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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., Competing Interests: Potential conflicts of interest. B. A. L. reports personal fees outside the submitted work from Epidemiologic Research and Methods, LLC and Hillevax, Inc; and has participated on the Data Safety Monitoring Board for the HICRota study in Zambia. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

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., (© 2023. The Author(s).)

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 10 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]., Competing Interests: Potential conflicts of interests. B. A. L. reports personal fees from Epidemiologic Research and Methods, LLC, and Hillevax, Inc, outside the subject of the submitted work and reports participation on a Data Safety Monitoring Board or Advisory Board for HICRota study in Zambia. L. A. W. reports honoraria and support for attending meetings and/or travel for serving as a Member of the Independent Advisory Committee for the Global Burden of Disease Study, University of Washington, received from London School of Tropical Medicine and Hygiene and outside the subject of the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Rotavirus vaccination has been shown to reduce rotavirus burden in many countries, but the long-term magnitude of vaccine impacts is unclear, particularly in low-income countries. We use a transmission model to estimate the long-term impact of rotavirus vaccination on deaths and disability adjusted life years (DALYs) from 2006 to 2034 for 112 low- and middle-income countries. We also explore the predicted effectiveness of a one- vs two- dose series and the relative contribution of direct vs indirect effects to overall impacts. To validate the model, we compare predicted percent reductions in severe rotavirus cases with the percent reduction in rotavirus positivity among gastroenteritis hospital admissions for 10 countries with pre- and post-vaccine introduction data. We estimate that vaccination would reduce deaths from rotavirus by 49.1 % (95 % UI: 46.6-54.3 %) by 2034 under realistic coverage scenarios, compared to a scenario without vaccination. Most of this benefit is due to direct benefit to vaccinated individuals (explaining 69-97 % of the overall impact), but indirect protection also appears to enhance impacts. We find that a one-dose schedule would only be about 57 % as effective as a two-dose schedule 12 years after vaccine introduction. Our model closely reproduced observed reductions in rotavirus positivity in the first few years after vaccine introduction in select countries. Rotavirus vaccination is likely to have a substantial impact on rotavirus gastroenteritis and its mortality burden. To sustain this benefit, the complete series of doses is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JMB reports personal fees from WHO outside the submitted work. EWH reports personal fees from Merck & Co for unrelated work. VEP is a member of the WHO Immunization and Vaccine-related Research Advisory Committee (IVIR-AC) and has received reimbursement from Merck and Pfizer for travel expenses to Scientific Input Engagements unrelated to the topic of this manuscript., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Estimates of rotavirus vaccine effectiveness (VE) in the United States 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 US surveillance sites on 8- to 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. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention 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 the 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., Competing Interests: Disclosure: J.A.E. has research support from Merck, Pfizer, and GlaxoSmithKline and consults for Sanofi Pasteur and Meissa Vaccines. G.A.W. received an honorarium from Merck for authorship of chapters in the Merck Manual. M.M.M. has laboratory agreements with Merck Sharp & Dohme and Sanofi. C.J.H. has research support from Merck, GlaxoSmithKline, Pfizer, and Astra-Zeneca and has received honoraria from Frontline Medical Communications for contributions to Pediatric News. J.E.S. has research support from Merck. T.L.L. is a member of the Amgen Methods Advisory Council, for which he receives consulting fees and travel support. B.A.L. reports grants and personal fees from Takeda Pharmaceuticals and personal fees from World Health Organization, outside the subject of the submitted work. The other authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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: A correlate of protection for rotavirus gastroenteritis would facilitate rapid assessment of vaccination strategies and the next generation of rotavirus vaccines. We aimed to quantify a threshold of postvaccine serum antirotavirus immunoglobulin A (IgA) as an individual-level immune correlate of protection against rotavirus gastroenteritis., Methods: Individual-level data on 5074 infants in 9 GlaxoSmithKline Rotarix Phase 2/3 clinical trials from 16 countries were pooled. Cox proportional hazard models were fit to estimate hazard ratios (HRs) describing the relationship between IgA thresholds and occurrence of rotavirus gastroenteritis., Results: Seroconversion (IgA ≥ 20 U/mL) conferred substantial protection against any and severe rotavirus gastroenteritis to age 1 year. In low child mortality settings, seroconversion provided near perfect protection against severe rotavirus gastroenteritis (HR, 0.04; 95% confidence interval [CI], .01-.31). In high child mortality settings, seroconversion dramatically reduced the risk of severe rotavirus gastroenteritis (HR, 0.46; 95% CI, .25-.86). As IgA threshold increased, risk of rotavirus gastroenteritis generally decreased. A given IgA threshold provided better protection in low compared to high child mortality settings., Discussion: Postvaccination antirotavirus IgA is a valuable correlate of protection against rotavirus gastroenteritis to age 1 year. Seroconversion provides an informative threshold for assessing rotavirus vaccine performance., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Rotavirus incidence remains relatively high in low-income countries (LICs) compared to high-income countries (HICs) after vaccine introduction. Ghana introduced monovalent rotavirus vaccine in April 2012 and despite the high coverage, vaccine performance has been modest compared to developed countries. The predictors of low vaccine effectiveness in LICs are poorly understood, and the drivers of subnational heterogeneity in rotavirus vaccine impact are unknown., Methods: We used mathematical models to investigate variations in rotavirus incidence in children <5 years old in Ghana. We fit models to surveillance and case-control data from three different hospitals: Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi, and War Memorial Hospital in Navrongo. The models were fitted to both pre- and post-vaccine data to estimate parameters describing the transmission rate, waning of maternal immunity, and vaccine response rate., Results: The seasonal pattern and age distribution of rotavirus cases varied among the three study sites in Ghana. Our model was able to capture the spatio-temporal variations in rotavirus incidence across the three sites and showed good agreement with the age distribution of observed cases. The rotavirus transmission rate was highest in Accra and lowest in Navrongo, while the estimated duration of maternal immunity was longer (~5 months) in Accra and Kumasi and shorter (~3 months) in Navrongo. The proportion of infants who responded to the vaccine was estimated to be high in Accra and Kumasi and low in Navrongo., Conclusions: Rotavirus vaccine impact varies within Ghana. A low vaccine response rate was estimated for Navrongo, where rotavirus is highly seasonal and incidence limited to a few months of the year. Our findings highlight the need to further explore the relationship between rotavirus seasonality, maternal immunity, and vaccine response rate to determine how they influence vaccine effectiveness and to develop strategies to improve vaccine impact., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prediction skill is a key test of models for epidemic dynamics. However, future validation of models against out-of-sample data is rare, partly because of a lack of timely surveillance data. We address this gap by analyzing the response of rotavirus dynamics to infant vaccination. Syndromic surveillance of emergency department visits for diarrhea in New York City reveals a marked decline in diarrheal incidence among infants and young children, in line with data on rotavirus-coded hospitalizations and laboratory-confirmed cases, and a shift from annual to biennial epidemics increasingly affecting older children and adults. A published mechanistic model qualitatively predicted these patterns more than 2 years in advance. Future efforts to increase vaccination coverage may disrupt these patterns and lead to further declines in the incidence of rotavirus-attributable gastroenteritis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Despite the success of rotavirus vaccines over the last decade, rotavirus remains a leading cause of severe diarrheal disease among young children. Further progress in reducing the burden of disease is inhibited, in part, by vaccine underperformance in certain settings. Early trials suggested that oral poliovirus vaccine (OPV), when administered concomitantly with rotavirus vaccine, reduces rotavirus seroconversion rates after the first rotavirus dose with modest or nonsignificant interference after completion of the full rotavirus vaccine course. Our study aimed to identify a range of individual-level characteristics, including concomitant receipt of OPV, that affect rotavirus vaccine immunogenicity in high- and low-child-mortality settings, controlling for individual- and country-level factors. Our central hypothesis was that OPV administered concomitantly with rotavirus vaccine reduced rotavirus vaccine immunogenicity., Methods and Findings: Pooled, individual-level data from GlaxoSmithKline's Phase II and III clinical trials of the monovalent rotavirus vaccine (RV1), Rotarix, were analyzed, including 7,280 vaccinated infants (5-17 weeks of age at first vaccine dose) from 22 trials and 33 countries/territories (5 countries/territories with high, 13 with moderately low, and 15 with very low child mortality). Two standard markers for immune response were examined including antirotavirus immunoglobulin A (IgA) seroconversion (defined as the appearance of serum antirotavirus IgA antibodies in subjects initially seronegative) and serum antirotavirus IgA titer, both collected approximately 4-12 weeks after administration of the last rotavirus vaccine dose. Mixed-effect logistic regression and mixed-effect linear regression of log-transformed data were used to identify individual- and country-level predictors of seroconversion (dichotomous) and antibody titer (continuous), respectively. Infants in high-child-mortality settings had lower odds of seroconverting compared with infants in low-child-mortality settings (odds ratio [OR] = 0.48, 95% confidence interval [CI] 0.43-0.53, p < 0.001). Similarly, among those who seroconverted, infants in high-child-mortality settings had lower IgA titers compared with infants in low-child-mortality settings (mean difference [β] = 0.83, 95% CI 0.77-0.90, p < 0.001). Infants who received OPV concomitantly with both their first and their second doses of rotavirus vaccine had 0.63 times the odds of seroconverting (OR = 0.63, 95% CI 0.47-0.84, p = 0.002) compared with infants who received OPV but not concomitantly with either dose. In contrast, among infants who seroconverted, OPV concomitantly administered with both the first and second rotavirus vaccine doses was found to be positively associated with antirotavirus IgA titer (β = 1.28, 95% CI 1.07-1.53, p = 0.009). Our findings may have some limitations in terms of generalizability to routine use of rotavirus vaccine because the analysis was limited to healthy infants receiving RV1 in clinical trial settings., Conclusions: Our findings suggest that OPV given concomitantly with RV1 was a substantial contributor to reduced antirotavirus IgA seroconversion, and this interference was apparent after the second vaccine dose of RV1, as with the original clinical trials that our reanalysis is based on. However, our findings do suggest that the forthcoming withdrawal of OPV from the infant immunization schedule globally has the potential to improve RV1 performance., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BAL has received personal fees from Takeda Pharmaceuticals, personal fees from CDC Foundation, and personal fees from Hall Booth Smith, P.C., outside the submitted work. All other authors declare no competing interests.

Rotavirus vaccination has substantially reduced the incidence of rotavirus-associated gastroenteritis (RVGE) in high-income countries, but vaccine impact and estimated effectiveness are lower in low-income countries for reasons that are poorly understood. We used mathematical modeling to quantify rotavirus vaccine impact and investigate reduced vaccine effectiveness, particularly during the second year of life, in Malawi, where vaccination was introduced in October 2012 with doses at 6 and 10 weeks. We fitted models to 12 years of prevaccination data and validated the models against postvaccination data to evaluate the magnitude and duration of vaccine protection. The observed rollout of vaccination in Malawi was predicted to lead to a 26 to 77% decrease in the overall incidence of moderate-to-severe RVGE in 2016, depending on assumptions about waning of vaccine-induced immunity and heterogeneity in vaccine response. Vaccine effectiveness estimates were predicted to be higher among 4- to 11-month-olds than 12- to 23-month-olds, even when vaccine-induced immunity did not wane, due to differences in the rate at which vaccinated and unvaccinated individuals acquire immunity from natural infection. We found that vaccine effectiveness during the first and second years of life could potentially be improved by increasing the proportion of infants who respond to vaccination or by lowering the rotavirus transmission rate. An additional dose of rotavirus vaccine at 9 months of age was predicted to lead to higher estimated vaccine effectiveness but to only modest (5 to 16%) reductions in RVGE incidence over the first 3 years after introduction, regardless of assumptions about waning of vaccine-induced immunity., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis (RVGE) in low- and middle-income countries. While susceptibility of children to rotavirus is known to vary within and between settings, implications for estimation of immune protection are not well understood. We sought to re-estimate naturally-acquired protection against rotavirus infection and RVGE, and to understand how differences in susceptibility among children impacted estimates. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 rotavirus-unvaccinated children experienced 1418 rotavirus infections and 371 episodes of RVGE over 17,636 child-months. We developed a model that characterized susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings. We tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors, and with the severity of RVGE symptoms. 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 rotavirus-negative diarrhea, and higher risk of moderate-to-severe symptoms when experiencing RVGE. Simulations suggested that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in susceptibility of children, but result primarily from the interaction of transmission rates with age-dependent risk for infections to cause RVGE. 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 unmeasured individual- and age-dependent susceptibility may influence estimates of naturally-acquired immune protection against RVGE., Competing Interests: The authors declare no competing interests.

Background: Rotavirus is the leading cause of severe diarrhea among children worldwide, and vaccines can reduce morbidity and mortality by 50-98%. The test-negative control (TNC) study design is increasingly used for evaluating the effectiveness of vaccines against rotavirus and other vaccine-preventable diseases. In this study design, symptomatic patients who seek medical care are tested for the pathogen of interest. Those who test positive (negative) are classified as cases (controls)., Methods: We use a probability model to evaluate the bias of estimates of rotavirus vaccine effectiveness (VE) against rotavirus diarrhea resulting in hospitalization in the presence of possible confounding and selection biases due to differences in the propensity of seeking medical care (PSMC) between vaccinated and unvaccinated children., Results: The TNC-based VE estimate corrects for confounding bias when the confounder's effects on the probabilities of rotavirus and non-rotavirus related hospitalizations are equal. If this condition is not met, then the estimated VE may be substantially biased. The bias is more severe in low-income countries, where VE is known to be lower. Under our model, differences in PSMC between vaccinated and unvaccinated children do not result in selection bias when the TNC study design is used., Conclusions: In practice, one can expect the association of PSMC (or other potential confounders) with the probabilities of rotavirus and non-rotavirus related hospitalization to be similar, in which case the confounding effects will only result in small bias in the VE estimate from TNC studies. The results of this work, along with those of our previous paper, confirm the TNC design can be expected to provide reliable estimates of rotavirus VE in both high- and low-income countries., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Rotavirus disease rates dramatically declined among children <5 years of age since the rotavirus vaccine was introduced in 2006; population-level impacts remain to be fully elucidated., Methods: Data from the Healthcare Cost and Utilization Project State Inpatient Databases were used to conduct a time-series analysis of monthly hospital discharges across age groups for acute gastroenteritis and rotavirus from 2000 to 2013. Rate ratios were calculated comparing prevaccine and postvaccine eras., Results: Following vaccine introduction, a decrease in rotavirus hospitalizations occurred with a shift toward biennial patterns across all ages. The 0-4-year age group experienced the largest decrease in rotavirus hospitalizations (rate ratio, 0.14; 95% confidence interval, .09-.23). The 5-19-year and 20-59-year age groups experienced significant declines in rotavirus hospitalization rates overall; the even postvaccine calendar years were characterized by progressively lower rates, and the odd postvaccine years were associated with reductions in rates that diminished over time. Those aged ≥60 years experienced the smallest change in rotavirus hospitalization rates overall, with significant reductions in even postvaccine years compared with prevaccine years (rate ratio, 0.51; 95% confidence interval, .39-.66)., Conclusions: Indirect impacts of infant rotavirus vaccination are apparent in the emergence of biennial patterns in rotavirus hospitalizations that extend to all age groups ineligible for vaccination. These observations are consistent with the notion that young children are of primary importance in disease transmission and that the initial postvaccine period of dramatic population-wide impacts will be followed by more complex incidence patterns across the age range in the long term., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The direct effectiveness of infant rotavirus vaccination implemented in 2006 in the United States has been evaluated extensively, however, understanding of population-level vaccine effectiveness (VE) is still incomplete., Methods: We analyzed time series data on rotavirus gastroenteritis (RVGE) and all-cause acute gastroenteritis (AGE) hospitalization rates in the United States from the MarketScan® Research Databases for July 2001-June 2016. Individuals were grouped into ages 0-4, 5-9, 10-14, 15-24, 25-44, and 45-64 years. Negative binomial regression models were fitted to monthly RVGE and AGE data to estimate the direct, indirect, overall, and total VE., Results: A total of 9211 RVGE and 726,528 AGE hospitalizations were analyzed. Children 0-4 years of age had the largest declines in RVGE hospitalizations with direct VE of 87% (95% CI: 83, 90%). Substantial indirect effects were observed across age groups and generally declined in each older group. Overall VE against RVGE hospitalizations for all ages combined was 69% (95% CI: 62, 76%). Total VE was highest among young children; a vaccinated child in the post-vaccine era has a 95% reduced risk of RVGE hospitalization compared to a child in the pre-vaccine era. We observed higher direct VE in odd post-vaccine years and an opposite pattern for indirect VE., Conclusions: Vaccine benefits extended to unvaccinated individuals in all age groups, suggesting infants are important drivers of disease transmission across the population. Imperfect disease classification and changing disease incidence may lead to bias in observed direct VE., Trial Registration: Not applicable.

Background: Rotavirus vaccination was introduced in the United States in 2006. Our objectives were to examine reductions in diarrhea-associated health care utilization after rotavirus vaccine implementation and to assess direct vaccine effectiveness (VE) in US children., Methods: Retrospective cohort study using claims data of US children under 5 years of age. We compared rates of diarrhea-associated health care utilization in prevaccine versus postvaccine introduction years. We also examined VE and duration of protection., Results: Compared with the average rate of rotavirus-coded hospitalizations in the prevaccine years, overall vaccine rates were reduced by 75% in 2007 to 2008, 60% in 2008 to 2009, 94% in 2009 to 2010, 80% in 2010 to 2011, 97% in 2011 to 2012, 88% in 2012 to 2013, 98% in 2013 to 2014 and 92% in 2014 to 2015. RotaTeq-adjusted VE was 88% against rotavirus-coded hospitalization among 3-11 months of age, 88% in 12-23 months of age, 87% in 24-35 months of age, 87% in 36-47 months of age and 87% in 48-59 months of age. Rotarix-adjusted VE was 87% against rotavirus-coded hospitalization among 3-11 months of age, 86% in 12-23 months of age and 86% in 24-35 months of age., Conclusion: Implementation of rotavirus vaccines has substantially reduced diarrhea-associated health care utilization in US children under 5 years of age. Both vaccines provided good and enduring protection through the fourth year of life against rotavirus hospitalizations.

Background: Epidemiologic studies that evaluate the relationship between previous antibiotic use and acute gastroenteritis (AGE) in the pediatric population are currently lacking., Methods: We analyzed inpatient and outpatient children with AGE and healthy controls from Vanderbilt University Medical Center between December 1, 2014, and November 30, 2015. The following 4 outcome groups were defined: overall AGE, norovirus-associated AGE, rotavirus-associated AGE, and nonnorovirus/nonrotavirus AGE. Multiple logistic regression was performed to evaluate the association between previous antibiotic use and the 4 AGE outcomes and with AGE severity., Results: Reported antibiotic use rates in the 3 months before illness onset were similar across the 4 AGE outcomes (overall AGE, 21%; norovirus-associated AGE, 23%; rotavirus-associated AGE, 28%; and nonnorovirus/nonrotavirus AGE, 22%) but were higher than that reported for healthy controls (9%). Compared with healthy controls, patients with AGE overall were 4.6 (95% confidence interval [CI], 1.8-11.4) times more likely to have reported antibiotic use in the 3 weeks before illness onset and 2.6 (95% CI, 1.7-4.1) times more likely to have reported antibiotic use within 3 months before illness onset. Similar results were found for the other specific AGE outcomes. For the overall AGE group, the odds of antibiotic use in the 3 months before illness onset was 3.5 (95% CI, 1.8-7.1) times higher for inpatients than for outpatients., Conclusions: Previous antibiotic use among children was associated with increased odds of AGE, irrespective of etiology, and this association was stronger with more recent antibiotic use. Previous antibiotic use was associated also with more severe AGE.

We compared acute gastroenteritis (AGE)-related hospitalization rates among children <5 years of age during the pre-rotavirus vaccine (2000-2006) and post-rotavirus vaccine (2008-2013) periods to estimate national reductions in AGE-related hospitalizations and associated costs. We estimate that between 2008 and 2013, AGE-related hospitalizations declined by 382000, and $1.228 billion in medical costs were averted.

Estimation of the effectiveness of rotavirus vaccines via the test-negative control study design has gained popularity over the past few years. In this study design, children with severe diarrhea who test positive for rotavirus infection are considered as cases, while children who test negative serve as controls. We use a simple probability model to evaluate and compare the test-negative control and the traditional case-control designs with respect to the bias of resulting estimates of rotavirus vaccine effectiveness (VE). Comparisons are performed under two scenarios, corresponding to studies performed in high-income and low-income countries. We consider two potential sources of bias: (a) misclassification bias resulting from imperfect sensitivity and specificity of the test used to diagnose rotavirus infection, and (b) selection bias associated with possible effect of rotavirus vaccination on the probability of contracting severe non-rotavirus diarrhea. Our results suggest that both sources of bias may produce VE estimates with substantial bias. Particularly, lack of perfect specificity is associated with severe negative bias. For example, if the specificity of the diagnostic test is 90% then VE estimates from both types of case-control studies may under-estimate the true VE by more than 20%. If the vaccine protects children against non-rotavirus diarrhea then VE estimates from test-negative control studies may be close to zero even though the true VE is 50%. However, the sensitivity and specificity of the enzyme immunoassay test currently used to diagnose rotavirus infections are both over 99%, and there is no solid evidence that the existing rotavirus vaccines affect the rates of non-rotavirus diarrhea. We therefore conclude that the test-negative control study design is a convenient and reliable alternative for estimation of rotavirus VE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Previous studies have found a strong correlation between internet search and public health surveillance data. Less is known about how search data respond to public health interventions, such as vaccination, and the consistency of responses in different countries. In this study, we aimed to study the correlation between internet searches for "rotavirus" and rotavirus disease activity in the United States, United Kingdom, and Mexico before and after introduction of rotavirus vaccine., Methods: We compared time series of internet searches for "rotavirus" from Google Trends with rotavirus laboratory reports from the United States and United Kingdom and with hospitalizations for acute gastroenteritis in the United States and Mexico. Using time and location parameters, Google quantifies an internet query share (IQS) to measure the relative search volume for specific terms. We analyzed the correlation between IQS and laboratory and hospitalization data before and after national vaccine introductions., Results: There was a strong positive correlation between the rotavirus IQS and laboratory reports in the United States (R2 = 0.79) and United Kingdom (R2 = 0.60) and between the rotavirus IQS and acute gastroenteritis hospitalizations in the United States (R2 = 0.87) and Mexico (R2 = 0.69) (P < .0001 for all correlations). The correlations were stronger in the prevaccine period than in the postvaccine period. After vaccine introduction, the mean rotavirus IQS decreased by 40% (95% confidence interval [CI], 25%-55%) in the United States and by 70% (95% CI, 55%-86%) in Mexico. In the United Kingdom, there was a loss of seasonal variation after vaccine introduction., Conclusions: Rotavirus internet search data trends mirrored national rotavirus laboratory trends in the United States and United Kingdom and gastroenteritis-hospitalization data in the United States and Mexico; lower correlations were found after rotavirus vaccine introduction., (Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Hospitalizations for rotavirus and acute gastroenteritis (AGE) have declined in the US with rotavirus vaccination, though biennial peaks in incidence in children aged less than 5 years occur. This pattern may be explained by lower rotavirus vaccination coverage in US children (59% to 73% from 2010-2015), resulting in accumulation of susceptible children over two successive birth cohorts., Methods: Retrospective cohort analysis of claims data of commercially insured US children aged <5 years. Age-stratified hospitalization rates for rotavirus and for AGE from the 2002-2015 rotavirus seasons were examined. Median age and rotavirus vaccination coverage for biennial rotavirus seasons during pre-vaccine (2002-2005), early post-vaccine (2008-2011) and late post-vaccine (2012-2015) years., Results: Age-stratified hospitalization rates decreased from pre-vaccine to early post-vaccine and then to late post-vaccine years. The clearest biennial pattern in hospitalization rates is the early post-vaccine period, with higher rates in 2009 and 2011 than in 2008 and 2010. The pattern diminishes in the late post-vaccine period. For rotavirus hospitalizations, the median age and the difference in age between biennial seasons was highest during the early post-vaccine period; these differences were not observed for AGE hospitalizations. There was no significant difference in vaccination coverage between biennial seasons., Conclusions: These observations provide conflicting evidence that incomplete vaccine coverage drove the biennial pattern in rotavirus hospitalizations that has emerged with rotavirus vaccination in the US. As this pattern is diminishing with higher vaccine coverage in recent years, further increases in vaccine coverage may reach a threshold that eliminates peak seasons in hospitalizations.

Concern has grown that children vaccinated against rotavirus in developing countries may be vulnerable to rotavirus diarrhea in the second year of life due to waning immunity. Adding a booster dose of rotavirus vaccine at 9 or 12 months of age with measles vaccine has been suggested as a strategy to address this. We evaluated the hypothetical potential benefits of a booster dose on reduction of rotavirus mortality. The projected number of deaths averted were calculated using national level full series vaccination coverage, estimated national rotavirus deaths by week of age, and VE at <12 months of age and ≥12 months of age derived from the published literature. We assumed three functional forms of waning based on the VE estimates: stepwise, linear, and logarithmic. We modeled three potential boosting scenarios: (a) reduced VE waning in the second year of life by 50%, (b) reestablished second year of life VE to the levels in the first year of life, and (c) boosted first year VE by 50% of the difference between VE in the first and second years. To express uncertainty resulting from the parameters, each of the nine models were run 1000 times using a random sample of input values. Across all WHO regions, with the stepwise models we estimated a median of 9800 (95%CI: 9400, 10,200), 19,600 (95%CI: 18,800, 20,400), and 29,400 (95%CI: 28,200, 30,700) additional rotavirus deaths averted in the reduced VE waning, reestablished VE, and boosted VE scenarios. These estimates were highly sensitive to the assumed functional form of waning with approximately 65-80% fewer deaths averted if immunity waned in a linear or logarithmic fashion compared to the stepwise model. While these projections will benefit from improved input data points, our resultsinform consideration of booster doses of rotavirus vaccine., (Published by Elsevier Ltd.)

Background: Observational studies in socioeconomically distinct populations have yielded conflicting conclusions about the strength of naturally acquired immunity against rotavirus gastroenteritis (RVGE), mirroring vaccine underperformance in low-income countries. We revisited birth cohort studies to understand naturally acquired protection against rotavirus infection and RVGE., Methods: We reanalyzed data from 200 Mexican and 373 Indian children followed from birth to 2 and 3 years of age, respectively. We reassessed protection against RVGE, decomposing the incidence rate into the rate of rotavirus infection and the risk of RVGE given infection, and tested for serum antibody correlates of protection using regression models., Results: Risk for primary, secondary, and subsequent infections to cause RVGE decreased per log-month of age by 28% (95% confidence interval [CI], 12%-41%), 69% (95% CI, 30%-86%), and 64% (95% CI, -186% to 95%), respectively, in Mexico City, and by 10% (95% CI, -1% to 19%), 51% (95% CI, 41%-59%) and 67% (95% CI, 57%-75%), respectively, in Vellore. Elevated serum immunoglobulin A and immunoglobulin G titers were associated with partial protection against rotavirus infection. Associations between older age and reduced risk for RVGE or moderate-to-severe RVGE given infection persisted after controlling for antibody levels., Conclusions: Dissimilar estimates of protection against RVGE may be due in part to age-related, antibody-independent risk for rotavirus infections to cause RVGE., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Case-control studies are often performed to estimate postlicensure vaccine effectiveness (VE), but the enrollment of controls can be challenging, time-consuming, and costly. We evaluated whether children enrolled in the same hospital-based diarrheal surveillance used to identify rotavirus cases but who test negative for rotavirus (test-negative controls) can be considered a suitable alternative to nondiarrheal hospital or community-based control groups (traditional controls)., Methods: We compared calculated VE estimates as a function of varying values of true VE, attack rates of rotavirus and nonrotavirus diarrhea in the population, and sensitivity and specificity of the rotavirus enzyme immunoasssay. We also searched the literature to identify rotavirus VE studies that used traditional and test-negative control groups and compared VE estimates obtained using the different control groups., Results: Assuming a 1% attack rate for severe rotavirus diarrhea, a 3% attack rate for severe nonrotavirus diarrhea in the population, a test sensitivity of 96%, and a specificity of 100%, the calculated VE estimates using both the traditional and test-negative control groups closely approximated the true VE for all values from 30% to 100%. As true VE decreased, the traditional case-control approach slightly overestimated the true VE and the test-negative case-control approach slightly underestimated this estimate, but the absolute difference was only ±0.2 percentage points. Field VE estimates from 10 evaluations that used both traditional and test-negative control groups were similar regardless of control group used., Conclusions: The use of rotavirus test-negative controls offers an efficient and cost-effective approach to estimating rotavirus VE through case-control studies., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Norovirus and rotavirus are prominent enteric viruses responsible for severe acute gastroenteritis disease burden around the world. Both viruses recognize and bind to histo-blood group antigens, which are expressed by the fucosyltransferase 2 (FUT2) gene. Individuals with a functional FUT2 gene are termed "secretors." FUT2 polymorphisms may influence viral binding patterns and, therefore, may influence host susceptibility to infection by these viruses., Methods: We performed a systematic review of the published literature on this topic. Data were abstracted and compiled for descriptive analyses and metaanalyses. We estimated pooled odds ratios (ORs) for infection using random-effects models., Results: We found that secretors were 9.9 times (95% confidence interval [CI], 3.9-24.8) as likely to be infected with genogroup II.4 noroviruses and 2.2 times as likely to be infected with genogroup II non-4 noroviruses (95% CI, 1.2-4.2) compared with nonsecretors. Secretors were also 26.6 times more susceptible to infections from P[8]-type rotaviruses compared with nonsecretors (95% CI, 8.3-85.0)., Conclusions: Our analyses indicate that host genetic susceptibility to norovirus and rotavirus infection may be strain specific. As strain distribution and the proportion of genetic phenotypes vary in different countries, future studies should focus on differences in susceptibility among various ethnicities. Knowledge of innate susceptibility to rotavirus and norovirus can lead to improved understanding of both vaccine performance and individual risk of disease., (Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Using data from rotavirus vaccine effectiveness (VE) studies, we assessed whether rotavirus season modifies rotavirus VE in infants. In the first year of life, adjusted VE was 72% for children born during rotavirus season and 84% for children born in other months (P = .01). Seasonal factors may interfere with vaccine performance., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: We discuss recent advances in the understanding of acquired immunity and susceptibility to the two major pediatric enteric viral pathogens, norovirus and rotavirus., Recent Findings: The prominent decline in severe rotavirus gastroenteritis in areas with mature rotavirus vaccination programmes has correspondingly unmasked the significant burden of disease associated with norovirus gastroenteritis among children. As epidemiologists and vaccinologists set their sights on this next vaccine target, we provide an update on norovirus vaccine development.In addition to these developments regarding acquired immunity, refinements to our understanding of innate susceptibility to norovirus has advanced. Significant recent advances now describe similar immunologic mechanisms in understanding susceptibility for both norovirus and rotavirus, involving histo-blood group antigenic associations, which may also prove to be genotype specific., Summary: This information can potentially be used to tailor both applied and developmental efforts to public health interventions against these important pediatric enteric viral pathogens.

Prior to the introduction of rotavirus vaccines in 2006, rotavirus was the leading cause of severe gastroenteritis among US children <5 years of age. In the first 7 years of vaccine use, both recommended rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) have been shown to be highly effective in preventing outcomes of severe disease in US children in a variety of settings. In addition, substantial decreases in severe diarrheal disease in US children, exceeding the level expected based on vaccine coverage, as well as the extension of benefits to older age groups ineligible for vaccination have demonstrated both the direct and indirect impacts of vaccination in the USA.

Rotavirus is the leading cause of severe diarrhea among children<5 years worldwide. Currently licensed rotavirus vaccines have been efficacious and effective, with many countries reporting substantial declines in diarrheal and rotavirus-specific morbidity and mortality. However, the full public health impact of these vaccines has not been realized. Most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs. Research activities that may help inform vaccine introduction decisions include (1) establishing effectiveness, impact, and safety for rotavirus vaccines in low-income settings; (2) identifying potential strategies to improve performance of oral rotavirus vaccines in developing countries, such as zinc supplementation; and (3) pursuing alternate approaches to oral vaccines, such as parenteral immunization. Policy- and program-level barriers, such as financial implications of new vaccine introductions, should be addressed to ensure that countries are able to make informed decisions regarding rotavirus vaccine introduction.

Background: Rotavirus vaccine introduction in the United States in 2006 led to substantial declines in rotavirus detections during 2007 to 2010. To further evaluate the long-term impact of the vaccine program, we assessed trends in rotavirus testing and detection in the 2010 to 2011 and 2011 to 2012 seasons compared with prevaccine seasons from 2000 to 2006., Methods: We examined data from July 2000 to June 2012 from 50 to 70 laboratories reporting to the National Respiratory and Enteric Viruses Surveillance System to compare rotavirus season timing and peak activity in the pre- and postvaccine introduction eras. To assess trends in rotavirus testing and detection, we restricted the analyses to 25 laboratories that consistently reported for ≥ 26 weeks for each season from 2000 to 2012., Results: The threshold for the start of the rotavirus season was never achieved nationally during the 2011 to 2012 season, and the 2010 to 2011 season was 8 weeks shorter in duration than the prevaccine baseline. During these seasons, nationally, the number of positive rotavirus tests declined 74%-90% compared with the prevaccine baseline and the total number of tests performed annually declined 28%-36%. The annual proportion positive at the 25 consistently reporting laboratories remained below 10% in both seasons compared with a prevaccine baseline median of 26%. A pattern of biennial increases in rotavirus activity emerged during the 5 postvaccine seasons from 2007 to 2012, but activity remained substantially below prevaccine levels., Conclusions: A substantial and sustained decline in rotavirus activity below the prevaccine baseline was observed in all 5 postvaccine introduction years, affirming the long-term health benefits of the US rotavirus vaccination program.

Objective: We sought to determine the impact of rotavirus vaccine implementation on gastroenteritis (GE)-related calls to a large telephone triage service in Tennessee., Methods: Total and GE-related calls received by the Vanderbilt Telephone Triage Program for children <5 years of age were examined from May 1, 2004 to April 30, 2010. Time series adapted Poisson regression models were used to compare weekly GE-related call proportions between the prevaccine (May 2004 to April 2007) and postlicensure (May 2007 to April 2010) periods. Separate models compared GE-related call proportions in the historical rotavirus (February to April) and nonrotavirus (May to January) seasons. Associations between call data and laboratory-confirmed rotavirus detections and regionally reported norovirus activity were also assessed., Results: There were 156362 total calls and 19731 GE-related calls. Annual GE-related call proportions declined by 8% (95% confidence interval, 3%-12%) in the postlicensure period; declines ranging from 23% to 31% occurred during the historical rotavirus season in all 3 postlicensure years. No declines occurred in the nonrotavirus season. After vaccine licensure, reductions in laboratory-confirmed rotavirus activity were associated with declines in GE-related call proportions. Peak GE-related call proportions in the postlicensure period occurred earlier than in prevaccine years and were not strongly associated with laboratory-confirmed rotavirus but instead showed good correlation with norovirus outbreaks., Conclusions: A decline in GE-related call proportions among young children after rotavirus vaccine licensure was documented by using a novel surveillance platform that captures mild GE not detected in other surveillance systems. Since rotavirus vaccine licensure, peak call proportions correlate with regional norovirus activity, highlighting the role of that pathogen in community GE.

Rotavirus causes one-third to one-half of severe diarrheal disease in children under the age of five years worldwide. In 2006 two rotavirus vaccines became available and, in the intervening years, approximately thirty countries have introduced them into their immunization programs, primarily in high-income and middle-income settings. Major reductions in rotavirus hospitalizations have been observed in a number of these locations, and in select countries, there have been impacts on gastroenteritis mortality associated with rotavirus vaccine introduction. In addition to these direct health benefits, reduced gastroenteritis risk has been documented in unvaccinated groups, including older children and adults, suggesting indirect benefits (i.e. herd immunity). In this paper, we summarize what has been learned from programs studying post-licensure vaccine effectiveness, impact on health-care utilization and death, safety issues (namely, intussception and the detection of adventitious viruses) and the potential selective pressure of vaccination on the diversity of rotavirus genotypes., (Published by Elsevier B.V.)

Google-based Internet query share (IQS) for rotavirus search terms correlated well with US rotavirus laboratory detections from 2004 to 2010 (r = 0.88; P < .001), capturing the reduction observed during postvaccine years (2008-2010). IQS analysis could become an inexpensive and reliable supplement for monitoring the impact of rotavirus vaccination in the United States.

Rotavirus vaccines have had a dramatic impact on morbidity and mortality from diarrhea among children in high- and middle-income countries that have introduced the vaccine into their national immunization programs. Widespread introduction of rotavirus vaccine in developing countries is imminent and their full potential in reducing the global burden from severe childhood diarrhea may soon be realized. The objectives of this paper are to describe the remaining issues and challenges in ensuring the success of the global rotavirus vaccination program and to discuss further research needed to help address them.

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research.

Introduction: Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance., Methods: We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy., Results: Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES., Discussion: The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements.

Understanding how immunity shapes the dynamics of multistrain pathogens is essential in determining the selective pressures imposed by vaccines. There is currently much interest in elucidating the strain dynamics of rotavirus to determine whether vaccination may lead to the replacement of vaccine-type strains. In developed countries, G1P[8] strains constitute the majority of rotavirus infections most years, but occasionally other genotypes dominate for reasons that are not well understood. We developed a mathematical model to examine the interaction of five common rotavirus genotypes. We explored a range of estimates for the relative strength of homotypic vs. heterotypic immunity and compared model predictions against observed genotype patterns from six countries. We then incorporated vaccination in the model to examine its impact on rotavirus incidence and the distribution of strains. Our model can explain the coexistence and cyclical pattern in the distribution of genotypes observed in most developed countries. The predicted frequency of cycling depends on the relative strength of homotypic vs. heterotypic immunity. Vaccination that provides strong protection against G1 and weaker protection against other strains will likely lead to an increase in the relative prevalence of non-G1 strains, whereas a vaccine that provides equally strong immunity against all strains may promote the continued predominance of G1. Overall, however, disease incidence is expected to be substantially reduced under both scenarios and remain below prevaccination levels despite the possible emergence of new strains. Better understanding of homotypic vs. heterotypic immunity, both natural and vaccine-induced, will be critical in predicting the impact of vaccination.

Rotavirus is a major cause of mortality in developing countries, and yet the dynamics of rotavirus in such settings are poorly understood. Rotavirus is typically less seasonal in the tropics, although recent observational studies have challenged the universality of this pattern. While numerous studies have examined the association between environmental factors and rotavirus incidence, here we explore the role of intrinsic factors. By fitting a mathematical model of rotavirus transmission dynamics to published age distributions of cases from 15 countries, we obtain estimates of local transmission rates. Model-predicted patterns of seasonal incidence based solely on differences in birth rates and transmission rates are significantly correlated with those observed (Spearman's ρ = 0.65, p < 0.05). We then examine seasonal patterns of rotavirus predicted across a range of different birth rates and transmission rates and explore how vaccination may impact these patterns. Our results suggest that the relative lack of rotavirus seasonality observed in many tropical countries may be due to the high birth rates and transmission rates typical of developing countries rather than being driven primarily by environmental conditions. While vaccination is expected to decrease the overall burden of disease, it may increase the degree of seasonal variation in the incidence of rotavirus in some settings.

Following the introduction of rotavirus vaccination in the United States, rotavirus and cause-unspecified gastroenteritis discharges significantly decreased in 2008 in the 0-4, 5-14, and 15-24-year age groups, with significant reductions observed in March, the historic peak rotavirus month, in all age groups. We estimate that 15% of the total 66 000 averted hospitalizations and 20% of the $204 million in averted direct medical costs attributable to the vaccination program were among unvaccinated 5-24 year-olds. This study demonstrates a previously unrecognized burden of severe rotavirus in the population >5 years and the primacy of very young children in the transmission of rotavirus.

Background: Routine rotavirus vaccination of US infants began in 2006. We conducted active, population-based surveillance for rotavirus gastroenteritis hospitalizations in 3 US counties to assess vaccine impact., Methods: Children <36 months old hospitalized with diarrhea and/or vomiting were enrolled from January through June each year during the period 2006-2009 and tested for rotavirus. Age-stratified rates of hospitalization for rotavirus infection were compared with corresponding vaccination coverage among a control group of children with acute respiratory illness. To assess direct and indirect benefits, vaccination coverage rates in the control group were multiplied by vaccine effectiveness estimates to calculate expected reductions in the rate of hospitalization for rotavirus infection. Rotavirus serotypes were compared across years., Results: Compared with 2006, a significant reduction in rates of hospitalization for rotavirus infection (P < .001) was observed in 2008 among all age groups. There was an 87% reduction in the 6-11-month-old age group (coverage, 77%), a 96% reduction in the 12-23-months-old age group (coverage, 46%), and a 92% reduction in the 24-35-month-old age group (coverage, 1%), which exceeded reductions expected on the basis of coverage and vaccine effectiveness estimates. Age-specific rate reductions were nearly equivalent to those expected on the basis of age-specific vaccine coverage in 2009. Predominant strains varied annually: G1P[8] (91%) in 2006; G1P[8] (45%) and G12P[8] (36%) in 2007; G1P[8] (89%) in 2008; and G3P[8] (43%), G2P[4] (34%), and G9P[8] (27%) in 2009., Conclusions: Rotavirus vaccination has dramatically decreased rates of hospitalization for rotavirus infection among children in these US counties. In 2008, reductions were prominent among both vaccine-eligible age groups and older, largely unvaccinated children; the latter likely resulted from indirect protection. Although rates among age groups eligible for vaccination remained low in 2009, indirect benefits disappeared.

Background: Following implementation of the rotavirus vaccination program in 2006, rotavirus activity in the United States declined dramatically in 2007-2008 but increased slightly in 2008-2009, despite greater vaccine uptake. To further evaluate impact of the vaccine program, we assessed trends in rotavirus testing and detection during 2009-2010., Methods: We examined rotavirus testing data from July 2000 to June 2010 from the National Respiratory and Enteric Viruses Surveillance System to compare rotavirus season timing and peak activity in the pre- and postvaccine introduction eras. Rotavirus season onset was defined as the first of 2 consecutive weeks during which the percentage of specimens testing positive for rotavirus was ≥ 10%. To assess trends in rotavirus testing and detection, we restricted the analyses to 25 laboratories that reported for ≥ 26 weeks per season from 2000 to 2010., Results: During 2009-2010, the threshold for the start of the rotavirus season was never achieved nationally or in the North, Midwest, or West. Activity in the South met this threshold but the season duration was substantially shorter and of lower magnitude than in all previous pre- and postvaccine introduction seasons. Nationally and within each region, the peak week was more delayed and the peak proportion of positive tests was substantially lower than all previous seasons. The total number of tests performed declined by 23%, and the number of positive tests declined by 86%., Conclusions: Rotavirus activity was substantially diminished during the 2009-2010 rotavirus season compared with the prevaccine baseline and the 2 previous postvaccine introduction seasons. These sustained declines over 3 rotavirus seasons reaffirm the health benefits of the US rotavirus vaccination program.

Background: Rotavirus vaccine was recommended for routine use in US infants in 2006. Before the introduction of vaccine, rotavirus was the most common cause of severe gastroenteritis in children <5 years of age in the United States., Methods: We reviewed published data to summarize the US experience during the first 3 years of its rotavirus vaccination program., Results: Rotavirus seasons have been delayed and diminished in magnitude during the postvaccine era compared with the prevaccine era. Hospitalizations, emergency department visits, and outpatient visits due to gastroenteritis have declined dramatically in children < 5 years of age including in children age-ineligible to have received vaccine, suggesting indirect benefits of vaccination. Rotavirus vaccine has been widely accepted by pediatricians. Vaccine coverage is steadily increasing but remains lower than coverage levels of other routine infant immunizations., Conclusions: The implementation of routine childhood immunization against rotavirus has rapidly and dramatically reduced the large health burden of rotavirus gastroenteritis in US children. Continued monitoring of rotavirus diarrhea is needed to determine if immunity wanes as vaccinated children get older and to better quantify the indirect benefits of vaccination. Ongoing surveillance will also enable monitoring of the long-term impact of vaccination on rotavirus epidemiology.

In Europe, rotavirus gastroenteritis peaks in late winter or early spring suggesting a role for weather factors in transmission of the virus. In this study, multivariate regression models adapted for time-series data were used to investigate effects of temperature, humidity and rainfall on reported rotavirus infections and the infection-rate parameter, a derived measure of infection transmission that takes into account population immunity, in England, Wales, Scotland and The Netherlands. Delayed effects of weather were investigated by introducing lagged weather terms into the model. Meta-regression was used to pool together country-specific estimates. There was a 13 per cent (95% confidence interval (CI), 11-15%) decrease in reported infections per 1 degrees C increase in temperature above a threshold of 5 degrees C and a 4 per cent (95% CI, 3-5%) decrease in the infection-rate parameter per 1 degrees C increase in temperature across the whole temperature range. The effect of temperature was immediate for the infection-rate parameter but delayed by up to four weeks for reported infections. There was no overall effect of humidity or rainfall. There is a direct and simple relationship between cold weather and rotavirus transmission in Great Britain and The Netherlands. The more complex and delayed temperature effect on disease incidence is likely to be mediated through the effects of weather on transmission.

This study investigates whether a child's risk of rotavirus diarrhoea is associated with season of birth in England and Wales, countries where rotavirus infections are highly seasonal. Poisson regression models were fitted to weekly counts of laboratory-confirmed rotavirus infections from children aged <5 years born between 1998 and 2007. In the first year of life, the risk of a laboratory-confirmed rotavirus infection was significantly higher for children born in summer compared with winter [relative risk (RR) 2.13, 95% confidence interval (CI) 2.07-2.19]. In the second to fifth years of life, the pattern reversed (second year of life: RR 0.73, 95% CI 0.71-0.75). The cumulative risk up to age 5 years remained significantly higher for children born in summer compared with winter due to the increased risk for summer births during their first year of life. Maternal immunity and age-specific levels of exposure to rotavirus could explain our findings.

Two rotavirus vaccines have recently been licensed in Europe. Rotavirus surveillance data in many European countries are based on reports of laboratory-confirmed rotavirus infections. If surveillance data based on routine laboratory testing data are to be used to evaluate the impact of vaccination programmes, it is important to determine how the data are influenced by differences in testing practices, and how these practices are likely to affect the ability of the surveillance data to represent trends in rotavirus disease in the community. We conducted a survey of laboratory testing policies for rotavirus gastroenteritis in England and Wales in 2008. 60% (94/156) of laboratories responded to the survey. 91% of reporting laboratories offered routine testing for rotavirus all year round and 89% of laboratories offered routine rotavirus testing of all stool specimens from children under the age of five years. In 96% of laboratories, rotavirus detection was presently done either by rapid immunochromatographic tests or by enzyme-linked immunosorbent assay. Currently, rotavirus testing policies among laboratories in England and Wales are relatively homogenous. Therefore, surveillance based on laboratory testing data is likely to be representative of rotavirus disease trends in the community in the most frequently affected age groups (children under the age of five years) and could be used to help determine the impact of a rotavirus vaccine.