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Background While rotavirus causes severe diarrheal disease in children aged Methods In the Vaccine Impact on Diarrhea in Africa study (2015–2018), we analyzed stool from children aged 0–59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5. The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality. Results Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia. Conclusions In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged

Background Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children Methods Saliva was collected and tested for HBGA phenotype in children who received rotavirus vaccine. The association between secretor and Lewis phenotypes and rotavirus vaccine failure was examined overall and by infecting rotavirus genotype using conditional logistic regression in 218 rotavirus-positive cases with moderate-to-severe diarrhea and 297 matched healthy controls. Results Both nonsecretor and Lewis-negative phenotypes (null phenotypes) were associated with decreased rotavirus vaccine failure across all sites (matched odds ratio, 0.30 [95% confidence interval: 0.16–0.56] or 0.39 [0.25–0.62], respectively]. A similar decrease in risk against rotavirus vaccine failure among null HBGA phenotypes was observed for cases with P[8] and P[4] infection and their matched controls. While we found no statistically significant association between null HBGA phenotypes and vaccine failure among P[6] infections, the matched odds ratio point estimate for Lewis-negative individuals was >4. Conclusions Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness.

Haiti introduced a monovalent human group A rotavirus (RVA) vaccine (Rotarix) into its routine infant immunization program in April 2014. The goal of the surveillance program was to characterize RVA strains circulating in Haiti before and after RVA vaccine introduction.Stool samples were collected from children5 years old presenting with acute gastroenteritis at 16 hospitals in Haiti. RVA antigen enzyme immunoassay (EIA) testing was performed, and G and P genotypes were determined for positive specimens. In this study, genotype data for samples collected from May 2012 through April 2014 (the pre-vaccine introduction era) and May 2014 through July 2019 (post-vaccine introduction era) were analyzed.A total of 809 specimens were tested by the Centers for Disease Control and Prevention. During the pre-vaccine introduction era (May 2012 through April 2014), G12P[8] was the predominant genotype, detected in 88-94% of specimens. There was a high prevalence of the equine-like G3P[8] genotype among Haitian children with RVA after vaccine introduction.The predominance of equine-like G3P[8] in three of five RVA seasons post-vaccine introduction suggests possible vaccine-specific selection pressure in Haiti. These temporal variations in RVA genotype predominance will require continued monitoring in Haiti as the vaccination program continues.

In November 2021, CDC was notified of a cluster of previously healthy children with hepatitis of unknown etiology evaluated at a single U.S. hospital (1). On April 21, 2022, following an investigation of this cluster and reports of similar cases in Europe (2,3), a health advisory* was issued requesting U.S. providers to report pediatric cases

For the 15 years before rotavirus vaccine introduction in 2006, annual rotavirus activity in the United States showed a distinct spatiotemporal pattern, peaking first in the Southwest and last in the Northeast. We modeled spatiotemporal trends in rotavirus laboratory detections from 2009 to 2021. Laboratories reporting to the National Respiratory and Enteric Virus Surveillance System were eligible for inclusion in a given surveillance year (July to June) if ≥1 polymerase chain reaction or enzyme immunoassay rotavirus test per week was reported during ≥26 weeks and totaling ≥100 annual tests. For each laboratory, the season peak was the week with the highest 7-week moving average of the number of rotavirus positive tests during the national season, defined as the period with a 3-week moving average of10% rotavirus positivity lasting ≥2 consecutive weeks. We input peak week as a continuous variable and the geospatial coordinates of each laboratory into a spherical variogram model for Kriging spatial interpolation. We also created a state-level bivariate choropleth map using tertiles of the 2010-2019 average birth rates and rotavirus vaccine coverage. Following the established biennial trend, the 2010-2011, 2012-2013, 2014-2015, 2016-2017, and 2018-2019 surveillance years had10% rotavirus positivity for ≥2 weeks and were included in the geospatial analysis. During all 5 seasons included in the geospatial analysis, the earliest peak week occurred in Oklahoma, Arkansas, and the western Gulf coast, a pattern markedly different from prevaccine seasons. These states also had the average lowest rotavirus vaccine coverage and highest birth rate, suggesting that more rapid accumulation of susceptible children drives annual rotavirus season activity. Increasing vaccine coverage remains a key tool in reducing rotavirus burden.

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.

In 2006, two rotavirus vaccines were licensed in Taiwan but were not added to the national immunization schedule. National Health Insurance data from 2003 through 2017 were used to compare rotavirus-associated pediatric hospitalizations before and after vaccine introduction. Rotavirus hospitalization rates among children < 5 years of age significantly declined by 24% (95% confidence interval [CI] 23 - 25%) in post-vaccine compared to pre-vaccine rotavirus seasons. Rotavirus hospitalization rates declined by 42% (95% CI 39 - 44%) among infants < 12 months of age, and by 38% (95% CI 36 - 40%) among children 12 - 23 months of age. These findings suggest that, despite not being included in the national immunization schedule, rotavirus vaccines had a measurable impact on reducing rotavirus hospitalization burden among Taiwanese children.

Background Human adenoviruses (HAdV) are a common cause of respiratory and gastrointestinal infections but rarely cause end-organ disease in children. From October 2021 to February 2022, several previously healthy children admitted to a single center for significant hepatitis also tested positive for HAdV. The aim of this investigation is to describe characteristics of these children. Methods Children admitted to Children’s of Alabama (COA) from October 2021 to February 2022 with hepatitis who tested positive for HAdV by whole blood RT-PCR were included. Demographic, clinical, laboratory and treatment data were collected from medical records. Residual blood specimens were sent for adenovirus typing. Results Nine pediatric patients with hepatitis and HAdV infection were identified (78% female; median age 3.0 years; IQR 1.7-3.0). Before admission, six reported diarrhea and three had respiratory symptoms. At presentation, eight had scleral icterus, six had jaundice, seven had hepatomegaly, and one was encephalopathic. All patients had elevated transaminases (AST range: 447-4000 U/L, ALT range: 784-4695 U/L); initial total bilirubin varied [range 0.23-13.5 mg/dL]). All had confirmed HAdV by RT-PCR on whole blood (initial qPCR range: 991-70,680 copies/mL). Notably, two children who transferred to another facility were negative for HAdV by RT-PCR when plasma was tested (instead of whole blood). Six children underwent liver biopsy showing varying degrees of hepatitis with no adenovirus detected on immunohistochemistry stains. Five children had HAdV type 41 confirmed. Three children presented or progressed to acute liver failure, two children were treated with cidofovir, and two underwent successful liver transplantation. No known epidemiologic links between patients were identified and all were from geographically distinct parts of Alabama. Conclusion HAdV is a potentially underrecognized cause of hepatitis. Whole blood specimens may be preferred over plasma for HAdV RT-PCR testing. HAdV type 41 was identified in all patients with typing results available. Improved type-based surveillance may help determine HAdV patterns of circulation and inform future diagnostic testing. Disclosures William Britt, MD, First Energy Corporation: Stocks/Bonds|Hookipa Pharma: Advisor/Consultant|Kroger Care: Stocks/Bonds|MDU Resources Group: Stocks/Bonds|PG&E Corporation: Stocks/Bonds.

Background Viruses are a leading cause of pediatric diarrheal illness, resulting in over 200,000 childhood deaths annually worldwide. Rotavirus is the most common viral cause of moderate-to-severe diarrhea in low to middle-income countries, but adenovirus 40/41, norovirus, sapovirus, and astrovirus are increasingly recognized as important contributors to the global viral gastroenteritis burden. Comparisons of clinical severity between these five viruses among infants and young children are currently limited. Methods The objective of this analysis was to describe the clinical severity of rotavirus, adenovirus 40/41, norovirus, sapovirus, and astrovirus among children enrolled in the Global Enteric Multicenter Study (GEMS). Stool samples from children younger than 5 years of age with moderate-to-severe diarrhea at four sites in Africa and three in Asia were tested by enzyme immunoassays (rotavirus, adenovirus) and multiplex reverse transcriptase polymerase chain reaction (norovirus, sapovirus, astrovirus). A modified Vesikari score (MVS) to assess clinical severity was calculated based on symptoms and clinical characteristics. Results Among 3,305 viral diarrhea cases, rotavirus had the highest median MVS (9 [interquartile range [IQR: 7,11]) followed by adenovirus 40/41 (8 [IQR]: 6,10]); sapovirus and astrovirus had a similar MVS distribution to norovirus (7 [IQR: 6, 9]). The proportion of patients experiencing > 3 episodes of vomiting was high for those with rotavirus (66.3%) and adenovirus 40/41 (55.7%); astrovirus (40.8%), sapovirus (40.0%), and norovirus (35.9%) patients also experienced substantial episodes of vomiting. A high proportion of cases with adenovirus 40/41 (54.0%) and rotavirus (46.3%) experienced ≥ 7 episodes of diarrhea within 24 hours. While hospitalization or intravenous fluids were required most frequently for patients with rotavirus (42.1%), the proportion was also high in those with adenovirus 40/41 (30.6%). Conclusion These findings demonstrate the clinical severity of viral diarrheal pathogens besides rotavirus, in particular adenovirus 40/41, warranting the continued development of vaccines and therapeutics to prevent morbidity and mortality due to viral enteric pathogens. Disclosures All Authors: No reported disclosures.

On April 21, 2022, CDC issued a health advisory

Rotavirus causes 215,000 deaths from severe childhood diarrhea annually. Concerns exist that a monovalent vaccine (RV1) and a pentavalent vaccine (RV5) may be less effective against rotavirus strains not contained in the vaccines. We estimated the vaccine effectiveness (VE) of RV1 and RV5 against severe rotavirus gastroenteritis caused by vaccine (homotypic) and nonvaccine (partially and fully heterotypic) strains. METHODS: After conducting a systematic review, we meta-analyzed 31 case-control studies (N = 27,293) conducted between 2006 and 2020 using a random-effects regression model. RESULTS: In high-income countries, RV1 VE was 10% lower against partially heterotypic (P = 0.04) and fully heterotypic (P = 0.10) compared with homotypic strains (homotypic VE: 90% [95% confidence intervals (CI): 82–94]; partially heterotypic VE: 79% [95% CI: 71–85]; fully heterotypic VE: 80% [95% CI: 65–88]). In middle-income countries, RV1 VE was 14–16% lower against partially heterotypic (P = 0.06) and fully heterotypic (P = 0.04) compared with homotypic strains (homotypic VE: 81% [95% CI: 69–88]; partially heterotypic VE: 67% [95% CI: 54–76]; fully heterotypic VE: 65% [95% CI: 51–75]). Strain-specific RV5 VE differences were less pronounced, and primarily derived from high-income countries. Limited data were available from low-income countries. CONCLUSIONS: Vaccine effectiveness of RV1 and RV5 was somewhat lower against nonvaccine than vaccine strains. Ongoing surveillance is important to continue long-term monitoring for strain replacement, particularly in low-income settings where data are limited.

IntroductionDiarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions.MethodsWe established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale.ResultsDuring 2017–2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516).ConclusionsDespite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality.

Background Rotavirus causes 215,000 deaths from severe childhood diarrhea annually. Two rotavirus vaccines – a monovalent vaccine containing a single rotavirus strain (RV1) and a pentavalent vaccine containing 5 rotavirus strains (RV5) – are used in routine immunization programs of nearly 100 countries. Concerns exist that rotavirus vaccines may be less effective against rotavirus strains not contained in the vaccines which could subsequently cause selective pressure and strain replacement. We estimated the vaccine effectiveness (VE) of RV1 and RV5 against vaccine (homotypic) and non-vaccine (partially and fully heterotypic) strains. Methods After conducting a systematic review, we meta-analyzed 31 case-control studies (N=27,293) conducted between 2006 and 2020 using a random-effect regression model. Results In high-income countries, RV1 VE was 10% lower against partially heterotypic (p-value=0.04) and fully heterotypic (p-value=0.10) compared to homotypic strains (homotypic VE: 90% [95% CI: 82, 94]; partially heterotypic VE: 79% [95% CI: 71, 85]; fully heterotypic VE: 80% [95% CI: 65, 88]; Figure 1). In middle-income countries, RV1 VE was 14 to 16% lower against partially heterotypic (p-value=0.06) and fully heterotypic (p-value=0.04) compared to homotypic strains (homotypic VE: 81% [95% CI: 69, 88]; partially heterotypic VE: 67% [95% CI: 54, 76]; fully heterotypic VE: 65% [95% CI: 52, 75]; Figure 1). Strain-specific RV5 VE differences were less pronounced (Figure 2). Limited data were available from low-income countries. Figure 1. Vaccine effectiveness by country income level and strain type, for RV1. Figure 2. Vaccine effectiveness by country income level and strain type, for RV5. Conclusion Vaccine effectiveness of RV1 and RV5 was somewhat lower VE against non-vaccine than vaccine strains. Ongoing surveillance is crucial to continue long-term monitoring for strain replacement, particularly in low-income settings where data are limited. Disclosures All Authors: No reported disclosures