title: Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Oral cholera vaccines consisting of killed whole cells have been available for many years, but they have not been used extensively in populations with endemic disease. An inexpensive, locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam. To expand the use of this vaccine, it was modified to comply with WHO standards. We assessed the efficacy and safety of this modified vaccine in a population with endemic cholera.
  
  
  METHODS
  In this double-blind trial, 107 774 non-pregnant residents of Kolkata, India, aged 1 year or older, were cluster-randomised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine (n=52 212; 1966 clusters) or heat-killed Escherichia coli K12 placebo (n=55 562; 1967 clusters), both delivered orally. Randomisation was done by computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for the patient to seek treatment in a health-care facility. We undertook an interim, per-protocol analysis at 2 years of follow-up that included individuals who received two completely ingested doses of vaccine or placebo. We assessed first episodes of cholera that occurred between 14 days and 730 days after receipt of the second dose. This study is registered with ClinicalTrials.gov, number NCT00289224.
  
  
  RESULTS
  31 932 participants assigned to vaccine (1721 clusters) and 34 968 assigned to placebo (1757 clusters) received two doses of study treatment. There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group (protective efficacy 67%; one-tailed 99% CI, lower bound 35%, p<0.0001). The vaccine protected individuals in age-groups 1.0-4.9 years, 5.0-14.9 years, and 15 years and older, and protective efficacy did not differ significantly between age-groups (p=0.28). We recorded no vaccine-related serious adverse events.
  
  
  CONCLUSIONS
  This modified killed-whole-cell oral vaccine, compliant with WHO standards, is safe, provides protection against clinically significant cholera in an endemic setting, and can be used in children aged 1.0-4.9 years, who are at highest risk of developing cholera in endemic settings.
  
  
  BACKGROUND
  Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, Governments of South Korea, Sweden, and Kuwait.
authors.affiliation: National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Dipika
authors.initials: D
authors.lastname: Sur
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Lopez
authors.forename: Suman
authors.initials: S
authors.lastname: Kanungo
authors.forename: Allison
authors.initials: A
authors.lastname: Paisley
authors.forename: Byomkesh
authors.initials: B
authors.lastname: Manna
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ali
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Niyogi
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Park
authors.forename: Banawarilal
authors.initials: B
authors.lastname: Sarkar
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Puri
authors.forename: Deok Ryun
authors.initials: DR
authors.lastname: Kim
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Deen
authors.forename: Jan
authors.initials: J
authors.lastname: Holmgren
authors.forename: Rodney
authors.initials: R
authors.lastname: Carbis
authors.forename: Raman
authors.initials: R
authors.lastname: Rao
authors.forename: Thu Van
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Allan
authors.initials: A
authors.lastname: Donner
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Ganguly
authors.forename: G Balakrish
authors.initials: GB
authors.lastname: Nair
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: John D
authors.initials: JD
authors.lastname: Clemens
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002771:Cholera / Q000453:epidemiology / Q000382:microbiology / Q000517:prevention & control*; D022121:Cholera Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology* / Q000600:supply & distribution; D016000:Cluster Analysis; D004311:Double-Blind Method; D019353:Endemic Diseases / Q000517:prevention & control / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007115:Immunization Schedule; D007194:India / Q000453:epidemiology; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D016016:Proportional Hazards Models; D012449:Safety; D015164:Vaccines, Inactivated
chemical_list: D022121:Cholera Vaccines; D015164:Vaccines, Inactivated