Randomization and baseline transmission in vaccine field trials

Abstract

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.

Estimating the Per-Exposure Effect of Infectious Disease Interventions

“…8,9 We first propose a definition of a per-exposure effect based on Halloran and Struchiner's work, 8 and then describe the assumptions commonly made to estimate it.…”

“…We elected to define the average per-exposure effect as the effect at the first exposure after baseline, in order to simplify the example and because the literature on intervention effects conditional upon exposure has commonly used a single exposure as the relevant unit. 9 However, researchers could estimate the effect of an intervention after any specified number of exposures where the timing of each exposure is specified.…”

“…Notably, no confounding would arise in the presence of U - E t co-action if U were independent of exposure. 9 …”

“…Note that, unlike Struchiner and Halloran, 9 we use here a definition of confounding that is not based on collapsibility. 27,28 …”

Emerging, evolving, and established infectious diseases and interventions

“…However, the trial does not provide information on whether the vaccine protects against infection, or just disease, or whether it reduces the infectiousness of infected individuals for mosquitoes. The exact nature of the interaction of vaccine induced immunity with preexisting immunity and exposure to infection is also not well understood and can effect the interpretation of the vaccine effects [11]. All of these inputs are necessary to model the potential population level effects and cost-effectiveness of dengue vaccination programs in different populations.…”