A challenge to accepted wisdom: systematic review of 35 Years of cholera vaccine trials

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Graves P, Deeks J, Demicheli V, Pratt M, Jefferson T
Cholera killed whole-cell (KWC) vaccines have been discouraged since the 1970s in either endemic or epidemic areas on the grounds that they have low efficacy or short duration of efficacy (3-6 months), require multiple doses, and are less effective in children under five than in adults. Significant adverse effects are stated to occur in the majority of recipients of injected KWC vaccines. We re-examined the evidence for these statements through a systematic review of randomized or quasi-randomized controlled cholera vaccine trials conducted worldwide since 1963. Thirty-two trials fulfilled inclusion criteria, describing the experience of over 2.5 million participants. Vaccines used in efficacy trials (N=17) were either injected or oral KWC vaccines; vaccines evaluated in adverse effect trials (N=19) also included new live recombinant oral vaccines.

Overall vaccine efficacy compared to placebo was 57% (95% CI 50 to 64%) in the first seven months, 51% (CI 41 to 59%) in the first year as a whole, and 47% (CI 36 to 56%) in year 2. Most trials in this comparison (N= 17) used only a single dose, but 2 injected KWC trials and 3 oral trials used a two-dose short schedule, and 1 oral trial a three-dose schedule. Vaccine efficacy in the first year was as great in children under 5 years as in older individuals, but declined to 22% (CI -7 to 43%) in the second year. In year 3 the vaccines had no effect in under 5 year-olds but were still strongly protective in over 5 year-olds (efficacy 57%, CI 38 to 71%). A similar pattern of protection was found for both injected and oral KWC vaccines. Both short and booster schedules of injected KWC vaccination appeared to induce equivalent protection for two years. Addition of a booster dose extended protection into the fourth year (efficacy 39%, CI 2 to 62%). There was evidence that cholera deaths were reduced by vaccination. Whilst local reactions were common for injected vaccines, systemic reaction rates were low (<=13%) for all types of injected and oral vaccines.

The level and duration of efficacy of KWC cholera vaccines appears to have been routinely underestimated in the literature and the incidence of adverse effects overestimated. Factors contributing to this may include unnecessarily complicated trials, poor interpretation, and multiple reporting of selected results. The recommendations against use of cholera KWC vaccines should be reconsidered in the light of the results of this review.