Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 392 Records) |
Query Trace: Montgomery S[original query] |
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Assessing clinical improvement of infants hospitalized for respiratory syncytial virus-related critical illness
Leland SB , Zambrano LD , Staffa SJ , McNamara ER , Newhams MM , Halasa N , Amarin JZ , Stewart LS , Shein SL , Carroll CL , Fitzgerald JC , Michaels MG , Bline K , Cullimore ML , Loftis L , Montgomery VL , Jeyapalan AS , Pannaraj PS , Schwarz AJ , Cvijanovich NZ , Zinter MS , Maddux AB , Bembea MM , Irby K , Zerr DM , Kuebler JD , Babbitt CJ , Gaspers MG , Nofziger RA , Kong M , Coates BM , Schuster JE , Gertz SJ , Mack EH , White BR , Harvey H , Hobbs CV , Dapul H , Butler AD , Bradford TT , Rowan CM , Wellnitz K , Staat MA , Aguiar CL , Hymes SR , Campbell AP , Randolph AG . J Infect Dis 2025 BACKGROUND: Pediatric respiratory syncytial virus (RSV)-related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. METHODS: We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 U.S. PICUs from October through December 2022. We assigned CPS-Ped (0=discharged home at respiratory baseline to 8=death) at admission, days 2-7,10, and 14. We identified predictors of clinical improvement (CPS-Ped≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). RESULTS: Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV). Of the 49 (8.4%) infants whose CPS-Ped score worsened by 2 points after admission, one died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2,031 for hospital LOS. CONCLUSIONS: CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV. |
Improved water, sanitation, hygiene and waste services in health-care facilities, Ukraine
Montgomery M , Vodianyk A , Piven N , Hayter A , Schweitzer R , Skapa T , Gordon B , Schmoll O . Bull World Health Organ 2025 103 (1) 66-70 PROBLEM: Water, sanitation and waste infrastructure and services in Ukrainian health-care facilities often fail to meet global and national standards, hindering the provision of safe, quality care. The war has worsened existing problems. APPROACH: To incrementally improve water, sanitation, hand hygiene, environmental cleaning and health-care waste practices, the World Health Organization (WHO) is working with the health ministry, the Ukrainian Public Health Centre and regional United States Centers for Disease Prevention and Control (CDC) to implement the Water and Sanitation for Health Facility Improvement Tool (WASH FIT). In December 2022, WHO trained staff from the regional CDC, Ukrainian Public Health Centre and nine priority health-care facilities. Facility teams assessed services, and developed and implemented improvement plans in January 2023. Follow-up assessments were conducted after six months. LOCAL SETTING: About 4300 health-care facilities operate in Ukraine. Funding for new water and sanitation infrastructure, as well as operating and maintaining existing services, is likely inadequate. RELEVANT CHANGES: After implementation, the average WASH FIT score increased from 66 out of a maximum of 100 (range: 57-73) to 83 (range: 69-93). Facilities more effectively managed water-related risks, replaced broken taps, improved waste management practices and installed backup water supply and storage sources. LESSONS LEARNT: WASH FIT can be used to identify gaps in water, sanitation, hygiene and waste services and track progress towards addressing these gaps. Engaged local leaders, health-based national water, sanitation, hygiene standards, regular on-site training and mentoring drive these improvements. Strengthening public health entities is critical to institutionalize the process. |
Homelessness and birth outcomes in the Pregnancy Risk Assessment Monitoring System, 2016-2020
Meehan AA , Steele-Baser M , Machefsky AM , Cassell CH , Montgomery MP , Mosites E . Matern Child Health J 2025 OBJECTIVES: This study aimed to estimate the prevalence of homelessness shortly before or during pregnancy and describe differences in maternal characteristics and adverse birth outcomes between people reporting homelessness and not reporting homelessness. METHODS: We used 2016-2020 Pregnancy Risk Assessment Monitoring System (PRAMS) data from 31 sites to estimate the prevalence of self-reported homelessness during the 12 months before giving birth. We used logistic regression models to evaluate the association between homelessness and adverse birth outcomes, specifically small for gestational age (SGA), low birth weight (LBW), and preterm birth (PTB). RESULTS: Of 138,603 respondents, 4,045 reported homelessness, representing 2.4% of weighted respondents. Respondents reporting homelessness differed from respondents who did not report homelessness in maternal demographic characteristics, health conditions, behavioral and environmental risk factors, and adequacy of prenatal care. In unadjusted models, homelessness was associated with higher prevalences of SGA, LBW, and PTB (PR 1.38, 95% CI 1.21-1.57; PR 1.73, 95% CI 1.56-1.91; PR 1.42, 95% CI 1.25-1.61; respectively). After adjusting for maternal age, race and ethnicity, education, BMI, and cigarette smoking, prevalence ratios were attenuated and no longer significant. CONCLUSIONS FOR PRACTICE: Although homelessness was not independently associated with adverse birth outcomes in adjusted models, people reporting homelessness before or during pregnancy represent a group at increased risk of inadequate health care utilization and adverse birth outcomes due to other underlying demographic and social factors. Health care providers can play a critical role in identifying if patients may be experiencing homelessness and facilitating connections to social support. |
Ebola outbreak control in the Democratic Republic of the Congo
Garfield R , Fonjungo P , Soke G , Baggett H , Montgomery J , Luce R , Klena J , Mbala-Kingebeni P , Ahuka S , Mwamba D , Muyembe-Tamfam JJ , Agolory S . Disaster Med Public Health Prep 2024 18 e287 Health Security is a major concern for the Democratic Republic of the Congo (DRC). It is the second largest country in Africa, borders nine other countries, has more than 80 million inhabitants, and has suffered from decades of neglect and conflicts together with multiple recurrent disease outbreaks, including Ebola. |
Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease
Welch SR , Spengler JR , Westover JB , Bailey KW , Davies KA , Aida-Ficken V , Bluemling GR , Boardman KM , Wasson SR , Mao S , Kuiper DL , Hager MW , Saindane MT , Andrews MK , Krueger RE , Sticher ZM , Jung KH , Chatterjee P , Shrivastava-Ranjan P , Lo MK , Coleman-McCray JD , Sorvillo TE , Genzer SC , Scholte FEM , Kelly JA , Jenks MH , McMullan LK , Albariño CG , Montgomery JM , Painter GR , Natchus MG , Kolykhalov AA , Gowen BB , Spiropoulou CF , Flint M . Sci Transl Med 2024 16 (774) eado7034 Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4'-fluorouridine (4'-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4'-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4'-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4'-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4'-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4'-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens. |
Inflammation associated with monocyte/macrophage activation and recruitment corresponds with lethal outcome in a mouse model of Crimean-Congo hemorrhagic fever
Sorvillo TE , Ritter JM , Welch SR , Coleman-McCray JD , Davies KA , Hayes HM , Pegan SD , Montgomery JM , Bergeron É , Spiropoulou CF , Spengler JR . Emerg Microbes Infect 2024 2427782 Crimean-Congo hemorrhagic fever virus (CCHFV) causes human disease ranging from subclinical to a fatal hemorrhagic syndrome. Determinants of CCHF pathogenesis are largely unknown and animal models that recapitulate human disease are limited. A recently described mouse model uses a monoclonal antibody (mAb 5A3) targeting the interferon (IFN) alpha/beta receptor to suppress type I IFN responses, making animals transiently susceptible to infection. To advance utility of this model, we investigated effects of challenge route, timing of 5A3 delivery, mouse sex and age, and virus strain on clinical course and outcome. C57BL/6J mice received mAb 5A3 -1, 0, or -1/+1 days post-infection (dpi). Subsets were challenged with CCHFV strain Turkey04 or IbAr10200 subcutaneously or intraperitoneally, and serially euthanized 3- and 7-dpi, when meeting euthanasia criteria or at study completion (14 dpi). CCHFV-IbAr10200-infected mice almost uniformly succumbed to infection, whereas CCHFV-Turkey04-infected mice transiently lost weight but survived. These results were consistent regardless of mAb timing or route of challenge. Viral replication and dissemination were comparable between the two strains at 3 dpi. However, in the plasma and livers of non-survivors, expression of proinflammatory cytokines/chemokines that correspond with macrophage activation and recruitment were significantly elevated. Lethal disease was also associated with elevated levels of macrophage activation marker CD163 in plasma. Further, mouse macrophages were more permissive to IbAr1200 infection in vitro, suggesting tropism for these cells may influence pathogenesis. Our data suggest that early inflammation may be a critical determinant of CCHF outcome and therapeutics to control inflammation may be worthwhile targets for future investigation. |
Validation of a simplified laboratory-based HCV clearance definition using New York City hepatitis C program and surveillance data
Hwang CS , Montgomery MP , Diaz Munoz DI , Yin S , Teshale EH , Bocour A . J Public Health Manag Pract 2024 CONTEXT: Laboratory-based hepatitis C virus (HCV) clearance cascades are an important tool for health departments to track progress toward HCV elimination, but a laboratory-based definition of HCV clearance has not yet been validated. OBJECTIVE: To compare agreement between a laboratory-based HCV clearance definition with a clinical cure definition. DESIGN: Observational. SETTING: New York City Department of Health and Mental Hygiene HCV surveillance system data and New York City hepatitis C linkage-to-care program data. PARTICIPANTS: Linkage-to-care program participants who were diagnosed with hepatitis C and enrolled in the linkage-to-care program from July 1, 2016, through June 30, 2020. MAIN OUTCOME MEASURE: Percent agreement between a laboratory-based HCV clearance definition (surveillance system) and a clinical cure definition (program data). RESULTS: Among 591 program participants with known treatment outcome, the laboratory-based HCV clearance definition and clinical cure definition were concordant in 573 cases (97%). CONCLUSIONS: A laboratory-based HCV clearance definition based on public health surveillance data can be a reliable source for monitoring HCV elimination. |
Completed genome segments of Maciel, Lechiguanas, and Laguna Negra orthohantaviruses
Shedroff E , Whitmer SLM , Mobley M , Morales-Betoulle M , Martin ML , Brignone J , Sen C , Nazar Y , Montgomery JM , Klena JD . Microbiol Resour Announc 2024 e0044124 ![]() ![]() New World orthohantaviruses are rodent-borne tri-segmented viruses that cause hantavirus cardiopulmonary syndrome in humans in the Americas. Molecular diagnostics for orthohantaviruses can be improved with more sequence data. Reported here are completed genomes for Lechiguanas, Maciel, and Laguna Negra viruses. |
A toolkit to facilitate the selection and measurement of health equity indicators for cardiovascular disease
Wei D , McPherson S , Moeti R , Boakye A , Whiting-Collins L , Abbas A , Montgomery E , Toledo L , Vaughan M . Prev Chronic Dis 2024 21 E78 Cardiovascular disease (CVD) is the leading cause of illness and death in the US and is substantially affected by social determinants of health, such as social, economic, and environmental factors. CVD disproportionately affects groups that have been economically and socially marginalized, yet health care and public health professionals often lack tools for collecting and using data to understand and address CVD inequities among their populations of focus. The Health Equity Indicators for Cardiovascular Disease Toolkit (HEI for CVD Toolkit) seeks to address this gap by providing metrics, measurement guidance, and resources to support users collecting, measuring, and analyzing data relevant to their CVD work. The toolkit includes a conceptual framework (a visual model for understanding health inequities in CVD); a comprehensive list of health equity indicators (metrics of inequities that influence CVD prevention, care, and management); guidance in definitions, measures, and data sources; lessons learned and examples of HEI implementation; and other resources to support health equity measurement. To develop this toolkit, we performed literature scans to identify primary topics and themes relevant to addressing inequities in CVD, engaged with subject matter experts in health equity and CVD, and conducted pilot studies to understand the feasibility of gathering and analyzing data on the social determinants of health in various settings. This comprehensive development process resulted in a toolkit that can help users understand the drivers of inequities in their communities or patient populations, assess progress, evaluate intervention outcomes, and guide actions to address CVD disparities. |
Crimean-Congo hemorrhagic fever cases diagnosed during an outbreak of Sudan virus disease in Uganda, 2022-23
Balinandi S , Mulei S , Whitmer S , Nyakarahuka L , Cossaboom CM , Shedroff E , Morales-Betoulle M , Krapiunaya I , Tumusiime A , Kyondo J , Baluku J , Namanya D , Torach CR , Mutesi J , Kiconco J , Pimundu G , Muyigi T , Rowland J , Nsawotebba A , Ssewanyana I , Muwanguzi D , Kadobera D , Harris JR , Ario AR , Atek K , Kyobe HB , Nabadda S , Kaleebu P , Mwebesa HG , Montgomery JM , Shoemaker TR , Lutwama JJ , Klena JD . PLoS Negl Trop Dis 2024 18 (10) e0012595 ![]() ![]() BACKGROUND: In September 2022, Uganda experienced an outbreak of Sudan virus disease (SVD), mainly in central Uganda. As a result of enhanced surveillance activities for Ebola disease, samples from several patients with suspected viral hemorrhagic fever (VHF) were sent to the VHF Program at Uganda Virus Research Institute (UVRI), Entebbe, Uganda, and identified with infections caused by other viral etiologies. Herein, we report the epidemiologic and laboratory findings of Crimean-Congo hemorrhagic fever (CCHF) cases that were detected during the SVD outbreak response. METHODOLOGY: Whole blood samples from VHF suspected cases were tested for Sudan virus (SUDV) by real-time reverse transcription-polymerase chain reaction (RT-PCR); and if negative, were tested for CCHF virus (CCHFV) by RT-PCR. CCHFV genomic sequences generated by metagenomic next generation sequencing were analyzed to ascertain strain relationships. PRINCIPAL FINDINGS: Between September 2022 and January 2023, a total of 2,626 samples were submitted for VHF testing at UVRI. Overall, 13 CCHF cases (including 7 deaths; case fatality rate of 53.8%), aged 4 to 60 years, were identified from 10 districts, including several districts affected by the SVD outbreak. Four cases were identified within the Ebola Treatment Unit (ETU) at Mubende Hospital. Most CCHF cases were males engaged in livestock farming or had exposure to wildlife (n = 8; 61.5%). Among confirmed cases, the most common clinical symptoms were hemorrhage (n = 12; 92.3%), fever (n = 11; 84.6%), anorexia (n = 10; 76.9%), fatigue (n = 9; 69.2%), abdominal pain (n = 9; 69.2%) and vomiting (n = 9; 69.2%). Sequencing analysis showed that the majority of identified CCHFV strains belonged to the Africa II clade previously identified in Uganda. Two samples, however, were identified with greater similarity to a CCHFV strain that was last reported in Uganda in 1958, suggesting possible reemergence. CONCLUSIONS/SIGNIFICANCE: Identifying CCHFV from individuals initially suspected to be infected with SUDV emphasizes the need for comprehensive VHF testing during filovirus outbreak responses in VHF endemic countries. Without expanded testing, CCHFV-infected patients would have posed a risk to health care workers and others while receiving treatment after a negative filovirus diagnosis, thereby complicating response dynamics. Additionally, CCHFV-infected cases could acquire an Ebola infection while in the ETU, and upon release because of a negative Ebola virus result, have the potential to spread these infections in the community. |
A public, cross-reactive glycoprotein epitope confounds Ebola virus serology
Kainulainen MH , Harmon JR , Karaaslan E , Kyondo J , Whitesell A , Twongyeirwe S , Malenfant JH , Baluku J , Kofman A , Bergeron É , Waltenburg MA , Nyakarahuka L , Balinandi S , Cossaboom CM , Choi MJ , Shoemaker TR , Montgomery JM , Spiropoulou CF . J Med Virol 2024 96 (10) e29946 ![]() ![]() Ebola disease (EBOD) in humans is a severe disease caused by at least four related viruses in the genus Orthoebolavirus, most often by the eponymous Ebola virus. Due to human-to-human transmission and incomplete success in treating cases despite promising therapeutic development, EBOD is a high priority in public health research. Yet despite almost 50 years since EBOD was first described, the sources of these viruses remain undefined and much remains to be understood about the disease epidemiology and virus emergence and spread. One important approach to improve our understanding is detection of antibodies that can reveal past human infections. However, serosurveys routinely describe seroprevalences that imply infection rates much higher than those clinically observed. Proposed hypotheses to explain this difference include existence of common but less pathogenic strains or relatives of these viruses, misidentification of EBOD as something else, and a higher proportion of subclinical infections than currently appreciated. The work presented here maps B-cell epitopes in the spike protein of Ebola virus and describes a single epitope that is cross-reactive with an antigen seemingly unrelated to orthoebolaviruses. Antibodies against this epitope appear to explain most of the unexpected reactivity towards the spike, arguing against common but unidentified infections in the population. Importantly, antibodies of cross-reactive donors from within and outside the known EBOD geographic range bound the same epitope. In light of this finding, it is plausible that epitope mapping enables broadly applicable specificity improvements in the field of serology. |
Optimization of Bangladesh and Malaysian genotype recombinant reporter Nipah viruses for in vitro antiviral screening and in vivo disease modeling
Lo MK , Jain S , Davies KA , Sorvillo TE , Welch SR , Coleman-McCray JD , Chatterjee P , Hotard AL , O'Neal T , Flint M , Ai H , Albariño CG , Spengler JR , Montgomery JM , Spiropoulou CF . Antiviral Res 2024 231 106013 ![]() ![]() Nipah virus (NiV) causes near-annual outbreaks of fatal encephalitis and respiratory disease in South Asia with a high mortality rate (∼70%). Since there are no approved therapeutics for NiV disease in humans, the WHO has designated NiV and henipaviral diseases priority pathogens for research and development. We generated a new recombinant green fluorescent reporter NiV of the circulating Bangladesh genotype (rNiV-B-ZsG) and optimized it alongside our previously generated Malaysian genotype reporter counterpart (rNiV-M-ZsG) for antiviral screening in primary-like human respiratory cell types. Validating our platform for rNiV-B-ZsG with a synthetic compound library directed against viral RNA-dependent RNA polymerases, we identified a hit compound and confirmed its sub-micromolar activity against wild-type NiV, green fluorescent reporter, and the newly constructed bioluminescent red fluorescent double reporter (rNiV-B-BREP) NiV. We furthermore demonstrated that rNiV-B-ZsG and rNiV-B-BREP viruses showed pathogenicity comparable to wild-type NiV-B in the Syrian golden hamster model of disease, supporting additional use of these tools for both pathogenesis and advanced pre-clinical studies in vivo. |
Fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease in the Democratic Republic of the Congo: a case report study
Mukadi-Bamuleka D , Edidi-Atani F , Morales-Betoulle ME , Legand A , Nkuba-Ndaye A , Bulabula-Penge J , Mbala-Kingebeni P , Crozier I , Mambu-Mbika F , Whitmer S , Tshiani Mbaya O , Hensley LE , Kitenge-Omasumbu R , Davey R , Mulangu S , Fonjungo PN , Wiley MR , Klena JD , Peeters M , Delaporte E , van Griensven J , Ariën KK , Pratt C , Montgomery JM , Formenty P , Muyembe-Tamfum JJ , Ahuka-Mundeke S . Lancet Microbe 2024 100905 ![]() ![]() BACKGROUND: During the 2018-20 Ebola virus disease outbreak in the Democratic Republic of the Congo, thousands of patients received unprecedented vaccination, monoclonal antibody (mAb) therapy, or both, leading to a large number of survivors. We aimed to report the clinical, virological, viral genomic, and immunological features of two previously vaccinated and mAb-treated survivors of Ebola virus disease in the Democratic Republic of the Congo who developed second episodes of disease months after initial discharge, ultimately complicated by fatal meningoencephalitis associated with viral persistence. METHODS: In this case report study, we describe the presentation, management, and subsequent investigations of two patients who developed recrudescent Ebola virus disease and subsequent fatal meningoencephalitis. We obtained data from epidemiological databases, Ebola treatment units, survivor programme databases, laboratory datasets, and hospital records. Following national protocols established during the 2018-20 outbreak in the Democratic Republic of the Congo, blood, plasma, and cerebrospinal fluid (CSF) samples were collected during the first and second episodes of Ebola virus disease from both individuals and were analysed by molecular (quantitative RT-PCR and next-generation sequencing) and serological (IgG and IgM ELISA and Luminex assays) techniques. FINDINGS: The total time between the end of the first Ebola virus episode and the onset of the second episode was 342 days for patient 1 and 137 days for patient 2. In both patients, Ebola virus RNA was detected in blood and CSF samples during the second episode of disease. Complete genomes from CSF samples from this relapse episode showed phylogenetic relatedness to the genome sequenced from blood samples collected from the initial infection, confirming in-host persistence of Ebola virus. Serological analysis showed an antigen-specific humoral response with typical IgM and IgG kinetics in patient 1, but an absence of an endogenous adaptive immune response in patient 2. INTERPRETATION: We report the first two cases of fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease who had received vaccination and mAb-based treatment in the Democratic Republic of the Congo. Our findings highlight the importance of long-term monitoring of survivors, including continued clinical, virological, and immunological profiling, as well as the urgent need for novel therapeutic strategies to prevent and mitigate the individual and public health consequences of Ebola virus persistence. FUNDING: Ministry of Health of the Democratic Republic of the Congo, Institut National de Recherche Biomédicale, Infectious Disease Rapid Response Reserve Fund, US Centers for Disease Control and Prevention, French National Research Institute for Development, and WHO. |
Streamlined detection of Nipah virus antibodies using a split nanoluc biosensor
Bergeron É , Chiang CF , Lo MK , Karaaslan E , Satter SM , Rahman MZ , Hossain ME , Aquib WR , Rahman DI , Sarwar SB , Montgomery JM , Klena JD , Spiropoulou CF . Emerg Microbes Infect 2024 2398640 ABSTRACTNipah virus (NiV) is an emerging zoonotic RNA virus that can cause fatal respiratory and neurological disease in animals and humans. Accurate NiV diagnostics and surveillance tools are crucial for the identification of acute and resolved infections and to improve our understanding of NiV transmission and circulation. Here, we have developed and validated a split NanoLuc luciferase NiV glycoprotein (G) biosensor for detecting antibodies in clinical and animal samples. This assay is performed by simply mixing reagents and measuring luminescence, which depends on the complementation of the split NanoLuc luciferase G biosensor following its binding to antibodies. This anti-NiV-G "mix-and-read" assay was validated using the WHO's first international standard for anti-NiV antibodies and more than 700 serum samples from the NiV-endemic country of Bangladesh. Anti-NiV antibodies from survivors persisted for at least 8 years according to both ⍺NiV-G mix-and-read and NiV neutralization assays. The ⍺NiV-G mix-and-read assay sensitivity (98.6%) and specificity (100%) were comparable to anti-NiV IgG ELISA performance but failed to detect anti-NiV antibodies in samples collected less than a week following the appearance of symptoms. Overall, the anti-NiV-G biosensor represents a simple, fast, and reliable tool that could support the expansion of NiV surveillance and retrospective outbreak investigations. |
Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice
Karaaslan E , Sorvillo TE , Scholte FEM , O'Neal TJ , Welch SR , Davies KA , Coleman-McCray JD , Harmon JR , Ritter JM , Pegan SD , Montgomery JM , Spengler JR , Spiropoulou CF , Bergeron É . NPJ Vaccines 2024 9 (1) 148 Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination conferred 100% protection from lethal outcome and was associated with mild clinical disease, while the NP + GP38 combination conferred even more robust protection by reducing morbidity compared to mice receiving NP alone. Thus, recombinant CCHFV NP alone is a promising vaccine candidate conferring 100% survival against heterologous challenge. Moreover, incorporation of GP38 should be considered as it further enhances subunit vaccine efficacy by reducing morbidity in surviving animals. |
Epidemiologic and Virologic Characteristics of Influenza in Lao PDR, 2016-2023
Wodniak N , Vilivong K , Khamphaphongphane B , Sengkeopraseuth B , Somoulay V , Chiew M , Ketmayoon P , Jiao M , Phimmasine S , Co KC , Leuangvilay P , Otsu S , Khanthamaly V , Keopaseuth P , Davis WW , Montgomery MP , Xangsayyarath P . Influenza Other Respir Viruses 2024 18 (8) e13353 ![]() BACKGROUND: Influenza sentinel surveillance in Lao PDR is used to inform seasonal vaccination programs. This analysis reviews epidemiologic and virologic characteristics of influenza virus infection over 8 years, before and after emergence of SARS-CoV-2. METHODS: Data collected for ILI and SARI surveillance during January 2016 through December 2023 were analyzed from nine hospitals. Respiratory specimens from ILI and SARI cases were tested by reverse transcriptase polymerase chain reaction to determine influenza positivity and subtype and lineage. Aggregate counts of outpatient visits and hospitalizations were collected from hospital logbooks. Epidemiologic trends of influenza activity were described, and the proportional contribution of influenza-associated ILI and SARI to outpatient and inpatient loads was estimated. RESULTS: Influenza was detected year-round with positivity peaking during September through January and occurring in most years approximately 1 month earlier in the south than the north. After decreasing in 2 years following the emergence of SARS-CoV-2, influenza positivity increased in 2022 and resumed its typical temporal trend. Influenza-associated ILI contribution to outpatient visits was highest among children ages 5-14 years (3.0% of all outpatient visits in 2023), and influenza-associated SARI contribution to inpatient hospitalizations was highest among children ages 2-4 years (2.2% of all hospitalizations in 2023). CONCLUSIONS: Influenza surveillance in Lao PDR provides clinicians and public health authorities with information on geographic and temporal patterns of influenza transmission. Influenza surveillance data support current vaccination timing and recommendations to vaccinate certain populations, especially young children. |
Acute febrile illness in Kenya: Clinical characteristics and pathogens detected among patients hospitalized with fever, 2017-2019
Verani JR , Eno EN , Hunsperger EA , Munyua P , Osoro E , Marwanga D , Bigogo G , Amon D , Ochieng M , Etau P , Bandika V , Zimbulu V , Kiogora J , Burton JW , Okunga E , Samuels AM , Njenga K , Montgomery JM , Widdowson MA . PLoS One 2024 19 (8) e0305700 Acute febrile illness (AFI) is a common reason for healthcare seeking and hospitalization in Sub-Saharan Africa and is often presumed to be malaria. However, a broad range of pathogens cause fever, and more comprehensive data on AFI etiology can improve clinical management, prevent unnecessary prescriptions, and guide public health interventions. We conducted surveillance for AFI (temperature ≥38.0°C <14 days duration) among hospitalized patients of all ages at four sites in Kenya (Nairobi, Mombasa, Kakamega, and Kakuma). For cases of undifferentiated fever (UF), defined as AFI without diarrhea (≥3 loose stools in 24 hours) or lower respiratory tract symptoms (cough/difficulty breathing plus oxygen saturation <90% or [in children <5 years] chest indrawing), we tested venous blood with real-time PCR-based TaqMan array cards (TAC) for 17 viral, 8 bacterial, and 3 protozoal fever-causing pathogens. From June 2017 to March 2019, we enrolled 3,232 AFI cases; 2,529 (78.2%) were aged <5 years. Among 3,021 with outcome data, 131 (4.3%) cases died while in hospital, including 106/2,369 (4.5%) among those <5 years. Among 1,735 (53.7%) UF cases, blood was collected from 1,340 (77.2%) of which 1,314 (98.1%) were tested by TAC; 715 (54.4%) had no pathogens detected, including 147/196 (75.0%) of those aged <12 months. The most common pathogen detected was Plasmodium, as a single pathogen in 471 (35.8%) cases and in combination with other pathogens in 38 (2.9%). HIV was detected in 51 (3.8%) UF cases tested by TAC and was most common in adults (25/236 [10.6%] ages 18-49, 4/40 [10.0%] ages ≥50 years). Chikungunya virus was found in 30 (2.3%) UF cases, detected only in the Mombasa site. Malaria prevention and control efforts are critical for reducing the burden of AFI, and improved diagnostic testing is needed to provide better insight into non-malarial causes of fever. The high case fatality of AFI underscores the need to optimize diagnosis and appropriate management of AFI to the local epidemiology. |
Continuous community engagement is needed to improve adherence to ebola response activities and survivorship during ebola outbreaks
Soke GN , Fonjungo P , Mbuyi G , Luce R , Klena J , Choi M , Kombe J , Makaya G , Mbuyi F , Bulambo H , Mossoko M , Mwanzembe C , Ikomo B , Adikey P , Montgomery J , Shoemaker T , Mbala P , Earle-Richardson G , Mwamba D , Tamfum JM . Glob Health Sci Pract 2024 |
Sudan Virus Disease among health care workers, Uganda, 2022
Wailagala A , Blair PW , Kobba K , Mubaraka K , Aanyu-Tumukahebwa H , Kiiza D , Sekikongo MT , Klena JD , Waitt P , Bahatungire RR , Kyobe HS , Atwine D , Adaku A , Bongomin B , Kirenga B , Boore A , Clark DV , Kaggwa D , Gregory M , Kabweru W , Kayondo W , Mbabazi SK , Kibuuka H , Kimuli I , Mulei S , Mutegeki M , Emmanuel B , Mwebesa H , Naluyima P , Okello S , Tumusiime A , Montgomery J , Vasireddy V , Olaro C , Wayengera M , Lamorde M . N Engl J Med 2024 391 (3) 285-287 |
Human Orthohantavirus disease prevalence and genotype distribution in the U.S., 2008–2020: a retrospective observational study
Whitmer SLM , Whitesell A , Mobley M , Talundzic E , Shedroff E , Cossaboom CM , Messenger S , Deldari M , Bhatnagar J , Estetter L , Zufan S , Cannon D , Chiang CF , Gibbons A , Krapiunaya I , Morales-Betoulle M , Choi M , Knust B , Amman B , Montgomery JM , Shoemaker T , Klena JD . Lancet Reg Health - Am 2024 37 ![]() ![]() Background: In the United States (U.S.), hantavirus pulmonary syndrome (HPS) and non-HPS hantavirus infection are nationally notifiable diseases. Criteria for identifying human cases are based on clinical symptoms (HPS or non-HPS) and acute diagnostic results (IgM+, rising IgG+ titers, RT-PCR+, or immunohistochemistry (IHC)+). Here we provide an overview of diagnostic testing and summarize human Hantavirus disease occurrence and genotype distribution in the U.S. from 2008 to 2020. Methods: Epidemiological data from the national hantavirus registry was merged with laboratory diagnostic testing results performed at the CDC. Residual hantavirus-positive specimens were sequenced, and the available epidemiological and genetic data sets were linked to conduct a genomic epidemiological study of hantavirus disease in the U.S. Findings: From 1993 to 2020, 833 human hantavirus cases have been identified, and from 2008 to 2020, 335 human cases have occurred. Among New World (NW) hantavirus cases detected at the CDC diagnostic laboratory (representing 29.2% of total cases), most (85.0%) were detected during acute disease, however, some convalescent cases were detected in states not traditionally associated with hantavirus infections (Connecticut, Missouri, New Jersey, Pennsylvania, Tennessee, and Vermont). From 1993 to 2020, 94.9% (745/785) of U.S. hantaviruses cases were detected west of the Mississippi with 45.7% (359/785) in the Four Corners region of the U.S. From 2008 to 2020, 67.7% of NW hantavirus cases were detected between the months of March and August. Sequencing of RT-PCR-positive cases demonstrates a geographic separation of Orthohantavirus sinnombreense species [Sin Nombre virus (SNV), New York virus, and Monongahela virus]; however, there is a large gap in viral sequence data from the Northwestern and Central U.S. Finally, these data indicate that commercial IgM assays are not concordant with CDC-developed assays, and that “concordant positive” (i.e., commercial IgM+ and CDC IgM+ results) specimens exhibit clinical characteristics of hantavirus disease. Interpretation: Hantaviral disease is broadly distributed in the contiguous U.S, viral variants are localised to specific geographic regions, and hantaviral disease infrequently detected in most Southeastern states. Discordant results between two diagnostic detection methods highlight the need for an improved standardised testing plan in the U.S. Hantavirus surveillance and detection will continue to improve with clearly defined, systematic reporting methods, as well as explicit guidelines for clinical characterization and diagnostic criteria. Funding: This work was funded by core funds provided to the Viral Special Pathogens Branch at CDC. © 2024 |
Influenza virus circulation and vaccine effectiveness during June 2021–May 2023 in Thailand
Prasert K , Praphasiri P , Nakphook S , Ditsungnoen D , Sapchookul P , Sornwong K , Naosri S , Akkapaiboon Okada P , Suntarattiwong P , Chotpitayasunondh T , Montgomery MP , Davis WW , Pittayawonganon C . Vaccine X 2024 19 Thai Ministry of Public Health recommends influenza vaccination for certain risk groups. We evaluated 2023 Southern Hemisphere influenza vaccine effectiveness against medically attended influenza using surveillance data from nine Thai hospitals and a test-negative design. During June 2022–May 2023, influenza vaccine provided moderate protection against seeking care for influenza illness (adjusted vaccine effectiveness 51%; 95% confidence interval 28–67). Understanding vaccine effectiveness can help guide future antigen selection and support clinicians to make a strong influenza vaccine recommendation to patients. © 2024 The Author(s) |
Measures to prevent and treat Nipah virus disease: research priorities for 2024-29
Moore KA , Mehr AJ , Ostrowsky JT , Ulrich AK , Moua NM , Fay PC , Hart PJ , Golding JP , Benassi V , Preziosi MP , Broder CC , de Wit E , Formenty PBH , Freiberg AN , Gurley ES , Halpin K , Luby SP , Mazzola LT , Montgomery JM , Spiropoulou CF , Mourya DT , Parveen S , Rahman M , Roth C , Wang LF , Osterholm MT . Lancet Infect Dis 2024 Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses. |
Knowledge, attitudes, and practices and long-term immune response after rVSVΔG-ZEBOV-GP Ebola vaccination in healthcare workers in high-risk districts in Uganda
Waltenburg MA , Kainulainen MH , Whitesell A , Nyakarahuka L , Baluku J , Kyondo J , Twongyeirwe S , Harmon J , Mulei S , Tumusiime A , Bergeron E , Haberling DL , Klena JD , Spiropoulou C , Montgomery JM , Lutwama JJ , Makumbi I , Driwale A , Muruta A , Balinandi S , Shoemaker T , Cossaboom CM . Vaccine 2024 BACKGROUND: The rVSVΔG-ZEBOV-GP Ebola vaccine (rVSV-ZEBOV) has been used in response to Ebola disease outbreaks caused by Ebola virus (EBOV). Understanding Ebola knowledge, attitudes, and practices (KAP) and the long-term immune response following rVSV-ZEBOV are critical to inform recommendations on future use. METHODS: We administered surveys and collected blood samples from healthcare workers (HCWs) from seven Ugandan healthcare facilities. Questionnaires collected information on demographic characteristics and KAP related to Ebola and vaccination. IgG ELISA, virus neutralization, and interferon gamma ELISpot measured immunological responses against EBOV glycoprotein (GP). RESULTS: Overall, 37 % (210/565) of HCWs reported receiving any Ebola vaccination. Knowledge that rVSV-ZEBOV only protects against EBOV was low among vaccinated (32 %; 62/192) and unvaccinated (7 %; 14/200) HCWs. Most vaccinated (91 %; 192/210) and unvaccinated (92 %; 326/355) HCWs wanted to receive a booster or initial dose of rVSV-ZEBOV, respectively. Median time from rVSV-ZEBOV vaccination to sample collection was 37.7 months (IQR: 30.5, 38.3). IgG antibodies against EBOV GP were detected in 95 % (61/64) of HCWs with vaccination cards and in 84 % (162/194) of HCWs who reported receiving a vaccination. Geometric mean titer among seropositive vaccinees was 0.066 IU/mL (95 % CI: 0.058-0.076). CONCLUSION: As Uganda has experienced outbreaks of Sudan virus and Bundibugyo virus, for which rVSV-ZEBOV does not protect against, our findings underscore the importance of continued education and risk communication to HCWs on Ebola and other viral hemorrhagic fevers. IgG antibodies against EBOV GP were detected in most vaccinated HCWs in Uganda 2─4 years after vaccination; however, the duration and correlates of protection warrant further investigation. |
A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex
Michon M , Müller-Schiffmann A , Lingappa AF , Yu SF , Du L , Deiter F , Broce S , Mallesh S , Crabtree J , Lingappa UF , Macieik A , Müller L , Ostermann PN , Andrée M , Adams O , Schaal H , Hogan RJ , Tripp RA , Appaiah U , Anand SK , Campi TW , Ford MJ , Reed JC , Lin J , Akintunde O , Copeland K , Nichols C , Petrouski E , Moreira AR , Jiang IT , DeYarman N , Brown I , Lau S , Segal I , Goldsmith D , Hong S , Asundi V , Briggs EM , Phyo NS , Froehlich M , Onisko B , Matlack K , Dey D , Lingappa JR , Prasad DM , Kitaygorodskyy A , Solas D , Boushey H , Greenland J , Pillai S , Lo MK , Montgomery JM , Spiropoulou CF , Korth C , Selvarajah S , Paulvannan K , Lingappa VR . Open Biol 2024 14 (6) 230363 ![]() ![]() We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease. |
Identification of a macrocyclic compound targeting the Lassa virus polymerase
Aida-Ficken V , Kelly JA , Chatterjee P , Jenks MH , McMullan LK , Albariño CG , Montgomery JM , Seley-Radtke KL , Spiropoulou CF , Flint M . Antiviral Res 2024 105923 There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC(50) against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase. |
Sudan virus disease super-spreading, Uganda, 2022
Komakech A , Whitmer S , Izudi J , Kizito C , Ninsiima M , Ahirirwe SR , Kabami Z , Ario AR , Kadobera D , Kwesiga B , Gidudu S , Migisha R , Makumbi I , Eurien D , Kayiwa J , Bulage L , Gonahasa DN , Kyamwine I , Okello PE , Nansikombi HT , Atuhaire I , Asio A , Elayeete S , Nsubuga EJ , Masanja V , Migamba SM , Mwine P , Nakamya P , Nampeera R , Kwiringira A , Akunzirwe R , Naiga HN , Namubiru SK , Agaba B , Zalwango JF , Zalwango MG , King P , Simbwa BN , Zavuga R , Wanyana MW , Kiggundu T , Oonyu L , Ndyabakira A , Komugisha M , Kibwika B , Ssemanda I , Nuwamanya Y , Kamukama A , Aanyu D , Kizza D , Ayen DO , Mulei S , Balinandi S , Nyakarahuka L , Baluku J , Kyondo J , Tumusiime A , Aliddeki D , Masiira B , Muwanguzi E , Kimuli I , Bulwadda D , Isabirye H , Aujo D , Kasambula A , Okware S , Ochien E , Komakech I , Okot C , Choi M , Cossaboom CM , Eggers C , Klena JD , Osinubi MO , Sadigh KS , Worrell MC , Boore AL , Shoemaker T , Montgomery JM , Nabadda SN , Mwanga M , Muruta AN , Harris JR . BMC Infect Dis 2024 24 (1) 520 ![]() ![]() BACKGROUND: On 20 September 2022, Uganda declared its fifth Sudan virus disease (SVD) outbreak, culminating in 142 confirmed and 22 probable cases. The reproductive rate (R) of this outbreak was 1.25. We described persons who were exposed to the virus, became infected, and they led to the infection of an unusually high number of cases during the outbreak. METHODS: In this descriptive cross-sectional study, we defined a super-spreader person (SSP) as any person with real-time polymerase chain reaction (RT-PCR) confirmed SVD linked to the infection of ≥ 13 other persons (10-fold the outbreak R). We reviewed illness narratives for SSPs collected through interviews. Whole-genome sequencing was used to support epidemiologic linkages between cases. RESULTS: Two SSPs (Patient A, a 33-year-old male, and Patient B, a 26-year-old male) were identified, and linked to the infection of one probable and 50 confirmed secondary cases. Both SSPs lived in the same parish and were likely infected by a single ill healthcare worker in early October while receiving healthcare. Both sought treatment at multiple health facilities, but neither was ever isolated at an Ebola Treatment Unit (ETU). In total, 18 secondary cases (17 confirmed, one probable), including three deaths (17%), were linked to Patient A; 33 secondary cases (all confirmed), including 14 (42%) deaths, were linked to Patient B. Secondary cases linked to Patient A included family members, neighbours, and contacts at health facilities, including healthcare workers. Those linked to Patient B included healthcare workers, friends, and family members who interacted with him throughout his illness, prayed over him while he was nearing death, or exhumed his body. Intensive community engagement and awareness-building were initiated based on narratives collected about patients A and B; 49 (96%) of the secondary cases were isolated in an ETU, a median of three days after onset. Only nine tertiary cases were linked to the 51 secondary cases. Sequencing suggested plausible direct transmission from the SSPs to 37 of 39 secondary cases with sequence data. CONCLUSION: Extended time in the community while ill, social interactions, cross-district travel for treatment, and religious practices contributed to SVD super-spreading. Intensive community engagement and awareness may have reduced the number of tertiary infections. Intensive follow-up of contacts of case-patients may help reduce the impact of super-spreading events. |
Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus
Sorvillo TE , Karaaslan E , Scholte FEM , Welch SR , Coleman-McCray JD , Genzer SC , Ritter JM , Hayes HM , Jain S , Pegan SD , Bergeron É , Montgomery JM , Spiropoulou CF , Spengler JR . NPJ Vaccines 2024 9 (1) 88 Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe human disease and is considered a WHO priority pathogen due to the lack of efficacious vaccines and antivirals. A CCHF virus replicon particle (VRP) has previously shown protective efficacy in a lethal Ifnar(-/-) mouse model when administered as a single dose at least 3 days prior to challenge. Here, we determine that non-specific immune responses are not sufficient to confer short-term protection, since Lassa virus VRP vaccination 3 days prior to CCHFV challenge was not protective. We also investigate how CCHF VRP vaccination confers protective efficacy by examining viral kinetics, histopathology, clinical analytes and immunity early after challenge (3 and 6 days post infection) and compare to unvaccinated controls. We characterize how these effects differ based on vaccination period and correspond to previously reported CCHF VRP-mediated protection. Vaccinating Ifnar(-/-) mice with CCHF VRP 28, 14, 7, or 3 days prior to challenge, all known to confer complete protection, significantly reduced CCHFV viral load, mucosal shedding, and markers of clinical disease, with greater reductions associated with longer vaccination periods. Interestingly, there were no significant differences in innate immune responses, T cell activation, or antibody titers after challenge between groups of mice vaccinated a week or more before challenge, but higher anti-NP antibody avidity and effector function (ADCD) were positively associated with longer vaccination periods. These findings support the importance of antibody-mediated responses in VRP vaccine-mediated protection against CCHFV infection. |
Evaluation of two inoculation routes of an adenovirus-mediated viral protein inhibitor in a Crimean-Congo hemorrhagic fever mouse model
Scholte FEM , Spengler JR , Welch SR , Harmon JR , Coleman-McCray JD , Davies KA , Pegan SD , Montgomery JM , Spiropoulou CF , Bergeron É . Virus Res 2024 345 199398 ![]() Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne nairovirus with a wide geographic spread that can cause severe and lethal disease. No specific medical countermeasures are approved to combat this illness. The CCHFV L protein contains an ovarian tumor (OTU) domain with a cysteine protease thought to modulate cellular immune responses by removing ubiquitin and ISG15 post-translational modifications from host and viral proteins. Viral deubiquitinases like CCHFV OTU are attractive drug targets, as blocking their activity may enhance cellular immune responses to infection, and potentially inhibit viral replication itself. We previously demonstrated that the engineered ubiquitin variant CC4 is a potent inhibitor of CCHFV replication in vitro. A major challenge of the therapeutic use of small protein inhibitors such as CC4 is their requirement for intracellular delivery, e.g., by viral vectors. In this study, we examined the feasibility of in vivo CC4 delivery by a replication-deficient recombinant adenovirus (Ad-CC4) in a lethal CCHFV mouse model. Since the liver is a primary target of CCHFV infection, we aimed to optimize delivery to this organ by comparing intravenous (tail vein) and intraperitoneal injection of Ad-CC4. While tail vein injection is a traditional route for adenovirus delivery, in our hands intraperitoneal injection resulted in higher and more widespread levels of adenovirus genome in tissues, including, as intended, the liver. However, despite promising in vitro results, neither route of in vivo CC4 treatment resulted in protection from a lethal CCHFV infection. |
Detection of a human adenovirus outbreak, including some critical infections, using multipathogen testing at a large university, September 2022-January 2023
Montgomery JP , Marquez JL , Nord J , Stamper AR , Edwards EA , Valentini N , Frank CJ , Washer LL , Ernst RD , Park JI , Price D , Collins J , Smith-jeffcoat sE , Hu f , Knox cL , Khan r , Lu x , Kirking hL , Hsu cH . Open Forum Infect Dis 2024 11 (5) ofae192 ![]() ![]() BACKGROUND: Human adenoviruses (HAdVs) can cause outbreaks of flu-like illness in university settings. Most infections in healthy young adults are mild; severe illnesses rarely occur. In Fall 2022, an adenovirus outbreak was identified in university students. METHODS: HAdV cases were defined as university students 17-26 years old who presented to the University Health Service or nearby emergency department with flu-like symptoms (eg, fever, cough, headache, myalgia, nausea) and had confirmed adenovirus infections by polymerase chain reaction (PCR). Demographic and clinical characteristics were abstracted from electronic medical records; clinical severity was categorized as mild, moderate, severe, or critical. We performed contact investigations among critical cases. A subset of specimens was sequenced to confirm the HAdV type. RESULTS: From 28 September 2022 to 30 January 2023, 90 PCR-confirmed cases were identified (51% female; mean age, 19.6 years). Most cases (88.9%) had mild illness. Seven cases required hospitalization, including 2 critical cases that required intensive care. Contact investigation identified 44 close contacts; 6 (14%) were confirmed HAdV cases and 8 (18%) reported symptoms but never sought care. All typed HAdV-positive specimens (n = 36) were type 4. CONCLUSIONS: While most students with confirmed HAdV had mild illness, 7 otherwise healthy students had severe or critical illness. Between the relatively high number of hospitalizations and proportion of close contacts with symptoms who did not seek care, the true number of HAdV cases was likely higher. Our findings illustrate the need to consider a wide range of pathogens, even when other viruses are known to be circulating. |
Ten years of high-consequence pathogens-research gains, readiness gaps, and future goals
McQuiston JH , Montgomery JM , Hutson CL . Emerg Infect Dis 2024 30 (4) 800-802 ![]() ![]() |
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