Rotavirus vaccine appears to perform sub-optimally in countries with higher rotavirus burden. We hypothesized that differences in the magnitude of rotavirus exposures may bias vaccine efficacy (VE) estimates, so true differences in country-specific rotavirus VE would be exaggerated without accommodating differences in exposure. We estimated VE against any-severity and severe rotavirus gastroenteritis (RVGE) using Poisson regression models fit to pooled individual-level data from Phase II and III monovalent rotavirus vaccine trials conducted between 2000 and 2012. The standard approach model included terms for vaccination, country, and a vaccination-country interaction. Other models used proxies for exposure magnitude like severe RVGE rate or age at severe RVGE instead of country. Country-specific proxies were calculated from placebo group data or extracted from an external meta-analysis. Analyses included 83,592 infants from 23 countries in the Americas, Europe, Africa, and Asia. Using the standard approach, VE against severe RVGE substantially varied (10-100%). Using the severe RVGE rate proxy brought VE from all but two countries between 80% and 86%. Heterogeneity for VE against any-severity RVGE was similarly attenuated. Adjusting for exposure proxies reduced heterogeneity in country-specific rotavirus VE estimates. This phenomenon may extend to other vaccines against partially immunizing pathogens with global disparities in burden.

BACKGROUND: Even moderate differences in rotavirus vaccine effectiveness against nonvaccine genotypes may exert selective pressures on circulating rotaviruses. Whether this vaccine effect or natural temporal fluctuations underlie observed changes in genotype distributions is unclear. METHODS: We systematically reviewed studies reporting rotavirus genotypes from children <5 years of age globally between 2005 and 2023. We compared rotavirus genotypes between vaccine-introducing and nonintroducing settings globally and by World Health Organization (WHO) region, calendar time, and time since vaccine introduction. RESULTS: Crude pooling of genotype data from 361 studies indicated higher G2P[4], a nonvaccine genotype, prevalence in vaccine-introducing settings, both globally and by WHO region. This difference did not emerge when examining genotypes over time in the Americas, the only region with robust longitudinal data. Relative to nonintroducing settings, G2P[4] detections were more likely in settings with recent introduction (eg, 1-2 years postintroduction adjusted odds ratio [aOR], 4.39; 95% confidence interval [CI], 2.87-6.72) but were similarly likely in settings with more time elapsed since introduction, (eg, 7 or more years aOR, 1.62; 95% CI, .49-5.37). CONCLUSIONS: When accounting for both regional and temporal trends, there was no substantial evidence of long-term vaccine-related selective pressures on circulating genotypes. Increased prevalence of G2P[4] may be transient after rotavirus vaccine introduction.

Non-pharmaceutical interventions minimize social contacts, hence the spread of respiratory pathogens such as influenza and SARS-CoV-2. Globally, there is a paucity of social contact data from the workforce. In this study, we quantified two-day contact patterns among USA employees. Contacts were defined as face-to-face conversations, involving physical touch or proximity to another individual and were collected using electronic self-kept diaries. Data were collected over 4 rounds from 2020 to 2021 during the COVID-19 pandemic. Mean (standard deviation) contacts reported by 1456 participants were 2.5 (2.5), 8.2 (7.1), 9.2 (7.1) and 10.1 (9.5) across round 1 (April-June 2020), 2 (November 2020-January 2021), 3 (June-August 2021), and 4 (November-December 2021), respectively. Between round 1 and 2, we report a 3-fold increase in the mean number of contacts reported per participant with no major increases from round 2-4. We then modeled SARS-CoV-2 transmission at home, work, and community settings. The model revealed reduced relative transmission in all settings in round 1. Subsequently, transmission increased at home and in the community but remained exceptionally low in work settings. To accurately parameterize models of infection transmission and control, we need empirical social contact data that capture human mixing behavior across time.

Norovirus is attributed to nearly 1 out of every 5 episodes of diarrheal disease globally and is estimated to cause approximately 200,000 deaths annually worldwide, with 70,000 or more among children in developing countries. Noroviruses remain a leading cause of sporadic disease and outbreaks of acute gastroenteritis even in industrialized settings, highlighting that improved hygiene and sanitation alone may not be fully effective in controlling norovirus. Strengths in global progress towards a Norovirus vaccine include a diverse though not deep pipeline which includes multiple approaches, including some with proven technology platforms (e.g., VLP-based HPV vaccines). However, several gaps in knowledge persist, including a fulsome mechanistic understanding of how the virus attaches to human host cells, internalizes, and induces disease. © 2023 The Author(s)

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.

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.

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

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 &lt;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

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=&lt;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=&lt;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

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.

Variation in susceptibility is a known contributor to bias in studies estimating immune protection acquired from vaccination or natural infection. However, difficulty measuring this heterogeneity hinders assessment of its influence on estimates. Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis in low- and middle-income countries (LMICs). We sought to understand differences in susceptibility among children enrolled in two birth-cohort studies of rotavirus in LMICs, and to explore the implications for estimation of immune protection. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 unvaccinated children experienced 1418 rotavirus infections and 371 episodes of rotavirus gastroenteritis (RVGE) over 17,636 child-months. We developed a model characterizing susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings, and tested whether modelgenerated susceptibility measurements were associated with demographic and anthropometric factors. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of diarrhea due to other causes. Simulations suggest that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in transmission intensity and susceptibility of children. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that bias owing to differences in rotavirus transmission intensity and population susceptibility may hinder comparison of estimated immune protection against RVGE.Author summary Differences in susceptibility can help explain why some individuals, and not others, acquire infection and exhibit symptoms when exposed to infectious disease agents. However, it is difficult to distinguish between differences in susceptibility versus exposure in epidemiological studies. We developed a modeling approach to distinguish transmission intensity and susceptibility in data from cohort studies of rotavirus infection among children in Mexico City, Mexico, and Vellore, India, and evaluated how these factors may have contributed to differences in estimates of naturally-acquired immune protection between the studies. We found that more children were at “high risk” of acquiring rotavirus infection, and of experiencing gastroenteritis when infected, in Vellore versus Mexico City. The probability of belonging to this high-risk stratum was associated with recognized risk factors such as lower socioeconomic status, lower birth weight, and risk of diarrhea due to other causes. We also found the risk for rotavirus infections to cause symptoms declined with age, and was independent of acquired immunity. Together, these findings can account for estimates of lower protective efficacy of acquired immunity against rotavirus gastroenteritis in high-incidence settings, which mirrors estimates of reduced effectiveness of live oral rotavirus vaccines in low- and middle-income countries.

The transmission patterns of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases in 2017. Modeling TB transmission networks can provide insight into the nature and drivers of transmission, but incomplete and non-random sampling of TB cases can pose challenges to making inferences from epidemiologic and molecular data. We conducted a quantitative bias analysis to assess the effect of missing cases on a transmission network inferred from Mtb sequencing data on extensively drug-resistant (XDR) TB cases in South Africa. We tested scenarios in which cases were missing at random, differentially by clinical characteristics, or differentially by transmission (i.e., cases with many links were under or over-sampled). Under the assumption cases were missing at random, cases in the complete, modeled network would have had a mean of 20 or more transmission links, which is far higher than expected, in order to reproduce the observed, partial network. Instead, we found that the most likely scenario involved undersampling of high-transmitting cases, and further models provided evidence for superspreading behavior. This is, to our knowledge, the first study to define and assess the support for different mechanisms of missingness in a study of TB transmission. Our findings should caution interpretation of results of future studies of TB transmission in high-incidence settings, given the potential for biased sampling, and should motivate further research aimed at identifying the specific host, pathogen, or environmental factors contributing to superspreading.

The role of individual case characteristics, such as symptoms or demographics, in norovirus transmissibility is poorly understood. Six nursing home norovirus outbreaks occurring in South Carolina, U.S. from 2014 to 2016 were examined. We aimed to quantify the contribution of symptoms and other case characteristics in norovirus transmission using the reproduction number (REi) as an estimate of individual case infectivity and to examine how transmission changes over the course of an outbreak. Individual estimates of REi were calculated using a maximum likelihood procedure to infer the average number of secondary cases generated by each case. The associations between case characteristics and REi were estimated using a multivariate mixed linear model. Outbreaks began with one to three index case(s) with large estimated REi’s (range: 1.48 to 8.70) relative to subsequent cases. Of the 209 cases, 155 (75%) vomited, 164 (79%) had diarrhea, and 158 (76%) were nursing home residents (vs. staff). Cases who vomited infected 2.74 (95% CI: 1.90, 3.94) more individuals than non-vomiters, cases with diarrhea infected 1.62 (95% CI: 1.09, 2.41) more individuals than cases without diarrhea, and resident-cases infected 1.69 (95% CI: 1.18, 2.42) more individuals than staff-cases. Index cases tended to be residents (vs. staff) who vomited and infected considerably more secondary cases compared to non-index cases. Results suggest that individuals, particularly residents, who vomit are more infectious and tend to drive norovirus transmission in U.S. nursing home norovirus outbreaks. While diarrhea also plays a role in norovirus transmission, it is to a lesser degree than vomiting in these settings. Results lend support for prevention and control measures that focus on cases who vomit, particularly if those cases are residents.Author summary The majority of all norovirus outbreaks reported to the CDC occur in long-term care facilities (LTCFs), including nursing homes, where older residents are at risk for more severe or prolonged infection. Because there is currently no publicly available norovirus vaccine, sound control measures are key to controlling norovirus outbreaks, but there is little evidence that standard control measures are effective in reducing the size and/or duration of LTCF norovirus outbreaks. Hence, studies leading to a better understanding of disease spread and prevention of additional cases, and thus more effective control measures, are needed. To this end, we aimed to quantify factors associated with norovirus transmission and to examine how transmission changes over the course of an outbreak. We show that vomiting and, to a lesser extent, diarrhea are critical in initiating and sustaining norovirus transmission in U.S. nursing home norovirus outbreaks. We also show that nursing home residents, rather than staff, are the primary drivers of transmission. Results suggest that control measures focusing on cases who vomit, particularly if those cases are residents, would be most effective at curtailing norovirus transmission in these settings.

BACKGROUND: To reduce the burden from the COVID-19 pandemic in the United States, federal and state local governments implemented restrictions such as limitations on gatherings, restaurant dining, and travel, and recommended non-pharmaceutical interventions including physical distancing, mask-wearing, surface disinfection, and increased hand hygiene. Resulting behavioral changes impacted other infectious diseases including enteropathogens such as norovirus and rotavirus, which had fairly regular seasonal patterns prior to the COVID-19 pandemic. The study objective was to project future incidence of norovirus and rotavirus gastroenteritis as contacts resumed and other NPIs are relaxed. METHODS: We fitted compartmental mathematical models to pre-pandemic U.S. surveillance data (2012-2019) for norovirus and rotavirus using maximum likelihood estimation. Then, we projected incidence for 2022-2030 under scenarios where the number of contacts a person has per day varies from70%, 80%, 90%, and full resumption (100%) of pre-pandemic levels. RESULTS: We found that the population susceptibility to both viruses increased between March 2020 and November 2021. The 70-90% contact resumption scenarios led to lower incidence than observed pre-pandemic for both viruses. However, we found a greater than two-fold increase in community incidence relative to the pre-pandemic period under the 100% contact scenarios for both viruses. With rotavirus, for which population immunity is driven partially by vaccination, patterns settled into a new steady state quickly in 2022 under the 70-90% scenarios. For norovirus, for which immunity is relatively short-lasting and only acquired through infection, surged under the 100% contact scenario projection. CONCLUSIONS: These results, which quantify the consequences of population susceptibility build-up, can help public health agencies prepare for potential resurgence of enteric viruses.

Norovirus is the most common cause of gastroenteritis outbreaks in long-term care facilities (LTCFs) in the United States, causing a high burden of disease in both residents and staff. Understanding how case symptoms and characteristics contribute to norovirus transmission can lead to more informed outbreak control measures in LTCFs. We examined line lists for 107 norovirus outbreaks that took place in LTCFs in five U.S. states from 2015 to 2019. We estimated the individual effective reproduction number, R(i), to quantify individual case infectiousness and examined the contribution of vomiting, diarrhea, and being a resident (vs. staff) to case infectiousness. The associations between case characteristics and R(i) were estimated using a multivariable, log-linear mixed model with inverse variance weighting. We found that cases with vomiting infected 1.28 (95 % CI: 1.11, 1.48) times the number of secondary cases compared to cases without vomiting, and LTCF residents infected 1.31 (95 % CI: 1.15, 1.50) times the number of secondary cases compared to staff. There was no difference in infectiousness between cases with and without diarrhea (1.07; 95 % CI: 0.90, 1.29). This suggests that vomiting, particularly by LTCF residents, was a primary driver of norovirus transmission. These results support control measures that limit exposure to vomitus during norovirus outbreaks in LTCFs.

BACKGROUND: Rotavirus vaccine performance appears worse in countries with high rotavirus genotype diversity. Evidence suggests diminished vaccine efficacy (VE) against G2P[4], which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive. METHODS: We pooled individual-level data from ten Phase II and III clinical trials of rotavirus vaccine containing G1 and P[8] antigens (RV1) conducted between 2000 and 2012. We estimated VE against both any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for non-specific VE against any RVGE, genotype-specific VE, and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with RV1 antigens. We adjusted models for concomitant oral poliovirus and RV1 vaccination and the country's designated child mortality stratum. RESULTS: Analysis included 87,644 infants from 22 countries in the Americas, Europe, Africa, and Asia. For VE against severe RVGE, non-specific VE was 91% (95% confidence interval (CI): 87-94%). Genotype-specific VE ranged from 96% (95% CI: 89-98%) against G1P[8] to 71% (43-85%) against G2P[4]. RV1-typic VE was 92% (95% CI: 84-96%) against partially heterotypic genotypes but 83% (67-91%) against fully heterotypic genotypes. For VE against any-severity RVGE, non-specific VE was 82% (95% CI: 75-87%). Genotype-specific VE ranged from 94% (95% CI: 86-97%) against G1P[8] to 63% (41-77%) against G2P[4]. RV1-typic VE was 83% (95% CI: 72-90%) against partially heterotypic genotypes but 63% (40-77%) against fully heterotypic genotypes. CONCLUSIONS: RV1 VE is comparatively diminished against fully heterotypic genotypes including G2P[4].

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the U.S. appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight U.S. surveillance sites on 8-59-month olds with acute gastroenteritis symptoms. Children's stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention (CDC). We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with CDC confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year-vaccination interaction, and the second including annual percent of rotavirus positive tests plus a percent positive-vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year-vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive-vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.

Norovirus infection causing acute gastroenteritis could lead to adverse effects on the gut microbiome. We assessed the association of microbiome diversity with norovirus infection and secretor status in patients from Veterans Affairs medical centers. Alpha diversity metrics were lower among patients with acute gastroenteritis but were similar for other comparisons.

OBJECTIVE: Determine the incidence of SARS-CoV-2 infection among healthcare personnel (HCP) and assess occupational risks for SARS-CoV-2 infection. DESIGN: Prospective cohort of HCP followed for 6-months from May-December 2020. SETTING: Large academic healthcare system including four hospitals and affiliated clinics in Atlanta, GA. PARTICIPANTS: HCP, including those with and without direct patient care activities, working during the COVID-19 pandemic. METHODS: Incident SARS-CoV-2 infections were determined through serologic testing for SARS-CoV-2 IgG at enrollment, 3 and 6 months. HCP completed monthly surveys regarding occupational activities. Multivariable logistic regression was used to identify occupational factors that increased the risk of SARS-CoV-2 infection. RESULTS: Of the 304 evaluable HCP that were seronegative at enrollment, 26 (9%) seroconverted for SARS-CoV-2 IgG by 6 months. Participants self-identified predominantly as White (n=219, 73%), nurses (n=119, 40%), and working in inpatient medical/surgical floors (n=121, 40%). In a multivariable analysis, HCP who identified as Black were more likely to seroconvert than HCP who identified as White (odds ratio 4.5, 95% confidence interval 1.3-14.2). Increased risk for SARS-CoV-2 infection was not identified for any occupational activity, including spending >50% of a typical shift at a patient's bedside, working in COVID-19 units, or performing/being present for aerosol generating procedures (AGPs). CONCLUSIONS: In our study cohort of HCP working in an academic healthcare system, <10% had evidence of SARS-CoV-2 infection over six months. No specific occupational activities were identified as increasing risk for SARS-CoV-2 infection.

INTRODUCTION: Vaccination has significantly reduced morbidity and mortality resulting from rotavirus infection worldwide. However, rotavirus vaccine efficacy (VE) appears to wane over the first 2 years since vaccination, particularly in developing countries. Statistical methods for detecting VE waning and estimating its rate have been used in a few studies, but comparisons of methods for evaluating VE waning have not yet been performed. In this work we present and compare three methods - Durham's method, Tian's method, and time-dependent covariate (TDC) method - based on generalizations of the Cox proportional hazard model. METHODS: We developed a new stochastic agent-based simulation model to generate data from a hypothetical rotavirus vaccine trial where the protective efficacy of the vaccine may vary over time. Input parameters to the simulation model were obtained from studies on rotavirus infections in four developing countries. We applied each of the methods to four simulated datasets and compared the type-1 error probabilities and the powers of the resulting statistical tests. We also compared estimated and true values of VE over time. RESULTS: Durham's method had the highest power of detecting true VE waning of the three methods. This method also provided quite accurate estimates of VE in each period and of the per-period drop in VE. CONCLUSIONS: Durham's method is somewhat more powerful than the other two Cox proportional hazards model-based methods for detecting VE waning and provides more information about the temporal behavior of VE.

BACKGROUND: Although most norovirus outbreaks in high-income countries occur in healthcare facilities, information on associations between control measures and outbreak outcomes in these settings are lacking. METHODS: We conducted a systematic review/meta-analysis of published papers to assess associations between norovirus outbreak control measures and outcomes in hospitals and long-term care facilities (LTCFs), globally. Using regression analyses stratified by setting (hospital/LTCF), we compared durations, attack rates and case counts for outbreaks in which control measures were reportedly implemented to those in which they were not. RESULTS: We identified 102 papers describing 162 norovirus outbreaks. Control measures were reportedly implemented in 118 (73%) outbreaks and were associated with 0.6 (95% CI: 0.3-1.1) times smaller patient case counts and 0.7 (95% CI: 0.4, 1.0) times shorter durations in hospitals but 1.5 (95% CI: 1.1, 2.2), 1.5 (95% CI: 1.0-2.1) and 1.6 (95% CI: 1.0-2.6) times larger overall, resident and staff case counts, respectively, and 1.4 (95% CI: 1.0-2.0) times longer durations in LTCFs. CONCLUSIONS: Reported implementation of control measures was associated with smaller/shorter outbreaks in hospitals but larger/longer outbreaks in LTCFs. Control measures were likely implemented in response to larger/longer outbreaks in LTCFs, rather than causing them. Prospective observational or intervention studies are needed to determine effectiveness.

We measured contact patterns using online diaries for 304 employees of 3 U.S. companies working remotely. The median number of daily contacts was 2 (IQR 1-4); majority were conversation (55 %), occurred at home (64 %) and lasted >4 h (38 %). These data are crucial for modeling outbreak control among the workforces.

Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. Such studies are now underway amid the ongoing rollout of SARS-CoV-2 vaccines globally. Although traditional case-control and test-negative design 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 traditional case-control and test-negative design 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, nonspecific 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 traditional case-control design may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The test-negative design reduces but may not eliminate this confounding, for instance, if individuals who receive vaccination seek care or testing for less-severe illness. 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.

Severe acute respiratory syndrome coronavirus 2 can persist on surfaces, suggesting possible surface-mediated transmission of this pathogen. We found that fomites might be a substantial source of transmission risk, particularly in schools and child daycares. Combining surface cleaning and decontamination with mask wearing can help mitigate this risk.

OBJECTIVE: Noroviruses are the leading cause of acute gastroenteritis in the United States and outbreaks frequently occur in daycare settings. Results of norovirus vaccine trials have been promising, however there are open questions as to whether vaccination of daycare children would be cost-effective. We investigated the incremental cost-effectiveness of a hypothetical norovirus vaccination for children in daycare settings compared to no vaccination. METHODS: We conducted a model-based cost-effectiveness analysis using a disease transmission model of children attending daycare. Vaccination with a 90% coverage rate in addition to the observed standard of care (exclusion of symptomatic children from daycare) was compared to the observed standard of care. The main outcomes measures were infections and deaths averted, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Cost-effectiveness was analyzed from a societal perspective, including medical costs to children as well as productivity losses of parents, over a two-year time horizon. Data sources included outbreak surveillance data and published literature. RESULTS: A 50% efficacious norovirus vaccine averts 571.83 norovirus cases and 0.003 norovirus-related deaths per 10,000 children compared to the observed standard of care. A $200 norovirus vaccine that is 50% efficacious has a net cost increase of $178.10 per child and 0.025 more QALYs, resulting in an ICER of $7,028/QALY. Based on the probabilistic sensitivity analysis, we estimated that a $200 vaccination with 50% efficacy was 94.0% likely to be cost-effective at a willingness-to-pay of $100,000/QALY threshold and 95.3% likely at a $150,000/QALY threshold. CONCLUSION: Due to the large disease burden associated with norovirus, it is likely that vaccinating children in daycares could be cost-effective, even with modest vaccine efficacy and a high per-child cost of vaccination. Norovirus vaccination of children in daycare has a cost-effectiveness ratio similar to other commonly recommended childhood vaccines.

IMPORTANCE: Risks for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among health care personnel (HCP) are unclear. OBJECTIVE: To evaluate the risk factors associated with SARS-CoV-2 seropositivity among HCP with the a priori hypothesis that community exposure but not health care exposure was associated with seropositivity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted among volunteer HCP at 4 large health care systems in 3 US states. Sites shared deidentified data sets, including previously collected serology results, questionnaire results on community and workplace exposures at the time of serology, and 3-digit residential zip code prefix of HCP. Site-specific responses were mapped to a common metadata set. Residential weekly coronavirus disease 2019 (COVID-19) cumulative incidence was calculated from state-based COVID-19 case and census data. EXPOSURES: Model variables included demographic (age, race, sex, ethnicity), community (known COVID-19 contact, COVID-19 cumulative incidence by 3-digit zip code prefix), and health care (workplace, job role, COVID-19 patient contact) factors. MAIN OUTCOME AND MEASURES: The main outcome was SARS-CoV-2 seropositivity. Risk factors for seropositivity were estimated using a mixed-effects logistic regression model with a random intercept to account for clustering by site. RESULTS: Among 2 749 HCP, most were younger than 50 years (17 233 [69.6%]), were women (19 361 [78.2%]), were White individuals (15 157 [61.2%]), and reported workplace contact with patients with COVID-19 (12 413 [50.2%]). Many HCP worked in the inpatient setting (8893 [35.9%]) and were nurses (7830 [31.6%]). Cumulative incidence of COVID-19 per 10 000 in the community up to 1 week prior to serology testing ranged from 8.2 to 275.6; 20 072 HCP (81.1%) reported no COVID-19 contact in the community. Seropositivity was 4.4% (95% CI, 4.1%-4.6%; 1080 HCP) overall. In multivariable analysis, community COVID-19 contact and community COVID-19 cumulative incidence were associated with seropositivity (community contact: adjusted odds ratio [aOR], 3.5; 95% CI, 2.9-4.1; community cumulative incidence: aOR, 1.8; 95% CI, 1.3-2.6). No assessed workplace factors were associated with seropositivity, including nurse job role (aOR, 1.1; 95% CI, 0.9-1.3), working in the emergency department (aOR, 1.0; 95% CI, 0.8-1.3), or workplace contact with patients with COVID-19 (aOR, 1.1; 95% CI, 0.9-1.3). CONCLUSIONS AND RELEVANCE: In this cross-sectional study of US HCP in 3 states, community exposures were associated with seropositivity to SARS-CoV-2, but workplace factors, including workplace role, environment, or contact with patients with known COVID-19, were not. These findings provide reassurance that current infection prevention practices in diverse health care settings are effective in preventing transmission of SARS-CoV-2 from patients to HCP.

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: Including immunity in the model led to attack rates that were consistent with the data. However, immunity alone resulted in the majority of outbreak durations being relatively short. 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. More studies on how best to design interventions which leverage population immunity and encourage more rigorous individual exclusion may improve venue-level control measures.

In April 2020, the incidence of norovirus outbreaks reported to the National Outbreak Reporting System (NORS) dramatically declined. We used regression models to determine if this decline was best explained by underreporting, seasonal trends, or reduced exposure due to non-pharmaceutical interventions (NPIs) implemented for SARS-CoV-2 using data from 9 states from July 2012-July 2020. The decline in norovirus outbreaks was significant for all 9 states and underreporting or seasonality are unlikely to be the primary explanations for these findings. These patterns were similar across a variety of settings. NPIs appear to have reduced incidence of norovirus, a non-respiratory pathogen.

Among 353 healthcare personnel in a longitudinal cohort in four hospitals in Atlanta, GA (May-June 2020), 23 (6.5%) had SARS-CoV-2 antibodies. Spending >50% of a typical shift at bedside (OR 3.4, 95% CI: 1.2-10.5) and Black race (OR 8.4, 95% CI: 2.7-27.4) were associated with SARS-CoV-2 seropositivity.

Norovirus is the leading cause of acute gastroenteritis outbreaks in the United States. We estimated the basic (R(0)) and effective (R(e)) reproduction numbers for 7,094 norovirus outbreaks reported to the National Outbreak Reporting System (NORS) during 2009-2017 and used regression models to assess whether transmission varied by outbreak setting. The median R(0) was 2.75 (interquartile range [IQR] 2.38-3.65), and median R(e) was 1.29 (IQR 1.12-1.74). Long-term care and assisted living facilities had an R(0) of 3.35 (95% CI 3.26-3.45), but R(0) did not differ substantially for outbreaks in other settings, except for outbreaks in schools, colleges, and universities, which had an R(0) of 2.92 (95% CI 2.82-3.03). Seasonally, R(0) was lowest (3.11 [95% CI 2.97-3.25]) in summer and peaked in fall and winter. Overall, we saw little variability in transmission across different outbreaks settings in the United States.