RV1 Salinas 2005‐LA.

Methods	RCT Length of follow‐up: up to 2 years (stated in GlaxoSmithKline report) Adverse event data collection methods: diary cards were supplied to the parents to record occurrence of specific solicited symptoms for 15 days after each vaccination (passive method); any other unsolicited symptoms were recorded during 43 days after each vaccination (passive method); serious adverse events were recorded throughout the study
Participants	Number: 2155 enrolled; 2004 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants, born after a normal gestation period of 36 to 42 weeks or with a birth weight > 2000 g; aged 6 to 12 weeks at the time of the first vaccination; free of obvious health problems as established by medical history and clinical examination before entering into the study Exclusion criteria: previous confirmed occurrence of rotavirus gastroenteritis; previous vaccination against or history of diphtheria, tetanus, pertussis, polio and/or H. influenzae type b vaccine (HiB); any clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of gastrointestinal tract; use of antibiotics within 7 days preceding dose 1; immunocompromised or were in household contact with an immunosuppressed individual or pregnant woman
Interventions	RV1 1. RIX4414 (RV1) 1.1. 104.7 PFU; 538 participants (randomized) 1.2. 105.2 PFU; 540 participants (randomized) 1.3. 105.8 PFU; 540 participants (randomized) 2. Placebo: 537 participants (randomized) Schedule: 2 doses given every 2 months An additional 200 participants were randomized to RV1 x placebo to receive 3 doses. This is not mentioned in the main publication, only in the GlaxoSmithKline report (no data available)
Outcomes	Clinical outcome measures (safety and efficacy) 1. Serious adverse events: no definition; measured during follow‐up (2 years) 2. Reactogenicity: no definition; measured up to 43 days after vaccination 3. All‐cause diarrhoea: gastroenteritis defined as diarrhoea characterized by ≥ 3 looser than normal stools within a day; minimum of 5 days required between episodes for them to be considered as separate events; measured during follow‐up (2 years) 4. Severe all‐cause diarrhoea: information on diary cards was used to assess the severity of each gastroenteritis episode according to a 20‐point scoring system; measured during follow‐up (2 years) 5. Rotavirus diarrhoea: all rotavirus‐positive specimens were tested by RT‐PCR at GlaxoSmithKline to determine the G type; any G1 rotavirus detected until 2 months after the second dose were analyzed to differentiate between vaccine strain and wild G1 strains; only gastroenteritis episodes in which wild rotavirus other than the vaccine strain was identified in a stool specimen were included in the efficacy analysis; measured during follow‐up (2 years) 6. Severe rotavirus diarrhoea: see above; measured during follow‐up (2 years) 7. All‐cause hospital admission: no definition; measured during follow‐up (2 years) 8. All‐cause mortality: no definition; measured during follow‐up (2 years) 9. Rotavirus diarrhoea resulting in hospitalization Outcomes to measure immunogenicity 10. Vaccine take: rotavirus shedding in stool specimens (review includes data from day 7 after dose 2) 11. Seroconversion: "percentages of infants with post‐antirotavirus IgA antibody concentration 20 units/mL in infants who were negative for rotavirus before the first dose of RIX4414 or placebo" (review includes data from 2 months after dose 1 and 2 months after dose 2)
Immunization status	Oral polio vaccine given after 2 weeks, not together with RV1
Location	Belem (Brazil), Mexico City (Mexico), Valencia (Venezuela) WHO mortality stratum B
Notes	Date: 25 May 2001 to 8 November 2003 Source of funding: GlaxoSmithKline Biologicals Malnutrition: reported in Journal of Infectious Disease, 2007, 196(4): 537‐40 Other: 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 Immunogenicity sampling: "A subset of infants (N 800) provided blood samples 2 months after the first dose (serology for antirotavirus IgA antibodies) and 2 months after the second dose (serology for antirotavirus IgA antibodies and antibodies against antigens of routine infant vaccines). The first 200 enrolled infants in each participating country constituted this subset, and the remaining 200 infants were included according to the order of enrolment irrespective of country".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated Quote:"The participating infants were randomly assigned to one of the 4 study groups (3 vaccine groups and a placebo group) following a 1:1:1:1 allocation ratio according to a computer‐generated randomization list"
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "Double blinding was maintained during the entire study period"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data balanced across groups
Selective reporting (reporting bias)	High risk	Not all prespecified outcomes reported
Other bias	Unclear risk	GlaxoSmithKline final report stated that part of the population received 3 doses of rotavirus vaccine. This was not mentioned on the original published report