Correlates of Rotavirus Vaccine Shedding and Seroconversion in a US Cohort of Healthy Infants.

BACKGROUND: Rotavirus is a leading cause of severe pediatric gastroenteritis; 2 highly effective vaccines are used in the United States (US). We aimed to identify correlates of immune response to rotavirus vaccination in a US cohort. METHODS: Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis Longitudinal (PREVAIL) is a birth cohort of 245 mother-child pairs enrolled in 2017-2018 and followed for 2 years. Infant stool samples and symptom information were collected weekly. Shedding was defined as reverse-transcription polymerase chain reaction detection of rotavirus vaccine virus in stools collected 4-28 days after dose 1. Seroconversion was defined as a 3-fold rise in immunoglobulin A between the 6-week and 6-month blood draws. Correlates were analyzed using generalized estimating equations and logistic regression. RESULTS: Prevaccination immunoglobulin G (IgG) (odds ratio [OR], 0.84 [95% confidence interval {CI}, .75-.94] per 100-unit increase) was negatively associated with shedding. Shedding was also less likely among infants with a single-nucleotide polymorphism inactivating FUT2 antigen secretion ("nonsecretors") with nonsecretor mothers, versus all other combinations (OR, 0.37 [95% CI, .16-.83]). Of 141 infants with data, 105 (74%) seroconverted; 78 (77%) had shed vaccine virus following dose 1. Prevaccination IgG and secretor status were significantly associated with seroconversion. Neither shedding nor seroconversion significantly differed by vaccine product. CONCLUSIONS: In this US cohort, prevaccination IgG and maternal and infant secretor status were associated with rotavirus vaccine response.

Clinical Impact of Multiplex Molecular Diagnostic Testing in Children With Acute Gastroenteritis Presenting to an Emergency Department: A Multicenter Prospective Study.

BACKGROUND: Multiplex molecular diagnostic panels have greatly enhanced detection of gastrointestinal pathogens. However, data on the impact of these tests on clinical and patient-centered outcomes are limited. METHODS: We conducted a prospective, multicenter, stepped-wedge trial to determine the impact of multiplex molecular testing at 5 academic children's hospitals on children presenting to the emergency department with acute gastroenteritis. Caregivers were interviewed on enrollment and 7-10 days after enrollment to determine symptoms, risk factors, subsequent medical visits, and impact on family members. During the pre-intervention period, diagnostic testing was performed at the clinician's discretion . During the intervention period, multiplex molecular testing was performed on all children, with results available to clinicians. The primary outcome was return visits to a healthcare provider within 10 days of enrollment. RESULTS: Potential pathogens were identified by clinician-ordered tests in 19 of 571 (3.3%) in the pre-intervention period compared with 434 of 586 (74%) in the intervention period; clinically relevant pathogens were detected in 2.1% and 15%, respectively. In the multivariate model, the intervention was associated with a 21% reduction in the odds of any return visit (odds ratio, 0.79; 95% confidence interval, .70-.90) after adjusting for potential confounders. Appropriate treatment was prescribed in 11.3% compared with 19.6% during the intervention period (P = .22). CONCLUSIONS: Routine molecular multiplex testing for all children who presented to the ED with acute gastroenteritis detected more clinically relevant pathogens and led to a 21% decrease in return visits. Additional research is needed to define patients most likely to benefit from testing. Clinical Trials Registration. NCT02248285.

The Impact of Rotavirus Vaccination on Discharges for Pediatric Gastroenteritis in Italy: An Eleven Year (2009-2019) Nationwide Analysis.

In Italy, despite the documented positive effects of rotavirus (RV) vaccination on reducing the burden of RV disease, an updated national assessment of its impact on clinical outcomes is still lacking. This study aims to analyze the implementation of RV vaccination in Italy, evaluating its impact on discharges for acute pediatric gastroenteritis (AGE). A retrospective analysis, including hospital discharge records and data on vaccination coverage for children aged 0-71 months from 2009 to 2019, was conducted. We examined trends in hospital discharge standardized incidence before and after vaccine introduction using a negative binomial mixture model with fixed effects to evaluate the impact of universal vaccination. The percentage of vaccination coverage increased over the years, from <5% between 2009 and 2013 to 26% in 2017, reaching 70% in 2019. The standardized incidence of discharges decreased over the period from 16.6/100,000 inhabitants in 2009-2013 to 9.9/100,000 inhabitants in 2018-2019. In this phase, about 15% of the estimated hospital discharges were avoided compared with those estimated in the first phase. The implementation of RV vaccination reduced AGE incidence discharges in children aged 0-71 months. Further efforts are needed to continue monitoring the vaccination effect over time and to increase vaccination coverage.

A Comparison of Pathogen Detection and Risk Factors among Symptomatic Children with Gastroenteritis Compared with Asymptomatic Children in the Post-rotavirus Vaccine Era.

OBJECTIVE: To describe demographics, pathogen distribution/seasonality, and risk factors in children seeking care for acute gastroenteritis (AGE) at a midwestern US emergency department during 5 postrotavirus vaccine years (2011-2016), and further, to compare the same data with matched healthy controls (HC). STUDY DESIGN: AGE and HC participants <11 years old enrolled in the New Vaccine Surveillance Network study between December 2011 to June 2016 were included. AGE was defined as ≥3 diarrhea episodes or ≥1 vomiting episode. Each HC's age was similar to an AGE participant's age. Pathogens were analyzed for seasonality effects. Participant risk factors for AGE illness and pathogen detections were compared between HC and a matched subset of AGE cases. RESULTS: One or more organisms was detected in 1159 of 2503 children (46.3%) with AGE compared with 99 of 537 HC (17.3%). Norovirus was detected most frequently among AGE (n = 568 [22.7%]) and second-most frequently in HC (n = 39 [6.8%]). Rotavirus was the second most frequently detected pathogen among AGE (n = 196 [7.8%]). Children with AGE were significantly more likely to have reported a sick contact compared with HC, both outside the home (15.6% vs 1.4%; P < .001) and inside the home (18.6% vs 2.1%; P < .001). Daycare attendance was higher among children with AGE (41.4%) compared with HC (29.5%; P < .001). The Clostridium difficile detection rate was slightly higher among HC (7.0%) than AGE (5.3%). CONCLUSIONS: Norovirus was the most prevalent pathogen among children with AGE. Norovirus was detected in some HC, suggesting potential asymptomatic shedding among HC. The proportion of AGE participants with a sick contact was approximately 10 times greater than that of HC.

Impact of rotavirus vaccine introduction in Abidjan, Côte d'Ivoire.

Côte d'Ivoire introduced rotavirus vaccine in March 2017. Rotavirus surveillance is conducted at Centre Hospitalier Universitaire de Yopougon in Abidjan, the capital city. Children <5 years of age are enrolled in rotavirus surveillance if admitted to the hospital with acute gastroenteritis. We used sentinel surveillance data from 2014 through mid-2019 to compare trends in rotavirus pediatric gastroenteritis hospitalizations before and after rotavirus vaccine introduction. We used Poisson regression to analyze changes in rotavirus prevalence, adjusting for calendar month and accounting for total monthly admissions; January 2014 - December 2016 was considered "pre-vaccine," and January 2017 - June 2019 was considered "post-vaccine." Age distribution and severity were compared between periods using the Mann-Whitney U test. Rotavirus-positive admissions declined 51% (95% CI: 28%-67%), from 31.5% pre-vaccine to 14.9% afterward. The median age of rotavirus-positive children increased from 7 months (interquartile range [IQR]: 5-11) in the pre-vaccine period to 11 months (IQR: 7-18, p = .005) in the post-vaccine period. The median severity score decreased from 11 to 9 (p = .008) among all children, and from 12 pre- to 10.5 post-vaccine (p = .35) among rotavirus-positive children. Our findings suggest that rotavirus vaccine introduction contributed to reduced rotavirus hospitalization in Abidjan and possibly more broadly.

Rotavirus Vaccine Impact Within an Integrated Healthcare Delivery System in the United States.

We assessed rotavirus vaccine impact using data on acute gastroenteritis (AGE) encounters within an integrated healthcare delivery system during 2000-2018. Following rotavirus vaccine introduction, all-cause AGE rates among children <5 years declined by 36% (95% confidence interval [CI]: 32%-40%) for outpatient and 54% (95% CI: 46%-60%) for inpatient encounters.

Impact and effectiveness of monovalent rotavirus vaccine in Tajik children.

BACKGROUND: In 2015, Tajikistan became the second country in Central Asia to introduce rotavirus vaccine into its national immunization program. Before vaccine introduction, rotavirus was estimated to cause > 40% of pediatric diarrhea hospitalizations in Tajikistan. We aimed to assess the impact of rotavirus vaccine introduction on rotavirus disease burden and estimate rotavirus vaccine effectiveness (VE). METHODS: Using surveillance data from 2013 through 2019, we examined trends in monthly hospital admissions among children < 5 years old, before and after rotavirus vaccine introduction. Poisson regression was used to quantify decreases. VE was estimated using a test-negative case control design, with data from admissions during 2017 - 2019. Immunization records were obtained from clinics. RESULTS: Among enrolled children, rotavirus positivity declined from 42% to 25% in the post-vaccine introduction period, a decrease of 41% (95% Confidence Interval [CI]: 36 - 45%). Declines were greatest in children < 12 months of age. Estimated VE of a complete course of rotavirus vaccine was 55% (95% CI: 21 - 73%) among children 5 - 59 months of age and 64% (95% CI: 36 - 80%) among children 5 - 23 months of age. VE point estimates were higher among children receiving both doses of rotavirus vaccine non-concurrently with OPV and among children receiving their first dose of rotavirus vaccine at 4 - 11 months of age, but CIs were wide and overlapping. CONCLUSIONS: Our data demonstrate that rotavirus vaccine introduction was associated with a substantial reduction in pediatric rotavirus hospitalization burden in Tajikistan, and that rotavirus vaccination is effective in Tajik children.

Impact of rotavirus vaccination on rotavirus hospitalizations in Taiwanese children.

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.

Global Experience With Rotavirus Vaccines.

Rotavirus is a major cause of severe pediatric diarrhea worldwide. In 2006, 2 live, oral rotavirus vaccines, Rotarix and RotaTeq, were licensed for use in infants and were rapidly adopted in many high- and middle-income settings where efficacy had been demonstrated in clinical trials. Following completion of successful trials in low-income settings, the World Health Organization (WHO) recommended rotavirus vaccination for all infants globally in 2009. In 2018, 2 new rotavirus vaccines, Rotasiil and Rotavac, were prequalified by WHO, expanding global availability. As of March 2021, rotavirus vaccines have been introduced nationally in 106 countries. Since, Rotavirus vaccines have demonstrated effectiveness against severe disease and mortality, even among age groups in eligible for vaccination. Cross-genotypic protection has been demonstrated, and the favorable benefit-risk profile of these vaccines continues to be confirmed. Ongoing research seeks to better understand reasons for the geographic disparities in effectiveness observed, in order to optimize vaccine strategies worldwide.

Molecular Epidemiology of Human Sapovirus among Children with Acute Gastroenteritis in Western Canada.

Sapovirus is increasingly recognized as an important cause of acute gastroenteritis (AGE) worldwide; however, studies of sapovirus prevalence, genetic diversity, and strain-specific clinical implications have been scarce. To fill this knowledge gap, we used reverse transcription-real-time PCR and sequencing of the partial major capsid protein VP1 gene to analyze stool specimens and rectal swabs obtained from 3,347 children with AGE and 1,355 asymptomatic controls (all <18 years old) collected between December 2014 and August 2018 in Alberta, Canada. Sapovirus was identified in 9.5% (317/3347) of the children with AGE and 2.9% of controls. GI.1 (36%) was the predominant genotype identified, followed by GI.2 (18%), GII.5 (8%), and GII.3 (6%). Rare genotypes GII.1, GII.2, GV.1, GII.4, GIV.1, GI.3, and GI.7 were also seen. Sapovirus was detected year-round, peaking during the winter months of November to January. The exception was the 2016-2017 season, when GI.2 overtook GI.1 as the predominant strain, with a high detection rate persisting into April. We did not observe significant difference in the severity of gastroenteritis by genogroup or genotype. Repeated infection by sapovirus of different genogroups occurred in three controls who developed AGE later. Our data suggest that sapovirus is a common cause of AGE in children with high genetic diversity.

Multiplex PCR Pathogen Detection in Acute Gastroenteritis Among Hospitalized US Children Compared With Healthy Controls During 2011-2016 in the Post-Rotavirus Vaccine Era.

BACKGROUND: Despite vaccine-induced decreases in US rotavirus (RV) disease, acute gastroenteritis (AGE) remains relatively common. We evaluated AGE pathogen distribution in hospitalized US children in the post-RV vaccine era. METHODS: From December 2011 to June 2016, the New Vaccine Surveillance Network (NVSN) conducted prospective, active, population-based surveillance in hospitalized children with AGE. We tested stools from 2 NVSN sites (Kansas City, Houston) with Luminex x-TAG Gastrointestinal Pathogen Panels (Luminex GPP) and analyzed selected signs and symptoms. RESULTS: For 660 pediatric AGE inpatients and 624 age-matched healthy controls (HCs), overall organism detection was 51.2% and 20.6%, respectively (P < .001). Among AGE subjects, GPP polymerase chain reaction detected >1 virus in 39% and >1 bacterium in 14% of specimens. Detection frequencies for AGE subjects vs HCs were norovirus (NoV) 18.5% vs 6.6%, RV 16.1% vs 9.8%, adenovirus 7.7% vs 1.4%, Shigella 4.8% vs 1.0%, Salmonella 3.1% vs 0.1%, and Clostridioides difficile in ≥2-year-olds 4.4% vs 2.4%. More co-detections occurred among AGE patients (37/660, 5.6%) than HCs (14/624, 2.2%; P = .0024). Per logistic regression analysis, ill contacts increased risk for NoV, RV, and Shigella (P < .001). More vomiting episodes occurred with NoV and RV, and more diarrheal episodes with Shigella and Salmonella. Modified Vesikari scores were highest for Shigella and lowest for C. difficile. CONCLUSIONS: NoV detection was most frequent; however, RV remained important in hospitalized AGE in the post-RV vaccine era. Continued active surveillance is important to document ongoing vaccine effects, pathogen emergence, and baseline disease burden for new vaccines.

Rotavirus Vaccine Is Effective Against Rotavirus Gastroenteritis Resulting in Outpatient Care: Results From the Medically Attended Acute Gastroenteritis (MAAGE) Study.

BACKGROUND: Rotavirus is a common cause of severe pediatric acute gastroenteritis. Two vaccines are licensed in the United States and have demonstrated high effectiveness against moderate to severe disease. However, fewer data are available on rotavirus vaccine effectiveness (VE) against milder disease. METHODS: We leveraged active surveillance data from Kaiser Permanente Northwest to calculate rotavirus VE against medically attended rotavirus illness among age-eligible children. We utilized a test-negative case-control design and applied 4 distinct case definitions based on reverse transcription-quantitative real-time PCR (qRT-PCR) assay and enzyme immunoassay (EIA) test results. VE was calculated as 100 × (1 - odds ratio), and models were adjusted for age group. RESULTS: The VE analysis population comprised 842 children, 799 (95%) of whom had mild disease requiring at most a clinic visit and 698 (83%) of whom were fully vaccinated against rotavirus. Age-adjusted VE was 70% (95% confidence interval [CI], 37-86%) against disease defined solely by qRT-PCR results, 72% (95% CI, 31-89%) against disease as defined by qRT-PCR with a quantification cycle (C q ) value <27, 73% (95% CI, 32-90%) against disease that was qRT-PCR positive but EIA negative, and 62% (95% CI, -20-88%) against disease defined solely by EIA. Results were similar when restricting to disease resulting in at most an ambulatory clinic or emergency department visit. CONCLUSIONS: These results support the effectiveness of rotavirus vaccination in protecting US children from mild to moderate and severe disease. Our findings are also useful to show the effectiveness of rotavirus vaccination against qRT-PCR-defined illness.

Rotavirus and Type 1 Diabetes-Is There a Connection? A Synthesis of the Evidence.

Although the etiology of type 1 diabetes (T1D) is not well understood, it is believed to comprise both genetic and environmental factors. Viruses are the most well studied environmental trigger, and there is a small but growing body of research on the potential influence of rotavirus on T1D. Rotavirus infections were initially identified as possible triggers of T1D given similarities between viral peptide sequences and T1D autoantigen peptide sequences. Furthermore, rotavirus infection has been shown to modify T1D risk in T1D-prone mice. However, research into associations of rotavirus infections with T1D development in humans have yielded mixed findings and suggested interactions with age and diet. As global availability of rotavirus vaccines increases, recent studies have assessed whether rotavirus vaccination modifies T1D development, finding null or protective associations. Overall, evidence to date suggests a possible triggering relationship between some wild-type rotavirus infections and T1D, but the potential effect of rotavirus vaccination remains unclear.

Rotavirus Vaccination Coverage During a Rotavirus Outbreak Resulting in a Fatality at a Subacute Care Facility.

BACKGROUND: The introduction of rotavirus vaccine in the United States has reduced rotavirus disease burden, but outbreaks still occur. Complete-series rotavirus vaccination coverage is <75% in the United States, and it might be lower among vulnerable populations. We describe here the clinical characteristics and vaccination status of children during a rotavirus outbreak in a pediatric subacute care facility in 2017. METHODS: Clinical history, signs and symptoms, and vaccination history were abstracted for the 26 patients residing in the facility during the time of the outbreak. A case-patient was defined as one who experienced 3 or more loose stools in a period of 24 hours with onset between April 17 and May 17, 2017. Stool samples from 14 resident patients were tested for rotavirus with reverse-transcription polymerase chain reaction. RESULTS: The median patient age at the facility was 2.9 years. Of the 26 resident patients, 22 (85%) met the case definition. One child died. Stool samples from 11 case-patients were positive according to reverse-transcription polymerase chain reaction for rotavirus. Fifteen case-patients were unvaccinated against rotavirus; 3 were partially vaccinated, and 2 were fully vaccinated. Vaccination status could not be completely determined in 2 cases. CONCLUSIONS: An outbreak of rotavirus affected nearly all resident patients of a subacute care facility and caused 1 death. Because of recommendations against giving rotavirus vaccine in an intensive care setting, infants who require a prolonged intensive care stay might age out of rotavirus vaccine eligibility (the first dose must be given before 15 weeks of age according to Advisory Committee on Immunization Practices recommendations). The result is a vulnerable population of unvaccinated infants who might later congregate in another care setting.

Evidence for Household Transmission of Rotavirus in the United States, 2011-2016.

BACKGROUND: Rotavirus is a leading cause of acute gastroenteritis (AGE) in children and is highly transmissible. In this study, we assessed the presence of AGE in household contacts (HHCs) of pediatric patients with laboratory-confirmed rotavirus. METHODS: Between December 2011 and June 2016, children aged 14 days to 11 years with AGE were enrolled at 1 of 7 hospitals or emergency departments as part of the New Vaccine Surveillance Network. Parental interviews, medical and vaccination records, and stool specimens were collected at enrollment. Stool was tested for rotavirus by an enzyme immunoassay and confirmed by real-time or conventional reverse transcription-polymerase chain reaction assay or repeated enzyme immunoassay. Follow-up telephone interviews were conducted to assess AGE in HHCs the week after the enrolled child's illness. A mixed-effects multivariate model was used to calculate odds ratios. RESULTS: Overall, 829 rotavirus-positive subjects and 8858 rotavirus-negative subjects were enrolled. Households of rotavirus-positive subjects were more likely to report AGE illness in ≥1 HHC than were rotavirus-negative households (35% vs 20%, respectively; P < .0001). A total of 466 (16%) HHCs of rotavirus-positive subjects reported AGE illness. Of the 466 ill HHCs, 107 (23%) sought healthcare; 6 (6%) of these encounters resulted in hospitalization. HHCs who were <5 years old (odds ratio, 2.2 [P = .004]) were more likely to report AGE illness than those in other age groups. In addition, 144 households reported out-of-pocket expenses (median, $20; range, $2-$640) necessary to care for an ill HHC. CONCLUSIONS: Rotavirus-associated AGE in children can lead to significant disease burden in HHCs, especially in children aged <5 years. Prevention of pediatric rotavirus illness, notably through vaccination, can prevent additional illnesses in HHCs.

Does Rotavirus Vaccination Affect Longer-Term Intussusception Risk in US Infants?

Rotavirus vaccination has been associated with a short-term increased risk of intussusception. Our analysis of insurance claims for 1 858 827 US children with 544 recorded cases of intussusception found a nonsignificant decrease in intussusception (hazard ratio, 0.79 [95% confidence interval, 0.57-1.09]) in fully rotavirus-vaccinated children followed up to the age of 2 years.

Impact of the Family Health Program on gastroenteritis in children in Bahia, Northeast Brazil: an analysis of primary care-sensitive conditions.

In seeking to provide universal health care through its primary care-oriented Family Health Program, Brazil has attempted to reduce hospitalization rates for preventable illnesses such as childhood gastroenteritis. We measured rates of Primary Care-sensitive Hospitalizations and evaluated the impact of the Family Health Program on pediatric gastroenteritis trends in high-poverty Northeast Brazil. We analyzed aggregated municipal-level data in time-series between years 1999-2007 from the Brazilian health system payer database and performed qualitative, in-depth key informant interviews with public health experts in municipalities in Bahia. Data were sampled for Bahia's Salvador microregion, a population of approximately 14 million. Gastroenteritis hospitalization rates among children aged less than 5 years were evaluated. Declining hospitalization rates were associated with increasing coverage by the PSF (P = 0.02). After multivariate adjustment for garbage collection, sanitation, and water supply, evidence of this association was no longer significant (P = 0.28). Qualitative analysis confirmed these findings with a framework of health determinants, proximal causes, and health system effects. The PSF, with other public health efforts, was associated with decreasing gastroenteritis hospitalizations in children. Incentives for providers and more patient-centered health delivery may contribute to strengthening the PSF's role in improving primary health care outcomes in Brazil.