Design and Analysis of Vaccine Trials for Emerging Infectious Disease Threats

摘要 新出现的病原体的爆发变得更加频繁，我们可能会面临未来的流行病， 我们还没有做好充分的准备。有效的疫苗是控制传染病的关键工具 威胁，但实验产品必须严格评估其有效性和安全性，然后才能 许可并部署。我们在2013-2016年西非埃博拉疫情中的经验突出表明， 针对新出现的病原体进行III期疫苗有效性试验的独特挑战。除了问题 在通常资源有限的环境中，基础设施紧张， 人口和时空难以预测。疫情可能会在足够的病例积累到 在三个埃博拉疫苗三期试验中，有两个试验证实了有效性。与标准疫苗相比 临床试验，研究人员在突发公共卫生事件期间进行试验， 关于疾病和/或疫苗的信息。 我们支持在几内亚进行的第三期埃博拉疫苗试验的设计和分析，该试验使用了一种新型环， 疫苗接种方法。根据根除天花的战略，集群被定义为 实验室确诊埃博拉病毒病病例的接触者和接触者的接触者，然后聚集在一起- 随机分为立即或延迟接种。该试验证明了候选药物的高疗效 疫苗，其成功部分归功于其创新的，反应迅速的战略， 随着它的发展，精确地瞄准了暴露风险最高的个人。这些经历激发了 国际上呼吁采用新方法进行疫苗试验设计和分析， 疾病威胁。 我们建议开发灵活的、自适应的试验设计策略，旨在提高效率， 在疫情环境中评估实验性疫苗的成功可能性。我们的第一个目标是发展一个 一类用于样本量计算和分析的响应设计和相关工具 环疫苗接种。我们的第二个目标是概述在不可预测的疾病暴发中实施试验的战略。 持续时间，包括如何定义数据监控规则，以及如何跨爆发聚合信息 当任何特定的爆发太小而无法支持试验时。我们的第三个目标是设计适应性的多臂疫苗 有或没有对照比较物的试验。对于每个目标，我们将描述设计和相关的 定性考虑，开发和验证支持统计方法，并评估其 鲁棒性使用现实的，数学和计算疾病传播模型。我们的研究 这是在实地实施这些战略之前对其进行评估的关键的第一步。

ABSTRACT Outbreaks of emerging pathogens have become more frequent, and we will likely face future epidemics for which we are not adequately prepared. Effective vaccines are a critical tool for controlling infectious disease threats, but experimental products must be rigorously evaluated for efficacy and safety before they can be licensed and deployed. Our experience with the 2013-2016 West African Ebola epidemic highlighted the unique challenges of conducting phase III vaccine efficacy trials for emerging pathogens. Besides issues of strained infrastructure in typically resource-limited settings, incidence may be highly heterogeneous in the population and spatiotemporally hard to predict. The outbreak may end before enough cases have accrued to establish efficacy, as occurred in two of the three phase III Ebola vaccine trials. Compared to standard vaccine clinical trials, researchers conducting trials during public health emergencies also generally have less information about the disease and/or vaccine. We supported the design and analysis of a third phase III Ebola vaccine trial in Guinea that used a novel ring vaccination approach. Modeled after the strategy used to eradicate smallpox, clusters were defined as the contacts and contacts of contacts of laboratory-confirmed Ebola virus disease cases and then cluster- randomized to immediate or delayed vaccination. This trial demonstrated high efficacy of the candidate vaccine, and its success was in part attributed to its innovative, responsive strategy that tracked the epidemic as it progressed, precisely targeting individuals at highest risk of exposure. These experiences have motivated an international call for novel methods for vaccine trial design and analysis adapted for emerging infectious disease threats. We propose the development of flexible, adaptive trial design strategies intended to increase the efficiency and likelihood of success when evaluating experimental vaccines in outbreak settings. Our first aim is to develop a class of responsive designs and associated tools for sample size calculation and analysis generalized beyond ring vaccination. Our second aim is to outline strategies for implementing trials in outbreaks of unpredictable duration, including how to define data monitoring rules and how to aggregate information across outbreaks when any given outbreak is too small to support a trial. Our third aim is to design adaptive, multi-arm vaccine trials with or without a control comparator. For each aim, we will describe the designs and the relevant qualitative considerations, develop and validate the supporting statistical methods, and evaluate their robustness using realistic, mathematical and computational disease transmission models. Our research represents a critical first step for evaluating these strategies before they could be implemented in the field.