Evaluation of the Influence of Gastrointestinal Coinfections on Rotavirus Vaccine Effectiveness in Botswana.
ABSTRACT: BACKGROUND:Studies have demonstrated reduced rotavirus vaccine effectiveness (VE) in resource-limited settings. Enteropathogen coinfections in rotavirus cases have been hypothesized to contribute to the lower VE in such settings. We sought to determine if coinfections affect rotavirus VE in Botswana. METHODS:Between June 2013 and April 2015, children <60 months old, presenting with severe gastroenteritis at 4 hospitals as part of a national rotavirus surveillance were enrolled. Rotavirus enzyme immunoassay (EIA)-positive samples were tested with an in-house real-time polymerase chain reaction (PCR) panel that detected 9 pathogens and a commercial 15 multiplex PCR gastrointestinal pathogen panel. Coinfection was defined as detection of rotavirus plus 1 of the 5 pathogens with the highest attributable fractions for diarrhea. Vaccine status was compared between rotavirus case patients and non-rotavirus "test-negative" controls. VE was also calculated restricting cases to those with rotavirus as the only pathogen detected. RESULTS:Two hundred and forty-two children tested rotavirus EIA positive, and 368 children were negative. Of the 182 rotavirus EIA-positive samples tested with the gastrointestinal pathogen panel assay, coinfections were detected in 60 (33%). The overall adjusted 2-dose VE was 59% (95% confidence interval [CI]: 27-77) in the rotavirus coinfection group and 51% (95% CI: -14 to 79) in the rotavirus monoinfection subgroup. Using in-house multiplex PCR panel, of 213 rotavirus EIA-positive subjects, coinfections were detected in 98 samples (46%). The overall adjusted VEs for 2 doses were 48% (95% CI: -2 to 74) and 62% (95% CI: 25-80) in rotavirus monoinfection subgroup. CONCLUSIONS:We could not find evidence of an effect of enteric coinfections on the effectiveness of rotavirus vaccine.
Project description:BACKGROUND:Rotavirus vaccine efficacy (VE) estimates in low-resource settings are lower than in developed countries. We detected coinfections in cases of severe rotavirus diarrhea in a rotavirus VE trial to determine whether these negatively impacted rotavirus VE estimates. METHODS:We performed TaqMan Array Card assays for enteropathogens on stools from rotavirus enzyme immunoassay-positive diarrhea episodes and all severe episodes (Vesikari score ≥11), from a phase 3 VE trial of Rotavac, a monovalent human-bovine (116E) rotavirus vaccine, carried out across 3 sites in India. We estimated pathogen-specific etiologies of diarrhea, described associated clinical characteristics, and estimated the impact of coinfections on rotavirus VE using a test-negative design. RESULTS:A total of 1507 specimens from 1169 infants were tested for the presence of coinfections. Rotavirus was the leading cause of severe diarrhea even among vaccinated children, followed by adenovirus 40/41, Shigella/enteroinvasive Escherichia coli, norovirus GII, sapovirus, and Cryptosporidium species. Bacterial coinfections in rotavirus-positive diarrhea were associated with a longer duration of diarrhea and protozoal coinfections with increased odds of hospitalization. Using the test-negative design, rotavirus VE against severe rotavirus gastroenteritis increased from 49.3% to 60.6% in the absence of coinfections (difference, 11.3%; 95% confidence interval, -10.3% to 30.2%). CONCLUSIONS:While rotavirus was the dominant etiology of severe diarrhea even in vaccinated children, a broad range of other etiologies was identified. Accounting for coinfections led to an 11.3% increase in the VE estimate. Although not statistically significant, an 11.3% decrease in VE due to presence of coinfections would explain an important fraction of the low rotavirus VE in this setting.
Project description:Studies on rotavirus vaccine shedding and its potential transmission within households including immunocompromised individuals are needed to better define the potential risks and benefits of vaccination. We examined fecal shedding of pentavalent rotavirus vaccine (RV5) for 9 days following the first dose of vaccine in infants between 6 and 12 weeks of age. Rotavirus antigen was detected by enzyme immunoassay (EIA), and vaccine-type rotavirus was identified by nucleotide sequencing based on genetic relatedness to the RV5 VP6 gene. Stool from 22 (21.4%) of 103 children contained rotavirus antigen-positive specimens on ? 1 post-vaccination days. Rotavirus antigen was detected as early as post-vaccination day 3 and as late as day 9, with peak numbers of shedding on post-vaccination days 6 through 8. Vaccine-type rotavirus was detected in all 50 antigen-positive specimens and 8 of 8 antigen-negative specimens. Nine (75%) of 12 EIA-positive and 1 EIA-negative samples tested culture-positive for vaccine-type rotavirus. Fecal shedding of rotavirus vaccine virus after the first dose of RV5 occurred over a wide range of post-vaccination days not previously studied. These findings will help better define the potential for horizontal transmission of vaccine virus among immunocompromised household contacts of vaccinated infants for future studies.
Project description:Background:The monovalent oral rotavirus vaccine Rotarix® was introduced into the UK infant immunisation programme in 2013. We estimated vaccine effectiveness (VE) in the first two years of the programme. Methods:We used a test-negative case-control design and enhanced national surveillance data for 1869 vaccine-eligible children tested for rotavirus infection to obtain adjusted odds ratios and VE against laboratory-confirmed rotavirus infections. Linked anonymised UK primary care and hospitalisation data from the Clinical Practice Research Datalink (40,723 children) and random-effects Poisson regression were used in a cohort study to estimate VE against all-cause acute gastroenteritis (AGE) and AGE hospitalisations. Results:VE against laboratory-confirmed infection was 69% (95% Confidence Interval: 40-84%) for one dose and 77% (95%CI: 66-85%) for two doses. Two-dose VE in children aged <12?months and ?12?months was 85% (95%CI: 74-91%) and 54% (95%CI: 15-75%), respectively. In contrast, we found no evidence that the vaccine was effective against all-cause AGE (VE?=?-20%, 95%CI: -36% to -5%), or against AGE hospitalisations (VE?=?35%, 95% CI: -86% to 77%). Conclusions:In this first detailed assessment of VE of the Rotarix® vaccine in the English national programme, we show that Rotarix® was highly effective in preventing laboratory-confirmed rotavirus infection in young children. This provides reassurance about the vaccine's performance in real-life settings and gives key information for future cost-effectiveness analyses. The high VE against rotavirus-specific AGE, and the exceptionally successful implementation of the national rotavirus vaccine programme (with >90% vaccine coverage), explains the lack of VE against all-cause AGE because most AGE in the post-vaccine era would not have been due to rotavirus, although some underestimation of VE could also have occurred due to differential healthcare utilisation by vaccinated and unvaccinated infants. This highlights the importance of using specific vaccine-preventable endpoints for these scenarios.
Project description:Background:Molecular diagnostics enable sensitive detection of respiratory viruses, but their clinical significance remains unclear in pediatric lower respiratory tract infection (LRTI). We aimed to determine whether viral coinfections increased life-threatening disease in a large cohort. Methods:Molecular testing was performed for respiratory viruses in nasopharyngeal aspirates collected from children aged <5 years within 24 hours of hospital admission during sentinel surveillance for severe acute respiratory illness (SARI) hospitalization conducted in South Africa during February 2009-December 2013. The primary outcome was life-threatening disease, defined as mechanical ventilation, intensive care unit admission, or death. Results:Of 2322 HIV-uninfected children with respiratory syncytial virus (RSV)-associated LRTI, 1330 (57.3%) had RSV monoinfection, 38 (1.6%) had life-threatening disease, 575 (24.8%) had rhinovirus, 347 (14.9%) had adenovirus (ADV), and 30 (1.3%) had influenza virus. RSV and any other viral coinfection was not associated with severe disease, ADV coinfection had increased odds of life-threatening disease (adjusted OR, 3.4; 95% CI, 1.6-7.2; P = .001), and influenza coinfection had increased odds of life-threatening disease and prolonged length of stay (adjusted OR, 2.1; 95% CI, 1.0-4.5; P = .05) compared with RSV monoinfection. Conclusions:RSV coinfection with any respiratory virus is not associated with more severe disease when compared to RSV alone in this study. However, increased life-threatening disease in RSV-ADV and RSV-influenza coinfection warrants further study.
Project description:Two rotavirus vaccines, RotaTeq and Rotarix, are licensed for global use; however, the protection they confer to unvaccinated individuals through indirect effects remains unknown. We systematically reviewed the literature and quantified indirect rotavirus vaccine effectiveness (VE) for preventing rotavirus hospitalization in children aged less than 5 years. From 148 identified abstracts, 14 studies met our eligibility criteria. In our main analysis using a random-effects model, indirect rotavirus VE was 48% (95% confidence interval [CI]: 39-55%). In a subgroup analysis by country income level, indirect VE was greater in high-income countries (52%; 95% CI: 43-60%) than in low- and middle-income countries (LMICs) (25%; 95% CI: 5-41%). In a sensitivity analysis using a quality-effects model, the indirect VE in LMICs was not statistically significant (25%; 95% CI: 0-44%). Our findings highlight the importance of increasing rotavirus vaccine coverage, particularly in LMICs where evidence for indirect VE is limited and rotavirus burden is high.
Project description:Previous US evaluations have not assessed monovalent rotavirus vaccine (RV1, a G1P human rotavirus strain) effectiveness, because of its later introduction (2008). Using case-control methodology, we measured the vaccine effectiveness (VE) of the 2-dose RV1 and 3-dose pentavalent vaccine (RV5) series against rotavirus disease resulting in hospital emergency department or inpatient care.Children were eligible for enrollment if they presented to 1 of 5 hospitals (3 in Georgia, 2 in Connecticut) with diarrhea of ?10 days' duration during January through June 2010 or 2011, and were born after RV1 introduction. Stools were collected; immunization records were obtained from providers and state electronic immunization information system (IIS). Case-subjects (children testing rotavirus antigen-positive) were compared with 2 control groups: children testing rotavirus negative and children selected from IIS.Overall, 165 rotavirus-case subjects and 428 rotavirus-negative controls were enrolled. Using the rotavirus-negative controls, RV1 VE was 91% (95% confidence interval [CI] 80 to 95) and RV5 VE was 92% (CI 75 to 97) among children aged ?8 months. The RV1 VE against G2P disease was high (94%, CI 78 to 98), as was that against G1P disease (89%, CI 70 to 96). RV1 effectiveness was sustained among children aged 12 through 23 months (VE 91%; CI 75 to 96). VE point estimates using IIS controls were similar to those using rotavirus-negative controls.RV1 and RV5 were both highly effective against severe rotavirus disease. RV1 conferred sustained protection during the first 2 years of life and demonstrated high effectiveness against G2P (heterotypic) disease.
Project description:<b>Background: </b>Using a multicenter, active surveillance network from 2 rotavirus seasons (2012 and 2013), we assessed the vaccine effectiveness of RV5 (RotaTeq) and RV1 (Rotarix) rotavirus vaccines in preventing rotavirus gastroenteritis hospitalizations and emergency department (ED) visits for numerous demographic and secular strata.<br><br><b>Methods: </b>We enrolled children hospitalized or visiting the ED with acute gastroenteritis (AGE) for the 2012 and 2013 seasons at 7 medical institutions. Stool specimens were tested for rotavirus by enzyme immunoassay and genotyped, and rotavirus vaccination histories were compared for rotavirus-positive cases and rotavirus-negative AGE controls. We calculated the vaccine effectiveness (VE) for preventing rotavirus associated hospitalizations and ED visits for each vaccine, stratified by vaccine dose, season, clinical setting, age, predominant genotype, and ethnicity.<br><br><b>Results: </b>RV5-specific VE analyses included 2961 subjects, 402 rotavirus cases (14%) and 2559 rotavirus-negative AGE controls. RV1-specific VE analyses included 904 subjects, 100 rotavirus cases (11%), and 804 rotavirus-negative AGE controls. Over the 2 rotavirus seasons, the VE for a complete 3-dose vaccination with RV5 was 80% (confidence interval [CI], 74%-84%), and VE for a complete 2-dose vaccination with RV1 was 80% (CI, 68%-88%).Statistically significant VE was observed for each year of life for which sufficient data allowed analysis (7 years for RV5 and 3 years for RV1). Both vaccines provided statistically significant genotype-specific protection against predominant circulating rotavirus strains.<br><br><b>Conclusions: </b>In this large, geographically and demographically diverse sample of US children, we observed that RV5 and RV1 rotavirus vaccines each provided a lasting and broadly heterologous protection against rotavirus gastroenteritis.
Project description:Background:Gastroenteritis caused by rotavirus accounts for considerable morbidity in young children. We aimed to assess the vaccine effectiveness (VE) of the oral rotavirus vaccine Rotarix, as measured by laboratory-confirmed rotavirus infection after referral to hospital and/or emergency departments in children aged <5 years with gastroenteritis. Methods:We performed a systematic search for peer-reviewed studies conducted in real-life settings published between 2006 and 2016 and a meta-analysis to calculate the overall Rotarix VE, which was further discriminated through stratified analyses. Results:The overall VE estimate was 69% (95% confidence interval [CI], 62% to 75%); stratified analyses revealed a non-negligible impact of factors such as study design and socioeconomic status. Depending on the control group, VE ranged from 63% (95% CI, 52% to 72%) to 81% (95% CI, 69% to 88%) for unmatched and matched rotavirus test-negative controls. VE varied with socioeconomic status: 81% (95% CI, 74% to 86%) in high-income countries, 54% (95% CI, 39% to 65%) in upper-middle-income countries, and 63% (95% CI, 50% to 72%) in lower-middle-income countries. Age, rotavirus strain, and disease severity were also shown to impact VE, but to a lesser extent. Conclusions:This meta-analysis of real-world studies showed that Rotarix is effective in helping to prevent hospitalizations and/or emergency department visits due to rotavirus infection.
Project description:Rotavirus was the leading cause of acute gastroenteritis (AGE) in infants and young children prior to the introduction of routine vaccination. Since 2006 there have been two licensed vaccines available; with successful clinical trials leading the World Health Organization to recommend rotavirus vaccination for all children worldwide. In order to inform immunisation policy we have conducted a systematic review and meta-analysis of observation studies to assess population effectiveness against acute gastroenteritis.We systematically searched PubMed, Medline, Web of Science, Cinhal and Academic Search Premier and grey literature sources for studies published between January 2006 and April 2014. Studies were eligible for inclusion if they were observational measuring population effectiveness of rotavirus vaccination against health care attendances for rotavirus gastroenteritis or AGE. To evaluate study quality we use used the Newcastle-Ottawa Scale for non-randomised studies, categorising studies by risk of bias. Publication bias was assessed using funnel plots. If two or more studies reported a measure of vaccine effectiveness (VE), we conducted a random effects meta-analysis. We stratified analyses by World Bank country income level and used study quality in sensitivity analyses.We identified 30 studies, 19 were from high-income countries and 11 from middle-income countries. Vaccine effectiveness against hospitalization for laboratory confirmed rotavirus gastroenteritis was highest in high-income countries (89% VE; 95% CI 84-92%) compared to middle-income countries (74% VE; 95% CI 67-80%). Vaccine effectiveness was higher for those receiving the complete vaccine schedule (81% VE; 95% CI 75-86%) compared to partial schedule (62% VE; 95% CI 55-69%). Two studies from high-income countries measured VE against community consultations for AGE with a pooled estimate of 40% (95% CI 13-58%; 2 studies).We found strong evidence to further support the continued use of rotavirus vaccines. Vaccine effectiveness was similar to that reported in clinical trials for both high and middle-income countries. There is limited data from Low income settings at present. There was lower effectiveness against milder disease. Further studies, should continue to report effectiveness against AGE and less-severe rotavirus disease because as evidenced by pre-vaccine introduction studies this is likely to contribute the greatest burden on healthcare resources, particularly in high-income countries.
Project description:Recent evidence suggests that the genes an organism needs to survive in an environment drastically differ when alone or in a community. However, it is not known if there are universal functions that enable microbes to persist in a community and if there are functions specific to interactions between microbes native to the same (sympatric) or different (allopatric) environments. Here, we ask how the essential functions of the oral pathogen Aggregatibacter actinomycetemcomitans change during pairwise coinfection in a murine abscess with each of 15 microbes commonly found in the oral cavity and 10 microbes that are not. A. actinomycetemcomitans was more abundant when coinfected with allopatric than with sympatric microbes, and this increased fitness correlated with expanded metabolic capacity of the coinfecting microbes. Using transposon sequencing, we discovered that 33% of the A. actinomycetemcomitans genome is required for coinfection fitness. Fifty-nine "core" genes were required across all coinfections and included genes necessary for aerobic respiration. The core genes were also all required in monoinfection, indicating the essentiality of these genes cannot be alleviated by a coinfecting microbe. Furthermore, coinfection with some microbes, predominately sympatric species, induced the requirement for over 100 new community-dependent essential genes. In contrast, in other coinfections, predominately with nonoral species, A. actinomycetemcomitans required 50 fewer genes than in monoinfection, demonstrating that some allopatric microbes can drastically alleviate gene essentialities. These results expand our understanding of how diverse microbes alter growth and gene essentiality within polymicrobial infections.