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/艾滋病研究的最终目标是开发一种预防艾滋病毒感染的疫苗， 在美国和全球范围内消除艾滋病毒/艾滋病是必要的。严格随机临床试验 评估候选艾滋病毒疫苗的功效是实现这一目标的核心研究方法。这 项目开发艾滋病毒疫苗功效试验和平行重复低剂量的统计方法 SIV 疫苗在非人类灵长类动物中的挑战试验。用于功效试验。目标 1 和 2 开发新颖且 交叉统计方法用于：（1）筛分分析，即评估疫苗的功效如何 HIV 感染因传播 HIV 的遗传特征而异； (2) 保护的免疫相关性 分析，即评估疫苗对 HIV 感染和基因型特异性的功效如何 HIV 感染随对疫苗接种的免疫反应而变化。这两个目标的总体目标是 保护的免疫相关性（CoP）的发展，这是指导最佳选择所必需的 疫苗中包含的 HIV 序列，用于指导选择免疫原性终点进行基准测试 l/ll 期试验中改进的疫苗方案，以及功效试验结果的免疫桥接以预测 新环境下的疫苗功效。这些方法将侧重于 (A) 有效且灵活地适应时间- 疫苗功效的变化； (B) 最大化 HIV 遗传特征的免疫相关性； (三) 改进测量免疫反应的抽样设计； (D) 制定最佳阈值或 对免疫 CoP 进行评分，该 CoP 结合了所评估的大量免疫反应的信息。 许多新方法将通过目标最大程度提高有效性、效率和鲁棒性。 可能性统计框架。该方法将应用于 13 项疫苗功效试验 （8 个用于艾滋病毒，3 个用于登革热，1 个用于带状疱疹，1 个用于流感）。 目标 3 与目标 1 和 2 平行，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激发试验 疫苗预防 SIV 感染的功效如何随着时间的推移而变化 具有暴露 SIV 的遗传特征以及对疫苗接种的免疫反应。目标 3 研究计划 重点关注问题 (A)、(B) 和 (D)”，并将在三个试验中进行开发 研究小组。 相关性（参见说明）： 为了消除美国和全球的艾滋病毒/艾滋病，需要一种预防艾滋病毒感染的疫苗。这样的 疫苗可以通过一系列疫苗功效试验来开发，以确定候选疫苗 提供针对 HIV 感染的部分保护，并确定保护如何随艾滋病毒感染而变化 HIV 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 改进和加速这一过程；这些方法也适用于疫苗的开发 其他传染病。