The duality of vaccine elicited HIV specific-IgA antibodies: Providing protection or diminishing protection

疫苗的双重性引发了 HIV 特异性 IgA 抗体：提供保护或减弱保护

• 批准号: 9229472
• 负责人: Saintedym Wills
• 金额: $ 3.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229472
• 关键词: AIDS prevention; ALVAC; Activities of Daily Living; Address; Antibodies; Antibody Binding Sites; Antibody Response; Antibody Specificity; Antigens; Antiviral Agents; Blocking Antibodies; Cell Culture Techniques; Cells; Characteristics; Clinical Trials; Data; Dimerization; Environment; Epithelial; Epitopes; Equilibrium; Evaluation; Fellowship; Follow-Up Studies; Goals; HIV; HIV Vaccine Trials Network; HIV-1; HIV-1 vaccine; Human; IgA1; IgA2; Immune; Immune Plasma; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Infection; Invaded; Lead; Liquid substance; Location; Mediating; Memory B-Lymphocyte; Molecular Conformation; Monoclonal Antibodies; Mucosal Immune Responses; Mucous Membrane; Natural Killer Cells; Outcome; Peptides; Plasma; Play; Population; Primates; Publishing; Regimen; Research; Risk; Role; Sampling; Secretory Immunoglobulin A; Sorting - Cell Movement; South Africa; Specificity; Surface; Testing; Thailand; Therapeutic; Training; Vaccination; Vaccines; Viral; Virion; Virus; Work; antibody-dependent cell cytotoxicity; base; career; design; dimer; env Gene Products; follow-up; immunogenicity; insight; mucosal site; nonhuman primate; novel strategies; particle; pathogen; prevent; protective effect; protective efficacy; public health relevance; rectal; response; simian human immunodeficiency virus; vaccine candidate; vaccine efficacy; vaccine trial

 DESCRIPTION (provided by applicant): The immune correlates analysis of the RV144 vaccine trial, demonstrated 31% vaccine efficacy (60.5% vaccine efficacy through the first twelve months after vaccination). V1/V2 IgG antibodies correlated with decreased risk of HIV-1 infection, whereas high levels of envelope-specific IgA antibodies correlated with increased risk of infection. Our lab showed that IgA could block the protective effects of IgG through competition of the same binding sites for antibody dependent cellular cytotoxicity (ADCC). In contrast to a role for IgA in diminishing protection, a non-human primate study revealed that IgA1 protected from infection better than paratope-matched IgA2 or IgG upon intrarectal SHIV challenge. Taken together, these studies suggest a dual role of vaccine-induced IgA where IgA may diminish protection by competing with protective IgG or provide a potentially protective role by acting to prevent HIV-1 acquisition. The potentially protective role or a role for diminishing protective efficacy for IgA likely depends on 1) antibody specificity (i.e. specificity for epitope on virion particles or infected cells), 2) location (systemic vs mucosal) and 3) form (IgA1, IgA2, secretory IgA, and dimeric IgA). In this proposal, I will define the characteristics of vaccine-induced HIV-1 specific IgA that contribute to the complexity of IgA antibody functions. My overall hypothesis is that the plasma IgA immune correlate of HIV-1 risk identified in RV144, blocks ADCC activity, and although found in the plasma, the IgA correlate of risk is not present in the mucosa due to the different antibody specificities and forms of IgA (dimeric and secretory). In Aim 1, I will isolate and characterize vaccine-elicited IgA from RV144 vaccinees with specificities that correlate with decreased HIV-1 vaccine efficacy. Once isolated from antibody secreting memory B cell cultures, the IgA will be evaluated for their capacity to block IgG mediated antiviral functions. In Aim 2, I will evaluate the differences in specificity and function between vaccine-induced mucosal and plasma antibodies. Since mucosal samples were not collected in RV144, studies have only addressed the ability of plasma IgA to block IgG effector function, and have not addressed whether there are vaccine-induced mucosal IgA and IgG specificities with the potential to interact. Follow-up studies of the RV144 trial, RV305 and HVTN097, used the same prime-boost regimen as RV144 and both mucosal and plasma samples are available for this proposal. I will determine if the plasma antibody specificities associated with the correlates of risk identified in RV144 are present in the mucosal fluid. Finally, I will assess the functional capacity of antibodies found in the mucosal compartments to determine the extent to which they differ from those found in the plasma. The results from this study will provide key information on potentially protective and protection- diminishing mucosal and plasma HIV-specific IgA responses induced by vaccination. Furthermore, the outcomes from this proposal will have a high impact on the criteria utilized for evaluation and selection of optimal vaccine regimens for induction of protective plasma and mucosal antibodies.

 描述（由申请人提供）：RV144 疫苗试验的免疫相关分析显示，疫苗功效为 31%（疫苗接种后前 12 个月内疫苗功效为 60.5%），V1/V2 IgG 抗体与 HIV-1 感染风险降低相关。 ，而高水平的包膜特异性 IgA 抗体与感染风险增加相关，我们的实验室表明，IgA 可以通过竞争抗体依赖性细胞毒性的相同结合位点来阻断 IgG 的保护作用。 (ADCC) 与 IgA 的减弱保护作用相反，一项非人类灵长类动物研究表明，在直肠内 SHIV 攻击后，IgA1 比互补位匹配的 IgA2 或 IgG 更能防止感染。疫苗诱导的 IgA，其中 IgA 可能通过与保护性 IgG 竞争来减弱保护作用，或通过阻止 HIV-1 获得而提供潜在的保护作用或减弱保护功效的作用。 IgA 可能取决于 1) 抗体特异性（即病毒粒子或感染细胞上表位的特异性）、2) 位置（全身与粘膜）和 3) 形式（IgA1、IgA2、分泌性 IgA 和二聚体 IgA）。我将定义疫苗诱导的 HIV-1 特异性 IgA 的特征，这些特征导致 IgA 抗体功能的复杂性。我的总体假设是血浆 IgA。 RV144 中鉴定出的 HIV-1 风险免疫相关物可阻断 ADCC 活性，尽管在血浆中发现，但由于 IgA（二聚体和分泌型）的抗体特异性和形式不同，粘膜中不存在风险相关性 IgA。目标 1，我将从 RV144 疫苗中分离和表征疫苗引发的 IgA，其特异性与 HIV-1 疫苗功效下降相关。一旦从分泌抗体的记忆 B 细胞培养物中分离出来，IgA 将被分离出来。评估它们阻断 IgG 介导的抗病毒功能的能力。在目标 2 中，我将评估特异性和功能的差异。 由于 RV144 中未收集粘膜样本，因此研究仅探讨了血浆 IgA 阻断 IgG 效应器功能的能力，而没有探讨疫苗诱导的粘膜 IgA 和 IgG 是否具有特异性。 RV144 试验、RV305 和 HVTN097 的后续研究使用了与 RV144 相同的初免-加强方案，并且都是粘膜。如果粘膜液中存在与 RV144 中确定的风险相关的血浆抗体特异性，我将评估粘膜区室中发现的抗体的功能能力。这项研究的结果将提供有关疫苗接种引起的潜在保护性和保护性减弱的粘膜和血浆 HIV 特异性 IgA 反应的关键信息。对评估和选择所使用的标准有很大影响 用于诱导保护性血浆和粘膜抗体的最佳疫苗方案。