New analytic approaches and endpoints in human HIV vaccine correlate studies

人类艾滋病毒疫苗相关研究的新分析方法和终点

• 批准号: 10613609
• 负责人: Margaret E Ackerman
• 金额: $ 79.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-17 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613609
• 关键词: Address; Algorithms; Antibodies; Antibody Response; Antibody Specificity; Antigens; Autologous; Benchmarking; Clinical Trials; Coupled; Data; Data Set; Effector Cell; Exclusion; Exposure to; Failure; Futility; Genetic; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immune response; Immunity; Individual; Infection; Investigation; Investments; Knowledge; Learning; Machine Learning; Measurement; Mediating; Methods; Nature; Outcome; Participant; Passive Transfer of Immunity; Phenotype; Population; Predisposition; Reagent; Risk; Role; Specificity; Supervision; Techniques; Technology; Testing; Vaccinated; Vaccine Research; Vaccinee; Vaccines; Viral; Virus; Work; base; data modeling; efficacy evaluation; efficacy study; efficacy trial; immunogenicity; immunoprophylaxis; improved; infection risk; innovation; insight; neutralizing antibody; next generation; novel; novel strategies; pandemic disease; pathogen; pathogen exposure; pre-clinical; research and development; response; supervised learning; vaccination strategy; vaccine efficacy; vaccine trial

SUMMARY HIV vaccine efficacy trials have been complicated by low rates of exposure and low levels of protection. Yet, despite these barriers, crucial correlates of infection risk (CoR) have been defined from trials that failed to meet overall efficacy criteria. Much has been learned about protective immune responses, host genetics, and viral susceptibility from analysis of ineffective and marginally effective trials. In particular, while neutralizing Ab breadth has long been considered key to vaccine-mediated protection, breadth of Fc-mediated effector functions has only more recently begun to be explored. Given the rich data from natural infection, passive Ab transfer studies probing mechanism of action, preclinical vaccine efficacy studies, and prior human HIV-1 vaccine efficacy trials that support the potential role of Ab effector functions to contribute to protection from infection, these activities represent an important avenue of investigation and optimization in vaccine research and development. To define these CoR, case-control analysis is typically conducted by comparing the response profiles of infected (case) and uninfected (control) subjects. However, the “control", or uninfected subject class is a mixture of individuals that lack the protective response and were simply not exposed to the pathogen, and those that possess the protective response and either were or were not exposed. For poorly effective vaccines, the majority of the control subjects are expected to show a response phenotype indistinguishable from the cases. Thus, traditional CoR analysis suffers from the dilution of the protected subjects with these unprotected but unexposed subjects. We propose to evaluate novel machine learning (ML) techniques that can robustly infer the protection status of vaccinated individuals on the basis of immunogenicity (or other) data in order to facilitate correlates discovery under these challenging circumstances. Accordingly, we propose tandem approaches to develop new insights into HIV vaccine efficacy · by developing new analytical approaches to correlates analysis relevant not only to this but other HIV vaccine trials and beyond, and · by collecting new humoral immune response data defining the breadth and potency of antibody effector function for the HVTN702 trial.

总结 艾滋病毒疫苗有效性试验由于暴露率低和保护水平低而变得复杂。 然而，尽管存在这些障碍，但感染风险的关键相关性（CoR）已经从未能确定的试验中得到了定义。 符合总体疗效标准。关于保护性免疫反应、宿主遗传学和 无效和边际有效试验的病毒易感性分析。特别是，当中和Ab 宽度长期以来被认为是疫苗介导的保护的关键，Fc介导的效应子的宽度 功能只是最近才开始探索。鉴于来自自然感染的丰富数据，被动抗体 探索作用机制的转移研究、临床前疫苗有效性研究和既往人类HIV-1 疫苗有效性试验，支持Ab效应子功能的潜在作用，有助于保护 感染，这些活动代表了疫苗研究中调查和优化的重要途径 发展先行者的要求 为了定义这些CoR，通常通过比较以下反应曲线进行病例对照分析： 感染（病例）和未感染（对照）受试者。但是，“控制”或未感染的主题类是 缺乏保护性反应的个体的混合物，只是没有暴露于病原体， 那些具有保护性反应的人，无论是暴露还是没有暴露。对于效果差的疫苗， 预期大多数对照受试者显示与对照受试者无区别的应答表型。 例因此，传统的CoR分析遭受受保护的主题与这些未受保护的主题的稀释。 但未暴露的实验对象我们建议评估新的机器学习（ML）技术， 根据免疫原性（或其他）数据推断接种个体的保护状态， 有助于在这些具有挑战性的情况下发现相关物。 因此，我们提出了串联的方法，以发展新的见解艾滋病毒疫苗的效力 ·通过开发新的分析方法，将不仅与艾滋病毒相关的分析与其他艾滋病毒相关的分析相关联 疫苗试验及以后， ·通过收集新的体液免疫应答数据，定义抗体效应物的宽度和效力， HVTN 702试验的功能。