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

 描述（由申请人提供）：RV 144疫苗试验的免疫相关性分析表明，疫苗有效率为31%（疫苗接种后前12个月内疫苗有效率为60.5%）。V1/V2 IgG抗体与HIV-1感染风险降低相关，而高水平的HIV特异性伊加抗体与感染风险增加相关。我们的实验室表明，伊加可以通过竞争抗体依赖性细胞毒性（ADCC）的相同结合位点来阻断IgG的保护作用。与伊加在减少保护中的作用相反，非人灵长类动物研究显示，在直肠内SHIV攻击后，IgA 1比对位匹配的IgA 2或IgG更好地保护免受感染。综上所述，这些研究表明疫苗诱导的伊加具有双重作用，其中伊加可能通过与保护性IgG竞争而减少保护，或通过防止HIV-1获得而提供潜在的保护作用。伊加的潜在保护作用或降低保护功效的作用可能取决于1）抗体特异性（即对病毒粒子颗粒或感染细胞上的表位的特异性），2）位置（全身性vs粘膜）和3）形式（IgA 1、IgA 2、分泌型伊加和二聚体伊加）。在这个提议中，我将定义疫苗诱导的HIV-1特异性伊加的特性，这些特性有助于伊加抗体功能的复杂性。我的总体假设是，在RV 144中鉴定的HIV-1风险的血浆伊加免疫相关性阻断ADCC活性，尽管在血浆中发现，但由于伊加的不同抗体特异性和形式（二聚体和分泌型），风险的伊加相关性不存在于粘膜中。在目标1中，我将从RV 144疫苗接种者中分离和表征疫苗引起的伊加，其特异性与HIV-1疫苗效力降低相关。一旦从分泌抗体的记忆B细胞培养物中分离，将评价伊加阻断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 疫苗诱导的粘膜抗体和血浆抗体之间的关系。由于在RV 144中未采集粘膜样本，因此研究仅讨论了血浆伊加阻断IgG效应子功能的能力，尚未讨论是否存在疫苗诱导的粘膜伊加和IgG特异性，并可能相互作用。RV 144试验的随访研究RV 305和HVTN 097使用了与RV 144相同的预充-加强方案，并且粘膜和血浆样本均可用于该提议。我将确定粘膜液中是否存在与RV 144中确定的风险相关性相关的血浆抗体特异性。最后，我将评估粘膜区室中发现的抗体的功能能力，以确定它们与血浆中发现的抗体的差异程度。本研究的结果将提供关于疫苗接种诱导的潜在保护性和保护-减少粘膜和血浆HIV特异性伊加应答的关键信息。此外，本提案的结果将对用于评价和选择的标准产生重大影响。 诱导保护性血浆和粘膜抗体的最佳疫苗方案。

 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.