Unmasking Herd Protection by an Oral Cholera Vaccine in a Cluster-Randomised Trial: A Reanalysis

Abstract

Background: Several studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection to vaccinees and herd protection to populations. Because our earlier cluster randomised, effectiveness trial (CRT) in urban, Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis. Methods: 267,270 persons were randomised to 90 approximately equal-sized clusters. In 60 clusters persons aged one year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesised that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households. Findings: During two years of follow-up of all residents of the clusters total protection (protection of OCV recipients relative to control residents) was 58% (95% CI: 43%, 70%; P<.0001), indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: -20%, 41%; P=.35), and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI:30%,59%; P<.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI:50%,87%, P<.0001), indirect protection 52% (95% CI:-9%,79%; P=.08), and overall protection 72% (95% CI:49%,84%; P<.0001) for the innermost 25% households. Interpretation: Consistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines. Trial Registration Number: Clinical Trials.gov NCT01339845 Funding: Bill and Melinda Gates Foundation Declaration of Interest: We declare no competing interests. Ethical Approval: The study protocol was approved by the Research Review Committee and the Ethical Review Committee of the icddr,b, Dhaka, Bangladesh and the Institutional Review Board of the International Vaccine Institute. Written informed consent was obtained from residents 18 years and older and from the parents or guardians of residents aged 1 to 17 years of age. Additional assent was obtained from residents aged 11 to 17 years.