Clemens 1988 Bangladesh.

Study characteristics
Methods	Design: Randomized controlled trial (individual randomization) Trial dates and duration: Vaccination January to March 1985; follow‐up 5 years Surveillance: Passive surveillance system at diarrhoea treatment centres serving the study population.
Participants	Number of participants: 89,596 received at least one dose of vaccine or placebo, 62,285 ingested three complete doses Inclusion criteria: children aged 2‐15 years and women over the age of 15 Exclusion criteria: Pregnancy, illness requiring bed rest
Interventions	Vaccine 1: Killed whole cell plus purified cholera B subunit vaccine (WC‐BS) Vaccine 2: Killed whole cell vaccine (WC) Placebo: Escherichia coli K12 strain placebo (K12) All subjects were randomized to receive three doses, at 6 week intervals. All doses were ingested with antacid.
Outcomes	Included in review: Cholera infection (faecal excretion of V. Cholerae 01) Symptomatic cholera infection (faecal excretion of V. Cholerae 01 from 48 hours before to 48 hours after a diarrhoea episode) Cases of cholera (non‐bloody diarrhoea, dehydration and excretion of V. cholerae 01). Cases of cholera, excluding cases that are clinically atypical or associated with mixed infections. Symptomatic and asymptomatic cholera infection detected using active surveillance of among persons residing in the same courtyard as a sentinel cases detected in active surveillance. Participants were surveyed for symptoms and rectal swabs taken and cultured for V. cholerae 01 each day for 7 days. Cases of diarrhoea, classified according to watery and non‐watery, and severe and non‐severe. Deaths from cholera. All deaths. Adverse events within 3 days of first dose and within 3 days of second dose. Cases of diarrhoea and cholera were only included in the analysis if they occurred at least 14 days after the third dose of vaccine or placebo. Not included in the review: Immunological response in participants with cholera, comparing those receiving placebo and placebo. Diarrhoeal episodes associated with other Vibrio and Aeromonas species. Antibacterial and anti‐toxic antibody responses in breast milk. Antibody responses following immunisation. Cases of cholera by neighbourhood vaccine coverage level (herd immunity). Diarrhoea associated with ETEC
Notes	Location: Matlab, Bangladesh Setting: Surveillance study area, served by three diarrhoea treatment centres. Source of funding: Bill and Melinda Gates Foundation; U.S. National Institutes of Health; U.S. National Science Foundation; Swedish International Development Cooperation Agency; governments of Korea, Japan and Kuwait, USAID, Word Health Organization
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote:"After computerisation of the census, we assigned every person in the eligible age‐gender categories to letters A, B or C, using simple randomisation"
Allocation concealment (selection bias)	Low risk	Quote: "The agents were identified only by the letters A, B and C" Comment: Allocation concealed
Blinding (performance bias and detection bias) Efficacy outcomes	Low risk	Quote: "During the conduct of the study, the identities of these letter...were unknown to all persons connected with the trial in Bangladesh"
Blinding (performance bias and detection bias) Safety outcomes	Low risk	As above
Incomplete outcome data (attrition bias) Efficacy outcomes	Low risk	Comment: Attrition between the first and third doses was high: 30.5%. The protective effect is reported as being similar in those who only received two doses, so these losses are unlikely to have introduced significant bias.
Incomplete outcome data (attrition bias) Safety outcomes	Low risk	Comment: There was no missing data for adverse events.
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting.
Other bias	Low risk	No evidence of other bias.