccine (IIV3) were assessed by hemagglutination inhibition (HI) assay on Day 0 (pre-vaccination) and Day 28 (one month post-vaccination) serum samples. Geometric mean titer (GMT), GMT ratio (GMR), seroconversion (defined as ≥4 fold increase in HI titer), and seroprotection (i.e. HI titer ≥1:40) were compared across the study groups using multilevel regression analyses, controlling for previous year vaccination from medical records and baseline antibody levels.Results A total of 132 participants were enrolled in the study (33 in each of the four study groups). The baseline GMTs were similar for influenza A(H1N1), A(H3N2), and B vaccine strains among all four groups (all p-values >0.05). After one month, both vaccinated groups had significantly higher GMT, GMR, seroconversion, and seroprotection than their unvaccinated controls (all p-values <0.05). The seroconversion rate was over 60% for any strain among the vaccinated groups, with the highest (88.8%) observed against A(H1N1) in the vaccinated pregnant group. Similarly, at least 75% of the vaccinated participants developed seroprotective antibody levels against all three strains; the highest seroprotection was found against A(H3N2) at 92.6% among vaccinated non-pregnant participants. Pregnant women had similar antibody responses (post-vaccination GMT, GMR, seroconversion, and seroprotection) to non-pregnant women for all three strains of IIV3 (all p>0.05).Conclusions The 2018 seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to IIV3. These findings support the current influenza vaccination recommendations for pregnant women.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialThai Clinical Trials Registry ID: TCTR20201014004Funding StatementThis study was partially supported by the Nakhon Phanom Provincial Hospital Foundation (ref no. NP 0032.202.3/7) secured by KP and SN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study protocol was reviewed and approved by the Ethical Review Committee of Thammasat University (Ref no. MTU-EC-ES-4-217/60). Approval of local ethics committee of Nakhon Phanom Hospital (No. NP-EC11-No.4/2560) was also received prior to the data collection.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are within the paper and the supporting files. |
Association of E484K and L452R spike protein mutations with SARS-CoV-2 infection in vaccinated persons---Maryland, January – May 2021 (preprint)
Feder KA , Patel A , Vepachedu VR , Dominguez C , Keller EN , Klein L , Kim C , Blood T , Hyun J , Williams TW , Feldman KA , Mostafa HH , Morris CP , Ravel J , Duwell M , Blythe D , Myers R . medRxiv 2021 2021.07.29.21261006 Background The E484K and L452R amino acid substitutions on the spike protein of SARS-CoV-2 are associated with reduced neutralization by antibodies from acquired immunity. This study examines the respective association of these mutations with infection in persons who had previously received a COVID-19 vaccine.Methods Genetic sequences from SARS-CoV-2 specimens collected from Maryland residents and reported to Maryland Department of Health were linked to vaccination history. The prevalence of infections in fully vaccinated persons -- defined as being at least two weeks past receiving the final scheduled dose of a COVID-19 vaccine series -- was compared between infections caused by viruses carrying E484K to those not carrying E484K, and between infections caused by viruses carrying L452R to those not carrying L452R, using logistic regression to adjust for confounding.Results Of 9,048 sequenced SARS-CoV-2 specimens examined, 265 (2.9%) were collected from fully vaccinated persons. In adjusted analysis, the E484K substitution was associated with an increase in the odds of the sequenced specimen being collected from a fully vaccinated person (OR 1.96, 95% CI, 1.36 to 2.83). The L452R mutation was not significantly associated with infections in vaccinated persons (OR 1.07, 95% CI, 0.69 to 1.68).Conclusion Though more than 97% of SARS-CoV-2 infections were in persons who were not fully vaccinated, the E484K mutation was associated with increased odds of SARS-CoV-2 infection in vaccinated persons. Linking vaccination and sequencing data can help identify and estimate the impact SARS-CoV-2 mutations may have on vaccine effectiveness.Summary In viruses sequenced for Maryland’s routine SARS-CoV-2 genomic surveillance, the spike protein amino acid substitution E484K was more prevalent in viruses that infected vaccinated people than in viruses that infected people who were not vaccinated.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding to report.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Case investigation, data collection, and analysis were conducted for public health purposes. This project was reviewed by the Division of Scientific Education and Professional Development within the Center for Surveillance, Epidemiology, and Laboratory Services at the Centers for Disease Control and Prevention (CDC). The project was determined to meet the requirements of public health surveillance covered by the U.S. Department of Health and Human Services Policy for the Protection of Human Research Subjects as defined in 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sec.241(d); 5 U.S.C. Sec.552a; 44 U.S.C. Sec.3501 et seq. In., and the decision was made that this project was nonresearch and did not require ethical review by the CDC Human Research Protection Office. Ethical approval was waived and informed consent was not required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData are the property of the U.S. state of Maryland and are collected for public health surveillance purposes. They are not available to the ublic. |
COVID-19-associated hospitalizations among vaccinated and unvaccinated adults ≥18 years – COVID-NET, 13 states, January 1 – July 24, 2021 (preprint)
Havers FP , Pham H , Taylor CA , Whitaker M , Patel K , Anglin O , Kambhampati AK , Milucky J , Zell E , Chai SJ , Kirley PD , Alden NB , Armistead I , Yousey-Hindes K , Meek J , Openo KP , Anderson EJ , Reeg L , Kohrman A , Lynfield R , Como-Sabetti K , Davis EM , Cline C , Muse A , Barney G , Bushey S , Felsen CB , Billing LM , Shiltz E , Sutton M , Abdullah N , Talbot HK , Schaffner W , Hill M , George A , Murthy BP , McMorrow M . medRxiv 2021 2021.08.27.21262356 Background As of August 21, 2021, >60% of the U.S. population aged ≥18 years were fully vaccinated with vaccines highly effective in preventing hospitalization due to Coronavirus Disease-2019 (COVID-19). Infection despite full vaccination (vaccine breakthrough) has been reported, but characteristics of those with vaccine breakthrough resulting in hospitalization and relative rates of hospitalization in unvaccinated and vaccinated persons are not well described, including during late June and July 2021 when the highly transmissible Delta variant predominated.Methods From January 1–June 30, 2021, cases defined as adults aged ≥18 years with laboratory-confirmed Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection were identified from >250 acute care hospitals in the population-based COVID-19-Associated Hospitalization Surveillance Network (COVID-NET). Through chart review for sampled cases, we examine characteristics associated with vaccination breakthrough. From January 24–July 24, 2021, state immunization information system data linked to both >37,000 cases representative cases and the defined surveillance catchment area population were used to compare weekly hospitalization rates in vaccinated and unvaccinated individuals. Unweighted case counts and weighted percentages are presented.Results From January 1 – June 30, 2021, fully vaccinated cases increased from 1 (0.01%) to 321 (16.1%) per month. Among 4,732 sampled cases, fully vaccinated persons admitted with COVID-19 were older compared with unvaccinated persons (median age 73 years [Interquartile Range (IQR) 65-80] v. 59 years [IQR 48-70]; p<0.001), more likely to have 3 or more underlying medical conditions (201 (70.8%) v. 2,305 (56.1%), respectively; p<0.001) and be residents of long-term care facilities [37 (14.5%) v. 146 (5.5%), respectively; p<0.001]. From January 24 – July 24, 2021, cumulative hospitalization rates were 17 times higher in unvaccinated persons compared with vaccinated persons (423 cases per 100,000 population v. 26 per 100,000 population, respectively); rate ratios were 23, 22 and 13 for those aged 18-49, 50-64, and ≥65 years respectively. For June 27 – July 24, hospitalization rates were ≥10 times higher in unvaccinated persons compared with vaccinated persons for all age groups across all weeks.Conclusion Population-based hospitalization rates show that unvaccinated adults aged ≥18 years are 17 times more likely to be hospitalized compared with vaccinated adults. Rates are far higher in unvaccinated persons in all adult age groups, including during a period when the Delta variant was the predominant strain of the SARS-CoV-2 virus. Vaccines continue to play a critical role in preventing serious COVID-19 illness and remain highly effective in preventing COVID-19 hospitalizations.Competing Interest StatementAll authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Evan J. Anderson reports grants from Pfizer, grants from Merck, grants from PaxVax, grants from Micron, grants from Sanofi-Pasteur, grants from Janssen, grants from MedImmune, grants from GSK, personal fees from Sanofi-Pasteur, personal fees from Pfizer, personal fees from Medscape, personal fees from Kentucky Bioprocessing, Inc, personal fees from Sanofi-Pasteur, personal fees from Janssen, outside the submitted work; and his institution has also received funding from NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines. Ruth Lynfield reports Associate Editor for American Academy of Pediatrics Red Book (Committee on Infectious Diseases), donated fee to Minnesota Department of Health. Laurie M. Billing reports grants from Council of State and Territorial Epidemiologists (CSTE), during the conduct of the study; grants from Centers for Disease Control and Prevention (CDC) outside the submitted work. William Schaffner reports personal fees from VBI Vaccines, outside the submitted work. No other potential conflicts of interest were disclosed.Funding StatementThis work was supported by the Centers of Disease Control and Prevention through an Emerging Infections Program cooperative agreement (grant CK17-1701) and through a Council of State and Territorial Epidemiologists cooperative agreement (grant NU38OT000297-02-00).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (see e.g., 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesPublicly available data referred to in this analysis can be found at: https://gis.cdc.gov/grasp/covidnet/covid19_3.html https://gis.cdc.gov/grasp/COVIDNet/COVID19_5.html https://gis.cdc.gov/grasp/covidnet/covid19_3.html https://gis.cdc.gov/grasp/COVIDNet/COVID19_5.html |
Modeling of rotavirus transmission dynamics and impact of vaccination in Ghana (preprint)
Asare EO , Al-Mamun MA , Armah GE , Lopman BA , Parashar UD , Binka F , Pitzer VE . medRxiv 2020 2020.03.12.20034801 Background Rotavirus incidence remains relatively high in low-income countries (LICs) compared to high-income countries (HICs) after vaccine introduction. Ghana introduced monovalent rotavirus vaccine in April 2012 and despite the high coverage, vaccine performance has been modest compared to developed countries. The predictors of low vaccine effectiveness in LICs are poorly understood, and the drivers of subnational heterogeneity in rotavirus vaccine impact are unknown.Methods We used mathematical models to investigate variations in rotavirus incidence in children <5 years old in Ghana. We fit models to surveillance and case-control data from three different hospitals: Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi, and War Memorial Hospital in Navrongo. The models were fitted to both pre- and post-vaccine data to estimate parameters describing the transmission rate, waning of maternal immunity, and vaccine response rate.Results The seasonal pattern and age distribution of rotavirus cases varied among the three study sites in Ghana. Our model was able to capture the spatio-temporal variations in rotavirus incidence across the three sites and showed good agreement with the age distribution of observed cases. The rotavirus transmission rate was highest in Accra and lowest in Navrongo, while the estimated duration of maternal immunity was longer (∼5 months) in Accra and Kumasi and shorter (∼3 months) in Navrongo. The proportion of infants who responded to the vaccine was estimated to be high in Accra and Kumasi and low in Navrongo.Conclusions Rotavirus vaccine impact varies within Ghana. A low vaccine response rate was estimated for Navrongo, where rotavirus is highly seasonal and incidence limited to a few months of the year. Our findings highlight the need to further explore the relationship between rotavirus seasonality, maternal immunity, and vaccine response rate to determine how they influence vaccine effectiveness and to develop strategies to improve vaccine impact.HighlightsMarked variations in rotavirus incidence and vaccine impact within GhanaSimilar rotavirus seasonality before and after vaccine introductionA shift in age distribution occurred following vaccine introductionThe models provide satisfactory predictions of rotavirus outbreaks and vaccine impactCompeting Interest StatementVEP has received reimbursement for travel expenses from Merck to attend a Scientific Input Engagement unrelated to the subject of this paperFunding StatementThe work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health [grant number R01AI112970 to V.E.P.].Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are available on request from the corresponding author, EOA |
Effectiveness of Influenza Vaccine for Preventing Laboratory-Confirmed Influenza Hospitalizations in Immunocompromised Adults (preprint)
Hughes K , Middleton DB , Nowalk MP , Balasubramani GK , Martin ET , Gaglani M , Talbot HK , Patel MM , Ferdinands JM , Zimmerman RK , Silveira FP . medRxiv 2020 2020.10.08.20208579 Background Yearly influenza immunization is recommended for immunocompromised (IC) individuals, although immune responses are lower than that for the non-immunocompromised and the data on vaccine effectiveness (VE) in the IC is scarce. We evaluated VE against influenza-associated hospitalization among IC adults.Methods We analyzed data from adults ≥ 18 years hospitalized with acute respiratory illness (ARI) during the 2017-2018 influenza season at 10 hospitals in the United States. IC adults were identified using pre-specified case-definitions, utilizing electronic medical record data. VE was evaluated with a test-negative case-control design using multivariate logistic regression with PCR-confirmed influenza as the outcome and vaccination status as the exposure, adjusting for age, enrolling site, illness onset date, race, days from onset to specimen collection, self-reported health, and self-reported hospitalizations.Results Of 3,524 adults hospitalized with ARI, 1,210 (34.3%) had an immunocompromising condition. IC adults were more likely to be vaccinated than non-IC (69.5% vs 65.2%), and less likely to have influenza (22% vs 27.8%). The mean age did not differ among IC and non-IC (61.4 vs 60.8 years old). The overall VE against influenza hospitalization, including immunocompetent adults, was 33% (95% CI, 21% to 44%). VE among IC vs non-IC adults was lower at 5% (−29% to 31%) vs. 41% (27% to 52%) (p<0.05 for interaction term).Conclusions VE in one influenza season was very low among IC individuals. Future efforts should include evaluation of VE among the different immunocompromising conditions and whether enhanced vaccines improve the suboptimal effectiveness among the immunocompromised.Competing Interest StatementDBM has received personal fees from Sequris, Pfizer, and Sanofi Pasteur, and grants from Pfizer. JF reports non-financial support from the Institute for Influenza Epidemiology. RKZ has received grants from Sanofi Pasteur and Merck & Co. All other authors report no potential conflicts.Clinical TrialThis study was not registered in ClinicalTrials.gov because it doesn't meet NIH's definition of a clinical trial.Funding StatementThis study was funded by the CDC (cooperative agreement IP15-002). Vanderbilt also received support from CTSA award number UL1 TR002243 from the National Center for Advancing Translational Sciences.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study protocol was reviewed by the Institutional Review Board at each participating institution and CDC, as detailed below: CDC's IRB: ethical approval given University of Pittsburgh IRB: ethical approval given University of Michigan IRB: ethical approval given Baylor Scott & White Health IRB: ethical approval given Vanderbilt University IRB: ethical approval given All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData may be made available after completion of the study. |
Using real-time data to guide decision-making during an influenza pandemic: a modelling analysis (preprint)
Haw DJ , Biggerstaff M , Prasad P , Walker J , Grenfell B , Arinaminpathy N . medRxiv 2021 2021.06.09.21258618 Influenza pandemics typically occur in multiple waves of infection, often associated with initial emergence of a novel virus, followed (in temperate regions) by a later resurgence accompanying the onset of the annual influenza season. Here, we examined whether data collected from an initial pandemic wave could be informative, for the need to implement non-pharmaceutical measures in any resurgent wave. Drawing from the 2009 H1N1 pandemic in 10 states in the USA, we calibrated simple mathematical models of influenza transmission dynamics to data for virologically confirmed hospitalisations during the initial ‘spring’ wave. We then projected pandemic outcomes (cumulative hospitalisations) during the fall wave, and compared these projections with data. Model results show reasonable agreement for all states that reported a substantial number of cases in the spring wave. Using this model we propose a probabilistic decision framework that can be used to determine the need for pre-emptive measures such as postponing school openings, in advance of a fall wave. This work illustrates how model-based evidence synthesis, in real-time during an early pandemic wave, could be used to inform timely decisions for pandemic response.Competing Interest StatementThe authors have declared no competing interest.Funding StatementAll work funded by the USA Centre for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:NAAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data (FluSurNet) is freely available online. https://www.cdc.gov/flu/weekly/influenza-hospitalization-surveillance.htm |
Identifying Cases of Shoulder Injury Related to Vaccine Administration (SIRVA) Using Natural Language Processing (preprint)
Zheng C , Duffy J , Liu IA , Sy LS , Navarro RA , Kim SS , Ryan DS , Chen W , Qian L , Mercado C , Jacobsen SJ . medRxiv 2021 2021.05.05.21256555 Background Shoulder injury related to vaccine administration (SIRVA) accounts for more than half of all claims received by the National Vaccine Injury Compensation Program. However, there is a lack of population-based studies due to the challenge of identifying SIRVA cases in large health care databases.Objective To develop a natural language processing (NLP) method to identify SIRVA cases from clinical notes.Methods We conducted the study among members of a large integrated health care organization who were vaccinated between 04/1/2016 and 12/31/2017 and had subsequent diagnosis codes indicative of shoulder injury. Based on a training dataset with a chart review reference standard of 164 individuals, we developed an NLP algorithm to extract shoulder disorder information, including prior vaccination, anatomic location, temporality and causality. The algorithm identified three groups of positive SIRVA cases (definite, probable and possible) based on the strength of evidence. We compared NLP results to a chart review reference standard of 100 vaccinated individuals. We then applied the final automated NLP algorithm to a broader cohort of vaccinated individuals with a shoulder injury diagnosis code and performed manual chart confirmation on a random sample of NLP-identified definite cases and all NLP-identified probable and possible cases.Results In the validation sample, the NLP algorithm had 100% accuracy for identifying 4 SIRVA cases and 96 individuals without SIRVA. In the broader cohort of 53,585 individuals, the NLP algorithm identified 291 definite, 124 probable, and 52 possible SIRVA cases. The chart-confirmation rates for these groups were 95.3%, 67.7% and 18.9%, respectively.Conclusions The algorithm performed with high sensitivity and reasonable specificity in identifying positive SIRVA cases. The NLP algorithm can potentially be used in future population-based studies to identify this rare adverse event, avoiding labor-intensive chart review validation.Competing Interest StatementLina Sy received research support from GlaxoSmithKline, Dynavax, Seqirus, and Novavax for studies unrelated to this paper. All other authors report no conflicts of interest related to the submitted work.Funding StatementThis study was funded through the Vaccine Safety Datalink under contract 200-2012-53580 from the Centers for Disease Control and Prevention (CDC). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Institutional Review Board at KPSC approved this study.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated and/or analyzed during the current study are not publicly available due to ethical standards. The authors do not have permission to share data.CIconfidence intervalEHRelectronic health recordsICD-10-CMInternational Classification of Diseases 10th Revision Clinical ModificationKPSCKaiser Permanente Southern CaliforniaNLPnatural language processingNPVnegative predictive valuePPVpos tive predictive valueSIRVAshoulder injury related to vaccine administrationVICPNational Vaccine Injury Compensation Program |
MicrobeTrace: Retooling Molecular Epidemiology for Rapid Public Health Response (preprint)
Campbell EM , Boyles A , Shankar A , Kim J , Knyazev S , Switzer WM . bioRxiv 2020 2020.07.22.216275 Motivation Outbreak investigations use data from interviews, healthcare providers, laboratories and surveillance systems. However, integrated use of data from multiple sources requires a patchwork of software that present challenges in usability, interoperability, confidentiality, and cost. Rapid integration, visualization and analysis of data from multiple sources can guide effective public health interventions.Results We developed MicrobeTrace to facilitate rapid public health responses by overcoming barriers to data integration and exploration in molecular epidemiology. Using publicly available HIV sequences and other data, we demonstrate the analysis of viral genetic distance networks and introduce a novel approach to minimum spanning trees that simplifies results. We also illustrate the potential utility of MicrobeTrace in support of contact tracing by analyzing and displaying data from an outbreak of SARS-CoV-2 in South Korea in early 2020.Availability and Implementation MicrobeTrace is a web-based, client-side, JavaScript application (https://microbetrace.cdc.gov) that runs in Chromium-based browsers and remains fully-operational without an internet connection. MicrobeTrace is developed and actively maintained by the Centers for Disease Control and Prevention. The source code is available at https://github.com/cdcgov/microbetrace.Contact ells{at}cdc.govCompeting Interest StatementThe authors have declared no competing interest. |
High Real-time Reporting of Domestic and Wild Animal Diseases Following Rollout of Mobile Phone Reporting System in Kenya (preprint)
Njenga MK , Kemunto N , Kahariri S , Holmstrom L , Oyas H , Biggers K , Riddle A , Gachohi J , Muturi M , Mwatondo A , Gakuya F , Lekolool I , Sitawa R , Apamaku M , Osoro E , Widdowson MA , Munyua P . bioRxiv 2020 2020.12.04.411348 Background To improve early detection of emerging infectious diseases in sub-Saharan Africa (SSA), many of them zoonotic, numerous electronic animal disease-reporting systems have been piloted but not implemented because of cost, lack of user friendliness, and data insecurity. In Kenya, we developed and rolled out an open-source mobile phone-based domestic and wild animal disease reporting system and collected data over two years to demonstrate its robustness and ability to track disease trends.Methods The Kenya Animal Biosurveillance System (KABS) application was built on the Java® platform, freely downloadable for android compatible mobile phones, and supported by web-based account management, form editing and data monitoring. The application was integrated into the surveillance systems of Kenya’s domestic and wild animal sectors by adopting their existing data collection tools, and targeting disease syndromes prioritized by national, regional and international animal and human health agencies. Smartphone-owning government and private domestic and wild animal health officers were recruited and trained on the application, and reports received and analyzed by Kenya Directorate of Veterinary Services. The KABS application performed automatic basic analyses (frequencies, spatial distribution), which were immediately relayed to reporting officers as feedback.Results Over 95% of trained domestic animal officers downloaded the application, and >72% of them started reporting using the application within three months. Introduction of the application resulted in 2- to 10-fold increase in number of disease reports when compared the previous year (p<0.05), and reports were more spatially distributed. Among domestic animals, food animals (cattle, sheep, goats, camels, and chicken) accounted for >90% of the reports, with respiratory, gastrointestinal and skin diseases constituting >85% of the reports. Herbivore wildlife (zebra, buffalo, elephant, giraffe, antelopes) accounted for >60% of the wildlife disease reports, followed by carnivores (lions, cheetah, hyenas, jackals, and wild dogs). Deaths, traumatic injuries, and skin diseases were most reported in wildlife.Conclusions This open-source system was user friendly and secure, ideal for rolling out in other countries in SSA to improve disease reporting and enhance preparedness for epidemics of zoonotic diseases.Authors Summary Taking advantage of a recently developed freely downloadable disease reporting application in the United States, we customized it for android smartphones to collect and submit domestic and wild animal disease data in real-time in Kenya. To enhance user friendliness, the Kenya Animal Biosurveillance System (KABS) was installed with disease reporting tools currently used by the animal sector and tailored to collected data on transboundary animal disease important for detecting zoonotic endemic and emerging diseases. The KABS database was housed by the government of Kenya, providing important assurance on its security. The application had a feedback module that performed basics analysis to provide feedback to the end-user in real-time. Rolling out of KABS resulted in >70% of domestic and wildlife disease surveillance officers using it to report, resulting in exponential increase in frequency and spatial distributions of reports regions. Utility of the system was demonstrated by successful detected a Rift Valley fever outbreak in livestock in 2018, resulting in early response and prevention of widespread human infections. For the wildlife sector in Eastern Africa, the application provided the first disease surveillance system developed. This open-source system is ideal for rolling out in other countries in sub-Saharan Africa to improve disease reporting and enhance preparedness for epidemics of zoonotic diseases. |
Development of a standards-based city-wide health information exchange for public health in response to COVID-19 (preprint)
Hota B , Casey P , McIntyre AF , Khan J , Rab S , Chopra A , Lateef O , Layden JE . medRxiv 2020 2020.08.12.20173559 Background Disease surveillance is a critical function of public health, provides essential information about disease burden, clinical and epidemiologic parameters of disease, and is an important element to effective and timely case and contact tracing. The COVID-19 pandemic has demonstrated the essential role these functions have to preserve public health. Syndromic surveillance, electronic laboratory reporting in the meaningful use program, and the growth of the National Healthcare Safety Network (NHSN) have created linkages between hospitals, commercial labs, and public health that can collect and organize data, often through EHR and order workflows, to improve the timeliness and completeness of reporting. In theory, the standard data formats and exchange methods provided by meaningful use should enable rapid healthcare data exchange in the setting of disruptive healthcare events like a pandemic. In reality, access to data remains challenging, and even if available, often lack conformity to regulated standards.Objective We sought to use regulated interoperability standards already in production to generate regional bed capacity awareness, enhance the capture of epidemiological risk factors and clinical variables among COVID-19 tested patients, and reduce the administrative burden of reporting for stakeholders in a manner that could be replicated by other public health agencies.Methods Following a public health order mandating data submission, we developed technical infrastructure to combine multiple data feeds from electronic health record systems. We measured the completeness of each feed, and the match rate between feeds.Results A cloud-based environment was created that received data from electronic lab reporting, consolidated clinical data architecture, and bed capacity data feeds from sites. Data governance was planned from the project beginning to aid in consensus and principles for data use. 88,906 total persons from CCDA data among 14 facilities, and 408,741 persons from ELR records among 88 facilities, were submitted. Fields routinely absent from ELR feeds included travel histories, clinical symptoms, and comorbidities. CCDA data provided an improvement in the quality of data available for surveillance and was highly complete with <5% for all records types with the exception of patient cell phone. 90.1% of records could be matched between CCDA and ELR feeds.Conclusions We describe the development of a city-wide public health data hub for the surveillance of COVID-19 infection. We were able to assess the completeness of existing ELR feeds, augment these feeds with CCDA documents, establish secure transfer methods for data exchange, develop cloud-based architecture to enable secure data storage and analytics, and produced meaningful dashboards for the monitoring of capacity and disease burden. We see this public health and clinical data registry as an informative example of the power of common standards across electronic records, and a potential template for future extension of the use of standards to improve public health surveillance.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was received for this work.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This work was conducted under a public health exemption through the Chicago Department of Public HealthAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectiv ly, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data used for this study was reported to the health department and is not publicly available at this time. |
Robustness of the ferret model for influenza risk assessment studies: a cross-laboratory exercise (preprint)
Belser JA , Lau EHY , Barclay W , Barr IG , Chen H , Fouchier RAM , Hatta M , Herfst S , Kawaoka Y , Lakdawala SS , Lee LYY , Neumann G , Peiris M , Perez DR , Russell C , Subbarao K , Sutton TC , Webby RJ , Yang H , Yen HL . bioRxiv 2022 2022.04.02.486825 Ferrets represent the preferred animal model for assessing the transmission potential of newly emerged zoonotic influenza viruses. However, heterogeneity among established experimental protocols and facilities across different laboratories may lead to variable results, complicating interpretation of transmission experimental data. Between 2018-2020, a global exercise was conducted by 11 participating laboratories to assess the range of variation in ferret transmission experiments using two common stock H1N1 influenza viruses that possess different transmission characteristics in ferrets. Inoculation route, dose, and volume were standardized, and all participating laboratories followed the same experimental conditions for respiratory droplet transmission, including a strict 1:1 donor:contact ratio. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored throughout. Overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. To attain high confidence in identifying zoonotic influenza viruses with moderate-to-high or low transmissibility, our analyses support that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment.Competing Interest StatementThe authors have declared no competing interest. |
Respiratory and intestinal epithelial cells exhibit differential susceptibility and innate immune responses to contemporary EV-D68 isolates (preprint)
Freeman MC , Wells AI , Ciomperlik-Patton J , Myerburg MM , Anstadt J , Coyne C . bioRxiv 2021 2021.01.05.425225 Enterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and acute flaccid myelitis (AFM) and is detected in patient respiratory samples and from stool and wastewater, suggesting both respiratory and enteric routes of transmission. Here, we used a panel of EV-D68 isolates, including a historical isolate and multiple contemporary isolates from AFM outbreak years, to define the dynamics of viral replication and the host response to infection in primary human airway cells and stem cell-derived enteroids. We show that some recent EV-D68 isolates have decreased sensitivity to acid and temperature compared with an earlier isolate and that the respiratory, but not intestinal, epithelium induces a robust type III interferon (IFN) response that restricts infection. Our findings define the differential responses of the respiratory and intestinal epithelium to contemporary EV-D68 isolates and suggest that some isolates have the potential to target both the human airway and gastrointestinal tracts.Competing Interest StatementThe authors have declared no competing interest. |
Stable Flow-induced Expression of KLK10 Inhibits Endothelial Inflammation and Atherosclerosis (preprint)
Williams D , Mahmoud M , Liu R , Andueza A , Kumar S , Kang DW , Zhang J , Tamargo I , Villa-Roel N , Baek KI , Lee H , An Y , Zhang L , Tate EW , Bagchi P , Pohl J , Mosnier LO , Diamandis EP , Mihara K , Hollenberg MD , Dai Z , Jo H . bioRxiv 2021 2021.08.10.455857 Introduction Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10, a secreted serine protease) as a flow-sensitive gene in arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown.Methods and Results Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated KLK10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced inflammation and permeability dysfunction in human artery ECs (HAECs). Further, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of KLK10-expressing plasmids inhibited atherosclerosis in ApoE-/- mice. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10’s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques.Conclusion KLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.Competing Interest StatementThe authors have declared no competing interest. |
Sustained replication of synthetic canine distemper virus defective genomes in vitro and in vivo (preprint)
Tilston-Lunel NL , Welch SR , Nambulli S , de Vries RD , Ho GW , Wentworth DE , Shabman R , Nichol ST , Spiropoulou CF , de Swart RL , Rennick LJ , Duprex WP . bioRxiv 2021 2021.06.11.448162 Defective interfering (DI) genomes restrict viral replication and induce type-I interferon. Since DI genomes have been proposed as vaccine adjuvants or therapeutic antiviral agents, it is important to understand their generation, delineate their mechanism of action, develop robust production capacities, assess their safety and in vivo longevity and determine their long-term effects. To address this, we generated a recombinant (r) canine distemper virus (CDV) from an entirely synthetic molecular clone designed using the genomic sequence from a clinical isolate obtained from a free-ranging raccoon with distemper. rCDV was serially passaged in vitro to identify DI genomes that naturally arise during rCDV replication. Defective genomes were identified by Sanger and next-generation sequencing techniques and predominant genomes were synthetically generated and cloned into T7-driven plasmids. Fully encapsidated DI particles (DIPs) were then generated using a rationally attenuated rCDV as a producer virus to drive DI genome replication. We demonstrate these DIPs interfere with rCDV replication in a dose-dependent manner in vitro. Finally, we show sustained replication of a fluorescent DIP in experimentally infected ferrets over a period of 14 days. Most importantly, DIPs were isolated from the lymphoid tissues which are a major site of CDV replication. Our established pipeline for detection, generation and assaying DIPs is transferable to highly pathogenic paramyxoviruses and will allow qualitative and quantitative assessment of the therapeutic effects of DIP administration on disease outcome.Importance Defective interfering (DI) genomes have long been considered inconvenient artifacts that suppressed viral replication in vitro. However, advances in sequencing technologies have led to DI genomes being identified in clinical samples, implicating them in disease progression and outcome. It has been suggested that DI genomes could be harnessed therapeutically. Negative strand RNA virus research has provided a rich pool of natural DI genomes over many years and they are probably the best understood in vitro. Here, we demonstrate identification, synthesis, production and experimental inoculation of novel CDV DI genomes in highly susceptible ferrets. These results provide important evidence that rationally designed and packaged DI genomes can survive the course of a wild-type virus infection. |
A whole transcriptomic approach reveals novel mechanisms of organophosphate and pyrethroid resistance in Anopheles arabiensis from Ethiopia (preprint)
Messenger LA , Impoinvil LM , Derilus D , Yewhalaw D , Irish S , Lenhart A . bioRxiv 2021 2021.07.09.451871 The development of insecticide resistance in malaria vectors is of increasing concern in Ethiopia because of its potential implications for vector control failure. To better elucidate the specificity of resistance mechanisms and to facilitate the design of control strategies that minimize the likelihood of selecting for cross-resistance, a whole transcriptomic approach was used to explore gene expression patterns in a multi-insecticide resistant population of Anopheles arabiensis from Oromia Region, Ethiopia. This field population was resistant to the diagnostic doses of malathion (average mortality of 71.9%) and permethrin (77.4%), with pools of survivors and unexposed individuals analyzed using Illumina RNA-sequencing, alongside insecticide susceptible reference strains. This population also demonstrated deltamethrin resistance but complete susceptibility to alpha-cypermethrin, bendiocarb and propoxur, providing a phenotypic basis for detecting insecticide-specific resistance mechanisms. Transcriptomic data revealed overexpression of genes including cytochrome P450s, glutathione-s-transferases and carboxylesterases (including CYP4C36, CYP6AA1, CYP6M2, CYP6M3, CYP6P4, CYP9K1, CYP9L1, GSTD3, GSTE2, GSTE3, GSTE4, GSTE5, GSTE7 and two carboxylesterases) that were shared between malathion and permethrin survivors. We also identified nineteen highly overexpressed cuticular-associated proteins (including CYP4G16, CYP4G17 and chitinase) and eighteen salivary gland proteins (including D7r4 short form salivary protein), which may be contributing to a non-specific resistance phenotype by either enhancing the cuticular barrier or promoting binding and sequestration of insecticides, respectively. These findings provide novel insights into the molecular basis of insecticide resistance in this lesser well-characterized major malaria vector species.Importance Insecticide-resistant mosquito populations remain a significant challenge to global malaria vector control. While substantial progress has been made unraveling resistance mechanisms in major vector species, such as Anopheles gambiae and An. funestus, comparatively less is known about An. arabiensis populations. Using a whole transcriptomic approach, we investigated genes associated with resistance to insecticides used to control An. arabiensis in Ethiopia. Study findings revealed shared detoxification genes between organophosphate- and pyrethroid-resistant vectors and highly overexpressed cuticular-associated proteins and salivary gland proteins, which may play a role in enhancing insecticide resistance. The whole transcriptomic analysis detected novel resistance-associated genes, which warrant functional validation to determine their specificity to particular insecticides and their potential to confer cross-resistance between different insecticides with the same mode of action. These genes may contribute to the development of diagnostic markers to monitor insecticide resistance dynamics in the field. |
Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray (preprint)
Camerini D , Randall AZ , Trappl-Kimmons K , Oberai A , Hung C , Edgar J , Shandling A , Huynh V , Teng AA , Hermanson G , Pablo JV , Stumpf MM , Lester SN , Harcourt J , Tamin A , Rasheed M , Thornburg NJ , Satheshkumar PS , Liang X , Kennedy RB , Yee A , Townsend M , Campo JJ . medRxiv 2021 2021.01.14.21249690 The emergence and rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of varying lengths and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multi-coronavirus arrays to identify specific antibody reactivity. High level IgG, IgM and IgA reactivity to structural proteins S, M and N, as well as accessory proteins, of SARS-CoV-2 were observed that was specific to COVID-19 patients. Overlapping 100, 50 and 30 amino acid fragments of SARS-CoV-2 proteins identified antigenic regions. Numerous proteins of SARS-CoV, MERS-CoV and the endemic human coronaviruses, HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients.Competing Interest StatementDavid Camerini, Arlo Z. Randall, Amit Oberai, Christopher Hung, Joshua Edgar, Adam Shandling, Vu Huynh, Andy A. Teng, Gary Hermanson, Jozelyn V. Pablo, Xiaowu Liang, Angela Yee and Joseph J. Campo are employees of Antigen Discovery Inc. In addition, Xiaowu Liang and Angela Yee have an equity interest in Antigen Discovery Inc. The other authors declare non competing interests.Funding StatementNo external funding was used in this study.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Mayo Clinic Human Subjects Institutional Review Board and the Centers for Disease Control and Prevention Human Subjects Office.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data are freely available. |
N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry (preprint)
Wang D , Zhou B , Keppel TR , Solano M , Baudys J , Goldstein J , Finn MG , Fan X , Chapman AP , Bundy JL , Woolfitt AR , Osman SH , Pirkle JL , Wentworth DE , Barr JR . bioRxiv 2021 2021.07.26.453787 N-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.Competing Interest StatementThe authors have declared no competing interest. |
Performance and Implementation Evaluation of the Abbott BinaxNOW Rapid Antigen Test in a High-throughput Drive-through Community Testing Site in Massachusetts (preprint)
Pollock NR , Jacobs JR , Tran K , Cranston AE , Smith S , O'Kane CY , Roady TJ , Moran A , Scarry A , Carroll M , Volinsky L , Perez G , Patel P , Gabriel S , Lennon NJ , Madoff LC , Brown C , Smole SC . medRxiv 2021 2021.01.09.21249499 Background Rapid diagnostic tests (RDTs) for SARS-CoV-2 antigens (Ag) that can be performed at point-of-care (POC) can supplement molecular testing and help mitigate the COVID-19 pandemic. Deployment of an Ag RDT requires an understanding of its operational and performance characteristics under real-world conditions and in relevant subpopulations. We evaluated the Abbott BinaxNOW™ COVID-19 Ag Card in a high-throughput, drive-through, free community testing site in Massachusetts (MA) using anterior nasal (AN) swab RT-PCR for clinical testing.Methods Individuals presenting for molecular testing in two of seven lanes were offered the opportunity to also receive BinaxNOW testing. Dual AN swabs were collected from symptomatic and asymptomatic children (≤ 18 years) and adults. BinaxNOW testing was performed in a testing pod with temperature/humidity monitoring. One individual performed testing and official result reporting for each test, but most tests had a second independent reading to assess inter-operator agreement. Positive BinaxNOW results were scored as faint, medium, or strong. Positive BinaxNOW results were reported to patients by phone and they were instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.Results Of 2482 participants, 1380 adults and 928 children had paired RT-PCR/BinaxNOW results and complete symptom data. 974/1380 (71%) adults and 829/928 (89%) children were asymptomatic. BinaxNOW had 96.5% (95% confidence interval [CI] 90.0-99.3) sensitivity and 100% (98.6-100.0) specificity in adults within 7 days of symptoms, and 84.6% (65.1-95.6) sensitivity and 100% (94.5-100.0) specificity in children within 7 days of symptoms. Sensitivity and specificity in asymptomatic adults were 70.2% (56.6-81.6) and 99.6% (98.9-99.9), respectively, and in asymptomatic children were 65.4% (55.6-74.4) and 99.0% (98.0-99.6), respectively. By cycle threshold (Ct) value cutoff, sensitivity in all subgroups combined (n=292 RT-PCR-positive individuals) was 99.3% with Ct ≤25, 95.8% with ≤30, and 81.2% with ≤35. Twelve false positive BinaxNOW results (out of 2308 tests) were observed; in all twelve, the test bands were faint but otherwise normal, and were noted by both readers. One invalid BinaxNOW result was identified. Inter-operator agreement (positive versus negative BinaxNOW result) was 100% (n = 2230/2230 double reads). Each operator was able to process 20 RDTs per hour. In a separate set of 30 specimens (from individuals with symptoms ≤7 days) run at temperatures below the manufacturer’s recommended range (46-58.5°F), sensitivity was 66.7% and specificity 95.2%.Conclusions BinaxNOW had very high specificity in both adults and children and very high sensitivity in newly symptomatic adults. Overall, 95.8% sensitivity was observed with Ct ≤ 30. These data support public health recommendations for use of the BinaxNOW test in adults with symptoms for ≤7 days without RT-PCR confirmation. Excellent inter-operator agreement indicates that an individual can perform and read the BinaxNOW test alone. A skilled laboratorian can perform and read 20 tests per hour. Careful attention to temperature is critical.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the MA Department of Public Health. The community testing site was funded by the Centers for Disease Control and Prevention Building and Enhancing Epidemiology, Laboratory and Health Information Systems Capacity in Massachusetts--Enhancing Detection COVID Supplement (Grant # 6 NU50CK000518-01-08). BinaxNOW kits were supplied as part of the federal allocation to state health departments.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was reviewed by the Massachusetts Department of Public Health IRB and deemed not human subject research.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data referred to in the manuscript are publicly available. |
Performance and Operational Evaluation of the Access Bio CareStart Rapid Antigen Test in a High-throughput Drive-through Community Testing Site in Massachusetts (preprint)
Pollock NR , Tran K , Jacobs JR , Cranston AE , Smith S , O'Kane CY , Roady TJ , Moran A , Scarry A , Carroll M , Volinsky L , Perez G , Patel P , Gabriel S , Lennon NJ , Madoff LC , Brown C , Smole SC . medRxiv 2021 2021.03.07.21253101 Background To facilitate deployment of point-of-care testing for SARS-CoV-2, we evaluated the Access Bio CareStart COVID-19 Antigen test in a high-throughput, drive-through, free community testing site using anterior nasal (AN) swab RT-PCR for clinical testing.Methods Consenting symptomatic and asymptomatic children (≤18 years) and adults received dual AN swabs. CareStart testing was performed with temperature/humidity monitoring. All tests had two independent reads to assess inter-operator agreement. Patients with positive CareStart results were called and instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.Results Of 1603 participants, 1245 adults and 253 children had paired RT-PCR/CareStart results and complete symptom data. 83% of adults and 87% of children were asymptomatic. CareStart sensitivity/specificity were 84.8% (95% confidence interval [CI] 71.1-93.7)/97.2% (92.0-99.4) and 85.7% (42.1-99.6)/89.5% (66.9-98.7) in adults and children, respectively, within 5 days of symptoms. Sensitivity/specificity were 50.0% (41.0-59.0)/99.1% (98.3-99.6) in asymptomatic adults and 51.4% (34.4-68.1)/97.8% (94.5-99.4) in asymptomatic children. Sensitivity in all 234 RT-PCR-positive people was 96.3% with cycle threshold (Ct) ≤25, 79.6% with Ct ≤30, and 61.4% with Ct ≤35. All 21 false positive CareStart tests had faint but normal bands. Inter-operator agreement was 99.5%. Operational challenges included identification of faint test bands and inconsistent swab elution volumes.Conclusions CareStart had high sensitivity in people with Ct ≤25 and moderate sensitivity in symptomatic people overall. Specificity was unexpectedly lower in symptomatic versus asymptomatic people. Excellent inter-operator agreement was observed, but operational challenges indicate that operator training is warranted.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the MA Department of Public Health. The community testing site and the work of N.R.P. were funded by the Centers for Disease Control and Prevention Building and Enhancing Epidemiology, Laboratory and Health Information Systems Capacity in Massachusetts - Enhancing Detection COVID Supplement (Grant # 6 NU50CK000518-01-08). CareStart kits were donated by the manufacturer.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was reviewed by the Massachusetts Department of Public Health IRB and deemed not human subjects research.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data referred to in the manuscript are available. |
Predicting future ocular Chlamydia trachomatis infection prevalence using serological, clinical, molecular, and geospatial data (preprint)
Tedijanto C , Aragie S , Tadesse Z , Haile M , Zeru T , Nash SD , Wittberg DM , Gwyn S , Martin DL , Sturrock HJW , Lietman TM , Keenan JD , Arnold BF . medRxiv 2021 2021.07.19.21260623 Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. Certain areas, particularly in Africa, pose persistent challenges to elimination of trachoma as a public health problem. Efficiently identifying communities with high infection burden could help target more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. We used measurements from 40 communities in the hyperendemic Amhara region of Ethiopia. Median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment to 29% by month 36. At baseline, correlation between seroprevalence and Ct infection was stronger among children 0-5 years old (ρ = 0.77) than children 6-9 years old (ρ = 0.48), and stronger than the correlation between clinical trachoma and Ct infection (0-5y ρ = 0.56; 6-9y ρ = 0.40). Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be an objective, programmatic tool for identifying communities with high levels of active ocular Ct infections, but accurate, future prediction in the context of changing transmission remains an open challenge.SIGNIFICANCE STATEMENT Trachoma is targeted for elimination as a public health problem by 2030. District-level estimates of clinical disease among children 1-9 years old are currently used to guide control programs and assess elimination. However, clinical trachoma is a subjective indicator. Serological markers present an objective, scalable alternative that could be measured in integrated platforms. In a hyperendemic region, community-level seroprevalence aligned more closely with concurrent infection prevalence than clinical trachoma. The correlation between seroprevalence and infection prevalence was stronger among 0–5-year-olds compared to 6–9-year-olds and was consistent over a three-year period of increasing transmission. Serosurveillance among children 0-5 years old may be a promising monitoring strategy to identify communities with the highest burdens of ocular chlamydial infection.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02754583Funding StatementWe would like to thank the WUHA study participants and field team without whom this research would not be possible. This work was supported by the National Institute of Allergy and Infectious Diseases (R03 AI147128 to BFA) and the National Eye Institute (U10 EY023939 to JDK). This work was also made possible in part by an Unrestricted Grant from Research to Prevent Blindness. We would also like to thank Abbott for its donation of the m2000 RealTime molecular diagnostics system and consumables.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval for the study was obtained from the University of California, San Francisco Institutional Review Board (14-14004).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDe-identified data and code to replicate this work is available on Github. https://github.com/ctedijanto/swift-spatial-prediction |
Quantitative Comparison of SARS-CoV-2 Nucleic Acid Amplification Test and Antigen Testing Algorithms: A Decision Analysis Simulation Model (preprint)
Salvatore PP , Shah MM , Ford L , Delaney A , Hsu CH , Tate JE , Kirking HL . medRxiv 2021 2021.03.15.21253608 Background Antigen tests for SARS-CoV-2 offer advantages over nucleic acid amplification tests (NAATs, such as RT-PCR), including lower cost and rapid return of results, but show reduced sensitivity. Public health organizations continue to recommend different strategies for utilizing NAATs and antigen tests in various settings. There has not yet been a quantitative comparison of the expected performance of these strategies.Methods We utilized a decision analysis approach to simulate the expected outcomes of six algorithms for implementing NAAT and antigen testing, analogous to testing strategies recommended by public health organizations. Each algorithm was simulated 50,000 times for four SARS-CoV-2 infection prevalence levels ranging from 5% to 20% in a population of 100000 persons seeking testing. Primary outcomes were number of missed cases, number of false-positive diagnoses, and total test volumes. Outcome medians and 95% uncertainty ranges (URs) were reported.Results Algorithms that use NAATs to confirm all negative antigen results minimized missed cases but required high NAAT capacity: 92,200 (95% UR: 91,200-93,200) tests (in addition to 100,000 antigen tests) at 10% prevalence. Substituting repeat antigen testing in lieu of NAAT confirmation of all initial negative antigen tests resulted in 2,280 missed cases (95% UR: 1,507-3,067) at 10% prevalence. Selective use of NAATs to confirm antigen results when discordant with symptom status (e.g., symptomatic persons with negative antigen results) resulted in the most efficient use of NAATs, with 25 NAATs (95% UR: 13-57) needed to detect one additional case at 10% prevalence compared to exclusive use of antigen tests.Conclusions No single SARS-CoV-2 testing algorithm is likely to be optimal across settings with different levels of prevalence and for all programmatic priorities; each presents a trade-off between prioritized outcomes and resource constraints. This analysis provides a framework for selecting setting-specific strategies to achieve acceptable balances and trade-offs between programmatic priorities and constraints.Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. See e.g., 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C. 552a; 44 U.S.C. 3501 et seq.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesCode for the algorithm simulations can be found on the CDC Epidemic Prediction Initiative GitHub site (https://github.com/cdcepi). |
Escaping the Fate of Sisyphus: Assessing Resistome Hybridization Baits for Antimicrobial Resistance Gene Capture (preprint)
Beaudry MS , Thomas JC , Baptista RP , Sullivan AH , Norfolk W , Devault A , Enk J , Kieran TJ , Rhodes OEJr , Perry KA , Rose LJ , Bayona-Vásquez NJ , Oladeinde A , Lipp EK , Sanchez S , Glenn TC . bioRxiv 2021 2021.07.20.452950 Finding, characterizing, and monitoring reservoirs for antimicrobial resistance (AMR) is vital to protecting public health. Hybridization capture baits are an accurate, sensitive, and cost-effective technique used to enrich and characterize DNA sequences of interest, including antimicrobial resistance genes (ARGs), in complex environmental samples. We demonstrate the continued utility of a set of 19,933 hybridization capture baits designed from the Comprehensive Antibiotic Resistance Database (CARD)v1.1.2 and Pathogenicity Island Database (PAIDB)v2.0, targeting 3,565 unique nucleotide sequences that confer resistance. We demonstrate the efficiency of our bait set on a custom-made resistance mock community and complex environmental samples to increase the proportion of on-target reads as much as >200-fold. However, keeping pace with newly discovered ARGs poses a challenge when studying AMR, because novel ARGs are continually being identified and would not be included in bait sets designed prior to discovery. We provide imperative information on how our bait set performs against CARDv3.3.1, as well as a generalizable approach for deciding when and how to update hybridization capture bait sets. This research encapsulates the full life cycle of baits for hybridization capture of the resistome from design and validation (both in silico and in vitro) to utilization and forecasting updates and retirement.Originality-Significance Statement This work is applicable to a wide range of research. It helps to define conditions under which hybridization capture is useful regarding not only antimicrobial resistance specifically, but also more generally how to assess the ongoing utility of existing bait sets - giving objective criteria for when and by what strategies baits should be updated. We also provide a method for quantifying and comparing antimicrobial resistance genes (ARGs) similar to what is used for RNAseq experiments. This approach improves comparison of ARGs across environments. Thus, the work provides an improved foundation for ARG future studies, while cutting across traditional areas of microbiology and extending beyond.Competing Interest StatementThe EHS DNA lab provides oligonucleotide aliquots and library preparation services at cost, including some oligonucleotides and services used in this manuscript (baddna.uga.edu). JE and AD were employed by, and thereby have financial interest in, Daicel Arbor Biosciences, who provided the in-solution capture reagents used in this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
Evaluation of commercially available high-throughput SARS-CoV-2 serological assays for serosurveillance and related applications (preprint)
Stone M , Grebe E , Sulaeman H , Di Germanio C , Dave H , Kelly K , Biggerstaff BJ , Crews BO , Tran N , Jerome KR , Denny TN , Hogema B , Destree M , Jones JM , Thornburg N , Simmons G , Krajden M , Kleinman S , Dumont LJ , Busch MP . medRxiv 2021 2021.09.04.21262414 SARS-CoV-2 serosurveys can estimate cumulative incidence for monitoring epidemics but require characterization of employed serological assays performance to inform testing algorithm development and interpretation of results. We conducted a multi-laboratory evaluation of 21 commercial high-throughput SARS-CoV-2 serological assays using blinded panels of 1,000 highly-characterized blood-donor specimens. Assays demonstrated a range of sensitivities (96%-63%), specificities (99%-96%) and precision (IIC 0.55-0.99). Durability of antibody detection in longitudinal samples was dependent on assay format and immunoglobulin target, with anti-spike, direct, or total Ig assays demonstrating more stable, or increasing reactivity over time than anti-nucleocapsid, indirect, or IgG assays. Assays with high sensitivity, specificity and durable antibody detection are ideal for serosurveillance. Less sensitive assays demonstrating waning reactivity are appropriate for other applications, including characterizing antibody responses after infection and vaccination, and detection of anamnestic boosting by reinfections and vaccine breakthrough infections. Assay performance must be evaluated in the context of the intended use.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by research contracts from the Centers for Disease Control and Prevention (CDC Contract 75D30120C08170).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All blood donors consented to use of de-identified, residual specimens for further research purposes. UCSF IRB provided explicit approval for VRI self-certification that use of the de-identified CCP donations in this study does not meet the criteria for human subjects research. CDC investigators reviewed and relied on this determination as consistent with applicable federal law and CDC policy (45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe analytic data set is available upon request. |
Gene flux and acid-imposed selection are the main drivers of antimicrobial resistance in broiler chicks infected with Salmonella enterica serovar Heidelberg (preprint)
Oladeinde A , Abdo Z , Press MO , Cook K , Cox NA , Zwirzitz B , Woyda R , Lakin SM , Thomas JCIV , Looft T , Cosby DE , Hinton AJr , Guard J , Line E , Rothrock MJ , Berrang ME , Herrington K , Zock G , Plumblee Lawrence J , Cudnik D , House S , Ingram K , Lariscy L , Wagner M , Aggrey SE , Chai L , Ritz C . bioRxiv 2021 2021.02.25.432983 Antimicrobial resistance (AR) spread is a worldwide health challenge, stemming in large part, from the ability of microbes to share their genetic material through horizontal gene transfer (HGT). Overuse and misuse of antibiotics in clinical settings and in food production have been linked to this increased prevalence and spread of AR. Consequently, public health and consumer concerns have resulted in a remarkable recent reduction in antibiotics used for food animal production. This is driven by the assumption that removing this selective pressure will favor the recovery of antibiotic susceptible taxa and will limit AR sharing through HGT, allowing the currently available antibiotic arsenal to be effective for a longer period. In this study we used broiler chicks raised antibiotic-free and Salmonella enterica serovar Heidelberg (SH), as a model food pathogen, to test this hypothesis. Our results show that neonatal broiler chicks challenged with an antibiotic susceptible SH strain and raised without antibiotics carried susceptible and multidrug resistance SH strains 14 days after challenge. SH infection perturbed the microbiota of broiler chicks and gavaged chicks acquired antibiotic resistant SH at a higher rate. We determined that the acquisition of a plasmid from commensal Escherichia coli population conferred multidrug resistance phenotype to SH recipients and carriage of this plasmid increased the fitness of SH under acidic selection pressure. These results suggest that HGT of AR shaped the evolution of SH and that antibiotic use reduction alone is insufficient to limit antibiotic resistance transfer from commensal bacteria to Salmonella.Importance The reported increase in antibiotic resistant bacteria in humans have resulted in a major shift away from antibiotics use in food animal production. This has been driven by the assumption that removing antibiotics will select for antibiotic susceptible bacterial taxa, and this in turn will allow the currently available antibiotic arsenal to be more effective. This shift in practice has highlighted new questions that need to be answered to assess the effectiveness of antibiotic removal in reducing the spread of antibiotic resistance bacteria. This research demonstrates that antibiotic susceptible Salmonella Heidelberg strains can acquire multidrug resistance from commensal bacteria present in the gut of neonatal broiler chicks, even in the absence of antibiotic selection. We demonstrate that exposure to acidic pH drove the horizontal transfer of antimicrobial resistance plasmids and suggests that simply removing antibiotics from food-animal production might not be sufficient to limit the spread of antimicrobial resistance.Competing Interest StatementThe authors have declared no competing interest. |
Characteristics of children and antigen test performance at a SARS-CoV-2 community testing site (preprint)
Ford L , Whaley MJ , Shah MM , Salvatore PP , Segaloff HE , Delaney A , Currie DW , Boyle-Estheimer L , O'Hegarty M , Morgan CN , Meece J , Ivacic L , Thornburg NJ , Tamin A , Harcourt JL , Folster JM , Medrzycki M , Jain S , Wong P , Goffard K , Gieryn D , Kahrs J , Langolf K , Zochert T , Tate JE , Hsu CH , Kirking HL . medRxiv 2021 2021.07.06.21259792 Background Performance characteristics of SARS-CoV-2 antigen tests among children are limited despite the need for point-of-care testing in school and childcare settings. We describe children seeking SARS-CoV-2 testing at a community site and compare antigen test performance to real-time reverse transcription-polymerase chain reaction (RT-PCR) and viral culture.Methods Two anterior nasal specimens were self-collected for BinaxNOW antigen and RT-PCR testing, along with demographics, symptoms, and exposure information from individuals ≥5 years at a community testing site. Viral culture was attempted on residual antigen or RT-PCR positive specimens. Demographic and clinical characteristics, and the performance of SARS-CoV-2 antigen tests, were compared among children (<18 years) and adults.Results About one in ten included specimens were from children (225/2110); 16.4% (37/225) were RT-PCR positive. Cycle threshold values were similar among RT-PCR positive specimens from children and adults (22.5 vs 21.3, p=0.46) and among specimens from symptomatic and asymptomatic children (22.5 vs 23.2, p=0.39). Sensitivity of antigen test compared to RT-PCR was 73.0% (27/37) among specimens from children and 80.8% (240/297) among specimens from adults; among specimens from children, specificity was 100% (188/188), positive and negative predictive value were 100% (27/27) and 94.9% (188/198) respectively. Virus was isolated from 51.4% (19/37) of RT-PCR positive pediatric specimens; all 19 had positive antigen test results.Conclusions With lower sensitivity relative to RT-PCR, antigen tests may not diagnose all positive COVID-19 cases; however, antigen testing identified children with live SARS-CoV-2 virus.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. See e.g., 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. 241(d); 5 U.S.C. 552a; 44 U.S.C. 3501 et seq.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request. |
Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial – BCPP/ Ya Tsie trial (preprint)
Magosi LE , Zhang Y , Golubchik T , DeGruttola V , Tchetgen Tchetgen E , Novitsky V , Moore J , Bachanas P , Segolodi T , Lebelonyane R , Pretorius Holme M , Moyo S , Makhema J , Lockman S , Fraser C , Essex MM , Lipsitch M . medRxiv 2021 2021.06.19.21259186 Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] versus 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] versus 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The trial was approved by the Botswana Health Research and Development Committee, the institutional review board of the Centers for Disease Control and Prevention and the Harvard School of Public Health Office of Regulatory Affairs and Research Compliance; and was monitored by a data and safety monitoring board and Westat. Written informed consent for enrollment in the trial and viral HIV genotyping was obtained from all participants.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are within the paper and the Supplemental Notes, figures and tables. HIV-1 reads are available on reasonable request through the PANGEA consortium (www.pangea-hiv.org) |
Rapid Development of Neutralizing and Diagnostic SARS-COV-2 Mouse Monoclonal Antibodies (preprint)
Chapman AP , Tang X , Lee JR , Chida A , Mercer K , Wharton RE , Kainulainen M , Harcourt JL , Martines RB , Schroeder M , Zhao L , Bryksin A , Zhou B , Bergeron E , Bollweg BC , Tamin A , Thornburg N , Wentworth DE , Petway D , Bagarozzi DA Jr , Finn MG , Goldstein JM . bioRxiv 2020 2020.10.13.338095 The need for high-affinity, SARS-CoV-2-specific monoclonal antibodies (mAbs) is critical in the face of the global COVID-19 pandemic, as such reagents can have important diagnostic, research, and therapeutic applications. Of greatest interest is the ~300 amino acid receptor binding domain (RBD) within the S1 subunit of the spike protein because of its key interaction with the human angiotensin converting enzyme 2 (hACE2) receptor present on many cell types, especially lung epithelial cells. We report here the development and functional characterization of 29 nanomolar-affinity mouse SARS-CoV-2 mAbs created by an accelerated immunization and hybridoma screening process. Differing functions, including binding of diverse protein epitopes, viral neutralization, impact on RBD-hACE2 binding, and immunohistochemical staining of infected lung tissue, were correlated with variable gene usage and sequence.Competing Interest StatementThe authors have declared no competing interest. |
Whole-Genome Enrichment and Sequencing of Chlamydia trachomatis Directly from Patient Clinical Vaginal and Rectal Swabs (preprint)
Bowden KE , Joseph SJ , Cartee JC , Ziklo N , Danavall D , Raphael BH , Read TD , Dean D . bioRxiv 2020 2020.09.04.282459 Chlamydia trachomatis is the most prevalent cause of bacterial sexually transmitted infections (STIs) worldwide. U.S. cases have been steadily increasing for more than a decade in both the urogenital tract and rectum. C. trachomatis is an obligate intracellular bacterium that is not easily cultured, limiting the capacity for genome studies to understand strain diversity and emergence among various patient populations globally. While Agilent SureSelectXT target-enrichment RNA bait libraries have been developed for whole-genome enrichment and sequencing of C. trachomatis directly from clinical urine, vaginal, conjunctival and rectal samples, efficiencies are only 60-80% for ≥95-100% genome coverage. We therefore re-designed and expanded the RNA bait library to augment enrichment of the organism from clinical samples to improve efficiency. We describe the expanded library, the limit of detection for C. trachomatis genome copy input, and the 100% efficiency and high-resolution of generated genomes where genomic recombination among paired vaginal and rectal specimens from four patients was identified. This workflow provides a robust approach for discerning genomic diversity and advancing our understanding of the molecular epidemiology of contemporary C. trachomatis STIs across sample types, among geographic populations, sexual networks, and outbreaks associated with proctitis/proctocolitis among women and men who have sex with men.Importance Chlamydia trachomatis is an obligate intracellular bacterium that is not easily cultured, and there is limited information on rectal C. trachomatis transmission and its impact on morbidity. To improve efficiency of previous studies involving whole genome target enrichment and sequencing of C. trachomatis directly from clinical urine, vaginal, conjunctival, and rectal specimens, we expanded the RNA bait library to augment enrichment of the organism from clinical samples. We demonstrate an increased efficiency in the percentage of reads mapping to C. trachomatis. We show the new system is sensitive for near identical genomes of C. trachomatis from two body sites in four women. Further, we provide a robust genomic epidemiologic approach to advance our understanding of C. trachomatis strains causing ocular, urogenital and rectal infections, and to explore geo-sexual networks, outbreaks of colorectal infections among women and men who have sex with men, and the role of these strains in morbidity.Competing Interest StatementThe authors have declared no competing interest. |
Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma (preprint)
Voss WN , Hou YJ , Johnson NV , Kim JE , Delidakis G , Horton AP , Bartzoka F , Paresi CJ , Tanno Y , Abbasi SA , Pickens W , George K , Boutz DR , Towers DM , McDaniel JR , Billick D , Goike J , Rowe L , Batra D , Pohl J , Lee J , Gangappa S , Sambhara S , Gadush M , Wang N , Person MD , Iverson BL , Gollihar JD , Dye J , Herbert A , Baric RS , McLellan JS , Georgiou G , Lavinder JJ , Ippolito GC . bioRxiv 2020 Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq (1) ) to the spike ectodomain (S-ECD (2) ) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro , we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 Å (2) ). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning (3,4) our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection. |
Evaluation of the Abbott ARCHITECT HIV Ag/Ab Combo Assay for Determining Recent HIV-1 Infection (preprint)
Curtis KA , Rudolph DL , Pan Y , Delaney K , Anastos K , DeHovitz J , Kassaye SG , Hanson CV , French AL , Golub E , Adimora AA , Ofotokun I , Bolivar H , Kempf MC , Peters PJ , Switzer WM . bioRxiv 2020 2020.11.09.374017 Background Given the challenges and costs associated with implementing HIV-1 incidence assay testing, there is great interest in evaluating the use of commercial HIV diagnostic tests for determining recent HIV infection. A diagnostic test with the capability of providing reliable data for the determination of recent HIV infection without substantial modifications to the test protocol would have a significant impact on HIV surveillance. The Abbott ARCHITECT HIV Ag/Ab Combo Assay is an antigen/antibody immunoassay, which meets the criteria as the first screening test in the recommended HIV laboratory diagnostic algorithm for the United States.Methods In this study, we evaluated the performance characteristics of the ARCHITECT HIV Ag/Ab Combo signal-to-cutoff ratio (S/Co) for determining recent infection, including estimation of the mean duration of recent infection (MDRI) and false recent rate (FRR), and selection of recency cutoffs.Results The MDRI estimates for the S/Co recency cutoff of 400 is within the 4 to 12 months range recommended for HIV incidence assays, and the FRR rate for this cutoff was 1.5%. Additionally, ARCHITECT Combo S/Co values were compared relative to diagnostic test results from two prior prospective HIV-1 diagnostic studies in order to validate the use of the S/Co for both diagnostic and recency determination.Conclusion Dual-use of the ARCHITECT Combo assay data for diagnostic and incidence purposes would reduce the need for separate HIV incidence testing and allow for monitoring of recent infection for incidence estimation and other public health applications. |
Evolution of the complex transcription network controlling biofilm formation in Candida species (preprint)
Mancera E , Nocedal I , Hammel S , Gulati M , Mitchell KF , Andes DR , Nobile CJ , Butler G , Johnson AD . bioRxiv 2020 2020.11.08.373514 We examine how a complex transcription network composed of seven “master” regulators and hundreds of target genes evolved over a span of approximately 70 million years. The network controls biofilm formation in several Candida species, a group of fungi that are present in humans both as constituents of the microbiota and as opportunistic pathogens. The ability to form biofilms is crucial for microbial colonization of different host niches, particularly when an implanted medical device is present. We examined and compared the network underlying biofilm formation across four Candida species (C. albicans, C. dubliniensis, C. tropicalis, and C. parapsilosis), all of which form biofilms composed of multiple cell types. To describe the salient features of the network across different species, we employed four approaches: (1) we phenotypically characterized the biofilms formed by these species using a variety of methods; (2) we knocked out — one by one — the master regulators identified in C. albicans in the four species and monitored their effect on biofilm formation; (3) we identified the target genes of 18 master regulator orthologs across the four species by performing ChIP-seq experiments; and (4) we carried out transcriptional profiling across each species during biofilm formation. Additional network information was obtained by analyzing an interspecies hybrid formed between the two most closely related species, C. albicans and C. dubliniensis. We observed two major types of changes that have occurred in the biofilm circuit since the four species last shared a common ancestor. Master regulator “substitutions” occurred over relatively long evolutionary times, resulting in different species having overlapping, but different sets of master regulators of biofilm formation. Second, massive changes in the connections between the master regulators and their target genes occurred over much shorter timescales. Both types of change are crucial to account for the structures of the biofilm networks in extant species. We believe this analysis is the first detailed, empirical description of how a complex transcription network has evolved.Competing Interest StatementThe authors have declared no competing interest. |
Genomic surveillance and improved molecular typing of Bordetella pertussis using wgMLST (preprint)
Weigand MR , Peng Y , Pouseele H , Kania D , Bowden KE , Williams MM , Tondella ML . bioRxiv 2020 2020.10.28.360149 Multi-Locus Sequence Typing (MLST) provides allele-based characterization of bacterial pathogens in a standardized framework. However, current MLST schemes for Bordetella pertussis, the causative agent of whooping cough, seldom reveal diversity among the small number of gene targets and thereby fail to delineate population structure. To improve discriminatory power of allele-based molecular typing of B. pertussis, we have developed a whole-genome MLST (wgMLST) scheme from 214 reference-quality genome assemblies. Iterative refinement and allele curation resulted in a scheme of 3,506 coding sequences and covering 81.4% of the B. pertussis genome. This wgMLST scheme was further evaluated with data from a convenience sample of 2,389 B. pertussis isolates sequenced on Illumina instruments, including isolates from known outbreaks and epidemics previously characterized by existing molecular assays, as well as replicates collected from individual patients. wgMLST demonstrated concordance with whole-genome single nucleotide polymorphisms (SNP) profiles, accurately resolved outbreak and sporadic cases in a retrospective comparison, and clustered replicate isolates collected from individual patients during diagnostic confirmation. Additionally, a re-analysis of isolates from two statewide epidemics using wgMLST reconstructed the population structures of circulating strains with increased resolution, revealing new clusters of related cases. Comparison with an existing core-genome (cgMLST) scheme highlights the genomic stability of this bacterium and forms the initial foundation for necessary standardization. These results demonstrate the utility of wgMLST for improving B. pertussis characterization and genomic surveillance during the current pertussis disease resurgence. |
Geographic heterogeneity in Anopheles albimanus microbiota is lost within one generation of laboratory colonization (preprint)
Dada N , Benedict AC , López F , Lol JC , Sheth M , Dzuris N , Padilla N , Lenhart A . bioRxiv 2020 2020.06.02.129619 Research on mosquito-microbe interactions may lead to new tools for mosquito and mosquito-borne disease control. To date, such research has largely utilized laboratory-reared mosquitoes that may lack the microbial diversity of wild populations. To better understand how mosquito microbiota may vary across different geographic locations and upon laboratory colonization, we characterized the microbiota of F1 progeny of wild-caught adult Anopheles albimanus from four locations in Guatemala using high throughput 16S rRNA amplicon sequencing. A total of 132 late instar larvae and 135 2-5day old, non-blood-fed virgin adult females were reared under identical laboratory conditions, pooled (3 individuals/pool) and analyzed. Larvae from mothers collected at different sites showed different microbial compositions (p=0.001; F = 9.5), but these differences were no longer present at the adult stage (p=0.12; F = 1.6). This indicates that mosquitoes retain a significant portion of their field-derived microbiota throughout immature development but shed them before or during adult eclosion. This is the first time the microbiota of F1 progeny of wild-caught mosquitoes has been characterized in relation to parental collection site, and our findings provide evidence that geographically associated heterogeneity in microbiota composition persists for a single generation, but only until the end of the larval stage. These findings advance our understanding of how the mosquito microbiota is altered upon first laboratory colonization, and raises considerations for how mosquito microbiome research may be extended beyond the laboratory to field settings.Competing Interest StatementThe authors have declared no competing interest. |
High-throughput quantitation of SARS-CoV-2 antibodies in a single-dilution homogeneous assay (preprint)
Kainulainen MH , Bergeron E , Chatterjee P , Chapman AP , Lee J , Chida A , Tang X , Wharton RE , Mercer KB , Petway M , Jenks HM , Flietstra TD , Schuh AJ , Satheshkumar PS , Chaitram JM , Owen SM , Finn MG , Goldstein JM , Montgomery JM , Spiropoulou CF . medRxiv 2020 2020.09.16.20195446 SARS-CoV-2 emerged in late 2019 and has since spread around the world, causing a pandemic of the respiratory disease COVID-19. Detecting antibodies against the virus is an essential tool for tracking infections and developing vaccines. Such tests, primarily utilizing the enzyme-linked immunosorbent assay (ELISA) principle, can be either qualitative (reporting positive/negative results) or quantitative (reporting a value representing the quantity of specific antibodies). Quantitation is vital for determining stability or decline of antibody titers in convalescence, efficacy of different vaccination regimens, and detection of asymptomatic infections. Quantitation typically requires two-step ELISA testing, in which samples are first screened in a qualitative assay and positive samples are subsequently analyzed as a dilution series. To overcome the throughput limitations of this approach, we developed a simpler and faster system that is highly automatable and achieves quantitation in a single-dilution screening format with sensitivity and specificity comparable to those of ELISA.One sentence summary Protein complementation enables mix-and-read SARS-CoV-2 serology that rivals sensitivity and specificity of ELISA but excels in throughput and quantitation.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis research was funded by the Centers for Disease Control and Prevention.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Residual specimen materials were used for diagnostics development under a protocol that was reviewed and approved by the CDC Institutional Review Board (See 45 C.F.R. part 46; 21 C.F.R. part 56)All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesNo external data links |
Serological and metagenomic interrogation of cerebrospinal fluid implicates enteroviruses in pediatric acute flaccid myelitis (preprint)
Schubert RD , Hawes IA , Ramachandran PS , Ramesh A , Crawford ED , Pak JE , Wu W , Cheung CK , O'Donovan BD , Tato CM , Lyden A , Tan M , Sit R , Sowa GA , Sample HA , Zorn KC , Banerji D , Khan LM , Bove R , Hauser SL , Gelfand AA , Johnson-Kerner BL , Nash K , Krishnamoorthy KS , Chitnis T , Ding JZ , McMillan HJ , Chiu CY , Briggs B , Glaser CA , Yen C , Chu V , Wadford DA , Dominguez SR , Ng TFF , Marine RL , Lopez AS , Nix WA , Soldatos A , Gorman MP , Benson L , Messacar K , Konopka-Anstadt JL , Oberste MS , DeRisi JL , Wilson MR . bioRxiv 2019 666230 Background Since 2014, the United States has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF) and only inconsistently identified from the respiratory tract, serum, or stool.Methods We interrogated CSF from children with AFM (n=42) and pediatric controls with other neurologic diseases (OND) (n=58). Samples were incubated with T7 bacteriophage expressing 481,966 sixty-two amino acid peptides with a fourteen amino acid overlap tiled across all known vertebrate virus and arbovirus genomes, an adaption of the VirScan method. Antibody-bound phage were deep sequenced to quantify enriched peptides with normalized counts expressed as reads per hundred thousand (rpK). EV antibody findings were confirmed with ELISA using whole viral protein 1 (VP1) from contemporary enterovirus (EV) A71 and D68 strains. Separately, metagenomic next-generation sequencing (mNGS) of CSF RNA, both unbiased and with targeted enrichment for EVs, was performed.Results The most significantly enriched viral family by VirScan of CSF in AFM versus OND controls was Picornaviridae (mean rpK 11,266 versus mean rpK 950, p-adjusted < 0.001, Wilcoxon signed-rank test with Bonferroni adjustment). Enriched Picornaviridae peptides belonged almost entirely to the genus Enterovirus. The mean EV VP1 ELISA signal in AFM (mean OD 0.51) was significantly higher than OND controls (mean OD 0.08, p-value < 0.001, Mann-Whitney test). mNGS did not detect additional enterovirus RNA in CSF.Conclusion Despite the rare detection of EV RNA in the CNS of patients with AFM, a pan-viral serologic assay identified high levels of CSF EV antibodies in AFM CSF compared to CSF from OND controls. These results provide further evidence for a causal role of non-polio enteroviruses in AFM. |
Evolution and rapid spread of a reassortant A(H3N2) virus that predominated the 2017-2018 influenza season (preprint)
Potter BI , Garten R , Hadfield J , Huddleston J , Barnes J , Rowe T , Guo L , Xu X , Neher RA , Bedford T , Wentworth DE . bioRxiv 2019 543322 The 2017-2018 North American influenza season caused more hospitalizations and deaths than any year since the 2009 H1N1 pandemic. The majority of recorded influenza infections were caused by A(H3N2) viruses, with most of the virus’s North American diversity falling into the A2 clade. Within A2, we observe a subclade which we call A2/re that rose to comprise almost 70% of A(H3N2) viruses circulating in North America by early 2018. Unlike most fast-growing clades, however, A2/re contains no amino acid substitutions in the hemagglutinin (HA) segment. Moreover, HI assays did not suggest substantial antigenic differences between A2/re viruses and viruses sampled during the 2016-2017 season. Rather, we observe that the A2/re clade was the result of a reassortment event that occurred in late 2016 or early 2017 and involved the combination of the HA and PB1 segments of an A2 virus with neuraminidase (NA) and other segments a virus from the clade A1b. The success of this clade shows the need for antigenic analysis that targets NA in addition to HA. Our results illustrate the potential for non-HA drivers of viral success and necessitate the need for more thorough tracking of full viral genomes to better understand the dynamics of influenza epidemics. |
CliqueSNV: Scalable Reconstruction of Intra-Host Viral Populations from NGS Reads (preprint)
Knyazev S , Tsyvina V , Melnyk A , Artyomenko A , Malygina T , Porozov YB , Campbell EM , Switzer WM , Skums P , Zelikovsky A . bioRxiv 2019 264242 Highly mutable RNA viruses such as influenza A virus, human immunodeficiency virus and hepatitis C virus exist in infected hosts as highly heterogeneous populations of closely related genomic variants. The presence of low-frequency variants with few mutations with respect to major strains may result in an immune escape, emergence of drug resistance, and an increase of virulence and infectivity. Next-generation sequencing technologies permit detection of sample intra-host viral population at extremely great depth, thus providing an opportunity to access low-frequency variants. Long read lengths offered by single-molecule sequencing technologies allow all viral variants to be sequenced in a single pass. However, high sequencing error rates limit the ability to study heterogeneous viral populations composed of rare, closely related variants.In this article, we present CliqueSNV, a novel reference-based method for reconstruction of viral variants from NGS data. It efficiently constructs an allele graph based on linkage between single nucleotide variations and identifies true viral variants by merging cliques of that graph using combinatorial optimization techniques. The new method outperforms existing methods in both accuracy and running time on experimental and simulated NGS data for titrated levels of known viral variants. For PacBio reads, it accurately reconstructs variants with frequency as low as 0.1%. For Illumina reads, it fully reconstructs main variants. The open source implementation of CliqueSNV is freely available for download at https://github.com/vyacheslav-tsivina/CliqueSNV |
Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens among children: A cluster-randomized, placebo-controlled trial in Niger (preprint)
Arzika AM , Maliki R , Goodhew EB , Rogier E , Priest JW , Lebas E , O'Brien KS , Le V , Oldenburg CE , Doan T , Porco TC , Keenan JD , Lietman TM , Martin DL , Arnold BF . medRxiv 2021 2021.04.23.21255957 Background The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality. Additional endpoints in the trial have attempted to elucidate the mechanisms for mortality reduction. In this pre-specified secondary analysis, we assessed the effect of azithromycin compared with placebo on IgG- based measures of infectious disease exposure with a multiplex bead assay that included antigens to malaria parasites (Plasmodium falciparum, P. vivax, P. malariae, P. ovale), bacterial pathogens (Campylobacter spp., enterotoxigenic Escherichia coli, Vibrio cholerae, Salmonella enterica, Streptococcus pyogenes) and protozoans (Cryptosporidium parvum, Giardia duodenales).Methods and Findings Thirty communities in rural Niger were randomized 1:1 to biannual distributions of azithromycin or placebo among children ages 1-59 months. The analysis included 5,642 blood specimens collected from 3,814 children ages 1-59 months, measured at 6, 12, 24, and 36 months of follow-up in a repeated cross-sectional design. Campylobacter spp. seroprevalence averaged over all study visits was lower in azithromycin communities compared to placebo (91% vs 94%, difference = –3%, 95% CI: –5%, –1%; P=0.03), which corresponded to a 29% lower seroconversion rate (1.30 versus 1.84 seroconversions per year, hazard ratio = 0.71, 95% CI: 0.56, 0.89; P=0.004). Antibody-based measures of infection with P. falciparum and group A streptococcus were consistently lower in azithromycin communities, but were not statistically different from placebo, and there were no other differences across pathogens. Strengths of the study included masking of participants, investigators, and analysts, high treatment coverage, large sample size, and objective outcomes. Principal limitations included the timing of blood collection with respect to treatment (approximately 6 months later, which could have missed transient effects in the weeks immediately following treatment), and the durability of IgG response following clearance of infection. Both limitations would lead the trial to under-estimate effects on antibody-based measures of infection.Conclusions The reduction in Campylobacter spp. despite these limitations suggests an effect on carriage, findings which align with an independent metagenomic analysis of rectal swabs collected in the same villages and with previously reported reductions in dysentery-associated mortality. Given significant sequelae of Campylobacter infection among preschool aged children, our results support at least one possible mechanism through which biannual mass distribution of azithromycin likely reduced mortality in this study population.Competing Interest StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data analysis, data interpretation, or writing of the report. The authors declare no competing interests. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services. Clinical TrialNCT02048007Funding StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data nalysis, data interpretation, or writing of the report.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The trial protocol was reviewed and approved by the Committee on Human Research at the University of California, San Francisco, and the Niger Ministry of Health's Ethical Committee. Parents or guardians of enrolled children provided oral consent before each azithromycin or placebo treatment and at each specimen collection visit. Parents or guardians were instructed to report any adverse event within 7 days of treatment by contacting their village representative, who then reported events to the site coordinator and UCSF. An independent Data and Safety Monitoring Committee provided additional oversight. CDC researchers had access to de-identified samples for analysis (no personally identifying information).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and computational notebooks used to conduct the analyses are available through the Open Science Framework (https://osf.io/954bt) and Dryad (xx DOI forthcoming xx). Analyses used R statistical software, version 4.0.2. https://osf.io/954bt |
Occupational exposures and mitigation strategies among homeless shelter workers at risk of COVID-19 (preprint)
Rao CY , Robinson T , Huster K , Laws RL , Keating R , Tobolowsky FA , McMichael TM , Gonzales E , Mosites E . medRxiv 2021 2021.02.22.21251646 Objective To describe the work environment and COVID-19 mitigation measures for homeless shelter workers and assess occupational risk factors for COVID-19 infectionMethods Between June 9-August 10, 2020, we conducted a self-administered survey among homeless shelter workers in Washington, Massachusetts, Utah, Maryland, and Georgia. We calculated frequencies for work environment, personal protective equipment use, and SARS-CoV-2 testing history. We used generalized linear models to produce unadjusted prevalence ratios (PR) to assess risk factors for SARS-CoV-2 infection.Results Of the 106 respondents, 43.4% reported frequent close contact with clients; 75% were worried about work-related SARS-CoV-2 infections; 15% reported testing positive. Close contact with clients was associated with testing positive for SARS-CoV-2 (PR 3.97, 95%CI 1.06, 14.93).Conclusions Homeless shelter workers may be at higher risk of being infected with SARS-CoV-2 during the course of their work. Protecting these critical essential workers by implementing mitigation measures and prioritizing for COVID-19 vaccination, is imperative during the pandemic.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding was receivedAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This project was reviewed by the Centers for Disease Control and Prevention (CDC) COVID-19 Response Human Subject Review panel. The project was determined to meet the requirements of public health surveillance covered by the U.S. Department of Health and Human Services Policy for the Protection of Human Research Subjects as defined in 45 CFR 46.102, and the decision was made that this project was nonresearch and did not require ethical review by the CDC Human Research Protection Office. Ethical approval was waived and informed consent was not required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData are not available. |
COVID-19 Vaccine Perceptions and Uptake in a National Prospective Cohort of Essential Workers (preprint)
Lutrick K , Groom H , Fowlkes AL , Groover KD , Gaglani M , Rivers P , Naleway AL , Nguyen K , Herring M , Dunnigan K , Phillips A , Parker J , Mayo Lamberte J , Prather K , Thiese MS , Baccam Z , Tyner H , Yoon S . medRxiv 2021 2021.10.20.21265288 Introduction In a multi-center prospective cohort of essential workers, we assessed knowledge, attitudes, and practices (KAP) by vaccine intention, prior SARS-CoV-2 positivity, and occupation, and their impact on vaccine uptake over time.Methods Initiated in July 2020, HEROES-RECOVER cohort provided socio-demographics and COVID-19 vaccination data. Using follow-up two surveys approximately three months apart, COVID-19 vaccine KAP, intention, and receipt was collected; the first survey categorized participants as reluctant, reachable, or endorsers.Results A total of 4,803 participants were included in the analysis. Most (70%) were vaccine endorsers, 16% were reachable, and 14% were reluctant. By May 2021, 77% had received at least one vaccine dose. KAP responses strongly predicted vaccine uptake, particularly positive attitudes about safety (aOR=5.46, 95% CI: 1.4-20.8) and effectiveness (aOR=5.0, 95% CI: 1.3-19.1). Participants prior SARS-CoV-2 infection were 22% less likely to believe the COVID-19 vaccine was effective compared with uninfected participants (aOR 0.78, 95% CI: 0.64-0.96). This was even more pronounced in first responders compared with other occupations, with first responders 42% less likely to believe in COVID-19 vaccine effectiveness (aOR=0.58, 95% CI 0.40-0.84). KAP responses shifted positively, with reluctant and reachable participant scores modestly increasing in positive responses for perceived vaccine effectiveness (7% and 12%, respectively) on the second follow-up survey; 25% of initially reluctant participants received the COVID-19 vaccine.Discussion Our study demonstrates attitudes associated with COVID-19 vaccine uptake and a positive shift in attitudes over time. First responders, despite potential high exposure to SARS-CoV-2, and participants with a history of SARS-CoV-2 infection were more vaccine reluctant.Conclusions COVID-19 vaccine KAP responses predicted vaccine uptake and associated attitudes improved over time. Perceptions of the COVID-19 vaccine can shift over time. Targeting messages about the vaccine’s safety and effectiveness in reducing SARS-CoV-2 virus infection and illness severity may increase vaccine uptake for reluctant and reachable participants.Competing Interest StatementThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Allison L. Naleway reported funding from Pfizer for a meningococcal B vaccine study unrelated to the submitted work.Funding StatementThis study was funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention (contracts 75D30120R68013 to Marshfield Clinic Research Institute, 75D30120C08379 to the University of Arizona, and 75D30120C08150 to Abt Associates).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:- Ethics committee/IRB of University of Arizona gave ethical approval for this work - Ethic committee/IRB of all RECOVER Abt sites (University of Utah, Baylor Scott & White, University of Miami, St Luke's, and Kaiser Permanente) gave ethical approval for this work - Ethics committee/IRB of Centers for Disease Control and Prevention deferred to RECOVER Abt sites and University of Arizona for this workI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study repo ted in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authorsFDAU.S. Food and Drug AdministrationCDCCenters for Disease Control and PreventionEUAEmergency Use AuthorizationKAPKnowledge, attitudes, and practicesHEROESArizona Healthcare, Emergency Response and Other Essential Workers SurveillanceRECOVERStudy and Research on the Epidemiology of SARS-CoV-2 in Essential Response PersonnelH-RHEROES-RECOVERHCPHealth care personnelFWFrontline workersPPEPersonal protective equipment |
Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia (preprint)
Feleke SM , Reichert EN , Mohammed H , Brhane BG , Mekete K , Mamo H , Petros B , Solomon H , Abate E , Hennelly C , Denton M , Keeler C , Hathaway NJ , Juliano JJ , Bailey JA , Rogier E , Cunningham J , Aydemir O , Parr JB . medRxiv 2021 2021.01.26.21250503 Malaria diagnostic testing in Africa is threatened by Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes. Among 12,572 subjects enrolled along Ethiopia’s borders with Eritrea, Sudan, and South Sudan and using multiple assays, we estimate HRP2-based rapid diagnostic tests would miss 9.7% (95% CI 8.5-11.1) of falciparum malaria cases due to pfhrp2 deletion. Established and novel genomic tools reveal distinct subtelomeric deletion patterns, well-established pfhrp3 deletions, and recent expansion of pfhrp2 deletion. Current diagnostic strategies need to be urgently reconsidered in Ethiopia, and expanded surveillance is needed throughout the Horn of Africa.Competing Interest StatementJBP reports research support from Gilead Sciences, honoraria from Virology Education for medical education teaching, and non-financial support from Abbott Diagnostics, all outside the scope of the current work. SMF reports research support from AccessBio, outside of the current work.Funding StatementThis work was funded by the Global Fund to Fight AIDS, Tuberculosis, and Malaria through the Ministry of Health-Ethiopia (EPHI5405 to SMF) and the World Health Organization (JAC, JBP). It was also partially supported by MSF Holland, which supported field work in Gambella Region, the Doris Duke Charitable Foundation (JBP), and the US National Institutes of Health (R01AI132547 to JJJ, JAB, OA, and JBP; K24AI134990 to JJJ).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the Ethiopia Public Health Institute (EPHI) Institutional Review Board (IRB; protocol EPHI-IRB-033-2017) and WHO Research Ethics Review Committee (protocol: ERC.0003174 001). Processing of de-identified samples and data at UNC was determined to constitute non-human subjects research by the UNC IRB (study 17-0155). The study was determined to be non-research by the Centers for Disease Control and Prevention Human Subjects office (0900f3eb81bb60b9).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesGenomic sequencing data will be available through the Sequence Read Archive (BioSample accession numbers pending). De-identified datasets generated during the current study will be available as supplementary files. Code used during data analysis will be made available on GitHub. |
Linked surveillance and genetic data uncovers programmatically relevant geographic scale of Guinea worm transmission in Chad (preprint)
Ribado JV , Li N , Thiele E , Lyons H , Cotton JA , Weiss A , Tchindebet Ouakou P , Moundai T , Zirimwabagabo H , Guagliardo SAJ , Chabot-Couture G , Proctor JL . medRxiv 2020 2020.10.05.20207324 Background Guinea worm (Dracunculus medinensis) was detected in Chad in 2010 after a supposed ten year absence, posing a challenge to the global eradication effort. Initiation of a village-based surveillance system in 2012 revealed a substantial number of dogs infected with Guinea worm, raising questions about paratenic hosts and cross-species transmission.Methodology/Principal Findings We coupled genomic and surveillance data from 2012-2018 cases to investigate the modes of transmission between hosts and the geographic connectivity for genetically similar worm populations. Eighty-six variants across three loci on the mitochondrial genome identified 41 genetically distinct worm genotypes. Spatiotemporal modeling reveals genetically identical worms are within a median range of 18.6 kilometers of each other, but largely within approximately 50 kilometers. Genetically identical worms vary in their degree of spatial clustering, suggesting there may be different factors that favor or constrain transmission. Each worm is surrounded by five to ten genetically distinct worms within a 50 kilometer radius. In an independent population, we show that more variants revealed in whole mitochondrial genome data improved the discrimination between worm pairs.Conclusions/Significance In the largest study linking genetic and surveillance data to date of Guinea worm cases in Chad, we show genetic similarity and modeling can contribute to understanding local transmission. The overlap of genetically distinct worms in quantitatively identified transmission ranges highlights the necessity for genomic tools to link cases. The improved discrimination between worm pairs from variants identified across the complete mitochondrial genome indicates expanding genomic markers could link cases at a finer scale. These results suggest that scaling up genomic surveillance for Guinea worm may provide additional value for programmatic decision-making critical for monitoring cases and intervention efficacy to achieve elimination.Competing Interest StatementThe authors have declared no competing interest.Funding StatementJR, GCC, HL, and JLP would like to thank Bill and Melinda Gates for their active support of the Institute for Disease Modeling and their sponsorship through the Global Good Fund. JAC was supported by funding from The Carter Center and Wellcome, via their core support for the Wellcome Sanger Institute (grant WT206194).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/A; Worm collection and associated metadata are routine in country surveillance efforts.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesGenomic data and source code will be made available upon publication. Requests for epidemiological data that includes case coordinates must be submitted to and approved by the Chad Guinea Worm Eradication Program. |
Potential strategies for strengthening surveillance of lymphatic filariasis in American Samoa after mass drug administration: targeting older age groups, hotspots, and household members of infected persons (preprint)
Lau CL , Sheel M , Gass K , Fuimaono S , David MC , Won KY , Sheridan S , Graves PM . medRxiv 2020 2020.04.07.20056549 Background Under the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted mass drug administration (MDA) from 2000-2006. Despite passing Transmission Assessment Surveys (TAS) in 2011/2012 and 2015, American Samoa failed TAS-3 in 2016, with antigen (Ag) prevalence of 0.7% (95%CI 0.3-1.8%) in 6-7 year-olds. A 2016 community survey (Ag prevalence 6.2% (95%CI 4.4-8.5%) in age ≥8 years) confirmed resurgence. Here, we explore the potential of targeted strategies to strengthen post-MDA surveillance.Methodology/Principal Findings Using Ag data plus new antibody data (Wb123, Bm14, Bm33) from the 2016 surveys, we identified risk factors for seropositivity using multivariable logistic regression. We compared TAS with strategies that targeted high-risk subpopulations (older ages, householders of Ag-positive TAS children [index children]) and/or known hotspots, and used NNTestav (average number needed to test to identify one positive) to compare sampling efficiency.Antibody prevalence in TAS-3 (n=1143) were 1.6% for Bm14 (95%CI 0.9-2.9%), 7.9% for Wb123 (95%CI 6.4-9.6%), and 20.2% for Bm33 (95%CI 16.7-24.3%); and in the community survey (n=2507), 13.9% for Bm14 (95%CI 11.2-17.2%), 27.9% for Wb123 (95%CI 24.6-31.4%), and 47.3% for Bm33 (95%CI 42.1-52.6%). Ag prevalence was 20.7% (95%CI 9.7-53.5%) in households of index children. Higher Ag prevalence was found in males (adjusted odds ratio [aOR] 3.01), age ≥18 years (aOR 2.18), residents of Fagali’i (aOR 15.81), and outdoor workers (aOR 2.61). Using Ag, NNTestav ranged from 142.5 for TAS, to <5 for households of index children. NNTestav was lower in older ages, and highest for Ag, followed by Bm14, Wb123 and Bm33 antibodies.Conclusions/Significance We propose a multi-stage surveillance strategy, starting with population-representative sampling (e.g. TAS), followed by targeted strategies in subgroups and locations with low NNTestav. This approach could potentially improve the efficiency of identifying remaining infected persons and residual hotspots. The utility of antibodies in surveillance should also be explored.AUTHOR SUMMARY Lymphatic filariasis (LF) is a parasitic infection transmitted by mosquito bites. Globally, tens of millions are infected, with many disfigured and disabled by severe damage to their lymphatic systems, such as severe swelling of the legs (elephantiasis) or scrotum (hydrocele). The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through mass drug administration (MDA), and to control illness and suffering in affected persons. The World Health Organization recommends conducting Transmission Assessment Surveys (TAS) in school children aged 6 to 7 years, to determine if infection rates have dropped to levels where disease transmission is no longer sustainable. From 2000-2006, American Samoa conducted MDA and made significant progress towards eliminating LF. However, despite passing TAS in 2011/2012 and 2015, surveys in 2016 showed evidence of resurgence. Our study explored alternative surveillance strategies and compared their efficiency with TAS. Based on our findings, we recommended that in addition to TAS, strategies that target high-risk populations and hotspots would strengthen surveillance and help countries achieve their goals of LF elimination.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work received financial support from the Coalition for Operational Research on Neglected Tropical Diseases (COR-NTD), which is funded at The Task Force for Global Health primarily by the Bill & Melinda Gates Foundation [OPP1053230], the United Kingdom Department for International Development, and by the United States Agency for International Development through its Neglected Tropical Diseases Program. CLL was supported by an Australian National Health and Medical Research Council Fellowship (1109035). MS was supported by a fellowship funded by the Westpac Scholars Trust. The funders had no role in study design, data collection and analysis, decisi n to publish, or preparation of the manuscript.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated and analysed during the present study are available from the corresponding author upon reasonable request. |
Evaluation of the durability of long-lasting insecticidal nets in Guatemala (preprint)
Castellanos ME , Rodas S , Juárez JG , Lol JC , Chanquin S , Morales Z , Vizcaino L , Smith SC , Vanden Eng J , Woldu HG , Lenhart A , Padilla N . medRxiv 2020 2020.07.30.20165316 Background Insecticide-treated bednets (ITNs) are widely used for the prevention and control of malaria. In Guatemala, since 2006, ITNs have been distributed free of charge in the highest risk malaria-endemic areas and constitute one of the primary vector control measures in the country. Despite relying on ITNs for almost 15 years, there is a lack of data to inform the timely replacement of ITNs whose effectiveness becomes diminished by routine use.Methods We assessed the survivorship, physical integrity, insecticide content and bio-efficacy of ITNs through cross-sectional surveys conducted at 18, 24 and 32 months after a 2012 distribution of PermaNet® 2.0 in a malaria focus in Guatemala. A total of 988 ITNs were analyzed (290 at 18 months, 349 at 24 months and 349 at 32 months).Results The functional survivorship of bednets decreased over time, from 92% at 18 months, to 81% at 24 months and 69% at 32 months. Independent of the time of the survey, less than 80% of the bednets that were still present in the household were reported to have been used the night before. Most of the bednets had been washed at least once (88% at 18 months, 92% at 24 months and 96% at 32 months). The proportion of bednets categorized as “in good condition” per WHO guidelines of the total hole surface area, diminished from 77% at 18 months to 58% at 32 months. The portion of ITNs with deltamethrin concentration less than 10mg/m2 increased over time (14% at 18 months, 23% at 24 months, and 35% at 32 months). Among the bednets for which bioassays were conducted, the percentage that met WHO criteria for efficacy dropped from 90% at 18 months to 52% at 32 months.Conclusion While our assessment demonstrated that nets were in relatively good physical condition over time, the combination of declining bio-efficacy over time and low use rates limited the overall effectiveness of the LLINs. Efforts to encourage the community to retain, use, and properly care for the LLINs may improve their impact. Durability assessments should be included in future campaigns.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe funding for this study was provided by the United States Agency for International Development (USAID) via the Amazon Malaria Initiative (AMI), Centers for Disease Control and Prevention (CDC) of the United States of America, Guatemalan Ministry of Public Health and Social Welfare and Center for Health Studies and Universidad del Valle de Guatemala. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of the data and in writing the manuscript.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Oral informed consent was obtained from all participants prior to study inclusion. This study was approved by the Ethics Committee of the Center for Health Studies at Universidad del Valle de Guatemala (Approval Number: 081-06-2013); CDC investigators were not considered to be engaged in human subjects research.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are availa le on request from the senior author, NP. The data are not publicly available due to containing information that could compromise the privacy of participants.GISgeographic information systemGISgeographic information systemGPSGlobal positioning systemIQRinterquartile rangeITNInsecticide-treated bednetLLINlong-lasting insecticide-treated bednetLOESSLocally Weighted Scatterplot SmoothingMoHMinistry of HealthPDApersonal digital assistantTHSAtotal hole surface areatmmedian survival timeWHOWorld Health OrganizationXRFx-ray fluorescence |
Fine-scale heterogeneity in Schistosoma mansoni force of infection measured through antibody response (preprint)
Arnold BF , Kanyi H , Njenga SM , Rawago FO , Priest JW , Secor WE , Lammie PJ , Won KY , Odiere MR . medRxiv 2020 2020.04.10.20061101 Identifying populations with active transmission and monitoring changes in transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected in stool using microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to schistosomiasis soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. Serological measures of transmission closely aligned with stool-based measures of infection, and serological measures provided better resolution for between-community differences at lower levels of infection. Serology enabled fine- scale measures of heterogeneity in force of infection both geographically and by age. Our results show that serologic surveillance platforms represent an important new opportunity to guide and monitor schistosomiasis control programs.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the National Institutes of Allergy and Infectious Diseases (K01 AI119180 to BFA) and the Bill & Melinda Gates Foundation (OPP1022543 to PJL). The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and replication files required to conduct the analyses are available through GitHub and the Open Science Framework: https://osf.io/rnme8. Community location data required to replicate the geostatistical model fits is not publicly available to protect participant confidentiality but is available from the corresponding author upon request, pending appropriate human subjects review and approval. https://osf.io/rnme8 |
Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen (preprint)
Bender NG , Khare P , Martinez J , Tweedell RE , Nyasembe VO , López-Gutiérrez B , Tripathi A , Miller D , Hamerly T , Vela EM , Howard RF , Nsango S , Cobb RR , Harbers M , Dinglasan RR . bioRxiv 2020 2020.11.29.402669 Malaria transmission-blocking vaccines (TBVs) are a critical tool for disease elimination. TBVs prevent completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen and structure-function studies have identified two Class II epitopes that induce potent transmission-blocking (T-B) antibodies. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ was immunogenic and immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity and establishing UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.Competing Interest StatementThe authors have declared no competing interest. |
Community-based surveys for Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions in selected regions of mainland Tanzania (preprint)
Bakari C , Jones S , Subramaniam G , Mandara CI , Chiduo MG , Rumisha S , Chacky F , Molteni F , Mandike R , Mkude S , Njau R , Herman C , Nace DP , Mohamed A , Udhayakumar V , Kibet CK , Nyanjom SG , Rogier E , Ishengoma DS . medRxiv 2020 2020.05.12.20097766 Background Despite recent reports of false negative results among histidine-rich protein 2 (HRP2) based-malaria rapid diagnostic tests (mRDTs) caused by pfhrp2/3 gene deletions in different countries, there is paucity of data in Tanzania.Methods This study assessed the status of pfhrp2/3 deletions in 7,543 blood samples using laboratory multiplex antigen detection (Plasmodium lactate dehydrogenase - pLDH, aldolase, and HRP2). Samples showing mRDT false negativity or aberrant relationship of HRP2 to pan-Plasmodium antigens were genotyped for pfhrp2/3genes.Results Of all samples, 2,417 (32.0%) were positive for any Plasmodium antigens while 5,126 (68.0%) were negative. About 99.8% (n=2,411) of antigen positive samples had HRP2, but 6 (0.2%) had only pLDH and/or pAldolase. Thirteen samples had atypical relationships between pan-Plasmodium antigens and HRP2, but were positive by PCR. An additional 16 samples with negative HRP2 mRDTs but positive by microscopy were also chosen; all giving 35 samples genotyped for pfhrp2/3. Of 35 samples, 4 (11.4%) failed to consistently amplify positive control genes (pfmsp1 and pfmsp2), and pfhrp2 and pfhrp3 genes were successfully amplified in 31 (88.6%) samples.Conclusions Lack of pfhrp2 and/or pfhrp3 genes deletions in Plasmodium falciparum parasites supports continued use of HRP2-based mRDTs for routine malaria diagnosis in Tanzania.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe field component of this study was supported by The Global Fund through National Malaria Control Programme of the Tanzanian Ministry of Health. The CDC laboratory work was supported by Malaria Branch and Catherine Bakari’s MSc studies was funded by the Developing Excellence in Leadership and Genomics for Malaria Elimination (DELGEME) project with funding from the Developing Excellence in Leadership and Training (DELTAS) Africa Initiative, of the African Academy of Sciences (AAS).Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request |
Seroprevalence of SARS-CoV-2 during pregnancy and associated outcomes: results from an ongoing prospective cohort study, New York City (preprint)
Molenaar NM , Rommel AS , de Witte L , Dolan SM , Lieb W , Ibroci E , Ohrn S , Lynch J , Capuano C , Stadlbauer D , Krammer F , Zapata LB , Brody RI , Rhoda SSperling , Omara Afzal , Mr Roy Missall , Amy Balbierz , Teresa Janevic , Joanne Stone , Elizabeth AHowell , Veerle Bergink . medRxiv 2021 2021.02.01.21250943 Background In May-July 2020 in the New York City area, up to 16% of pregnant women had reportedly been infected with SARS-CoV-2. Prior studies found associations between SARS-CoV-2 infection during pregnancy and certain adverse outcomes (e.g., preterm birth, cesarean delivery). These studies relied on reverse transcription polymerase chain reaction (RT-PCR) testing to establish SARS-CoV-2 infection. This led to overrepresentation of symptomatic or acutely ill cases in scientific studies.Objective To expand our understanding of the effects of SARS-CoV-2 infection during pregnancy on pregnancy outcomes, regardless of symptomatology and stage of infection, by using serological tests to measure IgG antibody levels.Study Design The Generation C Study is an ongoing prospective cohort study conducted at the Mount Sinai Health System. All pregnant women receiving obstetrical care at the Mount Sinai Hospital and Mount Sinai West Hospital from April 20, 2020 onwards are eligible for participation. For the current analysis, we included participants who had given birth to a liveborn singleton infant on or before August 15, 2020. Blood was drawn as part of routine clinical care; for each woman, we tested the latest sample available to establish seropositivity using a SARS-CoV-2 serologic enzyme-linked immunosorbent assay. Additionally, RT-PCR testing was performed on a nasopharyngeal swab taken during labor and delivery. Pregnancy outcomes of interest (i.e., gestational age at delivery, birth weight, mode of delivery, Apgar score, ICU/NICU admission, and neonatal hospital length of stay) and covariates were extracted from electronic medical records. Among all Generation C participants who had given birth by August 15, 2020 (n=708), we established the SARS-CoV-2 seroprevalence. Excluding women who tested RT-PCR positive at delivery, we conducted crude and adjusted linear and logistic regression models to compare antibody positive women without RT-PCR positivity at delivery with antibody negative women without RT-PCR positivity at delivery. We stratified analyses by race/ethnicity to examine potential effect modification.Results The SARS-CoV-2 seroprevalence based on IgG measurement was 16.4% (n=116, 95% CI 13.7-19.3). Twelve women (1.7%) were SARS-CoV-2 RT-PCR positive at delivery (11 of these women were seropositive). Seropositive women were generally younger, more often Black or Hispanic, and more often had public insurance and higher pre-pregnancy BMI compared with seronegative women. SARS-CoV-2 seropositivity without RT-PCR positivity at delivery was associated with decreased odds of caesarean delivery (aOR 0.48, 95%CI 0.27; 0.84) compared with seronegative women without RT-PCR positivity at delivery. Stratified by race/ethnicity, the association between seropositivity and decreased odds of caesarean delivery remained for non-Hispanic Black/African-American and Hispanic women, but not for non-Hispanic White women. No other pregnancy outcomes differed by seropositivity, overall or stratified by race/ethnicity.Conclusion Seropositivity for SARS-CoV-2 without RT-PCR positivity at delivery, suggesting that infection occurred earlier during pregnancy, was not associated with selected adverse maternal or neonatal outcomes among live births in a cohort sample of women from New York City. While non-Hispanic Black and Latina women in our cohort had a higher rate of SARS-CoV-2 seropositivity compared with non-Hispanic White women, we found no increase in adverse maternal or neonatal outcomes among these groups due to infection.Competing Interest StatementMount Sinai has licensed serological assays to commercial entities and has filed for patent protection for serological assays. D.S and F.K. are listed as inventors on the pending patent application. The other authors have nothing to report.Funding StatementThis study is partially funded (contract 75D30120C08186) by the US Centers for Disease Control and Prevention (CDC), who also provided technical assistance related to analysis and interpretation of data and writing the report. The find ngs and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. Initial assay development work in the Krammer laboratory was partially supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract HHSN272201400008C (FK, for reagent generation), Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (FK, for reagent generation), and the generous support of the JPB foundation, the Open Philanthropy Project (#2020-215611) and other philanthropic donations. These funding sources were not involved in the current study.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent per the institutional review board (IRB)-approved study protocol (IRB at the Icahn School of Medicine at Mount Sinai, protocol IRB-20-03352, April 15, 2020).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData not publicly available. Please contact the corresponding author for data requests. |
One Health Investigation of SARS-CoV-2 Infection and Seropositivity among Pets in Households with Confirmed Human COVID-19 Cases — Utah and Wisconsin, 2020 (preprint)
Goryoka GW , Cossaboom CM , Gharpure R , Dawson P , Tansey C , Rossow J , Mrotz V , Rooney J , Torchetti M , Loiacono CM , Killian ML , Jenkins-Moore M , Lim A , Poulsen K , Christensen D , Sweet E , Peterson D , Sangster AL , Young EL , Oakeson KF , Taylor D , Price A , Kiphibane T , Klos R , Konkle D , Bhattacharyya S , Dasu T , Chu VT , Lewis NM , Queen K , Zhang J , Uehara A , Dietrich EA , Tong S , Kirking HL , Doty JB , Murrell LS , Spengler JR , Straily A , Wallace R , Barton Behravesh C . bioRxiv 2021 2021.04.11.439379 Background Approximately 67% of U.S. households have pets. Limited data are available on SARS-CoV-2 in pets. We assessed SARS-CoV-2 infection in pet cohabitants as a sub-study of an ongoing COVID-19 household transmission investigation.Methods Mammalian pets from households with ≥1 person with laboratory-confirmed COVID-19 were eligible for inclusion from April–May 2020. Demographic/exposure information, oropharyngeal, nasal, rectal, and fur swabs, feces, and blood were collected from enrolled pets and tested by rRT-PCR and virus neutralization assays.Findings We enrolled 37 dogs and 19 cats from 34 of 41 eligible households. All oropharyngeal, nasal, and rectal swabs tested negative by rRT-PCR; one dog’s fur swabs (2%) tested positive by rRT-PCR at the first animal sampling. Among 47 pets with serological results from 30 households, eight (17%) pets (4 dogs, 4 cats) from 6 (20%) households had detectable SARS-CoV-2 neutralizing antibodies. In households with a seropositive pet, the proportion of people with laboratory-confirmed COVID-19 was greater (median 79%; range: 40–100%) compared to households with no seropositive pet (median 37%; range: 13–100%) (p=0.01). Thirty-three pets with serologic results had frequent daily contact (≥1 hour) with the human index patient before the person’s COVID-19 diagnosis. Of these 33 pets, 14 (42%) had decreased contact with the human index patient after diagnosis and none (0%) were seropositive; of the 19 (58%) pets with continued contact, 4 (21%) were seropositive.Interpretations Seropositive pets likely acquired infection from humans, which may occur more frequently than previously recognized. People with COVID-19 should restrict contact with animals.Funding Centers for Disease Control and Prevention, U.S. Department of AgricultureCompeting Interest StatementThe authors have declared no competing interest. |
The urgency of resuming disrupted dog rabies vaccination campaigns: a modeling and cost-effectiveness analysis (preprint)
Kunkel A , Jeon S , Joseph HC , Dilius P , Crowdis K , Meltzer MI , Wallace R . medRxiv 2021 2021.04.24.21256032 OBJECTIVE Dog vaccination is a cost-effective approach to preventing human rabies deaths. In Haiti, the 2019 dog vaccination campaign did not include the capital city, and the 2020 campaign was cancelled because of COVID-19 lockdown restrictions and redirection of funds. We estimated the number of human lives that could be saved by resuming dog vaccination in 2021 compared to 2022 and compared the cost-effectiveness of these two scenarios.METHODS We modified a previously published rabies transmission and economic model to estimate trends in dog and human rabies cases in Haiti from 2005-2025. We compared model outputs to surveillance data on human rabies deaths from 2005-2020 and animal rabies cases from 2018-2020. We then estimated the human health and cost implications of restarting dog vaccination programs in either 2021 or 2022.FINDINGS Model predictions and animal surveillance data from Haiti both suggest a 5-to 8-fold increase in animal rabies cases has occurred in the capital city between Fall 2019 and Fall 2020. We estimate that restarting dog vaccination in Haiti in 2021 compared to 2022 could save 285 human lives and prevent 6,541 human rabies exposures over a five-year period and may decrease program costs due to reduced need for human post-exposure prophylaxis.CONCLUSIONS A one-year delay in resuming dog vaccination in Haiti, from 2021 to 2022, could cost hundreds of lives over the next 5 years. Interruptions in dog vaccination campaigns before elimination is achieved can lead to significant human rabies epidemics if not promptly resumed.Competing Interest StatementThe authors have declared no competing interest.Funding StatementNo external funding.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/A modeling paperAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data are available in the manuscript or supplementary materials. |
US Dog Importations during the COVID-19 Pandemic: Do we have an erupting problem? (preprint)
Pieracci EG , Williams CE , Wallace RM , Kalapura CR , Brown CM . bioRxiv 2021 2021.07.23.453524 Dog importation data from 2018-2020 were evaluated to ascertain whether the dog importation patterns in the United States changed during the COVID-19 pandemic, specifically with regard to denial of entry. Dog denial of entry reports from January 1, 2018, to December 31, 2020, stored within the Centers for Disease Control and Prevention (CDC) Quarantine Activity Reporting System, were reviewed. Basic descriptive statistics were used to analyze the data. Reason for denial, country of origin, and month of importation were all examined to determine which countries of origin resulted in the largest number of denials, and whether there was a seasonal change in importations during the COVID-19 pandemic (2020), compared to previous years (2018 and 2019). During 2020, CDC denied entry to 458 dogs. This represents a 52% increase in dogs denied entry compared to the averages in 2018 and 2019. Dogs were primarily denied entry for falsified rabies vaccination certificates (56%). Three countries exported 74% of all dogs denied entry into the United States, suggesting that targeted interventions may be needed for certain countries. Increased attempts to import inadequately vaccinated dogs from countries with canine rabies in 2020 may have been due to the increased demand for domestic pets during the COVID-19 pandemic. Educational messaging should highlight the risk of rabies and the importance of making informed pet purchases from foreign entities to protect pet owners, their families, and the public.Competing Interest StatementThe authors have declared no competing interest.CBPCustoms and Border ProtectionCDCCenters for Disease Control and PreventionCFRCode of Federal RegulationsCOVID-19coronavirus disease 2019CRVVcanine rabies virus variantQARSQuarantine Activity Reporting SystemRVCrabies vaccination certificate |
Estimating incidence of infection from diverse data sources: Zika virus in Puerto Rico, 2016 (preprint)
Quandelacy TM , Healy JM , Greening B , Rodriguez DM , Chung KW , Kuehnert MJ , Biggerstaff BJ , Dirlikov E , Mier YTeran-Romero L , Sharp TM , Waterman S , Johansson MA . medRxiv 2020 2020.10.14.20212134 Emerging epidemics are challenging to track. Only a subset of cases is recognized and reported, as seen with the Zika virus (ZIKV) epidemic where large proportions of infection were asymptomatic. However, multiple imperfect indicators of infection provide an opportunity to estimate the underlying incidence of infection. We developed a modeling approach that integrates a generic Time-series Susceptible-Infected-Recovered epidemic model with assumptions about reporting biases in a Bayesian framework and applied it to the 2016 Zika epidemic in Puerto Rico using three indicators: suspected arboviral cases, suspected Zika-associated Guillain-Barré Syndrome cases, and blood bank data. Using this combination of surveillance data, we estimated the peak of the epidemic occurred during the week of August 15, 2016 (the 33rd week of year), and 120 to 140 (50% credible interval [CrI], 95% CrI: 97 to 170) weekly infections per 10,000 population occurred at the peak. By the end of 2016, we estimated that approximately 890,000 (95% CrI: 660,000 to 1,100,000) individuals were infected in 2016 (26%, 95% CrI: 19% to 33%, of the population infected). Utilizing multiple indicators offers the opportunity for real-time and retrospective situational awareness to support epidemic preparedness and response.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe author(s) received no specific funding for this work.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Exemption was obtained from the CDC Human Subjects Research Office as the data were collected as part of regular surveillance activities.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are within the manuscript and its Supporting Information files. |
Content Index (Achived Edition)
- Antimicrobial Resistance and Antibiotic Stewardship
- Communicable Diseases
- Community Health Services
- Disease Reservoirs and Vectors
- Environmental Health
- Epidemiology and Surveillance
- Food Safety
- Genetics and Genomics
- Health Economics
- Health Equity and Health Disparities
- Healthcare Associated Infections
- Immunity and Immunization
- Informatics
- Laboratory Sciences
- Maternal and Child Health
- Occupational Safety and Health
- Parasitic Diseases
- Reproductive Health
- Veterinary Medicine
- Zoonotic and Vectorborne Diseases
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