Randomization and baseline transmission in vaccine field trials.

In randomized trials, the treatment assignment mechanism is independent of the outcome of interest and other covariates thought to be relevant in determining this outcome. It also allows, on average, for a balanced distribution of these covariates in the vaccine and placebo groups. Randomization, however, does not guarantee that the estimated effect is an unbiased estimate of the biological effect of interest. We show how exposure to infection can be a confounder even in randomized vaccine field trials. Based on a simple model of the biological efficacy of interest, we extend the arguments on comparability and collapsibility to examine the limits of randomization to control for unmeasured covariates. Estimates from randomized, placebo-controlled Phase III vaccine field trials that differ in baseline transmission are not comparable unless explicit control for baseline transmission is taken into account.