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.

翻译：本文回顾了在随机疫苗试验中识别抗体效应时应用的标准中介分析假设，并提出了新的研究设计，以实现对先前无法识别的估计量的识别。在这些中介分析中，我们将随机疫苗试验的总比率效应（1减去疫苗效应）分解为间接效应（通过抗体产生的效应）和直接效应（其他效应）。识别λ（间接效应占总效应的比例）依赖于一个跨世界量——接种疫苗个体在抗体水平如同接种安慰剂时的潜在结局，反之亦然。我们回顾了识别λ所需的假设，并表明λ存在两个版本，除非在安慰剂组中添加抗体的效应与在疫苗组中去除抗体的效应在量级上相等。我们重点关注安慰剂组个体不太可能具备所需抗体的情形。在这种情况下，若标准假设（在给定混杂因素条件下，潜在中介变量与潜在结局相互独立）成立，则仅有一个版本的λ可被识别；若不成立，则两个版本均不可识别。我们提出了识别另一版本λ的替代方案，通过实验设计来识别原本属于跨世界量的参数。两种替代实验设计采用包含额外臂的三臂试验：被动免疫（施用单克隆抗体）联合或不联合结业疫苗接种。另一种替代方案是将安慰剂对照疫苗试验的信息与安慰剂对照被动免疫试验的信息相结合。