随机研究揭盲后随时间推移的疫苗有效性估计
Estimating Vaccine Efficacy Over Time After a Randomized Study is Unblinded
摘要：
新型冠状病毒SARS CoV-2导致的COVID-19大流行促使疫苗研发取得重大突破，并于二零二零年夏季启动多项第三阶段疫苗试验以评估疫苗效力（VE）。使用Pfizer-BioNTech和Moderna开发的mRNA递送系统进行的候选疫苗试验显示，VE高达94- 95%，导致美国食品和药物管理局发布紧急使用授权，随后广泛使用疫苗。随着试验的继续，一个关键问题是VE可能会随着时间的推移而减弱。出于伦理考虑，所有试验参与者均需揭盲，而随机分配至安慰剂组的受试者则需接种疫苗，从而导致对试验方案进行修订，规定了揭盲策略。安慰剂受试者与疫苗的交叉使VE减弱的推断复杂化。我们专注于Moderna试验的特定功能，并提出了一个基于潜在结果制定的统计框架，在该框架内，我们开发了用于推断VE是否随时间推移而减弱以及在任何接种后时间估计VE的方法。该框架澄清了对个人和人群现象的假设，并承认随着时间的推移，或多或少可能感染的受试者可能会有差异地交叉接种疫苗。该框架的原则可以直接适用于其他试验。
英文摘要：
The COVID-19 pandemic due to the novel coronavirus SARS CoV-2 has inspired remarkable breakthroughs in development of vaccines against the virus and the launch of several phase 3 vaccine trials in Summer 2020 to evaluate vaccine efficacy (VE). Trials of vaccine candidates using mRNA delivery systems developed by Pfizer-BioNTech and Moderna have shown substantial VEs of 94-95%, leading the US Food and Drug Administration to issue Emergency Use Authorizations and subsequent widespread administration of the vaccines. As the trials continue, a key issue is the possibility that VE may wane over time. Ethical considerations dictate that all trial participants be unblinded and those randomized to placebo be offered vaccine, leading to trial protocol amendments specifying unblinding strategies. Crossover of placebo subjects to vaccine complicates inference on waning of VE. We focus on the particular features of the Moderna trial and propose a statistical framework based on a potential outcomes formulation within which we develop methods for inference on whether or not VE wanes over time and estimation of VE at any post-vaccination time. The framework clarifies assumptions made regarding individual- and population-level phenomena and acknowledges the possibility that subjects who are more or less likely to become infected may be crossed over to vaccine differentially over time. The principles of the framework can be adapted straightforwardly to other trials.
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