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，但实验产品必须经过严格的有效性和安全性评估，才能 已获得许可并已部署。我们在2013-2016年西非埃博拉疫情中的经验突显了 对新出现的病原体进行第三阶段疫苗效力试验的独特挑战。除了以下问题 紧张的基础设施在通常资源有限的环境中，发病率可能在 人口和时空上很难预测。疫情可能会在足够多的病例累积到 确定效力，就像在三个第三阶段埃博拉疫苗试验中的两个试验中所发生的那样。与标准疫苗相比 临床试验，在突发公共卫生事件期间进行试验的研究人员通常也较少 有关疾病和/或疫苗的信息。 我们支持了几内亚第三阶段埃博拉疫苗试验的设计和分析，该试验使用了一种新的环 接种疫苗的方法。仿照根除天花的战略，集群被定义为 接触者和实验室确诊的埃博拉病毒病例的接触者，然后聚集- 随机选择立即或延迟接种疫苗。这项试验证明了候选人的高效性 疫苗，它的成功在一定程度上归功于其跟踪疫情的创新、反应战略 随着它的进展，准确地针对接触风险最高的个人。这些经历激发了人们 国际呼吁为适应新出现的传染病的疫苗试验设计和分析提供新的方法 疾病威胁。 我们建议开发灵活的、适应性的试验设计策略，旨在提高效率和 在暴发环境中评估实验疫苗时成功的可能性。我们的首要目标是开发一种 广义样本容量计算和分析的响应性设计及相关工具的类别 环状疫苗接种。我们的第二个目标是概述在不可预测的疾病爆发时实施试验的战略。 持续时间，包括如何定义数据监控规则以及如何跨疫情聚合信息 当任何给定的疫情太小而不能支持试验时。我们的第三个目标是设计适应性多臂疫苗 有或没有对照比较器的试验。对于每个目标，我们将描述设计和相关的 定性考虑，开发和验证支持性统计方法，并评估其 使用现实的、数学的和计算的疾病传播模型的稳健性。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.