RV1 Bernstein 1999‐USA.

Methods	RCT Length of follow‐up: outcomes measured at 2 years Adverse event data collection methods: "diary card for 7 days after vaccine. All moderate to severe side effects were reported by the investigator to an independent study monitor on a continuous basis during the study" (passive method); "telephoned parents every 2 weeks after the first immunisation, and then weekly during the expected rotavirus season (Jan 1‐May 31) as a reminder and to collect data on any adverse events" (active method)
Participants	Number: 215 randomized; 214 evaluable Age range: 3 to 6 months Inclusion criteria: healthy children aged 10 to 16 weeks at the time of the first dose Exclusion criteria: fever; premature labour; an immunosuppressed or pregnant individual in the same household; birth at < 36 weeks of gestation; participation in any other investigational clinical trial; or no telephone in the household
Interventions	89‐12 (a precursor of RIX4414 (RV1) 1. 89‐12 (a precursor of RIX4414 (RV1)): 105 PFU; 2 doses given 6 to 10 weeks apart; 108 participants 2. Placebo: 105 PFU; 2 doses given 6 to 10 weeks apart; 107 participants "Infants received an oral dose of 1.0 mL vaccine (105 PFU) or placebo immediately after 2.0 mL of an antacid containing 160 mg aluminium hydroxide and 160 mg magnesium hydroxide to buffer stomach acid. The infant was not fed for 1 h before or after the immunisation"
Outcomes	Clinical outcome measures 1. All‐cause diarrhoea: gastroenteritis defined as vomiting (> 1 hour after feeding), diarrhoea (≥ 3 looser than normal stools in a 24‐hour period), or both; measured up to 2 years 2. Severe rotavirus diarrhoea: severity assessed using a scoring system with a "20‐point scale identical to that used in previous rotavirus trials. In this system, points are assigned according to the duration and severity of diarrhoea and vomiting, the severity of fever, and the presence of dehydration or hospital admissions for each episode of gastroenteritis. A score greater than 8 was prospectively defined as severe, and a score more than 14 as very severe"; measured up to 2 years 3. Rotavirus diarrhoea: "An illness was classified as caused by rotavirus if a stool specimen collected no later than 7 days after resolution of symptoms contained rotavirus antigen. All episodes of rotavirus gastroenteritis occurring between the second vaccination and the end of the study were included"; measured up to 7 days 4. Reactogenicity: "Parents filled out a diary card for 7 days after each dose. Signs included were: daily (evening) rectal temperatures, diarrhoea, vomiting, and the number and consistency of all stools"; measured up to 7 days 5. All‐cause death; measured up to 2 years 6. Emergency department visit; measured up to 2 years 7. Rotavirus diarrhoea requiring hospitalization Outcomes to measure immunogenicity 8. Vaccine virus shedding (review includes after dose 2 data) 9. Immunogenicity (ELISA): "Serum samples were analysed for IgA and IgG antibody to rotavirus by an ELISA" and "neutralising antibody to the 89‐12 strains by an antigen reduction assay" (only rotavirus‐specific IgA results reported in this review from after dose 2 time point)
Immunization status	Other vaccines separated from the trial vaccines by at least 2 weeks
Location	Cincinnati, Baltimore, and Sellersviller, USA WHO mortality stratum A
Notes	Date: August 1997 to June 1998 Source of funding: Virus Research Institute, Inc. (now Avant Immunotherapeutics Inc.)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Infants were assigned to receive either 89‐12 or placebo according to a computer‐generated randomization schedule (one/one) in blocks of ten provided by the sponsor. The intention‐to‐treat analysis included all participants who received at least one dose of study vaccine. Before the code was broken, all cases of rotavirus gastroenteritis and the severity of each episode were verified"
Allocation concealment (selection bias)	Low risk	As above
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Double‐blind, no details
Incomplete outcome data (attrition bias) All outcomes	Low risk	No impact on intervention effect estimate Quote: "Of the 215 children enrolled, 213 received both doses of vaccine or placebo, and 214 were followed up for gastrointestinal disease. One child in the vaccine group did not receive the vaccine because of persistent fever at the time of the scheduled revaccination, and one child in the placebo group was found to have a congenital tracheal malformation while in the trial and was not revaccinated"
Selective reporting (reporting bias)	Low risk	All expected outcomes included
Other bias	Unclear risk	Insufficient information