RV1 Steele 2010a‐ZAF

Methods	RCT Length of follow‐up: up to 31 days after each vaccine dose and 42 days after the last vaccine dose Adverse event data collection methods: all solicited general symptoms (fever, fussiness /irritability, diarrhoea, vomiting, loss of appetite, cough/runny nose) and unsolicited symptoms were recorded during the 15‐day and 31‐day postvaccination follow‐up period after each RIX4414/placebo dose, respectively. The intensity of adverse events was assessed on a 4‐point scale, where '0' indicated no symptoms; '1' mild; '2' moderate; and '3' severe symptoms. Symptoms of Grade 3 intensity were defined as follows: rectal temperature ≥ 39.5 °C (fever), ≥6 looser‐than‐normal stools a day (diarrhoea), ≥ 3 episodes of vomiting a day (vomiting), refusing food intake (loss of appetite), and preventing normal activity (cough/runny nose, fussiness/irritability). Grade 2 symptoms were defined as rectal temperature of 38.5 °C to 39.5 °C (fever), 4 to 5 looser‐than‐normal stools a day (diarrhoea), 2 episodes of vomiting a day (vomiting), eating lesser than usual, which interfered with normal activity (loss of appetite), and interfering with normal activity (cough/runny nose, fussiness /irritability). Occurrence of SAEs was recorded throughout the study period
Participants	Number: 100 enrolled; 100 evaluable for safety, 50 for immunogenicity Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: only HIV‐positive infants (confirmed at screening) who were clinically asymptomatic or mildly symptomatic (clinical stages I and II according to WHO classification) and aged 6 to 10 weeks at the time of Dose 1 of RIX4414/placebo were enrolled. There were no restrictions on feeding the infants before or after vaccination Exclusion criteria: infants were not included in the study if they were confirmed HIV‐negative, had received any other investigational drug or vaccine 30 days before receiving the first dose of study vaccine, or had a history of chronic gastroenteritis or previous documented rotavirus gastroenteritis
Interventions	1. RV1: 3 doses at least 106.0 CCID50 viral concentration 2. Placebo
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity (see Adverse event data collection methods above) 2. All‐cause diarrhoea; A gastroentiritis episode was defined as diarrhoea (3 or more, looser‐than‐normal stools a day) with or without vomiting. Stool samples were collected on days 0, 7, 15, and 22 of Doses 1 and 2 and on days 0, 7, 15, 30, 45, and 60 of Dose 3 3. Rotavirus diarrhoea; measured from 1 week after second dose up to 2 months' follow‐up 4. Serious adverse events: infants who experienced a serious adverse event and required hospitalization were admitted at the local district hospital in the study sites or at Ga‐Rankuwa Hospital, the referral hospital for the study site and surrounding areas. Parents were informed on the symptoms of intussusception and were instructed to contact the study physician or clinic if any signs of intussusception became apparent. Any suspected cases were immediately referred to Ga‐Rankuwa Hospital. All serious adverse events were reported to the sponsor and the Ethics committees and followed up until resolved. Parents were contacted 6 months after the second dose of RIX4414 or placebo to obtain information on any serious adverse events since the final study visit. All serious adverse events were reviewed periodically by an independent safety monitoring committee 5. All‐cause death 6. Dropouts Outcomes to measure immunogenicity 7. Vaccine take: defined as serum antirotavirus IgA concentration 20 U/mL in post‐vaccination sera or rotavirus vaccine shedding in any stool sample collected from dose 1 to 2 months post‐dose 3 for infants initially negative for rotavirus 8. Seroconversion: appearance of anti‐rotavirus IgA antibody (concentration ≥ 20 U/mL) in participants negative for rotavirus before vaccination (review includes data from 289 participants)
Immunization status	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)
Location	Pretoria, South Africa WHO mortality stratum E
Notes	Registration number: ISRCTN11877362/NCT00263666 Source of funding: RAPID trials (USA); WHO (Switzerland) and GlaxoSmithKline Biologicals For infants who developed clinical symptoms of HIV (WHO stages III or IV disease) anytime 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.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Very likely Quote: "This study was conducted under the WHO RAPID (Rotavirus Action Partnership for Immunization and Development) programme that facilitates conduct of rotavirus vaccine trials in developing countries, specifically in Africa and Asia, to address specific developing country needs. The RAPID partnership consists of public sector partners (including the WHO, US Agency for International Development, National Institutes of Health, Children’s Vaccine Programme and the Centers for Disease Control), academic institutions (International Centre for Diarrhoeal Disease Research, Bangladesh and Medical University of Southern Africa) and GlaxoSmithKline Biologicals".
Allocation concealment (selection bias)	Unclear risk	1:1 randomization, no further details
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The placebo was similar to RIX4414 in appearance and contained the same constituents as the active vaccine except that it did not contain the vaccine virus"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All infants who had received at least one dose of RIX4414 or placebo (total vaccinated cohort) were included in the primary analysis of reactogenicity"
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No apparent other bias