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.

概括 HIV疫苗效率试验的暴露率低和保护率低，使其复杂化。 然而，绝望的这些障碍，感染风险的关键相关性（COR）是从未能的试验中定义的 满足整体效率标准。关于受保护的免疫复杂，宿主遗传学和 对无效和有效试验的分析分析的病毒敏感性。特别是中和AB 长期以来，宽度一直被认为是疫苗介导的保护的关键，FC介导的效应子的宽度 最近才开始探索功能。鉴于来自自然感染的丰富数据，被动AB 转移研究探测作用机理，临床前疫苗效率研究和先前的人类HIV-1 疫苗效率试验支持AB效应功能的潜在作用，从而有助于保护 感染，这些活动代表了疫苗研究的重要投资和优化途径 和发展。 为了定义这些COR，通常通过比较 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 缺乏保护性反应并且根本不暴露于病原体的个体的混合物， 那些具有保护性反应并且未暴露的人。对于有效疫苗不良， 预计大多数对照对象将显示出与 案例。这就是传统的COR分析遭受对受保护受试者的稀释 但是意外的主题。我们建议评估可以强大的机器学习（ML）技术 根据免疫原性（或其他）数据来推断接种个体的保护状态，以便 在这些挑战情况下，有助于发现的发现。 彼此之间，我们提出了串联方法，以开发出对HIV疫苗效率的新见解 ·通过开发新的分析方法来将分析不仅与此相关，而且还与其他艾滋病毒相关 疫苗试验及以后 ·通过收集定义抗体效应器的宽度和效力的新的体液免疫响应数据 HVTN702试验的功能。