Antigenic and virological traits of HIV-1 breakthrough infections in the VRC01 antibody-mediated prevention Phase 2b trial in sub-Saharan Africa

撒哈拉以南非洲 VRC01 抗体介导的预防 2b 期试验中 HIV-1 突破性感染的抗原和病毒学特征

• 批准号: 10609096
• 负责人: Peter B. Gilbert
• 金额: $ 33.34万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-17 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609096
• 关键词: AIDS prevention; Active Immunization; Address; Affect; Africa; Africa South of the Sahara; African; Amino Acids; Ancillary Study; Antibodies; Attenuated; Binding Sites; Biological Assay; CD4 Lymphocyte Count; Chimera organism; Clinical; Clinical Markers; Clinical Trials; Collaborations; Communicable Diseases; Complex; Consensus; Data; Data Coordinating Center; Effectiveness; Epidemic; Event; Failure; Fred Hutchinson Cancer Research Center; Future; Genetic Determinism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; HIV; HIV Infections; HIV Vaccine Trials Network; HIV-1; HIV-1 vaccine; Immune Evasion; Immunization; Infection; Infection prevention; Infusion procedures; Institution; Investigation; Kinetics; Laboratories; Measures; Mediating; Mutation; Natural Resistance; Outcome; Parents; Passive Immunization; Pathogenesis; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Predisposition; Prevention; Prevention approach; Prevention trial; Preventive; Protocols documentation; Research Personnel; Resistance; Safety; Sampling; Science; Seminal; Serum; Site; South Africa; South African; Standardization; Testing; Training; Underrepresented Populations; Universities; Update; Vaccines; Validation; Viral; Viral Load result; Virus; Woman; arm; breakthrough infection; case control; cost; env Gene Products; fitness; flexibility; genetic predictors; genetic resistance; improved; in silico; infection rate; insight; member; mutant; neutralizing antibody; next generation; novel; pressure; programs; secondary analysis; tool; trait; transmission process; vaccine access; viral fitness; viral transmission; virus genetics

PROJECT SUMMARY Whether through active or passive immunization, broadly neutralizing antibodies (bNAbs) will likely form a cornerstone of HIV prevention. This application proposes an ancillary study of the African component of the antibody-mediated prevention trial (AMP) (HVTN 703/HPTN 081). The AMP study is the first proof-of-concept trial to evaluate the safety and efficacy of a bNAb (VRC01) to block HIV acquisition. Our team is involved in the laboratory investigations to measure serum levels associated with protection, and through sieve analysis, to determine how predicted genotypic features correlate with prevention efficacy. The goal of this application is to provide a deeper understanding on how HIV-1 diversity affects the amount of antibody needed to prevent infection; and the clinical consequences of infection with VRC01-resistant viruses. The extreme diversity of circulating HIV strains, together with the flexibility of the Envelope protein (Env) in evading immune pressure, could threaten the effectiveness of immunization studies. Utilizing sequence data and functional env clones from AMP breakthrough infections, the first aim will provide an up-to-date bNAb sensitivity profile of circulating strains, providing data useful for future clinical trials. This analysis will be done using the standardized Env-pseudotyped assay, and a subset will also be evaluated using infectious env clones generated in PBMCs to verify these data. The parent protocol sieve analysis will predict genetic features that affect VRC01 neutralization susceptibility and resistance, and the second aim of this application will experimentally validate these predictions, as well as evaluate how the cognate Env of breakthrough infections influences the impact of these mutations. This will provide experimental data on how changes in envelope affect the amount of antibody needed for prevention of infection. Lastly, VRC01 escape mutations have been associated with reduced viral fitness and we will compare fitness of VRC01-resistant and sensitive viruses and determine how this affects key clinical markers such as HIV viral load and CD4 counts. The HVTN 703/HPTN 081 trial provides a unique opportunity to define the impact of diversity on bNAb efficacy in a sub-Saharan Africa setting where new prevention approaches are still urgently needed. This study will be led by investigators at the University of Cape Town and the Fred Hutchinson Cancer Research Center, in collaboration with the National Institute for Communicable Diseases, and includes a training partnership with North-West University in Mahikeng, South Africa. Information generated in this proposal will support the next phase of combination passive immunization trials and will provide seminal data to understand the prevention efficacy of VRC01.

项目概要 无论是主动免疫还是被动免疫，都可能形成广泛中和抗体 (bNAb) 艾滋病毒预防的基石。本申请提出了对非洲部分的辅助研究 抗体介导的预防试验 (AMP) (HVTN 703/HPTN 081)。 AMP 研究是第一个概念验证 评估 bNAb (VRC01) 阻止 HIV 感染的安全性和有效性的试验。我们的团队参与 实验室研究测量与保护相关的血清水平，并通过筛分分析， 确定预测的基因型特征如何与预防功效相关。该应用程序的目标是 更深入地了解 HIV-1 多样性如何影响所需的抗体量 预防感染；以及 VRC01 抗性病毒感染的临床后果。 流行的 HIV 毒株的极端多样性以及包膜蛋白 (Env) 的灵活性 在逃避免疫压力时，可能会威胁免疫研究的有效性。利用序列数据 以及来自 AMP 突破性感染的功能性 env 克隆，第一个目标将提供最新的 bNAb 循环菌株的敏感性概况，为未来的临床试验提供有用的数据。将进行此分析 使用标准化的环境假型检测，并且还将使用感染性环境克隆来评估子集 在 PBMC 中生成以验证这些数据。父协议筛分析将预测遗传特征 影响VRC01中和敏感性和耐药性，本申请的第二个目标是 通过实验验证这些预测，并评估突破性感染的同源环境如何 影响这些突变的影响。这将提供关于包络变化如何影响的实验数据 预防感染所需的抗体量。最后，VRC01 逃逸突变已被 与病毒适应性降低相关，我们将比较 VRC01 抗性和敏感病毒的适应性 确定这如何影响关键临床标志物，例如 HIV 病毒载量和 CD4 计数。 HVTN 703/HPTN 081 试验提供了一个独特的机会来定义多样性对 bNAb 的影响 撒哈拉以南非洲地区仍然迫切需要新的预防方法。这项研究 将由开普敦大学和弗雷德·哈钦森癌症研究中心的研究人员领导， 与国家传染病研究所合作，并包括与 位于南非马希肯的西北大学。本提案中产生的信息将支持下一个提案 联合被动免疫试验阶段，将为了解预防措施提供重要数据 VRC01的功效。