Epitope-targeted Vaccines for HIV-1 Prevention

用于预防 HIV-1 的表位靶向疫苗

• 批准号: 8301820
• 负责人: XIANGPENG KONG
• 金额: $ 238.67万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301820
• 关键词: Epitope; targeted; Vaccines; HIV; Prevention

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. PUBLIC HEALTH RELEVANCE: Current data suggest an HIV vaccine will need to induce Abs with potent and broad anti-viral activities as well as cell mediated immunity. Vaccines made with whole envelope proteins have not yet achieved this goal; therefore, new immunogens are needed. In this Program Project Grant we will develop vaccine candidates that focus the immune response on portion of the virus that induce protective Abs. Project 1 - Vaccines to Induce Functional Antibodies Targeting the V2 Loop Project Leader: Susan Zolla-Pazner (Description as provided by applicant) The various forms of the HIV-1 envelope (Env) glycoproteins do not serve as ideal immunogens because they poorly induce Abs (Abs) with broad antiviral functions, and the Ab response lasts less than 6 months. To overcome these limitations, epitope-scaffold immunogens can be used to focus the Ab response on vulnerable sites on the Env; however, the design of HIV epitope-scaffold immunogens has been fraught with many failures. Nevertheless, epitope-scaffold vaccines candidates have been successfully developed against influenza and Neisseria, and we and others have succeeded in designing several V3-scaffold and V3 peptide immunogens with demonstrable antigenicity and immunogenicity, resulting in the induction of HIV-1 cross-clade neutralizing Abs. In this Project, we propose to focus the immune response on the V2 region of gpl20. Until recently, this region was virtually overlooked as a target for vaccine development, but its importance as a vaccine target has been recently supported by data showing that anti-V2 Abs can be highly cross-reactive, display neutralizing activity, capture virus particles, and block gp120/a4p7 interaction. Support for pursuing V2 as a promising antigen for vaccine design also comes from pilot studies with specimens from the RV144 clinical vaccine trial. For this Project, we will apply the platform we developed for generating V3-scaffold immunogens to the production of V2-scaffold immunogens to be used for boosting the Ab response after priming with DNA Env. For Aim 1.1, we will construct V2 inserts for scaffolded immunogens based on the fine specificity of human V2 polyclonal and monoclonal Abs (mAbs), and on bioinformatics and molecular modeling data. In Aim 1.2, we will assess the prevalence and function of anti-V2 Abs of different specificities and clarify how these differ relative to the infecting HIV clade. For Aim 1.3, we will select and characterize new human V2-specific mAbs derived from non-clade B-infected donors from Cameroon infected with the clades that induce the most broad and functional anti-V2 Abs. Finally, after selecting V2-scaffold proteins which, from the results of Aim 1.2 and 1.3, react wit the most broad, potent and multifunctional anti-V2 polyclonal and mAbs, we will, in Aim 1.4, test the immunogenicity of selected V2 scaffold boosting immunogens in rabbits and non-human primates after priming with Env DNA. The ultimate goal of this Project is to induce antl-V2 Abs in rabbits and non-human primates that display cross-clade antiviral activities that mediate protection. RELEVANCE: Novel concepts are needed to develop an effective HIV vaccine. This project's goal is to design new HIV epitope-scaffold vaccines that will focus the host immune response on vulnerable sites on the V2 loop of the virus envelope glycoprotein. The project will provide important data that will advance the development of a more effective HIV vaccine.

描述（由申请人提供）：最近的 RV144 临床疫苗试验对健康个体针对 HIV-1 感染产生了适度且短暂的保护，被认为取得了一定程度的成功。为了提高抗体 (Ab) 反应的功效和持续时间，需要更好的免疫原。我们假设新型疫苗构建体诱导的抗体将具有更高的比活性、更强的抗体滴度，并且在总抗体反应中，更大的抗体滴度。 保护所需的 Abs 比例。这种新颖的构建体可以在整个包膜（Env）以外的环境中呈现病毒表位，也可以消除与整个包膜（Env）相关的瞬时抗体反应的问题。我们和其他人已经证明，通过将抗体反应集中在 V3 上，可以引发跨进化枝中和抗体，这些抗体在免疫后 1 年以上即可检测到。因此，我们现在建议扩展我们之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，将 Ab 反应集中在 Env 中另外两个脆弱位点：V2 环以及由V2和V3的部分组成的四级中和表位(QNE)簇。 HIVRAD 将由以下部分组成： 项目 1：针对 V2 环诱导功能性抗体的疫苗；项目2：针对HIV-1 V2/V3四级中和表位的免疫原的合理设计；核心A：行政核心；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单独或组合使用，并将构成诱导广泛且有效的保护性抗体的强大新​​工具。许多参与者已经合作超过 20 年，开发并表征了超过 100 种针对 HIV 和其他病原体的人类单克隆抗体。最近，该团队协同合作，制备并分析了>25种单克隆抗体（mAb）和mAb/表位复合物晶体，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最近才被认为对于预防艾滋病毒感染很重要的表位。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，这些免疫原和免疫方案将产生具有保护性抗病毒功能的抗体，专门针对 V2 环的保守区域和 HIV 的 V2/V3 四元中和表位-1 gp120。 公共健康相关性：目前的数据表明，HIV 疫苗需要诱导具有有效和广泛的抗病毒活性以及细胞介导的免疫的抗体。用全包膜蛋白制成的疫苗尚未实现这一目标；因此，需要新的免疫原。在该计划项目拨款中，我们将开发候选疫苗，将免疫反应集中在病毒中诱导保护性抗体的部分。 项目 1 - 诱导针对 V2 环的功能性抗体的疫苗 项目负责人：苏珊·佐拉-帕斯纳 （申请人提供的描述）各种形式的HIV-1包膜（Env）糖蛋白不能作为理想的免疫原，因为它们很难诱导具有广泛抗病毒功能的抗体（Abs），并且抗体反应持续不到6个月。为了克服这些限制，可以使用表位支架免疫原将抗体反应集中在 Env 上的脆弱位点上；然而，HIV表位支架免疫原的设计却充满了许多失败。尽管如此，针对流感和奈瑟菌的候选表位支架疫苗已经成功开发出来，我们和其他人已经成功设计了几种具有明显抗原性和免疫原性的 V3 支架和 V3 肽免疫原，从而诱导 HIV-1 跨进化枝中和绝对值。在这个项目中，我们建议将免疫反应集中在 gpl20 的 V2 区域。直到最近，该区域作为疫苗开发的目标实际上还被忽视，但最近有数据证明了其作为疫苗目标的重要性，显示抗 V2 抗体可以高度交叉反应，表现出中和活性，捕获病毒颗粒，并且阻止 gp120/a4p7 相互作用。 对 RV144 临床疫苗试验样本的初步研究也支持将 V2 作为疫苗设计的有前途的抗原。在这个项目中，我们将应用我们开发的用于生成 V3 支架免疫原的平台来生产 V2 支架免疫原，用于在用 DNA Env 引发后增强抗体反应。对于目标 1.1，我们将基于人 V2 多克隆和单克隆抗体 (mAb) 的精细特异性以及生物信息学和分子建模数据，构建支架免疫原的 V2 插入片段。在目标 1.2 中，我们将评估不同特异性的抗 V2 抗体的流行率和功能，并阐明它们相对于感染 HIV 分支的差异。对于目标 1.3，我们将选择并表征新的人类 V2 特异性 mAb，这些抗体源自来自喀麦隆的未进化枝 B 感染的供体，这些供体感染了可诱导最广泛和功能性抗 V2 抗体的进化枝。最后，根据目标 1.2 和 1.3 的结果选择与最广泛、有效和多功能的抗 V2 多克隆和单克隆抗体反应的 V2 支架蛋白后，我们将在目标 1.4 中测试所选 V2 支架增强的免疫原性用 Env DNA 引发后，兔子和非人灵长类动物体内产生免疫原。该项目的最终目标是在兔子和非人类灵长类动物中诱导antl-V2抗体，这些抗体表现出介导保护的跨进化枝抗病毒活性。 相关性：开发有效的艾滋病毒疫苗需要新的概念。该项目的目标是设计新的 HIV 表位支架疫苗，将宿主免疫反应集中在病毒包膜糖蛋白 V2 环上的脆弱位点。该项目将提供重要数据，推动更有效的艾滋病毒疫苗的开发。