Discussion
CHOLERA
Our analysis of the population considered for measurement of overall OCV protection revealed that a program of OCV vaccination, including both vaccinees and non-vaccinees in the population targeted for vaccination, and “Better WASH” preexisting in the households were independently associated with protection against all treated episodes of cholera as well as severe cholera, with protection against severe cholera higher than protection against all cholera episodes. However, when considered jointly, the combination of the OCV program and Better WASH in the household was not associated with greater protection than that for the OCV program among residents of “Not Better WASH” households or for residents of “Better WASH” households in clusters not assigned to OCV.To probe further into these findings, we analyzed the interplay between actual receipt of OCV, rather than merely being targeted by the OCV program, and “Better WASH” in the household by limiting the analysis to the population evaluated for total OCV protection. In this analysis, receipt of two doses of OCV and “Better WASH” preexisting in the household were also independently associated with protection against cholera overall and severe cholera, with higher levels of protection against severe cholera than against cholera overall. However, in contrast to the evaluation of the program of OCV and preexisting WASH in the household, this analysis found a gradient of protection against overall and severe cholera, with non-vaccinees in “Not Better WASH” households at highest risk, and progressively greater protection in non-vaccinees in “Better WASH” households, to vaccinees in “Not Better WASH” households, to vaccinees residing in “Better WASH” households.Our analysis had several strengths, including being based on a well-designed and conducted CRT of OCV, using a previously validated definition of “Better WASH” and “Not Better WASH”, and prospective and comprehensive, systematic surveillance for treated episodes of cholera, employing a prior definition of cholera and severe cholera. However, our analysis also had several important limitations. Although the analysis of overall OCV protection was randomized, for reasons described elsewhere [The literature available on the separate and combined effects of OCV and WASH is very limited. As mentioned earlier, the original purpose of this CRT was to assess whether a WASH intervention improved the protection conferred by OCV. The trial failed to find such a positive interaction between OCV and WASH but was limited by poor uptake of the WASH intervention Because of the limitations of our study and the divergent findings for the populations analyzed for overall and total OCV protection, we conclude that while our analysis suggests the potential for programs of OCV and WASH to act together to protect against cholera overall and against severe cholera, the analysis per se is insufficient to convincingly demonstrate a positive interaction. To address one limitation of our analysis, we plan to undertake further analysis of this CRT using the “fried egg” approach, which has been demonstrated to counter the bias caused by the ingress of cholera into the clusters from the outside 