Efficacy of a Low-Cost, Inactivated Whole-Cell Oral Cholera Vaccine: Results from 3 Years of Follow-Up of a Randomized, Controlled Trial

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Abstract
Killed oral cholera vaccines (OCVs) have been licensed for use in developing countries, but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in randomized, clinical trials. We conducted a cluster-randomized, placebo-controlled trial of a two-dose regimen of a low-cost killed whole cell OCV in residents 1 year of age and older living in 3,933 clusters in Kolkata, India. The primary endpoint was culture-proven Vibrio cholerae O1 diarrhea episodes severe enough to require treatment in a health care facility. Of the 66,900 fully dosed individuals (31,932 vaccinees and 34,968 placebo recipients), 38 vaccinees and 128 placebo-recipients developed cholera during three years of follow-up (protective efficacy 66%; one-sided 95%CI lower bound = 53%, p<0.001). Vaccine protection during the third year of follow-up was 65% (one-sided 95%CI lower bound = 44%, p<0.001). Significant protection was evident in the second year of follow-up in children vaccinated at ages 1–4 years and in the third year in older age groups. The killed whole-cell OCV conferred significant protection that was evident in the second year of follow-up in young children and was sustained for at least three years in older age groups. Continued follow-up will be important to establish the vaccine's duration of protection. ClinicalTrials.gov NCT00289224. New-generation vaccines against cholera are given orally, to stimulate intestinal immunity. An internationally available oral cholera vaccine (OCV) consists of killed vibrio whole cells together with the B subunit of cholera toxin, is safe, and protects vaccinated individuals against cholera for two years, but this vaccine has seen limited use due to its high cost. We developed a simpler, inactivated whole-cell only OCV that can be produced inexpensively and might therefore be attractive for use in developing countries, as well as for travelers from industrialized countries. We tested this new OCV in a randomized, controlled field trial that enrolled 69,328 individuals aged one year and older living in urban slums of Kolkata, India. At three years of follow-up after receiving at two-dose regimen of this OCV, the vaccinated population experienced 66% protection against all episodes of cholera occurring during the three years, and 65% protection against episodes occurring during the third year. Significant protection was evident in the second year in children vaccinated at ages 1–4 years and in the third year in persons vaccinated at ages of five years and older. Follow-up of the study population will continue for five years to ascertain the duration of vaccine protection.