RV5 Clark 2003‐USA.

Methods	RCT Length of follow‐up: up to 1 year Adverse event data collection methods: parents/guardians recorded temperatures 4 to 6 hours after each dose and then daily thereafter for 7 days and the number of episodes of vomiting and diarrhoea daily for 7 days (passive method); also recorded any behavioural or systemic adverse experience on a VRC and was asked to report any serious adverse experience immediately to the study site; telephone call made to each parent/guardian 14 days after each dose to verify that no serious adverse experiences had occurred (active)
Participants	Number: 731 enrolled; 681 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Special groups: breast‐fed; infants in the vaccine control group (Group 1) received the reassortants as administered in previous studies within 30 minutes 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 Inclusion criteria: healthy infants 2 to 4 months of age Exclusion criteria: known hypersensitivity to any component of the rotavirus vaccine; known or suspected immunologic impairment; prior administration of any rotavirus vaccine; fever at the time of vaccination; history of chronic diarrhoea; failure to thrive or gastrointestinal illness; recent receipt of oral polio vaccine or blood products; residence in the household with an immunocompromised person; and failure to fast for 1 hour before vaccination
Interventions	RV5 1. WC3 (RV5): 107 PFU; 581 participants (randomized) 2. Placebo: 150 participants (randomized) Schedule: 3 doses given 42 to 56 days apart
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity: parents/guardians recorded temperatures 4 to 6 hours after each dose and then daily thereafter for 7 days and the number of episodes of vomiting and diarrhoea daily for 7 days; fever defined as 38.1 °C (rectal) or 37.5 °C (oral, otic, or axillary); measured up to 42 days after vaccine/placebo 2. Rotavirus diarrhoea: case of rotavirus gastroenteritis defined as ≥ 3 watery or looser‐than‐normal stools within a 24‐hour period or forceful vomiting, or both, occurring at least 14 days after the third dose of vaccine/placebo and detection by ELISA of wild‐type G1 or G2 rotavirus or both in a stool specimen collected within 14 days of symptom onset; measured up to 1 year 3. Severe rotavirus diarrhoea: clinical scoring system used to assess severity of illness for each episode of rotavirus acute gastroenteritis; measured up to 1 year 4. Serious adverse events: defined as: death; life‐threatening events; experiences that resulted in hospitalization, persistent disability, or that prolonged a hospitalization; and other important medical events. Data on deaths or any serious adverse experiences judged to be vaccine‐related were collected for the duration of the study; measured up to 1 year 5. Intussusception, data from correspondence with Merck (Merck 2012) 6. Dropouts Outcomes to measure immunogenicity 7. Viral shedding: at least a 3‐fold rise in serum‐neutralizing antibody to total stool IgA (review includes data from after dose 3) 8. Seroconversion: at least a 3‐fold rise in serum‐neutralizing antibody to serum IgA (review includes data from after dose 3)
Immunization status	Children that had recently received oral polio vaccine were excluded from the study
Location	19 centres in the USA WHO mortality stratum A
Notes	Date: September 1997 through September 1998 Source of funding: Merck & Co., Inc. Other: active surveillance for cases of rotavirus gastroenteritis at each study site began when the local laboratory confirmed at least 3 cases of rotavirus gastroenteritis or on 31 January 1998, whichever came first
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details Quote: "Children who met all eligibility criteria were randomized to one of eight treatment groups"
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and key personnel Quote: "Parents of participating infants and study personnel were blinded to receipt of vaccine/placebo but not to the volume administered or to the prefeeding requirement"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of attrition/exclusions
Selective reporting (reporting bias)	High risk	Not all prespecified outcomes reported Quote: "Because there were relatively few confirmed cases of RV [rotavirus] caused by serotypes G1 and G2, the evidence is insufficient to declare that the efficacy of any buffered formulation is > 0.0%"
Other bias	High risk	Poor reporting of efficacy data