Epitope-targeted Vaccines for HIV-1 Prevention

描述（由申请人提供）：最近的RV 144临床疫苗试验在健康个体中诱导了适度和短暂的HIV-1感染保护，被认为是一个边际成功。为了提高抗体（Ab）应答的效力和持续时间，需要更好的免疫原。我们推测，由新型疫苗构建体诱导的Ab将具有更高的比活性，具有更强的Ab滴度，并且在总Ab应答中，具有更大的特异性。 保护所需的ABS比例。这种新的构建体，其可以在除了整个包膜（Env）的环境之外的环境中呈递病毒表位，也可以解决与整个Env相关的瞬时Ab应答的问题。我们和其他人已经证明，通过将Ab应答集中在V3上，引发了交叉进化枝中和Ab，其在免疫后>1年可检测到。因此，我们现在建议扩展我们先前开发的用于设计和开发V3-支架免疫原的平台，以创建和测试新的表位-支架蛋白免疫原，其将Ab反应集中在Env中的两个额外的脆弱性位点上：V2环和由V2和V3部分组成的四级中和表位（QNE）簇。HIVRAD将包括：项目1：诱导靶向V2环的功能性抗体的疫苗;项目2：靶向HIV-1 V2/V3四元中和表位的免疫原的合理设计;核心A：管理核心;核心B：蛋白质生产核心;以及核心C：动物研究核心。待开发的表位-支架免疫原可以单独使用或组合使用，并且将构成用于诱导广泛且有效的保护性Ab的强大新工具。许多参与者已经共同工作了超过20年，开发和表征了超过100种针对HIV和其他病原体的人类mAb。最近，该团队协同工作，制备和分析了超过25种单克隆抗体（mAb）和mAb/表位复合物的晶体，开发了DNA Env引物和表位支架免疫原，并进行了免疫实验。我们的经验使我们处于有利地位，可以将我们的研究扩展到表位，这些表位直到最近才被认为是保护免受艾滋病毒感染的重要因素。通过完成拟议的计划，我们计划确定表位靶向免疫原和免疫方案，这些免疫方案将产生具有保护性抗病毒功能的抗体，这些抗体特异性针对HIV-1 gp 120的V2环和V2/V3四级中和表位的保守区域。

DESCRIPTION (provided by applicant): The recent RV144 clinical vaccine trial induced modest and transient protection in healthy individuals against HIV-1 infection, and is considered to be a marginal success. To improve the efficacy and duration of the antibody (Ab) response, better immunogens are required. We postulate that Abs induced by novel vaccine constructs will have higher specific activity, with stronger Ab titers and, within the total Ab response, a greater proportion of the Abs needed for protection. Such novel constructs, which could present viral epitopes in a context other than that of the whole envelope (Env), may also obviate the problems of the transient Ab response associated with whole Env. We and other have demonstrated that, by focusing the Ab response on V3, cross-clade neutralizing Abs are elicited which are detectable >1 year after immunization. Therefore, we now propose to extend the platform we previously developed for designing and developing V3-scaffold immunogens in order to create and test new epitope-scaffold protein immunogens that will focus the Ab response on two additional sites of vulnerability in Env: the V2 loop and the cluster of quaternary neutralizing epitopes (QNEs) composed of portions of V2 and V3. The HIVRAD will be composed of: Project 1: Vaccines to Induce Functional Abs Targeting the V2 Loop; Project 2: Rational Design of Immunogens Targeting the HIV-1 V2/V3 Quaternary Neutralizing Epitopes; Core A: Administrative Core; Core B: Protein Production Core; and, Core C: Animal Studies Core. The epitope-scaffold immunogens to be developed can be used individually or in combination, and will constitute powerful new tools for inducing broad and potent protective Abs. Many of the participants have worked together for >20 years to develop and characterize >100 human mAbs to HIV and other pathogens. Recently, the team has worked collaboratively and synergistically, preparing and analyzing >25 crystals of monoclonal Abs (mAbs) and mAb/epitope complexes, developing DNA Env primes and epitope-scaffold immunogens, and performing immunization experiments. Our experience places us in a strong position to extend our studies to epitopes that only recently have been recognized as important for protection from HIV infection. By the completion of the proposed Program, we plan to have identified epitope-targeting immunogens and immunization protocols that will generate Abs with protective anti-viral functions directed specifically toward the conserved regions of the V2 loop and the V2/V3 quaternary neutralizing epitopes of HIV-1 gp120.