We review standard mediation assumptions as they apply to identifying antibody effects in a randomized vaccine trial and propose new study designs to allow identification of an estimand that was previously unidentifiable. For these mediation analyses, we partition the total ratio effect (one minus the vaccine effect) from a randomized vaccine trial into indirect (effects through antibodies) and direct effects (other effects). Identifying $\lambda$, the proportion of the total effect due to an 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 $\lambda$ and show that there are two versions of $\lambda$, unless the effect of adding antibodies to the placebo arm is equal in magnitude to the effect of subtracting antibodies from the vaccine arm. We focus on the case when individuals in the placebo arm are unlikely to have the needed antibodies. In that case, if a standard assumption (given confounders, potential mediators and potential outcomes are independent) is true, only one version of $\lambda$ is identifiable, and if not neither is identifiable. We propose alternatives for identifying the other version of $\lambda$, using experimental design to identify a formerly cross-world quantity. Two alternative experimental designs use a three arm trial with the extra arm being passive immunization (administering monoclonal antibodies), with or without closeout vaccination. Another alternative is to combine information from a placebo-controlled vaccine trial with a placebo-controlled passive immunization trial.

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