• Karla Soares-Weiser, Hanna Bergman, Nicholas Henschke, Femi Pitan, and Nigel Cunliffe.
• Editorial & Methods Department, Cochrane, St Albans House, 57 - 59 Haymarket, London, UK, SW1Y 4QX.
• Cochrane Db Syst Rev. 2019 Mar 25; 3: CD008521.

BackgroundRotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech).ObjectivesTo evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children.Search MethodsOn 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews.Selection CriteriaWe selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention.Data Collection And AnalysisTwo review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty.Main ResultsFifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac.RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence).RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence).Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up.Children vaccinated and followed up for two yearsRotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence).There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint.Authors' ConclusionsRV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events.

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