Mediation Analyses for the Effect of Antibodies in Vaccination
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We partition the total ratio effect (one minus the vaccine effect) from a vaccine trial into indirect (effects through antibodies) and direct effects (other effects). Identifying p, the proportion of the total effect due to the indirect effect, depends on a cross-world quantity, the potential outcome among vaccinated individuals with antibody levels as if given placebo, or vice versa. We review assumptions for identifying p, showing that, unless the effect of adding antibodies to the placebo arm is equal in magnitude to that of subtracting antibodies from the vaccine arm, there are two versions of p. We focus on the case when the placebo is unlikely to induce needed antibodies, and in that case if a standard assumption (given confounders, potential mediators and potential outcomes are independent) is true, only one version of p is identifiable, and if not neither is identifiable. We propose alternatives for identifying and estimating the other version of p, without making the standard independence assumption and instead experimentally modeling to identify the formerly cross-world quantity. First, a three arm trial with the extra arm being passive immunization (administering monoclonal antibodies), and using a model of antibody level amongst vaccinees. Second, combining information from a placebo-controlled vaccine trial with a placebo-controlled passive immunization trial.
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