Statistical Methods in HIV Vaccine Efficacy Trials

HIV 疫苗功效试验中的统计方法

• 批准号: 9251714
• 负责人: Peter B. Gilbert
• 金额: $ 36.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251714
• 关键词: AIDS/HIV problem; Affect; Antibodies; Benchmarking; Categories; Characteristics; Communicable Diseases; Data; Data Analyses; Dengue; Dependency; Development; Dose; Genetic; Genotype; Goals; HIV; HIV Infections; HIV vaccine; Herpes zoster disease; Immune; Immune response; Immunize; Immunologics; Infection; Influenza; Instruction; Link; Measures; Methods; Participant; Phase; Phenotype; Principal Investigator; Process; Randomized; Randomized Clinical Trials; Regimen; Research; Risk; SIV; SIV Vaccines; Sample Size; Sampling; Series; Statistical Methods; Subgroup; Surrogate Endpoint; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Vaccination; Vaccines; Variant; base; design; efficacy trial; flexibility; immunogenicity; improved; meetings; nonhuman primate; novel; prevent; randomized trial; response; response biomarker; structural biology; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial

An ultimate goal of HIV/AIDS research is the development of a vaccine that prevents HIV infection, which will be needed for eliminating HIV/AIDS in the U.S. and globally. Randomized clinical trials that rigorously assess the efficacy of candidate HIV vaccines are a core research approach to meeting this goal. This project develops statistical methods for HIV vaccine efficacy trials and for parallel repeated low-dose challenge trials of SIV vaccines in nonhuman primates. For efficacy trials. Aims 1 and 2 develop novel and interdigitating statistical methods for: (1) sieve analysis, i.e., the assessment of how vaccine efficacy against HIV infection varies with genetic features of transmitting HIVs; and (2) immune correlates of protection analysis, i.e., the assessment of how vaccine efficacy against HIV infection and against genotype-specific HIV infection varies with immune responses to vaccination. The overarching objective of these two aims is development of immune correlates of protection (CoPs), which are needed for guiding the optimal choice of HIV sequences to include in vaccines, for guiding the choice of immunogenicity endpoints for benchmarking refined vaccine regimens in Phase l/ll trials, and for immuno-bridging of efficacy trial results to predict vaccine efficacy in new settings. The methods will focus on (A) efficiently and flexibly accommodating time- variations in vaccine efficacy; (B) maximizing the immunological relevance ofthe HIV genetic features; (C) improving the sampling design for measuring immune responses; and (D) developing the best threshold or score immune CoPs that combine information from the large set of immune responses that are assessed. Many ofthe new methods will improve validity, efficiency, and robustness via the targeted maximum likelihood statistical framework. The methods will be developed with application to 13 vaccine efficacy trials (8 for HIV, 3 for dengue, 1 for herpes zoster, 1 for influenza). Aim 3 parallels Aims 1 and 2 by developing novel statistical methods for assessing within nonhuman primate repeated low-dose challenge trials how vaccine efficacy to prevent SIV infection over time varies with genetic features of exposing SIVs and with immune responses to vaccination. The Aim 3 research plan focuses on issues (A), (B), and (D)"and will be developed with application to several trials from three research groups. RELEVANCE (See instructions): A vaccine that prevents HIV infection is needed for eliminating HIV/AIDS in the U.S. and globally. Such avaccine may be developed through a series of vaccine efficacy trials that identify candidate vaccines conferring partial protection against HIV infection, and that identify how the protection varies with the genetics of HIV and with immune responses to vaccination. This project develops novel statistical methods for improving and accelerating this process; these methods also apply to the development of vaccines for other infectious diseases.

艾滋病毒/艾滋病研究的一个最终目标是开发一种预防艾滋病毒感染的疫苗， 将需要在美国和全球消除艾滋病毒/艾滋病。随机临床试验， 评估候选艾滋病毒疫苗的有效性是实现这一目标的核心研究方法。这 一个项目开发了艾滋病毒疫苗有效性试验和平行重复低剂量试验的统计方法 SIV疫苗在非人灵长类动物中的攻毒试验。做疗效试验。目标1和2开发新的和 交错的统计方法用于：（1）筛分析，即，评估疫苗对 HIV感染随HIV传播的遗传特征而变化;（2）保护的免疫相关性 分析，即，评估疫苗对艾滋病毒感染和对基因型特异性 艾滋病毒感染随着对疫苗接种的免疫反应而变化。这两个目标的首要目标是 开发免疫保护相关物（CoP），这是指导最佳选择所需的。 疫苗中包含的HIV序列，用于指导基准免疫原性终点的选择 在I/II期试验中改进疫苗方案，并用于有效性试验结果的免疫桥接，以预测 新环境下的疫苗效力。这些方法将侧重于（A）有效和灵活地适应时间- 疫苗效力的变化;（B）最大化HIV遗传特征的免疫相关性;（C） 改进用于测量免疫应答的采样设计;以及（D）开发最佳阈值或 对结合了来自所评估的免疫应答的大集合的联合收割机信息的免疫CoP进行评分。 许多新方法将通过目标最大值来提高有效性、效率和鲁棒性 概率统计框架。这些方法将应用于13个疫苗有效性试验 （艾滋病毒8例，登革热3例，带状疱疹1例，流感1例）。 目标3与目标1和目标2相似，通过开发新的统计方法来评估非人类 灵长类动物重复低剂量攻毒试验：疫苗预防SIV感染的效力如何随时间变化 具有暴露SIV的遗传特征和对疫苗接种的免疫应答。Aim 3研究计划 重点是问题（A），（B）和（D）“，并将开发应用于三个试验中的几个试验 研究团体。 相关性（参见说明）： 预防艾滋病毒感染的疫苗是在美国和全球消除艾滋病毒/艾滋病所必需的。等 通过一系列疫苗效力试验， 提供部分保护，防止艾滋病毒感染，并确定如何保护不同， 艾滋病毒的遗传学和对疫苗接种的免疫反应。该项目开发了新颖的统计方法 用于改善和加速这一过程;这些方法也适用于疫苗的开发， 其他传染病。