Vaccines for preventing rotavirus diarrhoea: vaccines in use

Karla Soares‐Weiser; Hanna Bergman; Nicholas Henschke; Femi Pitan; Nigel Cunliffe

doi:10.1002/14651858.CD008521.pub5

. 2019 Oct 28;2019(10):CD008521. doi: 10.1002/14651858.CD008521.pub5

Vaccines for preventing rotavirus diarrhoea: vaccines in use

Karla Soares‐Weiser ^1,^✉, Hanna Bergman ², Nicholas Henschke ², Femi Pitan ³, Nigel Cunliffe ⁴

Editor: Cochrane Infectious Diseases Group

PMCID: PMC6816010 PMID: 31684685

Abstract

Background

Rotavirus 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).

Objectives

To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children.

Search methods

On 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 criteria

We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention.

Data collection and analysis

Two 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 results

Fifty‐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 years

In 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 years

In 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 years

Rotavac 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' conclusions

RV1, 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.

21 October 2019

Up to date

All studies incorporated from most recent search

All published trials found in the last search (4 Apr, 2018) were included and 15 ongoing studies are currently awaiting completion (see 'Characteristics of ongoing studies').

Plain language summary

Vaccines for preventing rotavirus diarrhoea: vaccines in use

What is the aim of this review?

The aim of this Cochrane Review was to find out if rotavirus vaccines are effective in preventing diarrhoea and deaths in infants and young children. We also aimed to find out if the rotavirus vaccines are safe. We collected and analyzed all relevant studies to answer these questions, and found 55 studies.

Key messages

RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea (moderate‐ to high‐certainty evidence). We found no increased risk of serious adverse events (moderate‐ to high‐certainty evidence) including intussusception (where the bowel telescopes on itself, and can cause obstruction) (very low to low‐certainty evidence).

What was studied in the review?

Rotavirus infection is a common cause of diarrhoea in infants and young children, and can cause mild illness, hospitalization, and death. Since 2009, the World Health Organization (WHO) has recommended that a rotavirus vaccine be included in all national infant and child immunization programmes, and 95 countries have so far followed this recommendation. In the years before infants and children started receiving rotavirus vaccine, rotavirus infection resulted in about half a million deaths a year in children aged under five years, mainly in low‐ and middle‐income countries.

In this review we included randomized controlled trials in infants and young children that evaluated a monovalent rotavirus vaccine (RV1; Rotarix, GlaxoSmithKline) or a pentavalent rotavirus vaccine (RV5; RotaTeq, Merck). These vaccines have been evaluated in several large trials and are approved for use in many countries. We also included trials that evaluated another monovalent rotavirus vaccine (Rotavac; Bharat Biotech), which is used in India only. The rotavirus vaccines were compared with placebo or with no vaccine. The included studies did not allow comparisons between the vaccines.

What are the main results of the review?

We found 55 relevant studies with 216,480 participants. The trials took place in several locations worldwide. These studies compared a rotavirus vaccine versus placebo or versus no vaccine for infants and young children. The vaccines tested were RV1 (36 trials with 119,114 participants), RV5 (15 trials with 88,934 participants), and Rotavac (four trials with 8432 participants). Fifty‐one studies were funded or co‐funded by vaccine manufacturers, while four were independent of manufacturer funding.

In the first two years of life, RV1:

●prevents more than 80% of severe cases of rotavirus diarrhoea in countries with low death rates (high‐certainty evidence)  ●prevents 35% to 63% of severe rotavirus diarrhoea in countries with high death rates (high‐certainty evidence)  ●probably prevents 37% to 41% of severe cases of diarrhoea from all causes (such as any viral infection, bacterial infection, or parasitic infection) in countries with low death rates (moderate‐certainty evidence)  ●probably prevents 18% to 27% of severe cases of diarrhoea from all causes in countries with high death rates (moderate‐ to high‐certainty evidence).

In the first two years of life, RV5:

●probably prevents 82% to 92% of severe cases of rotavirus diarrhoea in countries with low death rates (moderate‐certainty evidence)  ●prevents 41% to 57% of severe cases of rotavirus diarrhoea in countries with high death rates (high‐certainty evidence)  ●probably prevents 15% of severe cases of diarrhoea from all causes in countries with high death rates (moderate‐ to high‐certainty evidence); we did not identify any studies that reported on diarrhoea from all causes in countries with low death rates.

In the first two years of life, Rotavac:

●probably prevents more than 50% of severe cases of rotavirus diarrhoea in India, a country with high death rates (moderate‐certainty evidence)  ●probably prevents 18% of severe cases of diarrhoea from all causes in India (moderate‐certainty evidence). Rotavac has not been evaluated in a randomized controlled trial in a country with low death rates.

We found little or no difference in the number of serious adverse events (moderate‐ to high‐certainty evidence), or intussusception cases (low‐ to very low‐certainty evidence), between those receiving RV1, RV5, or Rotavac compared with placebo or no intervention.

How up‐to‐date is this review?

We searched for studies that had been published up to 4 April 2018.

Summary of findings

Background

Description of the condition

The global impact of rotavirus infection

Rotavirus is the leading known cause of severe gastroenteritis in infants and young children worldwide (Parashar 2006a; Vesikari 1997; WHO 2013). While nearly every child experiences at least one rotavirus infection in early childhood regardless of setting, the vast majority of rotavirus‐associated deaths occur in children in low‐ and middle‐income countries, particularly in sub‐Saharan Africa and in the Indian subcontinent. Prior to the rollout of rotavirus vaccination, rotavirus caused 37% of diarrhoeal deaths (˜ 450,000 deaths worldwide in 2008) in children younger than five years. Five countries accounted for more than half of all deaths, and 22% of deaths attributable to rotavirus infection occurred in India (Tate 2012). In high‐income countries, where deaths due to rotavirus are rare, rotavirus accounted for 40% to 50% of hospital admissions due to diarrhoeal disease in the pre‐rotavirus vaccine period (Linhares 2008; Parashar 2006a; Tate 2012).

Epidemiology of rotavirus infection

Rotavirus is transmitted primarily via the faecal‐oral route, with symptoms typically developing one to two days following infection. Rotavirus infection occurs throughout life, and successive rotavirus infections occur during infancy and early childhood. The first rotavirus infection typically results in the most severe disease outcome; subsequent rotavirus infections are associated with milder disease or may be asymptomatic. However, differences in the age of first infection and number of infections required to acquire protection from symptomatic disease vary from one population to another. Rotavirus diarrhoea is particularly associated with severe outcomes between the ages of three and 35 months (Parashar 2006b), with a peak incidence of all episodes occurring between six and 24 months (CDC‐ASIP 1999; Linhares 2008). The peak incidence of severe rotavirus disease occurs earlier in high‐mortality countries than in low‐mortality countries; an estimated 43% of all rotavirus hospitalizations in children aged under five occur by eight months of age in Africa compared with 27% in Europe (Crawford 2017; Sanderson 2011). Typically, infants in low‐income countries experience a greater number of symptomatic episodes (Gladstone 2011; Velázquez 1996). In temperate countries rotavirus infections display marked seasonality, with distinct peaks during the winter months and few infections identified outside this period, whereas rotavirus infections occur year‐round in most tropical countries.

Rotavirus classification

Rotaviruses are double‐stranded (ds) RNA viruses: genus Rotavirus, family Reoviridae. Each of the 11 dsRNA segments, contained within the core of a triple‐layered viral particle, encodes one or more viral proteins. Rotavirus A, which causes most human disease, is genetically diverse in each of its 11 genome segments (called genotypes), and a nucleotide sequence‐based, complete genome classification system is used. Because of their importance in protective immunity, the outer capsid proteins VP7 and VP4 have been most extensively investigated. Species A rotaviruses are classified into G and P genotypes, based on the sequence diversity of the RNA segments encoding VP7 and VP4, respectively; 32 G genotypes and 47 P genotypes have been described (Crawford 2017) (see Figure 1 for details). Rotavirus vaccines are designed to protect against disease caused by the most prevalent strain types; globally, G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12 in combination with P[6] or P[8] account for over 90% of the genotypes that infect humans (Bányai 2012).

**A simplified diagram of the location of rotavirus structural proteins (source: Graham Cohn, Wikipedia (public domain image)):** Rotaviruses are segmented, double‐stranded RNA viruses. The mature, triple‐layered virus particle comprises a core (which contains the viral genome), a middle layer (comprised of viral protein (VP)6, and an outer layer (comprised of VP7 and VP4) as shown in the figure. VP6 defines rotavirus group, and most rotaviruses that infect humans are of group A. The two outer capsid proteins independently induce neutralizing antibodies: VP7, a glycoprotein, defines G‐serotype; and the protease‐sensitive VP4 protein defines P‐serotype. G‐serotype determined by serological methods correlates precisely with G‐genotype obtained through molecular assays, whereas there is an imperfect correlation of P‐serotype and P‐genotype; P‐genotype is thus included in square brackets.

Description of the intervention

Vaccines approved for use

This review evaluates three vaccines, including a monovalent rotavirus vaccine (RV1; Rotarix, GlaxoSmithKline Biologicals) and a pentavalent rotavirus vaccine (RV5; RotaTeq, Merck & Co., Inc.), which have been evaluated in several large trials and are in routine use in many countries; and a further monovalent vaccine (Rotavac, Bharat Biotech Ltd.), which is currently licensed in India only. All three vaccines are listed as prequalified vaccines by the WHO (Dellepiane 2015; WHO 2018). As of April 2018, 95 countries have introduced rotavirus vaccines into their immunization programmes (ROTA council 2018).

RV1 is an oral, live‐attenuated, human rotavirus vaccine derived from the most common circulating wild‐type strain G1P[8]. RV1 is based on a rotavirus of entirely human origin and is administered to infants in two oral doses with an interval of at least four weeks between doses. The manufacturer states that the "vaccination course should preferably be given before 16 weeks of age, but must be completed by the age of 24 weeks" (EMA 2011). As of May 2016, RV1 had been introduced in national immunization programmes in 63 countries around the world (PATH 2016).

RV5 is an oral, live, human‐bovine, reassortant, multivalent rotavirus vaccine developed from an original Wistar calf 3 (WC3) strain of bovine rotavirus. The vaccine contains five live, human‐bovine reassortant rotavirus strains. Four reassortant rotavirus strains each express one of the common human VP7 (G) types including G1, G2, G3, and G4, and the fifth reassortant expresses the common human VP4 (P) type P[8]. The three‐dose liquid vaccine is intended for infants aged between six and 32 weeks, with the first dose given at six to 12 weeks and subsequent doses administered at four‐ to 10‐week intervals; however, the third dose should not be given after 32 weeks of age (Merck 2008). As of May 2016, RV5 had been introduced in national immunization programmes in 22 countries around the world (PATH 2016).

Rotavac is a live‐attenuated, monovalent vaccine derived from a naturally‐occurring reassortant G9P[11] strain [116E] isolated from a newborn child in India (Yen 2014). This oral vaccine was developed by Bharat Biotech Ltd. in India and was licensed in India in 2014 (VAC Chandola 2017‐IND). Three doses are recommended, to be administered at 6, 10, and 14 weeks of age.

There are a further three rotavirus vaccines that have been licensed and approved for use in individual countries, but are not yet prequalified by the WHO. Lanzhou lamb rotavirus vaccine (LLR; Lanzhou Institute of Biomedical Products) which is licensed and used in China; a bovine rotavirus pentavalent vaccine (BRV‐PV, Rotasiil, Serum Institute of India Ltd.) which is licensed and used in India; and a monovalent vaccine (Rotavin‐M1, POLYVAC) which is licensed and used in Vietnam.

Vaccines no longer in use

Several vaccines, including the first licensed rotavirus vaccine (RRV‐TV; RotaShield, Wyeth Laboratories) were developed, tested in trials, and later abandoned or withdrawn from use. These vaccines are covered in a separate Cochrane Review (Soares‐Weiser 2004). RRV‐TV, a tetravalent rhesus‐human reassortant vaccine, was withdrawn from use in 1999 following reports of intussusception (bowel obstruction which occurs when one segment of bowel becomes enfolded within another segment). Evaluations have since suggested that the risk of intussusception was age‐related, with 80% of intussusception cases occurring in infants who were more than 90 days old when the first vaccine dose was administered (Simonsen 2005). Although it is still currently licensed, this vaccine is no longer in clinical use (Dennehy 2008).

How the intervention might work

Recommendations for rotavirus vaccine use

Vaccination with RV1 and RV5 was first recommended in 2006 in Europe and the Americas, where clinical trials had demonstrated vaccine efficacy of 85% to 100% (RV1 Ruiz‐Palac 06‐LA/EU; RV5 Vesikari 2006b‐INT). In April 2009, following clinical trials of RV1 and RV5 in low‐ and middle‐income countries in Africa and Asia, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended "the inclusion of rotavirus vaccination of infants into all national immunization programmes", with a stronger recommendation for countries where "diarrhoeal deaths account for ≥10% of mortality among children aged <5 years" (SAGE 2009). Due to an age‐related risk of intussusception identified with RRV‐TV (Murphy 2001), SAGE recommended administering the first dose of RV1 or RV5 to infants of six to 15 weeks of age, with the last dose administered before 32 weeks of age (SAGE 2009). In April 2012, SAGE relaxed the age restricted recommendation and advised to vaccinate "as soon as possible after the age of six weeks" because "the current age restrictions for the first dose (< 15 weeks) and last dose (< 32 weeks) are preventing vaccination of many vulnerable children" (Patel 2012; SAGE 2012).

Performance of oral rotavirus vaccines by setting

Many oral vaccines, including rotavirus vaccines, have demonstrated lower immunogenicity and efficacy in low‐ and middle‐income countries in Africa and Asia compared to high‐income countries in North America, South America, and Europe (Levine 2010). A systematic review demonstrated a correlation between lower vaccine efficacy against severe rotavirus diarrhoea and high child mortality rates (Fischer Walker 2011). The reasons for reduced oral vaccine efficacy in countries with higher child mortality rates are unknown; factors may include interference by maternal antibody, co‐administration with oral poliovirus vaccine, histoblood group antigen, diverse rotavirus strain types, micronutrient deficiencies, endemic infections such as malaria, tuberculosis, or HIV, concomitant enteric infections, gut inflammation, and altered gut microbiota (Czerkinsky 2015).

Outcomes of interest

The safety and efficacy of the licensed vaccines for the prevention of rotavirus gastroenteritis in infants have been assessed in several randomized controlled trials (RCTs) worldwide. The goal of this review is to systematically assess these trials and evaluate vaccine efficacy against rotavirus diarrhoea, all‐cause diarrhoea, and diarrhoea‐related medical visits and hospitalization. We also examine the occurrence of deaths and serious adverse events, including intussusception, to provide decision‐makers, clinicians, and caregivers with the relevant information to aid decisions about vaccine use.

Why it is important to do this review

Development of Cochrane systematic rotavirus vaccine reviews

The original Cochrane Review of rotavirus vaccines (Soares‐Weiser 2004) examined vaccines in use and other vaccines, including those that were no longer in use or were in development. Soares‐Weiser 2004 concluded that more trials were needed before routine vaccine use could be recommended. An update in 2009 included a new search, revised inclusion criteria (only vaccines in use in children), updated review methods and new authors. The review was updated again in 2010 with nine new studies (Soares‐Weiser 2010). The 2010 version of the review concluded that RV1 and RV5 are both effective vaccines for the prevention of rotavirus diarrhoea. Another update in February 2012 added a further nine new studies, GRADE ‘Summary of findings' tables and, again, new authors joined the team (Soares‐Weiser 2012a). The November 2012 update included a new search, major restructuring of analyses, including re‐evaluating primary outcomes in consultation with the WHO to reflect the observation that vaccine efficacy profiles are different in countries with different mortality rates (Soares‐Weiser 2012b). This current update adds a further 10 RV1 and RV5 studies to the review and four studies of a new vaccine, Rotavac, that has been prequalified by the WHO since the previous version of the review.

Objectives

To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs).

Types of participants

Children (age as defined in the trials).

Types of interventions

Intervention

Rotavirus vaccines approved by the WHO vaccine prequalification programme (Dellepiane 2015; WHO 2018).

Control

Placebo, no vaccination, or other vaccine.

Types of outcome measures

Primary

We selected our primary outcome measures in consultation with the WHO, and stratified them according to high‐ or low‐mortality rate, based on WHO mortality strata (WHO 1999), and up to one and up to two years follow‐up.

Rotavirus diarrhoea: severe (as defined in trial report)
All‐cause diarrhoea: severe
All‐cause death
Serious adverse events (that are fatal, life‐threatening, or result in hospitalization); e.g. Kawasaki disease
Intussusception

Secondary

Rotavirus diarrhoea: of any severity
All‐cause diarrhoea (as defined in trial report)
Rotavirus diarrhoea: requiring hospitalization
All‐cause diarrhoea: requiring hospitalization
Emergency department visit
Hospital admission: all‐cause
Reactogenicity (capacity to produce an adverse reaction, such as fever, diarrhoea, and vomiting)
Adverse events that require discontinuation of vaccination schedule

Other

Immunogenicity
- Vaccine virus shedding in stool
- Seroconversion: conversion from seronegative to seropositive for anti‐rotavirus IgA antibodies
Dropouts

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and ongoing).

For this review update, Dr Vittoria Lutje (Information Specialist, Cochrane Infectious Diseases Group) searched the following databases using the search terms and strategy described in Appendix 1.

Cochrane Infectious Diseases Group Specialized Register (4 April 2018)
Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2018, Issue 4)
MEDLINE (via PubMed; 1966 to April 2018)
Embase (1974 to 4 April 2018)
LILACS (1982 to 4 April 2018)
BIOSIS (1926 to 4 April 2018)

We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov Clinical Study Register (www.clinicaltrials.gov) on 4 April 2018, using ‘rotavirus' as the search term.

We searched manufacturers' websites for clinical trial reports. We also checked the reference lists of relevant systematic reviews and included studies.

Data collection and analysis

Selection of studies

For this review update, we uploaded and screened references in DistillerSR online. Two review authors independently screened each title and abstract identified in the search. We retrieved full texts for potentially relevant references and two review authors again screened them independently, resolving disagreements by recourse to a third review author. We tabulated the excluded studies along with the reason for excluding them in the Characteristics of excluded studies tables. We ensured that data from each trial were entered only once in our review. In previous versions of this review we had screened references in an EndNote database.

Data extraction and management

For this review update, we extracted data in DistillerSR online. We created forms for data collection, which were piloted and then revised after the review author team's discussion. For previous versions of this review we had used Microsoft Word or Excel data collection forms.

One review author extracted data and another review author cross‐checked them. All outcomes were dichotomous, and we extracted the total number of participants and the number of participants who experienced the event. We cross‐checked the extracted data to identify errors, resolving disagreements by referring to the trial report or by consulting a third review author. One review author entered data into Review Manager 5 (RevMan 5) (RevMan 2014).

The use and mentioning of trade names in this review represents no endorsement of or advertisement for any product. The use of trade names was unavoidable as no generic names were identified for some of the vaccines evaluated here.

Assessment of risk of bias in included studies

Two review authors independently assessed the risks of bias of each trial, using the Cochrane ‘Risk of bias' tool (Higgins 2017). Based on the guidance of the Cochrane ‘Risk of bias' tool (Higgins 2017), we created a form to make judgements on the risk of bias for the rotavirus diarrhoea outcome measure in six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other potential sources of bias. We categorized these judgements as ‘low', ‘high', or ‘unclear' risk of bias. We resolved disagreements through discussion with a third review author.

For the 2012 published version of this review, we asked for help from Dr Ana Maria Restrepo at the WHO Initiative for Vaccine Research, who contacted the vaccine manufacturers GlaxoSmithKline (RV1) and Merck (RV5), who were involved in designing and funding most of the included trials. We provided them with an Excel spreadsheet with specific details of each trial that would impact on the assessment of risk of bias. We received details from Merck (RV5), (see Characteristics of included studies for details). For this review update, we matched most of the previously‐included RV1 studies to the full clinical trial reports available on the manufacturer's website (www.gsk‐clinicalstudyregister.com). More details were available in these trial reports than in the published studies, that were helpful in assessing the risks of bias for these studies.

Measures of treatment effect

We analyzed dichotomous data of cases by calculating the risk ratio (RR) for each trial (expressed using blue squares in forest plots) with the uncertainty in each result expressed using 95% confidence intervals (CIs). For dichotomous data of events that could occur more than once in one participant, we calculated the rate ratio (expressed using red squares in forest plots) on the logarithmic scale using the generic inverse variance method (see Data synthesis for more details). For outcomes that included cluster‐RCTs we calculated risk ratios (expressed using red squares in forest plots) using the generic inverse variance method (see Unit of analysis issues for more details).

Unit of analysis issues

When trials had multiple treatment arms and we considered it suitable, we grouped the trial arms. We excluded irrelevant trial arms.

We pooled cluster‐RCT data that had been adjusted for clustering with data from trials that randomly assigned individuals (individual‐RCTs). For outcomes that included cluster‐RCTs, we pooled risk ratios on the logarithmic scale with their standard errors using the generic inverse variance method (16.3.3. in Higgins 2011). When the results of a cluster‐RCT had not been adjusted for clustering, we imputed the clustering effect (intracluster correlation coefficient (ICC)) from another study, and performed sensitivity analyses excluding these studies.

Dealing with missing data

We undertook a complete‐case analysis (the number analyzed) and an intention‐to‐treat analysis when data were available.

Assessment of heterogeneity

We initially assessed heterogeneity in the results of the trials by inspecting the graphical presentations and by calculating the Chi² test of heterogeneity. However, we were aware of the fact that the Chi² test has a poor ability to detect statistically significant heterogeneity among studies. We therefore also quantified the impact of heterogeneity in the meta‐analysis using a measure of the degree of inconsistency in the studies' results (Higgins 2003). This measure (the I² statistic) describes the percentage of total variation across studies that are due to heterogeneity rather than to the play of chance (Higgins 2003). The I² statistic values lie between 0% and 100%, and a simplified categorization of heterogeneity could be low, moderate, and high for I² statistic values of 25%, 50%, and 75% respectively (Higgins 2003).

Assessment of reporting biases

If 10 or more studies were included in an outcome, we examined a funnel plot for the primary outcome (severe rotavirus diarrhoea), estimating the precision of trials (plotting the RR against the standard error (SE) of the log of RR) to estimate potential asymmetry.

Data synthesis

We stratified all analyses by the type of vaccine, RV1, RV5 or Rotavac. Subsequently, we grouped all outcomes in the meta‐analyses according to the time point when the outcome was measured or the number of rotavirus seasons, or both, as follows: less than two months; up to one year (one rotavirus season); up to two years (up to two rotavirus seasons); and up to three years (three rotavirus seasons). If data were available for more than one time point, we used the number of completers for each time point in the trial.

For the current update, we stratified each primary outcome (rotavirus diarrhoea, all‐cause diarrhoea, all‐cause death, all serious adverse events, and intussusception) and selected secondary outcomes (rotavirus diarrhoea and all‐cause diarrhoea of any severity, and all‐cause hospitalization) by country mortality rate according to WHO mortality strata (WHO 1999), as follows:

Low‐mortality: countries in WHO strata A and B (very low/low child mortality and low adult mortality)
High‐mortality: countries in WHO strata D and E (high child mortality and high/very high adult mortality)

We used a fixed‐effect model, unless we found statistically significant heterogeneity (P < 0.10) for a specific outcome, in which case we used the random‐effects model.

We included separate analyses for cases of diarrhoea (e.g. a child who has diarrhoea regardless of the number of episodes) and episodes (i.e. one child can experience more than one episode), where data permitted. We combined episodes using the rate ratio in the logarithmic scale and SE, with the uncertainty in each result being expressed using a 95% CI (9.4.8. in Higgins 2011).

Certainty of the evidence

We interpreted the findings of this review using the GRADE approach (Schünemann 2017), and we used GRADE profiler (GRADE 2004) to import data from RevMan 5 (RevMan 2014) to create ‘Summary of findings' tables. These tables provide outcome‐specific information concerning the overall certainty of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rated as important to patient care and decision‐making, and is reflected as follows: high certainty ("vaccine prevents...."); moderate certainty ("vaccine probably prevents..."); low certainty ("vaccine may prevent...."); and very low certainty ("we do not know whether or not the vaccine prevents....").

We selected primary outcomes, all stratified by vaccine and high or low country mortality, for inclusion in the ‘Summary of findings' tables: severe rotavirus diarrhoea; severe all‐cause diarrhoea; all‐cause death; serious adverse events; and intussusception.

Subgroup analysis and investigation of heterogeneity

In addition to stratifying the results by country‐based high‐mortality and low‐mortality rates using WHO mortality country strata (WHO 1999), we planned to perform subgroup analyses to assess the impact of the following possible sources of heterogeneity for any of the included vaccines: vaccine protection against specific rotavirus G types; and vaccination of special groups, including immunocompromised (including HIV‐infected) children and children with malnutrition. In previous versions of this review (Soares‐Weiser 2010; Soares‐Weiser 2012a), we also analyzed vaccine effect according to each study's country income, use of other childhood vaccines, number of doses administered, source of funding, and whether infants were born prematurely or were breast‐ or formula‐fed. These subgroup analyses did not show any differences, and are not presented in this updated version; they can be found in Soares‐Weiser 2010 and Soares‐Weiser 2012a.

Sensitivity analysis

We also planned to conduct sensitivity analyses for the primary outcomes according to allocation concealment (high, low, and unclear risk of bias) for outcomes in which data could not be pooled because of significant heterogeneity (I² statistic > 75%).

Results

Description of studies

Results of the search

The update search in 2017 identified 1247 records and the update search in 2018 identified a further 488 records. After de‐duplication, we screened 1614 records and considered 1500 to be irrelevant. We reviewed the full texts of 114 records. In the previously published version of this review there were 41 included studies. The review now includes 55 independent trials (see Characteristics of included studies), 14 of which are new to this update (RV1 Colgate 2016‐BGD; RV1 Kim 2012‐KOR; RV1 Li 2013a‐CHN; RV1 Li 2013b‐CHN; RV1 Li 2014‐CHN; RV1 NCT00158756‐RUS; RV1 Zaman 2017‐BGD; RV5 Dhingra 2014‐IND; RV5 Levin 2017‐AF; RV5 Mo 2017‐CHN; VAC Bhandari 2006‐IND; VAC Bhandari 2009‐IND; VAC Bhandari 2014‐IND; VAC Chandola 2017‐IND) and we also added another 23 new companion papers to previously included trials with this update. The review also includes 15 ongoing studies (see Characteristics of ongoing studies). We excluded 78 studies for the reasons given in the Characteristics of excluded studies section.

Included studies

The 55 included trials enrolled about 216,480 participants (approximate number, as some trials provided only the number evaluable), and each trial compared a rotavirus vaccine with a placebo. The vaccines tested were RV1 (36 trials reported in 171 publications or reports; 119,114 participants), RV5 (15 trials reported in 60 publications or reports; 88,934 participants), and Rotavac (4 trials reported in 13 publications or reports; 8432 participants).

The trials were conducted in Africa, Asia, Europe, and the Americas, and the location can be identified in the study reference: AF, Africa; AS, Asia; EU, Europe; INT, several international locations; LA, Latin America; NA, North America; or country three‐letter acronym according to ISO 3166‐1 Alpha‐3 (e.g. BGD for Bangladesh) from www.all‐acronyms.com/special/countries_acronyms_and_abbreviations, if the study was conducted in a single country.

1. RV1

The 36 RV1 trials were published between 1998 and 2017. Five of the trials are unpublished and were located on the GlaxoSmithKline website through clinicalstudyresults.org or clinicaltrials.gov. One trial (RV1 Madhi 2010‐AF) provided country‐specific data for efficacy outcomes but not for safety outcomes, and was consequently split into RV1 Madhi 2010‐MWI and RV1 Madhi 2010‐ZAF for the Malawi‐ and South Africa‐specific data. Twenty‐five trials enrolled around 500 participants or fewer, three trials enrolled around 1000 participants, seven trials enrolled between 2155 and 12,318 participants, and one large trial enrolled 63,225 participants. Most children were aged between one and three months at the time of the first vaccination.

Population

Most trials included healthy infants. Two trials included HIV‐infected or ‐exposed infants (RV1 Madhi 2010‐AF; RV1 Steele 2010a‐ZAF), one trial included premature infants (RV1 Omenaca 2012‐EU), and one trial included children aged two to six years (RV1 Li 2013a‐CHN).

Outcome measures

Each trial reported on one or more of the outcome measures specified for this review (see Appendix 2). We included data on participants requiring medical visits, as this was reported in some trials and is a similar outcome measure to participants requiring hospitalization.

Twenty‐three trials were safety studies, reporting mainly safety outcomes (e.g. serious adverse events and reactogenicity), immunogenicity outcomes, or both. Eleven of these trials also reported efficacy outcomes with a follow‐up of up to two months. Eleven trials reported one or more efficacy outcomes (e.g. rotavirus diarrhoea) in addition to safety outcomes; most reported one or more immunogenicity outcomes. Two trials reported on efficacy or effectiveness but not safety or immunogenicity (RV1 Colgate 2016‐BGD; RV1 Zaman 2017‐BGD). The trials varied in the length of follow‐up, but in general the trials that specified efficacy outcome measures had longer follow‐up times (Appendix 2).

As shown in Appendix 3, rotavirus diarrhoea (of any severity) was the most common efficacy outcome reported (by 23 trials); 14 trials reported on severe rotavirus diarrhoea, and 10 reported on rotavirus diarrhoea requiring hospitalization. Data on all‐cause diarrhoea were provided by 17 trials, and severe all‐cause diarrhoea by nine trials. Most reported all‐cause death and dropouts, but other efficacy outcomes were reported by few trials.

For safety outcomes (Appendix 4), 29 trials reported on reactogenicity, all but four trials reported on serious adverse events, and 24 reported on adverse events leading to discontinuation of the intervention.

Most trials reported on one or more immunogenicity outcomes; see Appendix 4.

Location

Early trials were conducted in North America and Europe, but since 2005 trials have also been conducted in Asia (Bangladesh, China, India, Japan, Philippines, South Korea, Singapore, Thailand, Vietnam; 17 trials), Latin America (Argentina, Brazil, Chile, Colombia, Dominican Republic, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela; six trials), and Africa (South Africa, Malawi; four trials); see Appendix 5. Most trials had multiple sites, often in several countries; RV1 Vesikari 2007a‐EU included 98 sites in six European countries.

Country mortality rate

Most trials were conducted in countries with low mortality rates, corresponding to WHO mortality strata A and B. Eight trials were conducted in countries with high mortality rates (RV1 Colgate 2016‐BGD; RV1 Madhi 2010‐AF; RV1 Narang 2009‐IND; RV1 Steele 2008‐ZAF; RV1 Steele 2010a‐ZAF; RV1 Steele 2010b‐ZAF; RV1 Zaman 2009‐BGD; RV1 Zaman 2017‐BGD), corresponding to WHO mortality strata D and E; see Appendix 5. For RV1 Madhi 2010‐AF, available data were split between countries into RV1 Madhi 2010‐MWI and RV1 Madhi 2010‐ZAF. Two trials were conducted in several countries with both low and high mortality: RV1 GSK[033] 2007‐LA was conducted in four study centres in a high‐mortality country (Peru), but also in three study centres in two low‐mortality countries (Colombia and Mexico), and was placed in the high‐mortality group; and RV1 Ruiz‐Palac 06‐LA/EU was conducted mainly in low‐mortality countries in Latin America and in Finland, but also in two high‐mortality countries (Nicaragua and Peru), and was placed in the low‐mortality group.

Vaccine schedule

The trials varied in the vaccine dose and schedule (see Appendix 6). Most trials gave two doses of the vaccine with virus concentration of more than 10⁶ plaque‐forming units (PFUs). Older trials, conducted between 1998 and 2005, tended to include slightly lower PFUs or a range of PFUs for comparison.

RV1 was given as two doses in all but five trials: one trial conducted in partnership with GlaxoSmithKline and PATH Rotavirus Vaccine Program tested two and three doses of the vaccine (RV1 Madhi 2010‐AF); another trial conducted by GlaxoSmithKline in which the poliovirus vaccine was co‐administered with RV1, tested two or three vaccine doses to investigate differences in immune response (RV1 Steele 2010b‐ZAF); a third study tested three vaccine doses in HIV‐positive infants (RV1 Steele 2010a‐ZAF); a fourth study tested three vaccine doses in healthy infants (RV1 GSK[021] 2007‐PAN); a fifth study that included children aged two to six years administered one dose only (RV1 Li 2013a‐CHN).

Some trials compared more than one arm: different PFU virus concentrations (RV1 Vesikari 2004a‐FIN; RV1 Dennehy 2005‐NA; RV1 Phua 2005‐SGP; RV1 Salinas 2005‐LA; RV1 Ward 2006‐USA); different formulations (RV1 GSK[021] 2007‐PAN; RV1 GSK[033] 2007‐LA; RV1 GSK[101555] 2008‐PHL; RV1 Kerdpanich 2010‐THA; RV1 Vesikari 2011‐FIN); co‐administration of other vaccine (RV1 Steele 2008‐ZAF; RV1 Zaman 2009‐BGD; RV1 NCT00158756‐RUS; RV1 Li 2014‐CHN); and different intervals between doses (RV1 Anh 2011‐PHL; RV1 Anh 2011‐VNM).

Infant vaccination status

All but four trial reports referred to vaccination with other infant vaccines (see Appendix 6). Most trials co‐administered other routine infant vaccines, such as diphtheria‐tetanus‐acellular pertussis, Haemophilus influenzae type b (HiB), inactivated polio vaccine, and hepatitis B vaccine (HBV). Some trials also co‐administered oral polio vaccine. Other trials imposed a two‐week separation between other infant vaccines and rotavirus vaccine or placebo, or specified other vaccines as not allowed.

Methods for collecting adverse event data

Fifteen of the 36 trials did not provide details of how adverse event data were collected. Out of the trials that did report the method of collecting adverse event data, 13 trials used passive methods (e.g. diary cards), two used an active method ("active surveillance system"), and five used both passive and active methods (e.g. diary card plus regular telephone calls to parents); see Appendix 7.

Source of funding

Most trials were supported by GlaxoSmithKline Biologicals, three of which were in partnership with PATH Rotavirus Vaccine Program (RV1 Li 2014‐CHN; RV1 Madhi 2010‐AF; RV1 Zaman 2009‐BGD), and another two in partnership with RAPID trials and the WHO (RV1 Steele 2008‐ZAF; RV1 Steele 2010a‐ZAF). One trial was funded by The Bill and Melinda Gates Foundation (RV1 Colgate 2016‐BGD) and one by GAVI and PATH (RV1 Zaman 2017‐BGD). Three trials were sponsored by Avant Immunotherapeutics (formerly Virus Research Institute, Inc.) (RV1 Bernstein 1998‐USA; RV1 Bernstein 1999‐USA; RV1 Ward 2006‐USA).

2. RV5

We identified 15 trials of RV5 vaccine. The earliest was reported in 2003 and the most recent in 2017. One of the trials is unpublished and was accessed via clinicalstudyresults.org. Two trials (RV5 Armah 2010‐AF and RV5 Zaman 2010‐AS) provided country‐specific data for some outcomes but not for all outcomes, and were consequently split into RV5 Armah 2010‐GHA; RV5 Armah 2010‐KEN; and RV5 Armah 2010‐MLI for the Ghana‐, Kenya, and Mali‐specific data, and RV5 Zaman 2010‐BGD and RV5 Zaman 2010‐VNM for the Bangladesh‐ and Vietnam‐specific data. Overall, 88,934 participants were included in the trials; the largest trial included 70,301 participants (RV5 Vesikari 2006b‐INT) and the smallest included 48 participants (RV5 Lawrence 2012‐CHN). For the 2012 update of this review, we received new information from Merck (Merck 2012) for some of the trials on the outcomes serious adverse events, intussusception, and deaths. We have incorporated the new information into the analyses and have indicated this in the Characteristics of included studies section.

Population

Most trials included healthy infants. One trial included both healthy and HIV‐infected infants (RV5 Armah 2010‐KEN), another trial included HIV‐exposed but uninfected and HIV‐infected infants (RV5 Levin 2017‐AF), and one trial included prematurely‐born infants as well as those born at normal gestation (RV5 Vesikari 2006b‐INT). All but two trials enrolled children aged between one month and three months; the children in RV5 Vesikari 2006a‐FIN were aged between three months and six months, and there was a child cohort (2‐ to 6‐year‐old children) in addition to an infant cohort in RV5 Lawrence 2012‐CHN.

Outcome measures

Six trials were safety studies (Appendix 2), reporting safety outcomes (e.g. serious adverse events and reactogenicity) and generally immunogenicity outcomes as well. The other nine trials reported one or more efficacy and safety outcomes, and seven out of those nine also reported immunogenicity outcomes (Appendix 2). The trials varied in the length of follow‐up (Appendix 2), but in general the trials that specified efficacy outcome measures had longer follow‐up times (up to three years). Similar to the RV1 trials, we included data on participants requiring medical visits, as this was reported in some trials and is a similar outcome measure to participants requiring hospitalization.

As shown in Appendix 3, rotavirus diarrhoea, severe cases and cases of any severity, were the most common efficacy outcomes reported (by eight trials); only one of these reported rotavirus diarrhoea requiring hospitalization. Three trials provided data on severe cases of all‐cause diarrhoea; two also presented data on cases with any severity. Eleven trials reported all‐cause death, and 13 of the 15 trials reported dropouts.

For safety outcomes, all trials reported on serious adverse events and reactogenicity, and 13 trials reported on adverse events leading to discontinuation of the intervention; see Appendix 4.

Twelve trials reported on an immunogenicity outcome (Appendix 4).

Location

Half of the trials were conducted in low‐mortality countries in North America and Europe. Six trials, including the smallest and the largest trials, were conducted in other regions: RV5 Armah 2010‐AF was conducted in Ghana, Kenya and Mali; RV5 Levin 2017‐AF was conducted in Botswana, Tanzania, Zambia and Zimbabwe, RV5 Dhingra 2014‐IND was conducted in India, RV5 Kim 2008‐KOR was conducted in South Korea; RV5 Iwata 2013‐JPN was conducted in Japan; RV5 Lawrence 2012‐CHN and RV5 Mo 2017‐CHN were conducted in China; RV5 Vesikari 2006b‐INT was conducted in 12 countries in Asia, the Caribbean, Europe, Latin America, North America; and RV5 Zaman 2010‐AS was conducted in Bangladesh and Vietnam. Each trial had multiple sites, ranging from three (RV5 Vesikari 2006a‐FIN) to 356 sites (RV5 Vesikari 2006b‐INT); see Appendix 5.

Country mortality rate

Most trials were conducted in countries with low mortality rates, corresponding to WHO mortality strata A and B; see Appendix 5. One trial was conducted in high‐mortality India (RV5 Dhingra 2014‐IND). Four trials were conducted in several low‐ and high‐mortality countries. RV5 Armah 2010‐AF was conducted in three high‐mortality countries, Ghana, Kenya, and Mali, and when available the data were split into RV5 Armah 2010‐GHA, RV5 Armah 2010‐KEN and RV5 Armah 2010‐MLI. RV5 Levin 2017‐AF was conducted in four high‐mortality countries (Botswana, Tanzania, Zambia and Zimbabwe). RV5 Vesikari 2006b‐INT was conducted mainly in European and Latin American low‐mortality countries, but also in Guatemala, a high‐mortality country, and was placed in the low‐mortality group. RV5 Zaman 2010‐AS was conducted in one high‐mortality country (Bangladesh) with 1136 participants, and in one low‐mortality country (Vietnam) with 900 participants, and was placed in the high‐mortality group, except when data could be split into RV5 Zaman 2010‐BGD and RV5 Zaman 2010‐VNM.

Vaccine schedule

Each trial used three doses of RV5 vaccine, with intervals between doses of four and 10 weeks (see Appendix 6). All but two trials had one vaccine and one placebo arm; RV5 Vesikari 2006a‐FIN included three vaccine arms in which there were different RV5 components (G1‐4, P1A, G1‐4, and P1A), and RV5 Dhingra 2014‐IND included a RV5 arm, a placebo arm, and three arms with different concentrations of BRV‐TV vaccine.

Infant vaccination status

Most trials did not restrict the use of other childhood vaccines (see Appendix 6). Two trials co‐administered hepatitis B, diphtheria‐tetanus‐pertussis, poliovirus, and H influenzae type b vaccines with RV5 (RV5 Ciarlet 2009‐EU; RV5 Dhingra 2014‐IND). One trial randomized participants to either concomitant or staggered administration of other childhood vaccines (OPV, DTaP) with RV5 or placebo (RV5 Mo 2017‐CHN). Three trials allowed the use of oral polio vaccine, in addition to other licensed childhood vaccines (RV5 Armah 2010‐AF; RV5 Mo 2017‐CHN; RV5 Zaman 2010‐AS). Three trials did not allow the use of other vaccines (RV5 Clark 2003‐USA; RV5 Clark 2004‐USA; RV5 Lawrence 2012‐CHN), and one trial did not mention their use (RV5 Iwata 2013‐JPN).

Methods for collecting adverse event data

As shown in Appendix 7, seven trials used a combination of passive methods (e.g. diary cards for parents) and active methods (directly contacting parents) to collect adverse event data. The other trials used passive methods only (diary cards, three trials), active methods only ("active surveillance", three trials), or the information was not provided (two trials).

Source of funding

All but one trial was funded by Merck & Co., Inc. Two of those trials also received funding and were run by PATH (GAVI Alliance grant) (RV5 Armah 2010‐AF; RV5 Zaman 2010‐AS), and one trial also received funding from the International Maternal, Pediatric, and Adolescent AIDS Clinical Trial Network (IMPAACT) through the National Institute of Health (RV5 Levin 2017‐AF). One trial was funded by Shantha Biotechnics Ltd (RV5 Dhingra 2014‐IND).

3. Rotavac

We identified four trials of Rotavac vaccine. The earliest was reported in 2006 and the most recent in 2017. Overall, 8432 participants were included in the trials; the largest trial included 6799 participants (VAC Bhandari 2014‐IND) and the smallest included 90 participants (VAC Bhandari 2006‐IND).

Population

All trials included healthy infants. Trials enrolled infants aged between six weeks and nine weeks.

Outcome measures

Three trials were safety studies (Appendix 2) reporting safety outcomes and immunogenicity outcomes. They reported on follow‐up results for one to 12 months after the last vaccine dose. The other trial (VAC Bhandari 2014‐IND) reported on efficacy, safety, and immunogenicity outcomes until the infants were two years of age.

As shown in Appendix 3, VAC Bhandari 2014‐IND reported on rotavirus diarrhoea (severe cases, cases of any severity, and cases requiring medical attention). The same trial also provided data on severe cases of all‐cause diarrhoea. Two trials reported all‐cause death, and three of the four trials reported dropouts.

For safety outcomes, all trials reported on serious adverse events and two reported on reactogenicity. All trials reported on an immunogenicity outcome (Appendix 4).

Location

All trials were conducted in India, one at three sites in the cities of Delhi, Pune, and Vellore (VAC Bhandari 2014‐IND), and the remaining three studies at one site in Delhi.

Country mortality rate

All trials were conducted in India, a high‐mortality country (WHO mortality stratum D).

Vaccine schedule

Most trials used three doses of Rotavac vaccine, with intervals between doses of four to eight weeks (see Appendix 6). One trial (VAC Bhandari 2006‐IND) administered one dose. One trial had one vaccine and one placebo arm (VAC Bhandari 2014‐IND). VAC Bhandari 2006‐IND included an additional vaccine arm for a rotavirus vaccine candidate (I321) that we did not include for analysis in this review. VAC Bhandari 2009‐IND randomized participants to high‐ (1 x 10⁵ ffu) and low‐dose (1 x 10⁴ ffu) vaccine arms which we combined in this review. VAC Chandola 2017‐IND randomized participants to three vaccine production lots as well as to placebo. We combined the different production lot arms in our analyses.

Infant vaccination status

Two trials separated the use of other routine childhood vaccines from Rotavac administration by at least two weeks (VAC Bhandari 2006‐IND; VAC Bhandari 2009‐IND). Two trials co‐administered other routine childhood vaccines (OPV, DPT, Hep B and Hib) with Rotavac (VAC Bhandari 2014‐IND; VAC Chandola 2017‐IND).

Methods for collecting adverse event data

As shown in Appendix 7, three trials used a combination of passive methods (e.g. diary cards for parents) and active methods (directly contacting parents) to collect adverse event data. The other trial (VAC Chandola 2017‐IND) used active methods only (directly contacting parents).

Source of funding

One trial was funded by Bharat Biotech (VAC Bhandari 2006‐IND), one trial was co‐funded by Bharat Biotech (VAC Bhandari 2009‐IND) and the other two trials were funded by PATH, the Government of India, and other not‐for‐profit organizations (VAC Bhandari 2014‐IND; VAC Chandola 2017‐IND).

Ongoing studies

We identified 15 ongoing trials, three of RV1, one of RV5 and 11 others (RV1 together with RV5; RV3‐BB; Rotasiil; Rotavac; BRV‐TV; Trivalent P2VP8; Bio Farma's rotavirus vaccine) (see Characteristics of ongoing studies). As shown in Appendix 8, the RV1 trials are being conducted in South Africa and Bangladesh. The ongoing RV5 trial is in Bangladesh, and the studies testing other vaccines are located in Australia, Bangladesh, China, India, Indonesia, Malawi, Mexico, South Africa, and the USA.

Excluded studies

There are 78 excluded studies with 100 references (Figure 2). We excluded most studies because they were not RCTs (34 studies). We excluded 27 studies because they reported on comparisons not relevant to this review, three studies because they did not report on RV vaccines, three because they included adult populations, 10 because they reported on unlicensed vaccines in development (OTHER Bines 2015; OTHER Bines 2018; OTHER Cowley 2017; OTHER Groome 2017) or licensed vaccines that have not been prequalified by the WHO (OTHER CTRI/2009/091/000821; OTHER Dang 2012; OTHER Isanaka 2017‐NER; OTHER Kulkarni 2017; OTHER Zade 2014a‐IND; OTHER Zade 2014b‐IND), and one because it reported on a withdrawn vaccine (OTHER Armah 2013).

Risk of bias in included studies

We prepared a ‘Risk of bias' assessment for each trial, with a focus on the rotavirus diarrhoea outcome measure. Of the 55 RCTs analyzed in this review, 48 (87%) reported an adequate generation of allocation sequence, while the method of assignment was unclear in the remaining studies. We considered the methods used to conceal allocation to be adequate in 46 trials (84%), and unclear in the remaining studies. Information about blinding of participants, care providers, or outcome assessors was provided and we considered it to be adequate in 42 studies (76%), unclear for nine studies, and at high risk of bias for four studies (RV1 Colgate 2016‐BGD; RV1 Kerdpanich 2010‐THA; RV1 Zaman 2017‐BGD; RV5 Dhingra 2014‐IND). Incomplete outcome data were adequately addressed in 46 studies (84%), unclear in eight studies, and was not addressed adequately in one study. Thirty‐eight (69%) trials were free from selective reporting bias, nine were not, and the remaining eight trials were unclear. No other bias was apparent for 31 trials (56%). An overall pictorial summary of the ‘Risk of bias' assessment is shown in Figure 3 and Figure 4.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

RV1

Since the previous update of this review, detailed clinical study reports of most of the GlaxoSmithKline‐sponsored studies (another five, totaling 27 of the 36 trials) have been published online (gsk‐clinicalstudyregister.com). Full details of blinding, participant selection, and attrition are available from these reports, and we could subsequently update risks of bias for these studies, where previously there was no information available. We rated five trials as at high risk of bias for at least one domain; three trials for blinding (RV1 Colgate 2016‐BGD; RV1 Kerdpanich 2010‐THA; RV1 Zaman 2017‐BGD), and three trials for selective reporting bias (RV1 Ruiz‐Palac 06‐LA/EU; RV1 Salinas 2005‐LA; RV1 Zaman 2017‐BGD).

RV5

Based on unpublished information provided by Merck, many of the trials' risks of bias were upgraded for the previous 2012 version of this review. Details of the new information are indicated in the ‘Risk of bias' tables in the Characteristics of included studies section. We judged 10 of the 15 RV5 trials as having a low risk of bias for sequence generation, allocation concealment, and blinding, and varying risks of bias for attrition, selective reporting and other bias. We rated two of these trials (RV5 Armah 2010‐AF; RV5 Zaman 2010‐AS) at an overall low risk of bias. Seven of the 15 RV5 trials had a high risk of bias for one or more domains, most commonly a high risk of selective reporting.

Rotavac

Peer‐reviewed articles for most Rotavac studies reported clearly on how the trials were conducted. Full details about blinding, participant selection, attrition, and outcome reporting could be obtained from most of these reports. We rated only one of the trials at unclear risk of performance and detection bias, since no details about blinding were provided and unclear risk of attrition bias since not all outcomes were assessed with the full study population and the reason for this was not clear (VAC Bhandari 2009‐IND).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5

Summary of findings for the main comparison. RV1 compared to placebo for preventing rotavirus diarrhoea in low‐mortality countries.

Patient or population: children  Setting: low‐mortality countries (WHO strata A and B)  Intervention: RV1  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	RV1
Severe cases of rotavirus diarrhoea  Follow‐up: up to 1 year	13 per 1000	2 per 1000  (1 to 3)	RR 0.16   (0.09 to 0.26)	43,779  (7 studies)	⊕⊕⊕⊕  high^a	RV1 reduces severe rotavirus diarrhoea compared to placebo at up to one year follow‐up. One study (RV1 Vesikari 2007a‐EU) reported higher efficacy compared to the pooled data. When we excluded this study from the analysis, there was no heterogeneity observed in the pooled data
Severe cases of rotavirus diarrhoea  Follow‐up: up to 2 years	24 per 1000	4 per 1000  (3 to 5)	RR 0.18   (0.14 to 0.23)	36,002  (9 studies)	⊕⊕⊕⊕  high	RV1 reduces severe rotavirus diarrhoea compared to placebo at up to two years follow‐up.
Severe cases of all‐cause diarrhoea  Follow‐up: up to 1 year	41 per 1000	24 per 1000   (19 to 30)	RR 0.59   (0.47 to 0.74)	28,051  (3 studies)	⊕⊕⊕⊝  moderate^b due to reporting bias	RV1 probably reduces severe all‐cause diarrhoea compared to placebo at up to one year follow‐up.
Severe episodes of all‐cause diarrhoea  Follow‐up: up to 2 years	39 per 1000	24 per 1000   (22 to 28)	Rate Ratio 0.63   (0.56 to 0.71)	39,091  (2 studies)	⊕⊕⊕⊝  moderate^c due to reporting bias	RV1 probably reduces severe all‐cause diarrhoea compared to placebo at up to two years follow‐up. Three additional studies reported on cases of children with severe all‐cause diarrhoea (RR 0.60, 95% CI 0.36 to 1.02; 9417 participants); these data could not be pooled with the studies reporting on number of episodes
All‐cause death  Follow‐up: 2 months to 2 years	1 per 1000	2 per 1000  (1 to 2)	RR 1.22   (0.87 to 1.71)	97,597  (22 studies)	⊕⊕⊝⊝  low^d due to imprecision	RV1 may make little or no difference to all‐cause death compared to placebo.
All serious adverse events  Follow‐up: 2 months to 2 years	45 per 1000	40 per 1000  (37 to 42)	RR 0.88   (0.83 to 0.93)	96,233  (24 studies)	⊕⊕⊕⊕  high	RV1 slightly reduces serious adverse events compared to placebo.
Serious adverse events: intussusception  Follow‐up: 2 months to 2 years	1 per 1000	1 per 1000  (0 to 1)	RR 0.69   (0.45 to 1.04)	96,513  (17 studies)	⊕⊕⊝⊝  low^e due to imprecision	RV1 may make little or no difference to intussusception compared to placebo.
The basis for the assumed risk* is the control group risk across studies included in the meta‐analysis. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High‐certainty: further research is very unlikely to change our confidence in the estimate of effect.  Moderate‐certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low‐certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low‐certainty: we are very uncertain about the estimate.

Patient or population: children Settings: one high‐mortality country (India) (WHO stratum D) Intervention: Rotavac Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Rotavac
Severe cases of rotavirus diarrhoea follow‐up: up to 1 year	31 per 1000	13 per 1000  (9 to 19)	RR 0.43  (0.30 to 0.60)	6799  (1 study)	⊕⊕⊕⊝  moderate^a due to indirectness	Rotavac probably reduces severe rotavirus diarrhoea compared to placebo at up to one year follow‐up.
Severe cases of rotavirus diarrhoea follow‐up: up to 2 years	47 per 1000	21 per 1000  (16 to 28)	RR 0.46  (0.35 to 0.60)	6541  (1 study)	⊕⊕⊕⊝  moderate^a due to indirectness	Rotavac probably reduces severe rotavirus diarrhoea compared to placebo at up to two years follow‐up.
Severe cases of all‐cause diarrhoea follow‐up: up to 2 years	93 per 1000	78 per 1000  (66 to 91)	RR 0.84  (0.71 to 0.98)	6799  (1 study)	⊕⊕⊕⊝  moderate^a due to indirectness	Rotavac probably slightly reduces severe all‐cause diarrhoea compared to placebo at up to one year follow‐up.
All‐cause death follow‐up: up to 2 years	7 per 1000	6 per 1000  (4 to 11)	RR 0.92  (0.52 to 1.62)	8155  (2 studies)	⊕⊝⊝⊝  very low^b,c due to indirectness and imprecision	We are uncertain whether Rotavac reduced all‐cause death as the certainty of the evidence is very low.
All serious adverse events follow‐up: up to 2 years	204 per 1000	189 per 1000  (173 to 208)	RR 0.93  (0.85 to 1.02)	8210  (3 studies)	⊕⊕⊕⊝  moderate^b due to indirectness	Rotavac probably makes little or no difference to serious adverse events compared to placebo.
Serious adverse events: intussusception follow‐up: up to 2 years	1 per 1000	1 per 1000  (0 to 5)	RR 1.33  (0.35 to 5.02)	8582  (4 studies)	⊕⊝⊝⊝  very low^b,d due to indirectness and imprecision	No events were reported in three of the four studies. We are uncertain whether Rotavac has an effect on intussusception as the certainty of the evidence is very low.
The basis for the assumed risk* is the control group risk across studies included in the meta‐analysis. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Date	Event	Description
21 October 2019	New citation required but conclusions have not changed	The review author team made two amendments to the review text, in response to the comments submitted by V Singh and B Benninghoff.
21 October 2019	Amended	In response to comments submitted on the Cochrane Library by V Singh and B Benninghoff, the review author team made two amendments to the Methods and Implications for practice sections.

Date	Event	Description
19 March 2019	New citation required but conclusions have not changed	This is the fourth update of the original rotavirus vaccines review (Soares‐Weiser 2004). This review concerns vaccines that have been prequalified for global use by the WHO (WHO 2018). In the previous versions of this review we included any rotavirus vaccine in use.
19 March 2019	New search has been performed	We amended the protocol to include only vaccines prequalified for use by the World Health Organization (WHO). We included 14 new studies from the April 2018 search, including four studies on a new vaccine (Rotavac). Nicholas Henschke joined the author team.
10 May 2012	New search has been performed	No new trials were identified from the updated May 2012 search.
10 May 2012	New citation required but conclusions have not changed	Review updated to incorporate different country mortality strata and outcomes changed to reflect the different rotavirus vaccines’ efficacy and safety in countries with different mortality rates.
8 January 2012	New search has been performed	Review updated to include nine trials identified in a new literature search, which was conducted in October 2011 (MEDLINE via PubMed) and June 2011 (other databases).
11 November 2011	New citation required but conclusions have not changed	Hanna Bergman and Sukkrti Nagpal joined the author team.
10 May 2010	Amended	Minor typographical errors corrected.
2 February 2010	New citation required and conclusions have changed	A new search on 2 February 2010 identified 9 new potentially relevant studies. We independently assessed these studies and incorporated data from the eligible trials into the review.
21 July 2009	New search has been performed	The original rotavirus vaccines review (Soares‐Weiser 2004) was split into two reviews: rotavirus vaccines in use (this review); and other rotavirus vaccines, including those no longer in use or in development (Soares‐Weiser 2004). This involved a new search, revised inclusion criteria, updated review methods. All data from those trials also included in the original review were re‐extracted. New authors joined the review team for this review.

Search set	CIDG SR^a	CENTRAL	MEDLINE^b	Embase^b	LILACS^b	BIOSIS
1	rotavirus	rotavirus	rotavirus	rotavirus	rotavirus	rotavirus
2	diarrhoea	diarrhoea	ROTAVIRUS INFECTIONS	ROTAVIRUS	diarrhoea	diarrhoea
3	diarrhoea	diarrhoea	1 or 2	1 or 2	diarrhea	diarrhoea
4	gastroenteritis	gastroenteritis	diarrhoea	diarrhoea	gastroenteritis	gastroenteritis
5	2 or 3 or 4	2 or 3 or 4	gastroenteritis	gastroenteritis	2 or 3 or 4	2 or 3 or 4
6	1 and 5	1 and 5	4 or 5	4 or 5	1 and 5	1 and 5

Trial	Type: efficacy or safety	Follow‐up time
RV1 Anh 2011‐PHL	Safety	1 month after last dose
RV1 Anh 2011‐VNM	Safety	1 month after last dose
RV1 Bernstein 1998‐USA	Safety	1 month
RV1 Bernstein 1999‐USA	Efficacy/Safety	2 years
RV1 Colgate 2016‐BGD	Efficacy	1 year
RV1 Dennehy 2005‐NA	Safety	10 to 12 months
RV1 GSK[021] 2007‐PAN	Safety	1 month after dose 3
RV1 GSK[033] 2007‐LA	Safety	1 month
RV1 GSK[041] 2007‐KOR	Safety	2 months
RV1 GSK[101555] 2008‐PHL	Safety	1 month
RV1 Kawamura 2011‐JPN	Efficacy/Safety	Up to the age of 2 years
RV1 Kerdpanich 2010‐THA	Safety	2 months after last dose
RV1 Kim 2012‐KOR	Safety	1 month after last dose
RV1 Li 2013a‐CHN	Safety	1 month
RV1 Li 2013b‐CHN	Safety	1 month
RV1 Li 2014‐CHN	Efficacy/Safety	2 years
RV1 Madhi 2010‐AF	Efficacy/Safety	2 years
RV1 Narang 2009‐IND	Safety	1 month
RV1 NCT00158756‐RUS	Safety	1 year
RV1 Omenaca 2012‐EU	Safety	At least 1 month after dose 2
RV1 Phua 2005‐SGP	Efficacy/Safety	Until infant aged 18 months (ie 13 to 15 months)
RV1 Phua 2009‐AS	Efficacy/Safety	3 years
RV1 Rivera 2011‐DOM	Safety	17 weeks after each dose
RV1 Ruiz‐Palac 06‐LA/EU	Efficacy/Safety	9 to 10 months
RV1 Salinas 2005‐LA	Efficacy/Safety	Up to 2 years
RV1 Steele 2008‐ZAF	Safety	Up to 6 months
RV1 Steele 2010a‐ZAF	Safety	31 days after each dose, 42 days after the last dose
RV1 Steele 2010b‐ZAF	Safety	Up to 6 months
RV1 Tregnaghi 2011‐LA	Efficacy/Safety	Up to age 1 year
RV1 Vesikari 2004a‐FIN	Safety	8 to 30 days after each dose
RV1 Vesikari 2004b‐FIN	Efficacy/Safety	1 and 2 years (both reported)
RV1 Vesikari 2007a‐EU	Efficacy/Safety	1 and 2 years (plus 3 years in Finland)
RV1 Vesikari 2011‐FIN	Safety	2 months
RV1 Ward 2006‐USA	Safety	7 days after each vaccination; 3 to 5 weeks after dose 2
RV1 Zaman 2009‐BGD	Safety	31 days
RV1 Zaman 2017‐BGD	Effectiveness	2 years
RV5 Armah 2010‐AF	Efficacy/Safety	Up to 43 days for safety outcomes, up to 21 months for efficacy outcomes
RV5 Block 2007‐EU/USA	Efficacy/Safety	42 days for safety/immunogenicity; 1 year for efficacy
RV5 Ciarlet 2009‐EU	Safety	42 days
RV5 Clark 2003‐USA	Efficacy/Safety	1 year
RV5 Clark 2004‐USA	Efficacy/Safety	1 year
RV5 Dhingra 2014‐IND	Safety	1 month
RV5 Iwata 2013‐JPN	Efficacy/Safety	25 months
RV5 Kim 2008‐KOR	Safety	42 days
RV5 Lawrence 2012‐CHN	Safety	2 weeks after last dose
RV5 Levin 2017‐AF	Safety	1 month
RV5 Merck[009] 2005‐USA	Safety	42 days
RV5 Mo 2017‐CHN	Efficacy/Safety	2 years
RV5 Vesikari 2006a‐FIN	Efficacy/Safety	1 to 3 years
RV5 Vesikari 2006b‐INT	Efficacy/Safety	43 days for safety; 2 years for efficacy
RV5 Zaman 2010‐AS	Efficacy/Safety	Up to 43 days for safety outcomes, up to 2 years for efficacy outcomes
VAC Bhandari 2006‐IND	Safety	1 month
VAC Bhandari 2009‐IND	Safety	12 weeks
VAC Bhandari 2014‐IND	Efficacy/Safety	up to 2 years of age
VAC Chandola 2017‐IND	Safety	1 year

Trial	Rotavirus diarrhoea (any severity)			All‐cause diarrhoea		ED visit	Hospitalization (all‐cause)	All‐cause death	Dropouts
Trial	All	Severe	Hospital	All	Severe	ED visit	Hospitalization (all‐cause)	All‐cause death	Dropouts
RV1 Anh 2011‐PHL	X	‐	‐	X	‐	‐	‐	X	X
RV1 Anh 2011‐VNM	X	‐	‐	X	‐	‐	‐	X	X
RV1 Bernstein 1998‐USA	‐	‐	‐	‐	‐	‐	‐	‐	‐
RV1 Bernstein 1999‐USA	X	X	X	X^a	‐	X^a	‐	X	‐
RV1 Colgate 2016‐BGD	X	X	‐	X	X	‐	‐	X	X
RV1 Dennehy 2005‐NA	‐	‐	‐	‐	‐	‐	‐	‐	‐
RV1 GSK[021] 2007‐PAN	‐	‐	‐	‐	‐	‐	‐	X	X
RV1 GSK[033] 2007‐LA	‐	‐	‐	‐	‐	‐	‐	X	X
RV1 GSK[041] 2007‐KOR	X	‐	‐	‐	‐	‐	‐	X	X
RV1 GSK[101555] 2008‐PHL	X	‐	‐	‐	‐	‐	‐	X	X
RV1 Kawamura 2011‐JPN	‐	X	X	‐	‐	‐	‐	X	X
RV1 Kerdpanich 2010‐THA	X	‐	‐	X	‐	‐	‐	X	X
RV1 Kim 2012‐KOR	X	‐	‐	X	‐	‐	‐	X	X
RV1 Li 2013a‐CHN	‐	‐	‐	‐	‐	‐	‐	X	X
RV1 Li 2013b‐CHN	‐	‐	‐	‐	‐	‐	‐	‐	‐
RV1 Li 2014‐CHN	X	X	X	X	X	‐	‐	X	X
RV1 Madhi 2010‐AF	X	X	X	‐	X	‐	‐	X	X
RV1 Narang 2009‐IND	X	‐	‐	‐	‐	‐	‐	X	X
RV1 NCT00158756‐RUS	‐	‐	‐	‐	‐	‐	‐	X	X
RV1 Omenaca 2012‐EU	X	‐	‐	X	‐	‐	‐	‐	X
RV1 Phua 2009‐AS	X^a	X	X	X^a	X		X^a	X
RV1 Phua 2005‐SGP	X	X	X	X	X	X	X	X	X
RV1 Rivera 2011‐DOM	X	‐	‐	X	‐	‐	‐	‐	X
RV1 Ruiz‐Palac 06‐LA/EU	X^a	X	X	X^a	X	‐	X^a	X	X^a
RV1 Salinas 2005‐LA	X	X	X	X	X^a	‐	X^a	X
RV1 Steele 2008‐ZAF	‐	‐	‐	‐	‐	‐	‐	X	X
RV1 Steele 2010a‐ZAF	X	‐	‐	X	‐	‐	‐	X	X
RV1 Steele 2010b‐ZAF	X	X	‐	‐	‐	‐	‐	X	X
RV1 Tregnaghi 2011‐LA	‐	X	‐	‐	X^a	‐	‐	X	X
RV1 Vesikari 2004a‐FIN	‐	‐	‐	‐	‐	‐	‐	X^a	X
RV1 Vesikari 2004b‐FIN	X	X	X	X	‐	‐	‐	X	X
RV1 Vesikari 2007a‐EU	X	X	X	X^a	X	X^a	X^a	‐	‐
RV1 Vesikari 2011‐FIN	X	‐	‐	X	‐	‐	‐	X	X
RV1 Ward 2006‐USA	‐	‐	‐	‐	‐	‐	‐	‐	‐
RV1 Zaman 2009‐BGD	X	‐	‐	‐	‐	‐	‐	X
RV1 Zaman 2017‐BGD	‐	X	‐	‐	‐	‐	‐	‐	‐
RV5 Armah 2010‐AF	X	X	‐	X	X	‐	‐	X	X
RV5 Block 2007‐EU/USA	X	X	‐	‐	‐	‐	‐	X	X
RV5 Ciarlet 2009‐EU	‐	‐	‐	‐	‐	‐	‐	X	‐
RV5 Clark 2003‐USA	X	X^a	‐	‐	‐	‐	‐	‐	X
RV5 Clark 2004‐USA	X	X	‐	‐	‐	‐	‐	‐	X
RV5 Dhingra 2014‐IND	‐	‐	‐	‐	‐	‐	‐	‐	X
RV5 Iwata 2013‐JPN	X	X	‐	‐	‐	‐	‐	X	X
RV5 Kim 2008‐KOR	‐	‐	‐	‐	‐	‐	‐	‐	‐
RV5 Lawrence 2012‐CHN	‐	‐	‐	‐	‐	‐	‐	X	X
RV5 Levin 2017‐AF	‐	‐	‐	‐	‐	‐	‐	X	X
RV5 Merck[009] 2005‐USA	‐	‐	‐	‐	‐	‐	‐	X	X
RV5 Mo 2017‐CHN	‐	‐	‐	‐	‐	‐	‐	X	X
RV5 Vesikari 2006a‐FIN	X	X	‐	‐	‐	‐	‐	X	X
RV5 Vesikari 2006b‐INT	X	X	X	‐	‐	X^a	X^a	X	X
RV5 Zaman 2010‐AS	X	X	‐	‐	X	‐	‐	X	X
VAC Bhandari 2006‐IND	‐	‐	‐	‐	‐	‐	‐	‐	X
VAC Bhandari 2009‐IND	‐	‐	‐	‐	‐	‐	‐	‐	‐
VAC Bhandari 2014‐IND	X	X	X	‐	X	‐	‐	X	X
VAC Chandola 2017‐IND	‐	‐	‐	‐	‐	‐	‐	X	X

Trial	Safety			Immunogenicity
Trial	Serious AE	Reactogenicity	AE to discontinuation	Vaccine virus shedding	Seroconversion
RV1 Anh 2011‐PHL	X	X	X	‐	X
RV1 Anh 2011‐VNM	X	X	X	‐	X
RV1 Bernstein 1998‐USA	X	X	X	X	X
RV1 Bernstein 1999‐USA	‐	X	‐	X	X
RV1 Colgate 2016‐BGD	‐	‐	‐	‐	‐
RV1 Dennehy 2005‐NA	X	X	X	X	X
RV1 GSK[021] 2007‐PAN	X	X	X	X	X
RV1 GSK[033] 2007‐LA	X	X	X	X	X
RV1 GSK[041] 2007‐KOR	X	X	X	‐	X
RV1 GSK[101555] 2008‐PHL	X	X	X	X	X
RV1 Kawamura 2011‐JPN	X	X	X	‐	X
RV1 Kerdpanich 2010‐THA	X	X	X	X	X
RV1 Kim 2012‐KOR	X	X	X	‐	X
RV1 Li 2013a‐CHN	X	X	X	X	X
RV1 Li 2013b‐CHN	‐	‐	‐	‐	‐
RV1 Li 2014‐CHN	X	X	X	‐	X
RV1 Madhi 2010‐AF	X	‐	‐	‐	‐
RV1 Narang 2009‐IND	X	X	X	‐	X
RV1 NCT00158756‐RUS	X	‐	X	‐	X
RV1 Omenaca 2012‐EU	X	X	‐	‐	X
RV1 Phua 2005‐SGP	X	X	X^a	X^a	X
RV1 Phua 2009‐AS	X	‐	X	‐	‐
RV1 Rivera 2011‐DOM	X	X	‐	‐	X
RV1 Ruiz‐Palac 06‐LA/EU	X	X	X	‐	X^a
RV1 Salinas 2005‐LA	X	X	‐	X	X
RV1 Steele 2008‐ZAF	X	X	X	X	X
RV1 Steele 2010a‐ZAF	X	X^a	‐	X	X
RV1 Steele 2010b‐ZAF	X	X	X	X	X
RV1 Tregnaghi 2011‐LA	X	‐	X	‐	X
RV1 Vesikari 2004a‐FIN	X	X	X	X	X
RV1 Vesikari 2004b‐FIN	X	X	X	‐	X
RV1 Vesikari 2007a‐EU	X	X	‐	‐	X
RV1 Vesikari 2011‐FIN	X	X	X	X	X
RV1 Ward 2006‐USA		X^a	‐	X	X^a
RV1 Zaman 2009‐BGD	X	X	‐	X	X
RV1 Zaman 2017‐BGD	X	‐	‐	‐	‐
RV5 Armah 2010‐AF	X	X^a	X	‐	X
RV5 Block 2007‐EU/USA	X	X	X	‐	X
RV5 Ciarlet 2009‐EU	X	X	‐	‐	X
RV5 Clark 2003‐USA	X	X	X	X	X
RV5 Clark 2004‐USA	X^a	X	X	X	X
RV5 Dhingra 2014‐IND	X	X	X	X	X
RV5 Iwata 2013‐JPN	X^a	X	X	‐	‐
RV5 Kim 2008‐KOR	X	X^a	‐	‐	X^a
RV5 Lawrence 2012‐CHN	X	X^a	X	X	‐
RV5 Levin 2017‐AF	X	X	X	X	X
RV5 Merck[009] 2005‐USA	X	X	X	‐	‐
RV5 Mo 2017‐CHN	X	X	X	‐	‐
RV5 Vesikari 2006a‐FIN	X	X	X	‐	X
RV5 Vesikari 2006b‐INT	X	X	X^a	‐	X
RV5 Zaman 2010‐AS	X	X^a	X	‐	X^a
VAC Bhandari 2006‐IND	X	X	‐	X	‐
VAC Bhandari 2009‐IND	X	X	‐	X	X
VAC Bhandari 2014‐IND	X	‐	‐	‐	X
VAC Chandola 2017‐IND	X	‐	‐	‐	X

Trial	Year	Location	Sites	Country mortality rate	WHO mortality strata	Region
RV1 Anh 2011‐PHL	2007	Philippines	1	Low‐mortality	B	Asia
RV1 Anh 2011‐VNM	2007	Vietnam	11	Low‐mortality	B	Asia
RV1 Bernstein 1998‐USA	1998	USA	1	Low‐mortality	A	North America
RV1 Bernstein 1999‐USA	1999	USA	2	Low‐mortality	A	North America
RV1 Colgate 2016‐BGD	2014	Bangladesh	1	High‐mortality	D	Asia
RV1 Dennehy 2005‐NA	2005	USA and Canada	41	Low‐mortality	A	North America
RV1 GSK[021] 2007‐PAN	2007	Panama	1	Low‐mortality	B	Latin America
RV1 GSK[033] 2007‐LA	2007	Colombia, Mexico, and Peru	(2 in Colombia, 1 in Mexico, and 4 in Peru)	High‐mortality^a	B, D	Latin America
RV1 GSK[041] 2007‐KOR	2007	South Korea	6	Low‐mortality	B	Asia
RV1 GSK[101555] 2008‐PHL	2008	Philippines	1	Low‐mortality	B	Asia
RV1 Kawamura 2011‐JPN	2009	Japan	18	Low‐mortality	A	Asia
RV1 Kerdpanich 2010‐THA	2005	Thailand	2	Low‐mortality	B	Asia
RV1 Kim 2012‐KOR	2010	Republic of Korea	19	Low‐mortality	B	Asia
RV1 Li 2013a‐CHN	2010	China	1	Low‐mortality	B	Asia
RV1 Li 2013b‐CHN	2010	China	1	Low‐mortality	B	Asia
RV1 Li 2014‐CHN	2012	China	4	Low‐mortality	B	Asia
RV1 Madhi 2010‐AF	2010	South Africa and Malawi	2	High‐mortality	E	Africa
RV1 Narang 2009‐IND	2009	India	4	High‐mortality	D	Asia
RV1 NCT00158756‐RUS	2006	Russian Federation	9	Low‐mortality	C	Europe
RV1 Omenaca 2012‐EU	2008	France, Poland, Portugal, and Spain	Multiple sites in each country	Low‐mortality	A, B	Europe
RV1 Phua 2005‐SGP	2005	Singapore	8	Low‐mortality	A	Asia
RV1 Phua 2009‐AS	2009	Hong Kong, Singapore, and Taiwan	3	Low‐mortality	A	Asia
RV1 Rivera 2011‐DOM	2008	Dominican Republic	1	Low‐mortality	B	Latin America
RV1 Ruiz‐Palac 06‐LA/EU	2006	Argentina, Brazil, Chile, Colombia, Dominican Republic, Finland, Honduras, Mexico, Nicaragua, Panama, Peru, and Venezuela	Multiple	Low‐mortality^b	A, B, D	Latin America/Europe
RV1 Salinas 2005‐LA	2005	Brazil, Mexico, and Venezuela	3	Low‐mortality	B	Latin America
RV1 Steele 2008‐ZAF	2007	South Africa	1	High‐mortality	E	Africa
RV1 Steele 2010a‐ZAF	2008	South Africa	5	High‐mortality	E	Africa
RV1 Steele 2010b‐ZAF	2007	South Africa	7	High‐mortality	E	Africa
RV1 Tregnaghi 2011‐LA	2008	Argentina, Brazil, Colombia, Dominican Republic, Honduras, and Panama	Multiple sites in each country	Low‐mortality	B	Latin America
RV1 Vesikari 2004a‐FIN	2004	Finland	2	Low‐mortality	A	Europe
RV1 Vesikari 2004b‐FIN	2004	Finland	6	Low‐mortality	A	Europe
RV1 Vesikari 2007a‐EU	2007	Czech Republic, Finland, France, Germany, Italy, and Spain	98	Low‐mortality	A	Europe
RV1 Vesikari 2011‐FIN	2005	Finland	5	Low‐mortality	A	Europe
RV1 Ward 2006‐USA	2006	USA	2	Low mortality	A	North America
RV1 Zaman 2009‐BGD	2005	Bangladesh	1	High‐mortality	D	Asia
RV1 Zaman 2017‐BGD	2011	Bangladesh	142	High‐mortality	D	Asia
RV5 Armah 2010‐AF	2009	Ghana, Kenya, and Mali	3	High‐mortality	D, E	Africa
RV5 Block 2007‐EU/USA	2007	Finland and USA	30	Low‐mortality	A	Europe and North America
RV5 Ciarlet 2009‐EU	2008	Austria, Belgium, and Germany	26	Low‐mortality	A	Europe
RV5 Clark 2003‐USA	2003	USA	19	Low‐mortality	A	North America
RV5 Clark 2004‐USA	2004	USA	10	Low‐mortality	A	North America
RV5 Dhingra 2014‐IND	2012	India	2	High‐mortality	D	Asia
RV5 Iwata 2013‐JPN	2009	Japan	32	Low‐mortality	A	Asia
RV5 Kim 2008‐KOR	2008	South Korea	8	Low‐mortality	B	Asia
RV5 Lawrence 2012‐CHN	2010	China	Not reported	Low‐mortality	B	Asia
RV5 Merck[009] 2005‐USA	2005	USA	10	Low‐mortality	A	North America
RV5 Mo 2017‐CHN	2015	China	5	Low‐mortality	B	Asia
RV5 Vesikari 2006a‐FIN	2006	Finland	4	Low‐mortality	A	Europe
RV5 Vesikari 2006b‐INT	2006	Belgium, Costa Rica, Finland, Germany, Guatemala, Italy, Jamaica, Mexico, Puerto Rico, Sweden, Taiwan, and USA	356	Low‐mortality^b	A, B, D	Asia, Caribbean, Europe, Latin America, North America
RV5 Zaman 2010‐AS	2009	Bangladesh and Vietnam	Multiple	High‐mortality^a	B, D	Asia
VAC Bhandari 2006‐IND	2005	India	1	High‐mortality	D	Asia
VAC Bhandari 2009‐IND	2006‐8	India	1	High‐mortality	D	Asia
VAC Bhandari 2014‐IND	2011‐13	India	3	High‐mortality	D	Asia
VAC Chandola 2017‐IND	2014‐15	India	1	High‐mortality	D	Asia

Trial	Number of doses	Time between doses (weeks)	Number of arms: vaccine/placebo	Infant vaccination status	Note
RV1 Anh 2011‐PHL	2	4 or 8	2/1	Commercially available diphtheria, tetanus, whole‐cell pertussis (DTPw), hepatitis B (HBV) and oral poliovirus (OPV) vaccines were administered concomitantly with the study vaccine/placebo as part of the routine Expanded Programme of Immunization (EPI) in the Philippines	Compares different schedules: (1) vaccine dose at month 1 and 2, and placebo at day 0; and (2) vaccine dose at day 0 and month 2, and placebo at month 1
RV1 Anh 2011‐VNM	2	4 or 8	2/1	Commercially available diphtheria, tetanus, whole‐cell pertussis (DTPw), hepatitis B (HBV) and oral poliovirus (OPV) vaccines were administered concomitantly with the study vaccine/placebo as part of the routine Expanded Programme of Immunization (EPI) in Vietnam	Compares different schedules: (1) vaccine dose at day 0 and month 1, and placebo at month 2; and (2) vaccine dose at day 0 and month 2, and placebo at month 1
RV1 Bernstein 1998‐USA	2	6 to 10	1/1	Rotavirus vaccine was separated from all other infant vaccines by at least 2 weeks	—
RV1 Bernstein 1999‐USA	2	6 to 10	1/1	Other vaccines separated from the trial vaccines by at least 2 weeks	—
RV1 Colgate 2016‐BGD	2	7	1/1 (no RV1)	Alongside Rotarix at 10 and 17 weeks of age the polio vaccine intervention was the administration of an injected, inactivated polio vaccine (IPV) dose replacing the 4th dose of tOPV at 39 weeks of age. Study children also received all standard EPI vaccines (BCG at birth; pentavalent vaccine (DPT, HepB, Hib) at 6, 10, and 14 weeks; bivalent Measles‐Rubella at 40 weeks; and monovalent Measles at 65 weeks)	RV1 plus polio vacccine (IPV), observational control group only
RV1 Dennehy 2005‐NA	2	7	2/1	Vaccine or placebo given concomitantly with diphtheria‐tetanus‐acellular pertussis, inactivated poliovirus, H influenzae type b, and S pneumoniae conjugate vaccines for participants in USA or with a diphtheria‐tetanus‐acellular pertussis/inactivated poliovirus/H influenza type b combination vaccine for participants in Canada "Routine hepatitis B vaccinations were administered according to local practice."	2 different PFUs compared
RV1 GSK[021] 2007‐PAN	3	8	2/2	Use of other vaccines not mentioned	Licensed formulation versus modified formulation
RV1 GSK[033] 2007‐LA	2	8	3/1	Use of other vaccines not mentioned	3 ‘Lots’ of RV1 vaccine compared
RV1 GSK[041] 2007‐KOR	2	8	1/1	H influenzae type b vaccine administered concomitantly along with the 2 doses of vaccine/placebo and at 2 months after dose 2; other routine childhood vaccines were to be given at least 14 days before trial vaccine/placebo	—
RV1 GSK[101555] 2008‐PHL	2	8	2/2	No mention of whether infants received other vaccines	Data from the lyophilized formulation, which is not yet approved or marketed, are not reported
RV1 Kawamura 2011‐JPN	2	4	1/1	Combined diphtheria and tetanus toxoids and acellular pertussis (DTPa) and Hepatitis B (HBV) vaccines were allowed to be co‐administered along with RV1 vaccine/placebo	—
RV1 Kerdpanich 2010‐THA	2	8	3/2	Diphtheria toxoid, tetanus toxoid, acellular pertussis, inactivated polio and H influenzae type b combination vaccine (Infanrix™‐IPV/Hib) at 2 and 4 months of age and diphtheria toxoid, tetanus toxoid, acellular pertussis, hepatitis B, inactivated polio andH influenzae type b combination vaccine (Infanrix hexa^TM) at 6 months of age	Compares: regular vaccine reconstituted in buffer; vaccine reconstituted in water; vaccine stored above recommended temperature; placebo reconstituted in water; placebo reconstituted in buffer
RV1 Kim 2012‐KOR	2	4	1/1	Routine childhood vaccines as recommended by the local vaccination schedule were allowed to be administered concomitantly with RIX4414/placebo. These vaccines included the combined diphtheria‐tetanus‐acellular pertussis vaccine, Hemophilus influenzae type b vaccine, inactivated poliovirus vaccine and pneumococcal vaccine. The infants had received the BCG vaccine and 2 doses of hepatitis B vaccine prior to study enrolment	—
RV1 Li 2013a‐CHN	1	‐	1/1	Children were allowed to receive routine childhood vaccinations according to local immunization practice during the study period, with a minimum interval of at least 7 days between the administration of routine vaccines and the study vaccine or placebo	Child arm (2 ‐ 6 years of age) of the same study as RV1 Li 2013b‐CHN
RV1 Li 2013b‐CHN	1	‐	1/1	Infants were allowed to receive routine childhood vaccinations according to local immunization practice during the study period, with a minimum interval of at least 7 days between the administration of routine vaccines and the study vaccine or placebo	Infant arm (6‐16 weeks of age) of the same study as RV1 Li 2013a‐CHN
RV1 Li 2014‐CHN	2	4	2/2	As part of the routine childhood vaccination according to the EPI recommendations in China, participants also received 3 doses of Infanrix™ vaccine and 3 doses of the oral poliovirus vaccine. The Infanrix™ and the OPV vaccines were administered independently of (Sub‐cohort 1) or concomitantly with (Sub‐cohort 2) the Rotarix™ vaccine. When administered concomitantly, participants received the 3 doses of Infanrix™ vaccine at months 1, 2 and 3, and the 3 doses of the OPV vaccine at Day 0, Month 1 and Month 2	—
RV1 Madhi 2010‐AF	2 or 3	5 to 10	2/1	All participants received routine infant vaccinations according to EPI recommendations	—
RV1 Narang 2009‐IND	2	8	1/1	Routine vaccinations (diphtheria‐tetanus‐whole cell pertussis‐hepatitis b, H influenzae type b, and oral poliovirus vaccine) were administered at 6, 10, and 14 weeks of age (given with a 2‐week separation from the first and subsequent dose of the RV1 vaccine or placebo)	—
RV1 NCT00158756‐RUS	3	6	5	GlaxoSmithKline (GSK) Biologicals' Tritanrix™HepB and GSK Biologicals Kft's DTPwHBV vaccines as compared to concomitant administration of Commonwealth Serum Laboratory's (CSL's) DTPw (Triple Antigen™) and GSK Biologicals' HBV (Engerix™B), when coadministered With GSK Biologicals' Oral Live Attenuated Human Rotavirus (HRV) vaccine, to healthy infants at 3, 4½ and 6 months of age, after a birth dose of Hepatitis B vaccine	Hep B and DTPw‐HBV vaccines in combination with other vaccines/placebo were compared in the study arms
RV1 Omenaca 2012‐EU	2	4 or 8	1/1	All participants received routine infant vaccinations in accordance with the local National Plan of Immunization schedule in each of the respective participating countries	—
RV1 Phua 2005‐SGP	2	4	3/1	Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, poliovirus, and H influenzae type b co‐administered with interventions	3 different PFUs compared
RV1 Phua 2009‐AS	2	6 to 10	1/1	Infants received other routine paediatric immunizations (combined diphtheria toxoid‐tetanus toxoid‐acellular pertussis (DTPa) – inactivated poliovirus [IPV] and H influenzae type B (Hib) vaccine and hepatitis B vaccine (HBV)) during the study period according to local schedules. Almost all infants received BCG dose at birth. If oral polio vaccine (OPV) was given as part of the routine schedule in the participating countries, a time interval of 2 weeks was observed between the OPV doses and RIX4414 vaccine/placebo doses	—
RV1 Rivera 2011‐DOM	2	7	1/1	All infants received 3 doses of combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and H influenzae vaccine.	1 complimentary dose of RV1 was administered to all infants enrolled in this study (both study groups) who were aged < 6 months at Visit 3 (Week 13) as a benefit to the placebo group for participation in the study
RV1 Ruiz‐Palac 06‐LA/EU	2	4 or 8	1/1	Routine immunizations according to local regulations; oral poliovirus vaccination at least 2 weeks before or after rotavirus vaccine	—
RV1 Salinas 2005‐LA	2	8	3/1	Oral polio vaccine given after 2 weeks, not together with RV1	3 different PFUs compared Main publication did not report that the trial included 2 subsets: 2 doses of human rotavirus or placebo subset: these participants received 2 oral doses of RV1 vaccine or placebo according to a 0, 2 months schedule, and routine vaccinations (DTPw‐ Hepatitis B vaccine (HBV) + Hib vaccine) at a 0, 2, and 4 months schedule 3 doses of RV1 or placebo subset: these participants received 3 oral doses of RV1 vaccine or placebo, and routine vaccinations (DTPw‐HBV + Hib vaccine) concomitantly with each dose of human rotavirus vaccine and placebo at a 0, 2, and 4 months schedule
RV1 Steele 2008‐ZAF	2	4	3/1	RV1 plus (1) oral polio vaccine (OPV) + diphtheria‐tetanus‐acellular pertussis/H influenzae type b (DTPA/HIB) vaccine; (2) OPV placebo + diphtheria‐tetanus‐acellular pertussis inactivated polio‐H influenzae type b (DTPA‐IPV/HIB) vaccine; or (3) OPV + DTPA/HIB vaccine	Compares different co‐administration combinations (see previous column)
RV1 Steele 2010a‐ZAF	3	4	1/1	RV1 vaccine was concomitantly administered with 3 doses of combined diphtheria, tetanus and whole‐cell pertussis, hepatitis B, and H influenzae type b vaccine (TritanrixHepBHib) and OPV (PolioSabin)	For infants who developed clinical symptoms of HIV (WHO stages III or IV disease) any time after enrolment, access to antiretroviral therapy (cotrimoxazole) according to the South African national guidelines was facilitated. Infants who needed treatment were referred to antiretroviral therapy centres by the investigators
RV1 Steele 2010b‐ZAF	2 or 3	4	2/1	Infants received routine vaccinations according to the local EPI schedule in South Africa. BCG and OPV vaccinations were given at birth; all other routine vaccinations (including diphtheria‐tetanus toxoids‐whole cell pertussis, hepatitis B, H influenzae type b, and OPV) were administered concomitantly with the study vaccine	Compares number of doses (2 or 3)
RV1 Tregnaghi 2011‐LA	2	4 or 8	1/1	All participants received routine infant vaccinations (Hepatitis B vaccine), diphtheria‐tetanus‐acellular pertussis, poliovirus, and H influenzae type b) according to EPI recommendations in each country. First 2 doses of routine EPI vaccinations were co‐administered with the RV1 vaccine or placebo doses; the 3ird routine EPI vaccination was administered 1 to 2 months later according to the national plan of immunization in each country	—
RV1 Vesikari 2004a‐FIN	2	8	3/1	Infant routine vaccinations were separated from the study vaccines by 2 weeks	3 different PFUs compared
RV1 Vesikari 2004b‐FIN	2	8	1/1	Infant routine vaccinations (diphtheria tetanus toxoids‐pertussis, H influenzae type b, and inactivated poliovirus vaccines) were separated from the study vaccines by at least 2 weeks	—
RV1 Vesikari 2007a‐EU	2	4 or 8	1/1	Concomitant vaccines included 7 valent pneumococcal polysaccharide conjugate vaccine (Prevenar) and meningococcal group c conjugate vaccine (Meningitec); Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, polio virus, and H influenzae type b vaccines were co‐administered	—
RV1 Vesikari 2011‐FIN	2	4	2/2	Routine childhood vaccinations were allowed according to local practice, but at least 14 days apart from each dose of study vaccine	Compares liquid and lyophilized vaccine formulations
RV1 Ward 2006‐USA	2	4	2/1	Not specified	2 different PFUs compared
RV1 Zaman 2009‐BGD	2	—	2/2	All children in the study received the standard EPI vaccines starting at 6 weeks of age. Oral polio vaccine (OPV) co‐administered in trial: either concomitantly with RV1 or 15 days before RV1.	Compared RV1 plus oral polio vaccine with RV1 alone
RV1 Zaman 2017‐BGD	2	4	1/1 (no RV1 vaccine)	HRV was scheduled to be given along with other standard infant vaccines including OPV at the DTP1 and DTP2 immunization visits, recommended in Bangladesh to occur at 6 and 10 weeks of age	Cluster randomised trial
RV5 Armah 2010‐AF	3	4	1/1	All children in the study received the standard EPI vaccines (including oral poliovirus vaccine) starting at 6 weeks of age	—
RV5 Block 2007‐EU/USA	3	4 to 10	1/1	Use of oral poliovirus vaccine during the course of the study or within 42 days before first dose of vaccine/placebo was an exclusion criterion; administration of other vaccines permitted	—
RV5 Ciarlet 2009‐EU	3	4 to 6	1/1	Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, polio virus, and H influenzae type b co‐administered	—
RV5 Clark 2003‐USA	3	6 to 8	1/1	Children that had recently received oral polio vaccine were excluded from the study	Breastfed; infants in the vaccine control group (Group 1) received the reassortants as administered in previous studies within 30 mins of feeding Enfamil formula (30 ml) or Mylanta Double Strength (0.5 ml/kg). Infants in a corresponding placebo group (Group 2) were pre‐fed as in Group 1
RV5 Clark 2004‐USA	3	6 to 8	1/1	Receipt of any other vaccines within 14 days was not allowed.	—
RV5 Dhingra 2014‐IND	3	4	4/1	Infants in Cohort 2 concomitantly received a combined DTPw‐HB‐Hib pentavalent vaccine and Trivalent Oral Polio Vaccine	BRV‐TV at 3 different concentrations, compared to RV5 or placebo
RV5 Iwata 2013‐JPN	3	4 to 10	1/1	No information about use of other vaccines	—
RV5 Kim 2008‐KOR	3	4 to 10	1/1	Infants excluded if they had or were to receive oral poliovirus vaccine at any time during the study or in the 42 days before the first dose; concomitant administration of other licensed vaccines and breastfeeding was not restricted	—
RV5 Lawrence 2012‐CHN	3	4‐10	1/1	Other live vaccines 14 days before or after study vaccine were not allowed	—
RV5 Levin 2017‐AF	3	4‐10	1/1	Enrolment was closed in participating countries when RV1 was added to national vaccine schedules.	—
RV5 Merck[009] 2005‐USA	3	4 to 10	1/1	Infants were excluded if they had or were to receive oral poliovirus vaccine at any time during the study or in the 42 days before the first dose; concomitant administration of other licensed vaccines and breastfeeding was not reported	—
RV5 Mo 2017‐CHN	3	4	2/2	The routine China EPI vaccines (oral poliovirus vaccine and diphtheria, tetanus, and acellular pertussis vaccine) either staggered or concomitantly with RV5 or placebo.	—
RV5 Vesikari 2006a‐FIN	3	4 to 8	3/1	Licensed vaccines could be administered throughout the study, but were not given on the same day as study vaccine; inactivated poliovirus vaccine was exclusively used in Finland at the time of the study	Compares different RV5 components: G1‐4, P1A; G1‐4; and P1A
RV5 Vesikari 2006b‐INT	3	4 to 10	1/1	Administration of other licensed childhood vaccines and breastfeeding were not restricted; for a subset of participants in the USA (U.A. concomitant use cohort), Merck also provided the licensed paediatric vaccines that were administered concomitantly (same day) with RV5 or placebo, which included Comvax, Infanrix, Ipol, and Prevnar	—
RV5 Zaman 2010‐AS	3	4	1/1	All children in the study received the standard EPI vaccines (including oral poliovirus vaccine) starting at 6 weeks of age	—
VAC Bhandari 2006‐IND	1	‐	1/1 (/1)	Infants were vaccinated with DPT, Hep B and OPV separately from rotavirus vaccine	Included an additional vaccine arm for a rotavirus vaccine candidate (I321) that was not included for anaysis in this review
VAC Bhandari 2009‐IND	3	4	2/2	Infants received 3 doses of DTP; OPV; and Hep B at 6, 10, and 14 weeks of age; Rotavac was administered at 8, 12, and 16 weeks of age	Randomized participants to high‐ (1 x 10⁵ ffu) and low‐dose (1 x 10⁴ ffu) vaccine arms which were combined in this review
VAC Bhandari 2014‐IND	3	4	1/1	Other childhood vaccines (DTPw, Hib, Hep B, and OPV) given concurrently	—
VAC Chandola 2017‐IND	3	4‐8	3/1	Co‐administered with EPI vaccines: OPV and combined DPT, HepB and Hib	Randomized participants to 3 vaccine production lots as well as to placebo; we combined the different production lot arms in our analyses

Trial	Passive or active
RV1 Anh 2011‐PHL	Not reported
RV1 Anh 2011‐VNM	Not reported
RV1 Bernstein 1998‐USA	Passive
RV1 Bernstein 1999‐USA	Passive and active
RV1 Colgate 2016‐BGD	Passive
RV1 Dennehy 2005‐NA	Passive and active
RV1 GSK[021] 2007‐PAN	Not reported
RV1 GSK[033] 2007‐LA	Not reported
RV1 GSK[041] 2007‐KOR	Not reported
RV1 GSK[101555] 2008‐PHL	Not reported
RV1 Kawamura 2011‐JPN	Not reported
RV1 Kerdpanich 2010‐THA	Passive
RV1 Kim 2012‐KOR	Passive
RV1 Li 2013b‐CHN	Passive
RV1 Li 2014‐CHN	Not reported
RV1 Madhi 2010‐AF	Active
RV1 Narang 2009‐IND	Passive
RV1 NCT00158756‐RUS	Not reported
RV1 Omenaca 2012‐EU	Not reported
RV1 Phua 2005‐SGP	Passive
RV1 Phua 2009‐AS	Passive
RV1 Rivera 2011‐DOM	Passive
RV1 Ruiz‐Palac 06‐LA/EU	Active
RV1 Salinas 2005‐LA	Passive
RV1 Steele 2008‐ZAF	Not reported
RV1 Steele 2010a‐ZAF	Active and passive
RV1 Steele 2010b‐ZAF	Not reported
RV1 Tregnaghi 2011‐LA	Not reported
RV1 Vesikari 2004a‐FIN	Passive
RV1 Vesikari 2004b‐FIN	Passive
RV1 Vesikari 2007a‐EU	Passive and active
RV1 Vesikari 2011‐FIN	Passive
RV1 Ward 2006‐USA	Not reported
RV1 Zaman 2009‐BGD	Passive and active
RV1 Zaman 2017‐BGD	Not reported
RV5 Armah 2010‐AF	Active
RV5 Block 2007‐EU/USA	Passive and active
RV5 Ciarlet 2009‐EU	Passive and active
RV5 Clark 2003‐USA	Passive and active
RV5 Clark 2004‐USA	Passive and active
RV5 Dhingra 2014‐IND	Passive and active
RV5 Iwata 2013‐JPN	Passive
RV5 Kim 2008‐KOR	Passive
RV5 Lawrence 2012‐CHN	Not reported
RV5 Levin 2017‐AF	Active
RV5 Merck[009] 2005‐USA	Not reported
RV5 Mo 2017‐CHN	Passive
RV5 Vesikari 2006a‐FIN	Passive and active
RV5 Vesikari 2006b‐INT	Active
RV5 Zaman 2010‐AS	Active and passive
VAC Bhandari 2006‐IND	Passive and active
VAC Bhandari 2009‐IND	Passive and active
VAC Bhandari 2014‐IND	Passive and active
VAC Chandola 2017‐IND	Active

Trial	Rotavirus vaccine	Location
Trial	Rotavirus vaccine	Region	Country
OTHER ACTRN12610000525088	RV3‐BB	Oceania	Australia
OTHER CTRI/2015/07/006034	Rotasiil (Serum Institute of India Ltd.)	Asia	India
OTHER CTRI/2015/12/006428	RV1; Rotavac (Bharat)	Asia	India
OTHER NCT01061658	BRV‐TV	Asia	India
OTHER NCT02153866	RV vaccine, type not reported	Asia	China
OTHER NCT02193061	RV1; RV5	America	Mexico
OTHER NCT02542462	RV1; RV5	America	USA
OTHER NCT02646891	Trivalent P2VP8	Africa	South Africa
OTHER NCT02847026	RV1; RV5	Asia	Bangladesh
OTHER NCT03462108	Rotavirus vaccine (Bio Farma)	Asia	Indonesia
OTHER NCT03483116	RV3‐BB	Africa	Malawi
RV1 ISRCTN86632774	RV1	Africa	South Africa
RV1 NCT02941107	RV1	Oceania	Australia
RV1 Tatochenko 2008	RV1	Not reported	Not reported
RV5 NCT02728869	RV5	Asia	Bangladesh

Vaccine	Trial	No. of deaths				Cause of death
Vaccine	Trial	Vaccine	Placebo	Unclear	Total	Cause of death
RV1	RV1 Anh 2011‐PHL	1	0	0	1	Salmonella gastroenteritis
	RV1 Anh 2011‐VNM	0	0	0	0	—
	RV1 Bernstein 1998‐USA	0	0	0	0	—
	RV1 Bernstein 1999‐USA	0	0	1 (1)	1	Pneumococcal sepsis
	RV1 Colgate 2016‐BGD	1	1	0	2	Reasons not reported
	RV1 GSK[021] 2007‐PAN	0	0	0	0	—
	RV1 Tregnaghi 2011‐LA	10	2	0	12	Meningitis bacterial (1 vaccine, 1 placebo), pneumonia (3 vaccine), aortic valve stenosis (1 vaccine), bronchiolitis (1 vaccine), dengue fever (1 vaccine), endocarditis bacterial (1 vaccine), intussusception (1 vaccine), multi‐organ failure (1 placebo), respiratory failure (1 vaccine), sepsis (2 vaccine)
	RV1 GSK[033] 2007‐LA	3	0	0	3	Gastroenteritis (1 vaccine), bronchopneumonia (1 vaccine), aspiration (1 vaccine)
	RV1 GSK[041] 2007‐KOR	0	0	0	2	Not reported
	RV1 GSK[101555] 2008‐PHL	0	0	0	0	—
	RV1 Kawamura 2011‐JPN	0	0	0	0	—
	RV1 Kerdpanich 2010‐THA	0	0	0	0	—
	RV1 Kim 2012‐KOR	0	0	0	0	—
	RV1 Li 2013a‐CHN	0	0	0	0	—
	RV1 Li 2013b‐CHN	0	0	0	0	—
	RV1 Li 2014‐CHN	6	7	0	13	Vaccine (6): Asphyxia, Drowning, Central nervous system infection, Bronchopneumonia, Cortical dysplasia, Intracranial Haemorrhage, Asphyxia, Meningitis, Multi‐organ failure, Hemotophagic histiocytosis, Acute lymphocytic leukemia, Multi‐organ failure    Placebo (7): Diarrhea, Multi‐organ failure, Congenital heart disease, Respiratory failure, brain contusion, subarachnoid hemorrhage, skull fracture, cerebral hematoma, and brain herniation
	RV1 Madhi 2010‐AF	83	43	0	126	Reasons not stated
	RV1 Narang 2009‐IND	0	0	0	0	—
	RV1 NCT00158756‐RUS	0	0	0	0	—
	RV1 Phua 2005‐SGP	3	0	0	3	Leukaemia (1 vaccine); accident‐induced subarachnoid haemorrhage (1 vaccine); cardiorespiratory failure after acute viral pneumonitis (1 vaccine)
	RV1 Phua 2009‐AS	1	3	0	4	Aspiration and metabolic disorder, adenoviral pneumonia, interstitial pneumonia, and sudden infant death syndrome (not stated which group)
	RV1 Rivera 2011‐DOM	0	0	0	0	—
	RV1 Ruiz‐Palac 06‐LA/EU	56	43	0	99	Diarrhoea (4 vaccine, 2 placebo); pneumonia (16 vaccine, 6 placebo); other causes not mentioned
	RV1 Salinas 2005‐LA	2	1	0	3	Generalized visceral congestion (1 placebo); sepsis (1 vaccine); automobile accident (1 vaccine)
	RV1 Steele 2008‐ZAF	3	5	0	8	Bronchopneumonia (1 placebo), pneumonia (2 vaccine, 2 placebo), hepatic steatosis (1 placebo), brain oedema (1 vaccine, 1 placebo)
	RV1 Steele 2010a‐ZAF	6	9	0	15	Bronchopneumonia, sepsis, and gastroenteritis were the most common causes
	RV1 Steele 2010b‐ZAF	3	0	0	3	Bronchopneumonia and gastroenteritis (3 vaccines)
	RV1 Vesikari 2004b‐FIN	0	0	0	0	—
	RV1 Vesikari 2007a‐EU	0	0	0	0	—
	RV1 Vesikari 2011‐FIN	0	0	0	0	—
	RV1 Zaman 2009‐BGD	1	0	0	1	—
RV5	RV5 Armah 2010‐AF	76	82	0	158	Gastroenteritis (20 vaccine, 16 placebo); 11 deaths occurred in identified HIV‐infected participants in Kenya; sudden infant death syndrome (1 placebo); other causes not mentioned
	RV5 Block 2007‐EU/USA	1	0	0	1	Sudden infant death syndrome (1 vaccine)
	RV5 Ciarlet 2009‐EU	0	0	0	0	—
	RV5 Iwata 2013‐JPN	0	0	0	0	—
	RV5 Lawrence 2012‐CHN	0	0	0	0	—
	RV5 Levin 2017‐AF	1	2	0	3	Pneumonia
	RV5 Merck[009] 2005‐USA	0	0	0	0	—
	RV5 Mo 2017‐CHN	0	1	0	1	Reasons not reported
	RV5 Vesikari 2006a‐FIN	0	0	0	0	—
	RV5 Vesikari 2006b‐INT	24	20	0	44	Sudden infant death syndrome (7 vaccine and 7 placebo), other causes not mentioned
	RV5 Zaman 2010‐AS	3	4	0	7	Not all causes reported, most common causes were drowning and sepsis
Rotavac	VAC Bhandari 2014‐IND	30	18	0	48	The most common causes of death were infection and infestations followed by general disorders and administration site conditions. Days after vaccination not reported. None were considered to be vaccine‐related
Rotavac	VAC Chandola 2017‐IND	5	0	0	5	Cause of death: sepsis and aspiration (79 ‐ 141 days after Rotavac vaccination), unexplained sudden death (3 days after Rotavac vaccination). None were considered to be vaccine‐related

Vaccine	Vaccination schedule	Vaccine antigens	Manufacturer	License information
Lanzhou lamb rotavirus (LLR)	1 dose annually for children 2 months to 3 years and one booster dose at 3 to 5 years	Monovalent, live‐attenuated lamb G10 P[12] strain	Lanzhou Institute of Biological Products, China	2000 (China), nationally licenced
Rotasiil, Bovine rotavirus‐pentavalent vaccine (BRV‐PV)	3 doses  at 6, 10 and 14 weeks	Pentavalent, bovine‐human reassortant vaccine containing serotypes G1, G2, G3, G4 and G9	Serum Institute of India Ltd.	2017 (India), nationally licenced
Rotavin‐M1	2 doses Minimum 6 weeks given at least 30 days apart	Monovalent, live‐attenuated human G1 P[8] strain	Polyvac, Vietnam	2007 (Vietnam), nationally licenced

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Rotavirus diarrhoea: severe (up to 1 year follow‐up)	11	49893	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.14, 0.34]
1.1 Low‐mortality countries (WHO strata A & B)	7	43779	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.09, 0.26]
1.2 High‐mortality countries (WHO strata D & E)	4	6114	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.23, 0.60]
2 Rotavirus diarrhoea: severe (up to 2 years follow‐up)	12		Risk Ratio (Fixed, 95% CI)	0.34 [0.29, 0.41]
2.1 Low‐mortality countries (WHO strata A & B)	9		Risk Ratio (Fixed, 95% CI)	0.18 [0.14, 0.23]
2.2 High‐mortality countries (WHO strata D & E)	3		Risk Ratio (Fixed, 95% CI)	0.65 [0.51, 0.83]
3 All‐cause diarrhoea: severe cases (up to 1 year follow‐up)	6	33690	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.54, 0.80]
3.1 Low‐mortality countries (WHO strata A & B)	3	28051	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.47, 0.74]
3.2 High‐mortality countries (WHO strata D & E)	3	5639	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.56, 0.95]
4 All‐cause diarrhoea: severe cases (up to 2 years follow‐up)	5	12181	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.54, 0.92]
4.1 Low‐mortality countries (WHO strata A & B)	3	9417	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.36, 1.02]
4.2 High‐mortality countries (WHO strata D & E)	2	2764	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.72, 0.96]
5 All‐cause diarrhoea: severe episodes (up to 1 year follow‐up)	1		Rate Ratio (Fixed, 95% CI)	Totals not selected
5.1 Low‐mortality countries (WHO strata A & B)	1		Rate Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
6 All‐cause diarrhoea: severe episodes (up to 2 years follow‐up)	2		Rate Ratio (Fixed, 95% CI)	Subtotals only
6.1 Low‐mortality countries (WHO strata A & B)	2		Rate Ratio (Fixed, 95% CI)	0.63 [0.56, 0.71]
7 All‐cause death	30	105778	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.82, 1.30]
7.1 Low‐mortality countries (WHO strata A & B)	22	97597	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.87, 1.71]
7.2 High‐mortality countries (WHO strata D & E)	8	8181	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.64, 1.22]
8 All serious adverse events	31	103714	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.83, 0.93]
8.1 Low‐mortality countries (WHO strata A & B)	24	96233	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.83, 0.93]
8.2 High‐mortality countries (WHO strata D & E)	7	7481	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.76, 1.04]
9 Serious adverse events: intussusception	21		Risk Ratio (Fixed, 95% CI)	0.70 [0.46, 1.05]
9.1 Low‐mortality countries (WHO strata A & B)	17		Risk Ratio (Fixed, 95% CI)	0.69 [0.45, 1.04]
9.2 High‐mortality countries (WHO stratum E)	4		Risk Ratio (Fixed, 95% CI)	1.49 [0.06, 36.63]
10 Serious adverse events: Kawasaki disease	3	13117	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [0.30, 10.61]
11 Serious adverse events requiring hospitalization	2	63675	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.81, 0.96]
12 Rotavirus diarrhoea: of any severity (up to 2 months follow‐up)	12	4294	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.69, 2.00]
12.1 Low‐mortality countries (WHO strata A & B)	9	3537	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.66, 2.50]
12.2 High‐mortality countries (WHO strata D & E)	3	757	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.41, 2.41]
13 Rotavirus diarrhoea: of any severity (up to 1 year follow‐up)	8	15197	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.23, 0.50]
13.1 Low‐mortality countries (WHO strata A & B)	4	9083	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.13, 0.40]
13.2 High‐mortality countries (WHO stratum E)	4	6114	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.35, 0.68]
14 Rotavirus diarrhoea: of any severity (up to 2 years follow‐up)	7	11692	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.28, 0.47]
14.1 Low‐mortality countries (WHO strata A & B)	6	10441	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.25, 0.48]
14.2 High‐mortality countries (WHO stratum E)	1	1251	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.28, 0.62]
15 All‐cause diarrhoea: all cases (up to 2 months follow‐up)	7	3132	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.72, 1.10]
15.1 Low‐mortality countries (WHO strata A & B)	6	3032	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.67, 1.09]
15.2 High‐mortality countries (WHO stratum E)	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.69, 1.58]
16 All‐cause diarrhoea: all cases (up to 1 year follow‐up)	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
16.1 Low‐mortality countries (WHO strata A & B)	2	2204	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.82, 1.03]
16.2 High‐mortality countries (WHO strata D & E)	1	700	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.93, 1.05]
17 All‐cause diarrhoea: all cases (up to 2 years follow‐up)	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17.1 Low‐mortality countries (WHO strata A & B)	3	5937	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 1.00]
18 All‐cause diarrhoea: all episodes (up to 1 year follow‐up)	2		Rate Ratio (Fixed, 95% CI)	Subtotals only
18.1 Low‐mortality countries (WHO strata A & B)	2		Rate Ratio (Fixed, 95% CI)	0.98 [0.88, 1.10]
19 All‐cause diarrhoea: all episodes (up to 2 years follow‐up)	1		Rate Ratio (Fixed, 95% CI)	Totals not selected
19.1 Low‐mortality countries (WHO strata A & B)	1		Rate Ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
20 All‐cause hospitalizations (up to 2 years follow‐up)	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
20.1 Low‐mortality countries (WHO strata A & B)	2	65646	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.27, 1.47]
21 Rotavirus diarrhoea: requiring hospitalization	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
21.1 Up to 1 year follow‐up (at least 1 rotavirus season)	8	48718	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.09, 0.33]
21.2 Second year follow‐up (at least 2 rotavirus seasons)	7	35331	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.11, 0.22]
22 Rotavirus diarrhoea: requiring medical attention	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
22.1 Up to 1 year follow‐up (at least 1 rotavirus season)	1	3874	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.04, 0.16]
22.2 Second year follow‐up (at least 2 rotavirus seasons)	3	7017	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.16, 0.31]
23 All‐cause diarrhoea: cases requiring hospitalization	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
23.1 Up to one year of follow‐up (at least 1 rotavirus season)	2	14393	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.17, 1.11]
23.2 Second year of follow‐up (at least 2 rotavirus seasons)	2	14367	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.27, 0.99]
24 All‐cause diarrhoea: episodes requiring hospitalization	1		Rate Ratio (Fixed, 95% CI)	Subtotals only
24.1 Up to 1 year of follow‐up (at least 1 rotavirus season)	1		Rate Ratio (Fixed, 95% CI)	0.58 [0.47, 0.71]
24.2 Second year of follow‐up (at least 2 rotavirus seasons)	1		Rate Ratio (Fixed, 95% CI)	0.53 [0.46, 0.61]
25 Reactogenicity: fever	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
25.1 After dose 1	25	16192	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.97, 1.17]
25.2 After dose 2	24	15630	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.92, 1.06]
25.3 After dose 3	4	1390	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.86, 1.13]
25.4 End of follow‐up	18	11926	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.93, 1.01]
26 Reactogenicity: diarrhoea	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
26.1 After dose 1	25	18732	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.88, 1.17]
26.2 After dose 2	24	15630	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.86, 1.21]
26.3 After dose 3	4	1390	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.35, 1.36]
26.4 End of follow‐up	17	14305	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.84, 1.08]
27 Reactogenicity: vomiting	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
27.1 After dose 1	25	18732	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.94, 1.12]
27.2 After dose 2	24	15630	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.81, 1.05]
27.3 After dose 3	4	1390	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.71, 2.50]
27.4 End of follow‐up	17	14305	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.04]
28 Adverse events requiring discontinuation (end of follow‐up)	26	94980	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.83, 1.26]
29 Immunogenicity: rotavirus vaccine shedding (end of follow‐up)	16	2638	Risk Ratio (M‐H, Random, 95% CI)	10.94 [4.90, 24.43]
30 Immunogenicity: seroconversion	31		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
30.1 After dose 1	9	2537	Risk Ratio (M‐H, Random, 95% CI)	20.39 [8.48, 49.01]
30.2 After dose 2	27	8742	Risk Ratio (M‐H, Random, 95% CI)	11.44 [8.01, 16.32]
30.3 After dose 3	5	1137	Risk Ratio (M‐H, Random, 95% CI)	6.89 [3.59, 13.24]
31 Dropouts before the end of the trial	28	93106	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.90, 1.00]
32 Subgroup analysis: rotavirus diarrhoea of any severity (by G type)	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
32.1 G1	6	27583	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.10, 0.44]
32.2 G2	5	26835	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.31, 0.56]
32.3 G3	4	8968	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.05, 0.39]
32.4 G4	2	5720	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.07, 0.59]
32.5 G9	3	8868	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.18, 0.75]
33 Subgroup analysis: severe cases of rotavirus diarrhoea (by G type)	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
33.1 G1	7	39428	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.16, 0.38]
33.2 G2	7	44682	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.18, 0.50]
33.3 G3	5	20505	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.05, 0.56]
33.4 G4	1	2421	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.00, 2.95]
33.5 G8	2	4417	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 2.37]
33.6 G9	6	26815	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.13, 0.40]
33.7 G12	2	4417	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.23, 0.97]
34 Subgroup analysis: rotavirus diarrhoea in malnourished children	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
34.1 Up to 1 year of follow‐up (at least 1 rotavirus season)	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35 Subgroup analysis: rotavirus diarrhoea in HIV‐infected children	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.26, 3.78]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Rotavirus diarrhoea: severe (up to 1 year follow‐up)	9	10048	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.22, 0.44]
1.1 Low‐mortality countries (WHO strata A & B)	5	4132	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.03, 0.22]
1.2 High‐mortality countries (WHO strata D & E)	4	5916	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.29, 0.62]
2 Rotavirus diarrhoea: severe (up to 2 years follow‐up)	8	13203	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.23, 0.60]
2.1 Low‐mortality countries (WHO strata A & B)	4	7318	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.08, 0.39]
2.2 High‐mortality countries (WHO strata D & E)	4	5885	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.43, 0.82]
3 All‐cause diarrhoea: severe cases (up to 1 year follow‐up)	3	4085	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.58, 1.11]
3.1 Low‐mortality countries (WHO stratum A)	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 High‐mortality countries (WHO strata D & E)	3	4085	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.58, 1.11]
4 All‐cause diarrhoea: severe cases (up to 2 years follow‐up)	4	5977	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.98]
4.1 Low‐mortality countries (WHO strata A & B)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 High‐mortality countries (WHO strata D & E)	4	5977	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.98]
5 All‐cause death	14	84448	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.74, 1.25]
5.1 Low‐mortality countries (WHO strata A & B)	9	77642	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.65, 1.96]
5.2 High‐mortality countries (WHO strata D & E)	5	6806	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.68, 1.24]
6 All serious adverse events	14	82502	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 1.01]
6.1 Low‐mortality countries (WHO strata A & B)	8	75672	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 1.02]
6.2 High‐mortality countries (WHO strata D & E)	6	6830	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.66, 1.28]
7 Serious adverse events: intussusception	16	85495	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.41, 1.45]
7.1 Low‐mortality countries (WHO strata A & B)	12	78907	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.41, 1.45]
7.2 High‐mortality countries (WHO strata D & E)	4	6588	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Rotavirus diarrhoea: of any severity (up to 1 year follow‐up)	8	13450	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.28, 0.50]
8.1 Low‐mortality countries (WHO strata A & B)	5	8644	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.25, 0.37]
8.2 High‐mortality countries (WHO strata D & E)	3	4806	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.28, 0.94]
9 Rotavirus diarrhoea: of any severity (up to 2 years follow‐up)	7	12888	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.33, 0.65]
9.1 Low‐mortality countries (WHO strata A & B)	3	6144	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.26, 0.43]
9.2 High‐mortality countries (WHO strata D & E)	4	6744	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.45, 0.83]
10 All‐cause diarrhoea: of any severity (up to 1 year follow‐up)	1	1059	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.61, 1.11]
10.1 Low‐mortality countries (WHO strata A & B)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 High‐mortality countries (WHO stratum E)	1	1059	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.61, 1.11]
11 All‐cause diarrhoea: of any severity (up to 2 years follow‐up)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
11.1 High‐mortality countries (WHO stratum E)	1	1059	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.68, 1.16]
12 All‐cause hospitalizations (up to 2 years follow‐up)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
12.1 High‐mortality countries (WHO strata D & E)	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Rotavirus diarrhoea: requiring hospitalization	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
13.1 Up to 1 year of follow‐up	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Rotavirus diarrhoea: requiring medical attention	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
14.1 Up to 1 year of follow‐up	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Reactogenicity: fever	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.1 After dose 1	4	7124	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.91, 1.45]
15.2 After dose 2	2	4322	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.69, 1.01]
15.3 After dose 3	2	4294	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.90, 1.27]
15.4 End of follow‐up	11	18391	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.94, 1.09]
16 Reactogenicity: diarrhoea	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
16.1 After dose 1	2	4745	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.95, 1.32]
16.2 After dose 2	1	3905	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.72, 1.10]
16.3 End of follow‐up	10	17087	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.98, 1.10]
17 Reactogenicity: vomiting	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17.1 After dose 1	2	4745	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.63, 1.12]
17.2 After dose 2	1	3905	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.32, 1.49]
17.3 After dose 3	1	3878	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.16, 1.32]
17.4 End of follow‐up	9	16294	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.90, 1.06]
18 Adverse events requiring discontinuation (end of follow‐up)	10	15471	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.57, 1.39]
19 Immunogenicity: rotavirus vaccine shedding (after dose 3)	5		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
20 Immunogenicity: seroconversion	10		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
20.1 After dose 3	10		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
21 Dropouts before the end of the trial	13	85855	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.90, 1.08]
22 Subgroup analysis: rotavirus diarrhoea of any severity (by G type)	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
22.1 G1	4	11022	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.21, 0.32]
22.2 G2	3	9907	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.16, 0.78]
22.3 G3	4	11022	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.08, 2.02]
22.4 G4	3	9907	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.13, 1.33]
22.5 G9	2	9537	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.20, 0.54]
23 Subgroup analysis: severe cases of rotavirus diarrhoea (by G type)	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
23.1 G1	3	76606	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.03, 1.74]
23.2 G2	3	76606	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.13, 1.37]
23.3 G3	3	76606	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.05, 2.74]
23.4 G4	3	76606	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.03, 0.46]
23.5 G9	3	76606	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.05, 0.34]
24 Subgroup analysis: HIV‐infected children	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
24.1 Rotavirus diarrhoea: severe (up to two years follow‐up)	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	2.45 [0.11, 56.68]
24.2 All‐cause diarrhoea: severe (up to two years follow‐up)	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	4.05 [0.52, 31.43]
24.3 All‐cause death	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.51, 3.21]
24.4 Serious adverse events (up to 24 weeks)	2	113	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.59, 3.97]

Methods	RCT Length of follow‐up: 1 month after last dose Adverse event data collection methods: not reported
Participants	Number: 375 enrolled; ATP safety cohort: 345; ATP immunogenicity cohort: 292 Inclusion criteria: healthy infants aged 5 – 10 weeks at the time of the first study vaccination dose with a birth weight of > 2 kg Exclusion criteria: use of any investigational drug or vaccine other than the study vaccine or confirmed immunosuppression/immunodeficient conditions or allergy to RIX4414 vaccine/placebo components
Interventions	1. 2 doses of RIX4414* plus 1 dose of placebo according to a PL‐V‐V schedule 2. 2 doses of RIX4414* plus 1 dose of placebo according to a V‐PL‐V schedule 3. 3 placebo doses * Human rotavirus (RV1) liquid vaccine, oral suspension (GSK Biologicals, Belgium), containing at least 10^6.0 median Cell Culture Infective Dose 50 percent (CCID₅₀) of live attenuated RIX4414 human rotavirus strain (G1P[8]) Schedule: 3 doses according to a 0‐, 1‐, and 2‐month schedule
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity, including fever, diarrhoea and vomiting, 8 days after each dose (collected from GSK report) 2. Adverse events leading to discontinuation 3. Serious adverse events 4. Fatal serious adverse events 5. Dropouts 6. * Rotavirus diarrhoea, rotavirus antigen isolated from any of the stool samples collected from children with diarrhoea episodes, up to 1 month after last dose 7. * All‐cause diarrhoea, up to 1 month after last dose Outcomes to measure immunogenicity 8. Anti‐rotavirus IgA antibody seroconversion, ≥ 20 U/mL * Outcome reported as proportion (P) with 95% CI. Events (n) and totals (N) were estimated by using the values when 2 formulae for the standard error (SE) converged
Immunization status	Commercially‐available diphtheria, tetanus, whole‐cell pertussis (DTPw), hepatitis B (HBV) and oral poliovirus (OPV) vaccines were administered concomitantly with the study vaccine/placebo as part of the routine Expanded Programme of Immunization (EPI) in the Philippines
Location	Philippines (single centre) WHO mortality stratum B
Notes	Study known as RIX GSK[063] 2008‐AS in previously published versions of this review Date: March to September 2007 Source of funding: GlaxoSmithKline Biologicals Study rationale: "This study will provide data on the immune response and safety of GSK Biologicals' HRV [human rotavirus] liquid vaccine when given along with the routine infant immunizations in Philippines." "The study also[...]explored the potential effect of scheduling of the HRV [human rotavirus] vaccine doses with respect to the existing routine vaccination schedules"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated   Quote: "Block randomization scheme (2:2:1 ratio) with standard SAS program was used"
Allocation concealment (selection bias)	Low risk	Central allocation  Quote: "Based on the block size, the vaccine doses were distributed to each of the study centers"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Participants and key personnel were blinded  Quote: "The study was double‐blind with respect to the RIX4414 oral suspension (liquid formulation), placebo and scheduling of doses. The parents/guardians of infants, investigators and study personnel were unaware of the study vaccine/ placebo administered"  Quote: "The placebo was identical to the vaccine in composition"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition balanced across groups with reasons for dropout/exclusion reported
Selective reporting (reporting bias)	Low risk	All prepublished outcomes included
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: outcomes measured up to 1 month after the second dose Adverse event data collection methods: participants or their parents filled out a diary card for 7 days after each dose (passive method)
Participants	Number: 42 enrolled; 42 evaluable Inclusion criteria: all infants aged 6 to 26 weeks recruited from private practice offices in Cincinnati Exclusion criteria: not stated
Interventions	RV1 1. RIX4414 (RV1): 10⁵ PFU; 21 participants 2. Placebo: 20 participants Schedule: 2 doses given 6 to 10 weeks apart
Outcomes	Clinical outcome measures 1. Reactogenicity: diarrhoea defined as > 3 stools that were looser than normal in a 24‐hour period; fever defined as a temperature > 100.4 °F obtained rectally in infants 2. Serious adverse events 3. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 4. Vaccine virus shedding: rotavirus shedding after immunization; combined time points (review includes data from combined time points) 5. Seroconversion: ≥ 4‐fold rise in rotavirus IgA antibody (serum and stool) (review includes data from after dose 1 and dose 2)
Immunization status	Rotavirus vaccine was separated from all other infant vaccines by at least 2 weeks
Location	Cincinnati, USA WHO mortality stratum A
Notes	Date: August to November 1995 Source of funding: Virus Research Institute, Inc. (now Avant Immunotherapeutics Inc.) 1 participant in the placebo group did not complete the study because of persistent otitis media
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not reported
Selective reporting (reporting bias)	Unclear risk	Not reported
Other bias	Unclear risk	Trial report does not provide enough details

Methods	RCT, open‐label non‐placebo controlled trial Length of follow‐up: outcomes measured at 1 year Adverse event data collection methods: Passive: All adverse events following interventions were captured for 48 hours following each intervention and were scored for probable, possible, or unlikely relationship to each intervention. All missing protocol‐defined events were captured as protocol deviations and reported annually. Comprehensive safety reports were submitted semi‐annually to the study’s Independent Medical Monitor and to the Data and Safety Monitoring Board
Participants	Number: 700 enrolled; 593 evaluable Age range: birth to age 7 days at enrolment, 10 ‐ 17 weeks at vaccine administration Inclusion criteria: Healthy infant aged 0 to 7 days, no obvious congenital abnormalities or birth defects, no abnormal (frequency and consistency) stools since birth, stable household with no plans to leave the area for the next one year Exclusion criteria: Parents are not willing to have child vaccinated at the field clinic or to have child's blood drawn, parents are planning to enrol child into another clinical study, mother not willing to have blood drawn and breast milk extracted, parents not willing to have field research assistant in home twice a week, history of seizures or other apparent neurologic disorders, infant received any vaccines before start of study, except Bacillus Calmette‐Guerin (BCG), infant has any sibling currently or previously enrolled in this study (including a twin)
Interventions	1. RV1 dose 1 at 10 weeks, dose 2 at 17 weeks (350 enrolled participants) 2. No RV1 vaccine (350 enrolled participants)
Outcomes	Clinical outcome measures (safety and efficacy) 1. Rotavirus diarrhoea (severe) 2. All‐cause diarrhoea (severe) 3. All‐cause deaths 4. Rotavirus diarrhoea (any severity) 5. All‐cause diarrhoea (any severity) 6. Dropouts from the trial
Immunization status	Along with Rotarix at 10 and 17 weeks of age, the polio vaccine intervention was the administration of an injected, inactivated polio vaccine (IPV) dose replacing the fourth dose of tOPV at 39 weeks of age. In addition to the vaccine interventions, study children received all standard EPI vaccines through the study clinic.The national Bangladesh Expanded Program on Immunizations (EPI) schedule includes BCG at birth; pentavalent vaccine (DPT, HepB, Hib) at 6, 10, and 14 weeks; bivalent Measles‐Rubella at 40 weeks; and monovalent Measles at 65 weeks
Location	Single site, Bangladesh WHO mortality stratum D
Notes	Date: May 2011 to November 2013 Source of funding: Bill and Melinda Gates Foundation Study rationale: The primary objective was to determine the efficacy of a 2‐dose Rotarix oral rotavirus vaccine (given at 10 and 17 weeks of age) to prevent rotavirus diarrhoea in the first year of life
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized using permuted blocks with random block size selection.
Allocation concealment (selection bias)	Low risk	All clinical investigators and laboratories were masked to vaccine arm, but medical officers were not.
Blinding (performance bias and detection bias)   All outcomes	High risk	RV1 versus no intervention, unable to blind (no placebo)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Primary ITT analysis, moderate attrition.
Selective reporting (reporting bias)	Low risk	All relevant outcomes appear to be reported, protocol published
Other bias	Low risk	No other bias apparent

Methods	RCT Length of follow‐up: 10 to 12 months Adverse event data collection methods: "For the 15 days after each dose of vaccine, the parent or guardian maintained a daily record that included fever, irritability/fussiness, diarrhoea, vomiting, loss of appetite and cough/runny nose. In addition, the parent or guardian was asked to record any gastroenteritis episode occurring in the period from the first dose until 2 months after the second dose of vaccine." (passive method); "Subjects were also monitored for any serious adverse events occurring throughout participation in the study (10–12 months in total) and for unsolicited adverse events occurring within 43 days after each dose of vaccine or placebo" (active method)
Participants	Number: 529 enrolled; 479 evaluable Age range: 1 to 3 months (beginning) Inclusion criteria: healthy infants aged 5 to 15 weeks at the time of the first dose. Vaccine administration delayed if acute illness present (fever > 38 °C/gastroenteritis/antibiotics within 7 days before scheduled vaccination) Exclusion criteria: premature labour (< 36 weeks); chronic condition; (chronic gastrointestinal disease, immunosuppressive diseases); household contact with immunosuppressed individuals/pregnant women
Interventions	RV1 1. RIX4414 (RV1)  1.1. 10^5.2; 212 participants  1.2. 10^6.4; 209 participants 2. Placebo: 108 participants Schedule: 2 doses given 7 weeks apart
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity: fever, irritability/fussiness, diarrhoea, vomiting, loss of appetite and cough/runny nose; measured during 15 days post‐vaccination 2. Serious adverse events 3. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 4. Viral shedding: viral shedding in any stool specimen collected between first dose and 2 months after second vaccine dose (review includes after dose 2 data) 5. Seroconversion: anti‐rotavirus IgA ELISA ≥ 20 Units/mL in participants negative for rotavirus antibody before the first dose of vaccine (review includes data from 2 months after dose 2)
Immunization status	Vaccine or placebo given concomitantly with diphtheria‐tetanus‐acellular pertussis, inactivated poliovirus, H. influenzae type b, and Streptococcus pneumoniae conjugate vaccines for participants in USA or with a diphtheria‐tetanus‐acellular pertussis/inactivated poliovirus/H. influenza type b combination vaccine for participants in Canada "Routine hepatitis B vaccinations were administered according to local practice"
Location	41 centres in USA and Canada WHO mortality stratum A
Notes	Date: 13 December 2000 to 2 August 2002 Source of funding: GlaxoSmithKline Biologicals
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, using a SAS programme
Allocation concealment (selection bias)	Low risk	Central allocation  Quote: "double blind randomized unbalanced allocation scheme (2:2:1 ratio)"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Participants and key personnel; Quote: "Study personnel and families were blinded to group assignment until study completion"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data balanced across groups  Quote: "Fifty‐nine subjects, who were proportionately distributed among vaccine groups, did not complete the entire 10‐ to 12‐month study"
Selective reporting (reporting bias)	Unclear risk	No details
Other bias	Unclear risk	No details

Methods	RCT Length of follow‐up: 2 months after dose 2 Adverse event data collection methods: not reported
Participants	Number: 155 enrolled; 151 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: full‐term infants; healthy infants aged between 6 and 12 weeks (42 to 90 days) at the time of the first vaccination for whom the vaccination history was available Exclusion criteria: previous confirmed occurrence of rotavirus gastroenteritis
Interventions	RV1 1. RIX4414 (RV1): 10^6.5 PFU; 103 participants (randomized) 2. Placebo: 52 participants (randomized) Schedule: 2 oral doses starting at about 2 months of age; second dose at 4 months of age
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity: for each type of solicited symptom, occurrence of the symptom within the 15‐day (days 0 to 14) solicited follow‐up period after each dose; occurrence of unsolicited adverse events within 43 days (days 0 to 42) after each dose, according to MedDRA classification; up to 43 days after vaccine/placebo 2. Serious adverse events: no definition; occurrence throughout the entire study period (up to 2 months after dose 2) 3. Dropouts: measured up to 2 months after dose 2 4. Rotavirus diarrhoea: presence of rotavirus in gastroenteritis episode stools collected from dose 1 of vaccine/placebo up to 2 months after dose 2 5. All‐cause death 6. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 7. Seroconversion: appearance of anti‐rotavirus immunoglobulin A antibody concentration 20 U/mL in participants who were seronegative before vaccination (review includes data from 2 months after dose 2)
Immunization status	H. influenzae type b vaccine administered concomitantly along with the 2 doses of vaccine/placebo and at 2 months after dose 2; other routine childhood vaccines were to be given at least 14 days before trial vaccine/placebo
Location	6 centres in Korea WHO mortality stratum B
Notes	Date: 15 July 2005 to 11 May 2006 Registration number: NCT00134732 Source of funding: GlaxoSmithKline Biologicals Study rationale: "to assess immunogenicity and safety of 2 doses of the HRV [human rotavirus] vaccine in Korean infants aged approximately 2 months at the time of the first dose"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, using a SAS programme
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Parent/guardian and study personnel were not aware of the treatment administered
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4/103 participants in the vaccine arm did not complete the study
Selective reporting (reporting bias)	Low risk	All planned outcomes were reported
Other bias	Unclear risk	No details

PERMALINK

Vaccines for preventing rotavirus diarrhoea: vaccines in use

Karla Soares‐Weiser

Hanna Bergman

Nicholas Henschke

Femi Pitan

Nigel Cunliffe

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

The global impact of rotavirus infection

Epidemiology of rotavirus infection

Rotavirus classification

1.

Description of the intervention

Vaccines approved for use

Vaccines no longer in use

How the intervention might work

Recommendations for rotavirus vaccine use

Performance of oral rotavirus vaccines by setting

Outcomes of interest

Why it is important to do this review

Development of Cochrane systematic rotavirus vaccine reviews

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Intervention

Control

Types of outcome measures

Primary

Secondary

Other

Search methods for identification of studies

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Certainty of the evidence

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

1. RV1

Population

Outcome measures

Location

Country mortality rate

Vaccine schedule

Infant vaccination status

Methods for collecting adverse event data

Source of funding

2. RV5

Population

Outcome measures

Location

Country mortality rate

Vaccine schedule

Infant vaccination status

Methods for collecting adverse event data

Source of funding

Methods	RCT Length of follow‐up: up to the age of 2 years Adverse event data collection methods: not reported
Participants	Number: 765 Age range: 6 to 14 weeks Inclusion criteria: full‐term healthy infants aged 6 to 14 weeks at the time of the first dose Exclusion criteria: use of any other investigational or non‐registered product (drug or vaccine) within 30 days preceding the first dose of human rotavirus vaccine; history of use of experimental rotavirus vaccine; chronic administration of immunosuppressants or other immune‐modifying drugs since birth; concurrently participating in another clinical study; any clinically significant history of a serious medical condition; previous confirmed occurrence of rotavirus gastroenteritis
Interventions	1. RV1, 508 participants 2. Placebo, 257 participants Schedule: 2 doses according to a 0‐, 1‐month schedule
Outcomes	Clinical outcome measures (safety and efficacy) 1. Any rotavirus gastroenteritis leading to medical intervention and caused by the circulating wild‐type rotavirus strains, from 2 weeks after dose 2 up to 2 years of age, stool sample collected as soon as possible but preferably not later than 7 days after the start of the episode 2. Severe rotavirus gastroenteritis (≥ 11 on the Vesikari scale) leading to a medical intervention and caused by the circulating wild‐type rotavirus strains (a) of G1 type, (b) of non‐G1 types, from 2 weeks after dose 2 up to 2 years of age 3. Each type of solicited symptom (including: cough, diarrhoea, fever, irritability, loss of appetite and vomiting) during the 8‐day follow‐up period after each dose 4. Adverse events leading to discontinuation of the trial 5. Serious adverse events, including intussusception, up to 2 years of age 6. Fatal serious adverse events 7. Dropouts before the end of the trial Outcomes to measure immunogenicity 8. Seroconversion in terms of anti‐rotavirus IgA antibody, from 2 months after dose 2. Seroconversion was defined as the appearance of anti‐rotavirus immunoglobulin A antibody concentration over 20 units (U)/millilitre (mL) in infants initially (i.e. prior to the first dose of RV1) seronegative
Immunization status	Combined diphtheria and tetanus toxoids and acellular pertussis (DTPa) and Hepatitis B (HBV) vaccines were allowed to be co‐administered along with RV1 vaccine/placebo
Location	Japan WHO mortality stratum A
Notes	Date: June 2007 to November 2009 Source of funding: GlaxoSmithKline Registration number: NCT00480324
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, using a SAS programme
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Parent/guardian and study personnel were not aware of the treatment administered
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition/exclusions balanced between groups
Selective reporting (reporting bias)	Low risk	Protocol published a priori, all prepublished outcomes reported
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 2 months post‐dose 2 Adverse event data collection methods: passive; "Diary cards were provided to the parents/guardians of infants to record the solicited general symptoms occurring during the 15 day follow up period after each vaccine dose. The solicited general symptoms were loss of appetite, fussiness/irritability, fever, diarrhoea, vomiting and cough/runny nose. The intensity of each of these symptoms was graded on a 3‐point scale where “0” indicates normal and “3” indicates severe"
Participants	Number: 450 enrolled; ATP safety cohort: 447; ATP immunogenicity cohort: 339 Inclusion criteria: healthy infants aged 6 to 12 weeks at the time of the first vaccination Exclusion criteria: any other investigational drug or vaccine; a history of gastrointestinal disease or rotavirus gastroenteritis; allergy to any of the vaccine components; a history of immunosuppressive or immunodeficient condition
Interventions	1. RIX4414* vaccine reconstituted in buffer stored at 2 °C – 8 °C, n = 174 2. RIX4414* vaccine reconstituted in water stored at 2° C – 8 °C, n = 174 3. RIX4414* vaccine reconstituted in buffer stored at 37 °C for 7 days, n = 50 4. Placebo reconstituted in buffer, n = 26 5. Placebo reconstituted in water, n = 26 * Lyophilized formulation containing at least 10^6.0 CCID₅₀ of the RIX4414 strain Schedule: 2 doses at month 0 and 2
Outcomes	Clinical outcome measures 1. * Rotavirus diarrhoea, stool sample collected during diarrhoea episode, up to 2 months post‐dose 2 2. * All‐cause diarrhoea, up to 2 months post‐dose 2 3. Reactogenicity, including fever, vomiting and diarrhoea, 15‐day follow‐up period after each dose (collected from GSK report) 4. Serious adverse events, up to 2 months post‐dose 2 5. Fatal serious adverse events 6. Adverse events resulting in discontinuation (collected from GSK report) 7. Dropouts: measured up to 2 months after dose 2 (collected from GSK report) Outcomes to measure immunogenicity 8. Seroconversion, anti‐rotavirus IgA antibody levels (cut off: ≥ 20 U/mL by ELISA ), 2 months post‐dose 2 9. Rotavirus antigen shedding in stool (review includes data from combined time points) (collected from GSK report) * Outcome reported as proportion (P) with 95% CI. Events (n) and totals (N) were estimated by using the values when 2 formulae for the standard error (SE) converged
Immunization status	"During the study period, participating infants were offered commercially available GSK Biologicals’ diphtheria toxoid, tetanus toxoid, acellular pertussis, inactivated polio and H. influenzae type b combination vaccine (Infanrix^TM‐IPV/Hib) at two and four months of age and diphtheria toxoid, tetanus toxoid, acellular pertussis, hepatitis B, inactivated polio and H. influenzae type b combination vaccine (Infanrix hexa^TM) at six months of age"
Location	2 centres in Thailand WHO mortality stratum B
Notes	Study known as RIX GSK[039] 2007‐AS, in previously published versions of this review Date: March to December 2005 Source of funding: GSK Biologicals Study rationale: This study evaluated the stability of lyophilized RIX4414 vaccine in terms of immunogenicity when reconstituted in water instead of regular buffer, and when stored at tropical room temperature (37 °C) for 7 days before reconstitution
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, using a SAS programme
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias)   All outcomes	High risk	Partially blind study. Quote: “Single blind”, not reported whether personnel or participants were blinded  Quote: “The placebo was identical in appearance and composition to the active vaccine”
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition balanced across groups with reasons for withdrawal reported
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 1 month post‐dose 2 Adverse event data collection methods: Passive: Adverse events were recorded during the 8‐day and 31‐day follow‐up period after each dose of RIX4414/placebo, respectively. SAEs were recorded during the entire study period
Participants	Number: 684 enrolled; 642 evaluable Age range: 6 to 12 weeks Inclusion criteria: Infants who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study: male or female between, and including, 6 to 12 weeks of age at the time of the first dose of the vaccination, healthy infants as established by medical history and clinical examination, born after a normal gestation period of between 37 and 41 weeks + 6 days inclusive, available vaccination history from vaccination diary cards or medical charts Exclusion criteria: Use of any investigational or non‐registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the dose of study vaccine, or planned use during the study period, chronic administration (defined as more than 14 days) of immunosuppressants or other immune‐modifying drugs since birth, planned administration/ administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine, with the exception of the routine infant vaccines, concurrently participating in another clinical study, confirmed or suspected immunosuppressive or immunodeficient condition, clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of the gastrointestinal tract or other serious medical condition as determined by the investigator, history of allergic disease or reactions likely to be exacerbated by any component of the vaccine, acute disease at the time of enrolment, administration of immunoglobulins or any blood products, or both, since birth or planned administration during the study period, gastroenteritis (GE) within 7 days preceding the study vaccine administration, previous confirmed occurrence of RV GE, previous vaccination with rotavirus vaccine or planned use during the study period
Interventions	1. RV1 2. Placebo Schedule: 2 oral doses according to a 0‐, 1‐, or 2‐month schedule
Outcomes	Clinical outcome measures (safety and efficacy) 1. All‐cause deaths 2. All serious adverse events 3. Serious adverse events: intussusception 4. Rotavirus diarrhoea: of any severity (up to 2 months follow‐up) 5. All‐cause diarrhoea: of any severity (up to 2 months follow‐up) 6. Reactogenicity: vomiting, diarrhoea, fever 7. Adverse events requiring discontinuation 8. Dropouts from the trial Outcomes to measure immunogenicity 9. Seroconversion
Immunization status	Routine childhood vaccines as recommended by the local vaccination schedule were allowed to be administered concomitantly with RIX4414/placebo. These vaccines included the combined diphtheria‐tetanus‐acellular pertussis vaccine, Haemophilus influenzae type b vaccine, inactivated poliovirus vaccine and pneumococcal vaccine. The infants had received the BCG vaccine and 2 doses of hepatitis B vaccine prior to study enrolment
Location	19 sites, Republic of Korea WHO mortality stratum B
Notes	Date: August 2009 to July 2010 Source of funding: GlaxoSmithKline Study rationale: To evaluate Immunogenicity, Reactogenicity and Safety of Rotarix™ Vaccine in Korean Infants
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "All infants receiving RIX4414 or placebo were allocated into their respective groups using an internet based randomization tool SBIR (Internet based randomization system) according to 3:1 ratio"  Quote: "A standard SAS® program generated a randomization list used to number the vaccines. A randomized (3:1) blocking scheme maintained the balance between the two treatments where a unique treatment number identified the study vaccine to be administered to the infants."
Allocation concealment (selection bias)	Low risk	The person in charge of the vaccination accessed the randomization system on Internet. Upon providing a participant number and the age (6 ‐ 12 weeks) for the infant, the randomization system used the minimization algorithm to determine the treatment number to be used for the participant.  The actual treatment number used for first vaccination of the participant was recorded by the investigator in the eCRF (Randomisation/Treatment Allocation Section)
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "Each dose of RIX4414 or placebo was administered in a blinded manner where the parents/guardians and the physicians were unaware of the vaccine administered"
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	462/684 completed the study, reasons for attrition provided
Selective reporting (reporting bias)	Low risk	No indication of selective reporting bias
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 1 month Adverse event data collection methods: Passive: diary cards were provided to participants or their parents/guardians to record solicited adverse events for 8 days after each vaccination (day 0 – 7). Serious adverse events were recorded for the duration of the study
Participants	Number: 50 enrolled; 50 evaluable Age range: 2 to 6 years old Inclusion criteria: participants were required to be of Chinese origin, in good health and free of obvious health problems
Interventions	1. single dose of GlaxoSmithKline (GSK) Biologicals’ human rotavirus (HRV) vaccine (444563). Each 1.5 ml dose of the liquid human RV vaccine contained at least (CCID50) of the live attenuated RIX4414 human RV strain 2. single dose placebo
Outcomes	Clinical outcome measures (safety and efficacy) 1. Serious adverse events
Immunization status	Children were allowed to receive routine childhood vaccinations according to local immunization practice during the study period, with a minimum interval of at least 7 days between the administration of routine vaccines and the study vaccine or placebo
Location	Single site, China WHO mortality stratum B
Notes	Date: March 2010 to April 2010 Source of funding: GlaxoSmithKline Study rationale: To assess the safety of a single oral dose of HRV vaccine when compared to placebo group, in terms of solicited adverse events (AEs) in healthy children aged 2 to 6 years.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatment allocation at the investigator site was performed using an internet‐based randomization system (SBIR)
Allocation concealment (selection bias)	Low risk	Treatment allocation at the investigator site was performed using an internet‐based randomization system (SBIR)
Blinding (performance bias and detection bias)   All outcomes	Low risk	The study was conducted in a double‐blind manner with respect to HRV vaccine and placebo. The parents/LARs of the infants, the study personnel and the investigator were unaware of the study vaccine administered (liquid HRV vaccine or placebo). The laboratory in charge of the laboratory testing was blinded to the treatment, and codes were used to link the participant and study (without any link to the treatment attributed to the participant) to each sample
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants accounted for
Selective reporting (reporting bias)	Low risk	Planned outcomes fully reported
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 2 years Adverse event data collection methods: (not reported if active or passive) serious adverse events were recorded throughout the study period
Participants	Number: 3333 enrolled; 3148 evaluable Age range: 6 to 16 weeks Inclusion criteria: participants who the investigator believes that their parents/LARs can and will comply with the requirements of the protocol, male or female infant of Chinese origin between, and including, 6 and 16 weeks of age at the time of the first vaccination, healthy infants as established by medical history and clinical examination before entering into the study, born after a gestation period of 36 to 42 weeks inclusive Exclusion criteria: child in care; use of any investigational or non‐registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period; any clinically significant history of gastrointestinal disease; any confirmed or suspected immunosuppressive or immunodeficient condition; history of confirmed rotavirus gastroenteritis; acute disease and/or fever at the time of enrolment; gastroenteritis within 7 days preceding the study vaccine or placebo administration
Interventions	2 cohorts 1. 1st RV season RIX4414 (1575 participants) or placebo (1573 participants) 2. 2nd RV season RIX4414 (1500 participants) or placebo (1479 participants) Schedule: 2 doses of Rotarix™ vaccine, liquid formulation, at day 0 and at month 1
Outcomes	Clinical outcome measures (safety and efficacy) 1. All‐cause diarrhoea, severe and any severity 2. Rotavirus diarrhoea, severe and any severity 3. Rotavirus diarrhoea requiring hospitalization 4. All‐cause mortality 5. Serious adverse events 6. Intussusception 7. Reactogenicity: fever, diarrhoea, vomiting 8. Adverse events requiring discontinuation 9. Dropouts before end of the trial Outcomes to measure immunogenicity 10. Seroconversion
Immunization status	As part of the routine childhood vaccination according to the Expanded Program of Immunization (EPI) recommendations in China, participants also received 3 doses of Infanrix™ vaccine and 3 doses of the oral poliovirus vaccine manufactured by the Institute of Medical Biology of the Chinese Academy of Medical Sciences (OPV). The Infanrix™ and the OPV vaccines were administered independently of (sub‐cohort 1) or concomitantly with (sub‐cohort 2) the Rotarix™ vaccine. When administered concomitantly, participants received the 3 doses of Infanrix™ vaccine at months 1, 2, and 3, and the 3 doses of the OPV vaccine at day 0, month 1 and month 2. The Rotarix™ and OPV vaccines were administered orally; the Infanrix™ vaccine was administered intramuscularly in the left anterolateral thigh
Location	4 sites, China WHO mortality stratum B
Notes	Date: August 2010 to May 2012 Source of funding: GlaxoSmithKline Study rationale: The aim of this study was to assess the efficacy, immunogenicity and safety of two doses of GSK Biologicals’ HRV vaccine in healthy Chinese infants aged between 6 and 16 weeks at the time of the first dose of vaccination.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization sequence generated using software (MATEX developed for SAS)
Allocation concealment (selection bias)	Low risk	Treatment allocation at the investigator site was performed using SBIR (internet randomization tool)
Blinding (performance bias and detection bias)   All outcomes	Low risk	Concealed from parents/guardians, study personnel, and investigators, placebo‐controlled study
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Reasons for attrition provided
Selective reporting (reporting bias)	Low risk	Planned outcomes fully reported
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 1 year Adverse event data collection methods: Not reported
Participants	Number: 308 enrolled; 209 evaluated (1 study arm was not included in analyses of this review) Age range: 11 to 17 weeks of age at the time of the first vaccination Inclusion criteria: infants who the investigator believes that their parent/guardian can and will comply with the requirements of the protocol, administration of 1 dose of hepatitis B vaccine at birth, male or female between and including 11 and 17 weeks of age at the time of the first DTPw vaccination, free of obvious health problems as established by medical history and clinical examination before entering into the study Exclusion criteria: use of any investigational or non‐registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period, chronic administration of immunosuppressants or other immune‐modifying drugs since birth, any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination (no laboratory testing is required), administration of immunoglobulins or any blood products, or both, since birth or planned administration during the study period
Interventions	1. RV1 at 3 and 4½ months + DTPw‐HBV at 3, 4½ and 6 months (80 participants) 2. Placebo at 3 and 4½ months + DTPw‐HBV at 3, 4½ and 6 months (25 participants) 3. RV1 at 3 and 4½ months + DTPw‐HBV Kft. at 3, 4½ and 6 months (81 participants) 4. Placebo at 3 and 4½ months + DTPw‐HBV Kft. at 3, 4½ and 6 months (23 participants) 5. DTPwcsl + HBV at 3, 4½ and 6 months (99 participants), this group was not included in analyses of this review
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity 2. Serious adverse events 3. All‐cause death 4. Intussusception 5. Dropouts Outcomes to measure immunogenicity 6. Seroconversion
Immunization status	GlaxoSmithKline (GSK) Biologicals' Tritanrix™HepB and GSK Biologicals Kft's DTPwHBV Vaccines as compared to concomitant administration of Commonwealth Serum Laboratory's (CSL's) DTPw (Triple Antigen™) and GSK Biologicals' HBV (Engerix™B), when co‐administered with GSK Biologicals' oral live attenuated Human Rotavirus (HRV) vaccine, to healthy infants at 3, 4½ and 6 months of age, after a birth dose of Hepatitis B vaccine
Location	9 sites, Russian Federation WHO mortality strata: C
Notes	Date: September 2005 to November 2006 Source of funding: GlaxoSmithKline Study rationale: To compare the 2 formulations of GSK Biologicals' DTPw‐HBV vaccine to concomitant administration of CSL's DTPw vaccine and GSK Biologicals' HBV with respect to the antibody response to the diphtheria antigen after a 3‐dose primary vaccination course.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized (4:1:4:1:5) using GSK Biologicals central randomization system (SBIR)
Allocation concealment (selection bias)	Low risk	Cental allocation.
Blinding (performance bias and detection bias)   All outcomes	Low risk	The study was conducted in a double‐blind manner with respect to the Rotarix and placebo groups and in single‐blinded manner with respect to the Tritanrix‐HepB and Zilbrix groups. The study was open with respect to the Triple Antigen + Engerix‐B group
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants included in analysis
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 30 to 83 days after dose 2 Adverse events data collection methods: active surveillance: at each study visit parents were asked about AEs; passive surveillance: throughout the trial, parents were asked to immediately report AEs to the investigator
Participants	Number: 1009 Age range: 6 to 12 weeks of age at the time of the first study vaccination Inclusion criteria: medically stable pre‐term infants, born within a gestational period of 27 ‐ 36 weeks, planned to be discharged from hospital's neonatal stay on or before the day of the first human rotavirus vaccine/placebo administration Exclusion criteria: use of any investigational or non‐registered product (drug or vaccine) other than the human rotavirus vaccine within 30 days preceding the first dose of human rotavirus vaccine; any clinically significant history of chronic gastrointestinal disease; any confirmed or suspected immunosuppressive or immunodeficient condition; history of allergic disease; major congenital defects or serious chronic illness Each study group is further stratified into 2 subgroups depending on the gestational age at birth of the participant: Stratum I: very pre‐term infants, born after a gestational period of 27 to 30 weeks (189 to 216 days) (20% of enrolment);   Stratum II: mild pre‐term infants born after a gestational period of 31 to 36 weeks (217 to 258 days) (80% of enrolment)
Interventions	1. RV1, 670 participants 2. Placebo, 339 participants Schedule: 2 oral doses of vaccine or placebo, 1 dose at day 0 and 1 dose at months 1 or 2, depending on the country
Outcomes	Clinical outcome measures 1. Serious adverse events, including fatal events and intussusception, from day 0 up to 83 days after dose 2 of RV1 vaccine/placebo 2. Solicited symptoms, within 15 days after each RV1 vaccine/placebo dose. Solicited symptoms included diarrhoea (3 or more looser than normal stools/day), fever (axillary temperature over 37.5 °C), irritability, loss of appetite, and vomiting 3. All‐cause gastroenteritis and rotavirus gastroenteritis, from dose 1 up to 83 days after dose 2 of RV1 vaccine/placebo. Gastroenteritis: diarrhoea with or without vomiting. Rotavirus gastroenteritis: a gastroenteritis episode was a rotavirus gastroenteritis episode if a stool sample taken during or not later than 7 days after the episode was rotavirus positive by ELISA 4. Dropouts before the end of the trial Outcomes to measure immunogenicity 5. Seroconversion to anti‐rotavirus IgA antibody, at Visit 3, 1 month after Dose 2 of RV1 vaccine/placebo. Number of participants with anti‐rotavirus IgA antibody concentration over 20 units/mL
Immunization status	In accordance with the local National Plan of Immunisation schedule in each of the respective participating countries, GSK Biologicals' Infanrix Hexa® (DTPa‐HBV‐IPV/Hib), Infanrix Quinta® (DTPa‐IPV‐Hib), Infanrix®+IPV+Hib (DTPa+IPV+Hib) and/or Engerix‐B® (HBV) will be co‐administered (at a maximum interval of 2 days from each other) with each human rotavirus vaccine or placebo dose Hepatitis B and BCG vaccines at birth are allowed if included in the local National Plan of Immunisation schedule in participating countries At the discretion of the investigator the following vaccines may be administered during each infant's study participation: Vaccine against S. pneumoniae (Prevenar®) in France and Spain (concomitantly with human rotavirus vaccine/placebo). Vaccine against Neisseria meningitidis (Neis Vacc C®) is allowed if there is at least a 14‐day interval with respect to the administration of the human rotavirus vaccine/placebo
Location	France, Poland, Portugal, Spain WHO mortality strata A, B
Notes	Study known as RV1 NCT00420745 2009‐EU in previously published versions of this review Date: January 2007 to March 2008 Source of funding: GlaxoSmithKline Registration number: NCT00420745
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated block randomizations
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias)   All outcomes	Low risk	Parent/guardian and study personnel were not aware of the treatment administered
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data balanced between groups
Selective reporting (reporting bias)	Low risk	All expected outcomes included
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: until infants aged 18 months (i.e. about 13 to 15 months of follow‐up) Adverse events data collection methods: "diary cards during a 15‐day follow‐up period after each vaccine dose was administered, and the symptoms were graded according to severity. AEs occurring up to 42 days after administration of each study vaccine was recorded" (passive method)
Participants	Number: 2464 enrolled; 2365 evaluable Age range: 3 to 6 months Inclusion criteria: male or female infants, born after a normal gestation period of 36 to 42 weeks; aged 11 to 17 weeks at time of first dose of study vaccine; free of obvious health problems as established by medical history and clinical examination before entering into the study Exclusion criteria: "Subjects with previous confirmed occurrence of rotavirus gastroenteritis, previous vaccination against or history of diphtheria, tetanus, pertussis, polio and/or Hib, had a history of allergic reaction to any vaccine component, were immunocompromised or had contact with immunosuppressed individual or pregnant women in their household, had any clinically significant history of chronic gastrointestinal (GI) disease including any uncorrected congenital malformation of GI tract or subjects with use of antibiotics within 7 days preceding Dose 1"
Interventions	RV1 1. RIX4414 (RV1)  1.1. 10^4.7 FFU; 510 participants  1.2. 10^5.2 FFU; 648 participants  1.3. 10^6.1 FFU; 653 participants 2. Placebo; 653 participants All vaccines given in 2 doses with a 1‐month interval Outcomes measured at ˜15 months (efficacy data from 2 weeks after second dose to 18 months of age)
Outcomes	Clinical outcome measures 1. All‐cause diarrhoea: episodes of acute gastroenteritis; parents instructed to record (diary cards) body temperature, the number of episodes of vomiting, the number of looser‐than‐normal stools, and whether they sought medical intervention or medication, and were asked to obtain at least 2 stool samples on 2 different days within 7 days of the onset of symptoms; measured at 2 weeks to 18 months 2. Rotavirus diarrhoea: see all‐cause diarrhoea; "Rotavirus gastroenteritis was confirmed if at least 1 of the 2 stool specimens was found to be positive for rotavirus by ELISA. Rotavirus isolates were G‐typed by use of reverse‐transcriptase polymerase chain reaction (RT‐PCR)"; measured at 2 weeks to 18 months 3. Severe all‐cause diarrhoea: severity of each episode of gastroenteritis graded using a 20‐point scoring system described by Ruuska 1990 4. Severe rotavirus diarrhoea: see severe all‐cause diarrhoea 5. All‐cause death 6. All‐cause hospital admission 7. Emergency department visit 8. Serious adverse events 9. Reactogenicity: fever if rectal temperature > 38 ºC 10. Adverse events requiring discontinuation 11. Rotavirus diarrhoea requiring hospitalization 12. Dropouts Outcomes to measure immunogenicity 11. Shedding of vaccine virus: in stool samples on day of each vaccination and on days 7 and 15 after each vaccination (from 50 participants/group, the "stool sample subset") (review includes data from 1 month after dose 1 and 1 month after dose 2) 12. Seroconversion: serum anti‐rotavirus IgA antibody seroconversion rate; "seroconversion" "defined by an anti‐rotavirus IgA antibody concentration of ≥ 20 U/mL, for infants who were initially (i.e. before administration of the first vaccine dose) seronegative for anti‐rotavirus IgA antibodies (i.e. a concentration of <20 U/mL) and/or who had a stool sample that was negative for rotavirus antigen. Any detection of RIX4414 antigen in stool samples was taken as evidence of a vaccine response"
Immunization status	Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, poliovirus, and H. influenzae type b co‐administered with interventions
Location	8 centres in Singapore WHO mortality stratum A
Notes	Date: 4 January 2001 to 15 April 2003 Funding: GlaxoSmithKline Biologicals Other: 93% of population were Asian
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, using a SAS programme
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Parent/guardian and study personnel were not aware of the treatment administered
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data imputed appropriately
Selective reporting (reporting bias)	Unclear risk	Reasons for low number of rotavirus gastroenteritis; "A smaller number of rotavirus‐related gastroenteritis cases than expected were documented during the study. For 41% (160/387) of the reported gastroenteritis episodes, stool samples were not available for determination of the etiology of the gastroenteritis. No results were available for 6% (24/387) of the gastroenteritis episodes because of an insufficient quantity of stool samples collected or because of invalid results"
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 2 weeks post‐dose 2 to 3 years Adverse events data collection methods: passive method, using diary cards
Participants	Number: 10,708 enrolled; 10,519 evaluable Age range: 3 to 6 months Inclusion criteria: healthy infants 6 to 12 weeks of age in Hong Kong and Taiwan, or 11 to 17 weeks of age in Singapore at the time of the first dose Exclusion criteria: "they did not have a history of chronic administration of immunosuppressants since birth, any confirmed or suspected immunosuppressive or immunodeficient condition, history of allergic disease or reaction likely to be exacerbated by any vaccine component, had not received any investigational drugs/vaccines from 30 days before Dose 1 or planned use during the study, had not received immunoglobulins and/or blood products since birth or planned administration during the study period, did not have any clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of the gastrointestinal tract or other serious medical condition as determined by the investigator, and did not have first or second degree of consanguinity of parents"
Interventions	RV1 1. RIX4414 (RV1) 10⁶ FFU; 5359 participants  2. Placebo; 5349 participants All vaccines given in 2 doses with a 1 to 2 month interval
Outcomes	Clinical outcome measures 1. All‐cause diarrhoea: a gastroenteritis episode was defined as occurrence of diarrhoea with or without vomiting (diarrhoea was defined as the passage of 3 or more looser‐than‐normal stool within a 24‐hour period) 2. Severe all‐cause diarrhoea: severe gastroenteritis was defined as an episode of diarrhoea with or without vomiting that required overnight hospitalization or rehydration therapy, or both (equivalent to WHO plan B or C) in a medical facility and with a score of 11 points on the 20‐point Vesikari scale 3. Rotavirus diarrhoea: stool samples collected during gastroenteritis episodes were tested for the presence of rotavirus using ELISA method (Rotaclone^TM, Meridian Bioscience) at GlaxoSmithKline Biologicals’ laboratories in Rixensart, Belgium. All rotavirus‐positive stool samples were tested by reverse transcriptase polymerase chain reaction (RT‐PCR) followed by reverse hybridization assay, and optional sequencing, at Delft Diagnostic Laboratory, The Netherlands, to determine G and P types, and differentiation of G1P[8] vaccine type 4. Severe rotavirus diarrhoea: see above 5. Emergency department visit: active surveillance was conducted at hospitals and medical facilities in the study area to capture gastroenteritis episodes requiring hospitalization and/or re‐hydration therapy (equivalent to WHO plan B or C) in a medical facility from day of the first vaccine or placebo dose until the follow‐up visit at 24 months of age 6. Serious adverse events: intussusception and SAEs were followed during the study duration. A case of definite intussusception required confirmation at surgery or autopsy or by using imaging techniques such as gas or liquid contrast enema or abdominal ultrasound. Abstractable data for all serious adverse events and Kawasaki disease were only provided for the third year of follow‐up. Intussusception data for the third year follow‐up was not included in the analysis as the follow‐up population was smaller (RV1: 2/4272; placebo: 1/4226) 7. All‐cause deaths Outcomes to measure immunogenicity* None *G types for severe rotavirus diarrhoea up to two years follow‐up was reported and added to the analyses, data for the third year was reported but not included in the analysis as the follow‐up population was smaller"
Immunization status	Infants received other routine paediatric immunizations (combined diphtheria toxoid‐tetanus toxoid‐acellular pertussis (DTPa) inactivated poliovirus (IPV) and H. influenzae type b (HiB) vaccine and hepatitis B vaccine (HBV)) during the study period according to local schedules. Almost all infants received BCG dose at birth. If oral polio vaccine (OPV) was given as part of the routine schedule in the participating countries, a time interval of 2 weeks was observed between the OPV doses and RIX4414 vaccine/placebo doses. One dose of oral polio vaccine (OPV) was given at birth in Hong Kong (99.8% participants) and Taiwan (0.7% participants). However, during the study period, > 95% of infants in the 3 countries received DTPa‐IPV‐HiB concomitantly with both doses of RIX4414 vaccine/placebo as per local schedules. 50.9% of participants were male and the study population was predominantly Chinese (76.3%).
Location	Hong Kong, Singapore, Taiwan WHO mortality stratum A
Notes	Date: 8 December 2003 to 31 August 2005 Funding: GlaxoSmithKline Other: all enrolled infants received the first dose of RIX4414 vaccine or placebo, and 10,551 (98.5%) received both doses
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A randomization list was generated at GSK Biologicals, Rixensart, using a standard SAS® programme and was used to number the vaccines
Allocation concealment (selection bias)	Low risk	A randomization blocking scheme was used to ensure that the balance between treatments was maintained. Treatment allocation at the investigator sites was performed using a central randomization system on the Internet
Blinding (performance bias and detection bias)   All outcomes	Low risk	Data analysis was performed at GSK Biologicals. The treatment code remains masked, except for statisticians and the database administrator
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Primary analysis of efficacy was performed from 2 weeks post‐dose 2 until 2 years of age on the ATP cohort that included participants who completed the full 2‐dose vaccination course and complied with the protocol. The total vaccinated cohort was used to calculate vaccine efficacy starting from the first dose onwards
Selective reporting (reporting bias)	Low risk	All expected outcomes included
Other bias	Low risk	No apparent other bias

Methods	RCT Length of follow‐up: 17 weeks Adverse events data collection methods: not reported
Participants	Number: 200 Age range: 6 to 14 weeks of age at the time of the first study vaccination Inclusion criteria: healthy infants with a live twin living in the same household who is also enrolled in this study, born after a gestation period of over 32 weeks Exclusion criteria: use of any investigational or non‐registered product other than the study vaccine(s); any confirmed or suspected immunosuppressive or immunodeficient condition; any clinically significant history of chronic gastrointestinal disease; history of allergic disease; acute disease at time of enrolment; gastroenteritis within 7 days preceding the first study vaccine administration; documented HIV‐positive infant
Interventions	1. RV1 (RIX 4414) Vaccine, 100 participants 2. Placebo, 100 participants Schedule: both vaccine and placebo 2 doses at Day 0 (Visit 1) and Week 7 (Visit 2) Notes: 1 complimentary dose of RV1 was administered to all infants enrolled in this study (both study groups) who are aged less than 6 months at Visit 3 (Week 13) as a benefit to the placebo group for participation in the study
Outcomes	Clinical outcome measures (safety and efficacy) 1. Gastroenteritis, up to week 17 2. Rotavirus gastroenteritis, up to week 13. Rotavirus gastroenteritis episodes were defined as gastroenteritis episodes for which the stool sample temporally closest to the onset day of the gastroenteritis episode was positive for rotavirus by ELISA 3. Serious adverse events, including fatal serious adverse events and intussusception, up to week 17 4. Dropouts from the study Outcomes to measure immunogenicity 5. Anti‐rotavirus IgA antibody seroconversion and concentration in each group, at visit 3
Immunization status	All infants received 3 doses of combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and H. influenzae vaccine
Location	Dominican Republic WHO mortality stratum B
Notes	Study known as RV1 NCT00396630 2009‐LA in previously published versions of this review. Date: January 2007 to February 2008 Source of funding: GlaxoSmithKline Registration number: NCT00396630 Aim: "to explore horizontal transmission of the HRV [human rotavirus] vaccine strain within a family from the twin vaccinated with Rotarix to the twin receiving placebo"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A randomization list was generated at GlaxoSmithKline (GSK) Biologicals, Rixensart, using a standard SAS^® program. A randomization blocking scheme (1:1 ratio, block size = 2) was used to ensure balance between the treatment arms; a treatment number uniquely identified the vaccine doses to be administered to the same infant"
Allocation concealment (selection bias)	Low risk	Quote: "No investigator or any person involved in the clinical trial (including laboratory personnel, statisticians and data management) was aware of the treatment groups during the course of the study"
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "The study was double‐blinded and the parents/guardians of infants, investigator and the study personnel were unaware of the study vaccine administered"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition/exclusions balanced between groups
Selective reporting (reporting bias)	Low risk	Trial report does not provide enough details
Other bias	Low risk	No apparent other bias