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临床疫苗试验诱导健康个体免受HIV-1感染的适度和短暂性保护，被认为是边际成功。为了提高抗体（AB）反应的疗效和持续时间，需要更好的免疫原子。我们假设新型疫苗构建体引起的ABS具有更高的特异性活性，具有更强的AB滴度，并且在总AB响应中，更大 保护所需的腹肌比例。这种新颖的结构可以在整个包膜（ENK）以外的其他情况下呈现病毒表位，也可能消除与整个ENV相关的瞬时AB响应的问题。我们和其他人已经证明，通过将AB反应集中在V3上，可以引起中和ABS的交叉层，可在免疫后检测到> 1年。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-Scaffold免疫原的平台，以创建和测试新的表位 - 损伤蛋白免疫原蛋白免疫原，这些蛋白质将把AB的反应集中在ENV中的两个其他脆弱性地点上：V2环和Quaternarary中和中和epepope（QNES）组成V2和V2和V2和V2和V2和V2和V2和V2和V2的脆弱性。 Hivrad将由：项目1：诱导靶向V2环的功能性ABS的疫苗；项目2：靶向HIV-1 V2/V3四元中和表位的免疫原子的合理设计；核心A：行政核心；核心B：蛋白质生产核心；和Core C：动物研究核心。要开发的表位型免疫原子可以单独或结合使用，它将构成诱导广泛而有效的保护性ABS的强大新工具。许多参与者共同努力了20年，以开发和表征> 100个人的hiv和其他病原体。最近，该团队进行了协同工作，准备和分析了25种单克隆ABS（mAb）和mAb/表位复合体的晶体，开发了DNA env Primes和EpatiStope-Scaffold免疫原子，并进行免疫实验。我们的经验使我们处于强大的位置，将我们的研究扩展到直到最近才被认为对保护艾滋病毒感染很重要的表位。通过拟议程序的完成，我们计划确定了靶向表位的免疫原和免疫协议，这些方案将与专门针对V2 Loop的保守区域的保护性抗病毒功能以及V2/V3 QUATERNARY中和HIV-1 GP120的表现为ABS。 公共卫生相关性：当前的数据表明，艾滋病毒疫苗需要通过有效和广泛的抗病毒活性以及细胞介导的免疫力诱导ABS。用整个信封蛋白制造的疫苗尚未实现这一目标。因此，需要新的免疫原。在此计划项目赠款中，我们将开发候选疫苗，将免疫反应集中在诱导保护性ABS的病毒部分。 项目1-诱导针对V2环的功能抗体的疫苗 项目负责人：Susan Zolla-Pazner （申请人提供的描述）各种形式的HIV-1包膜（ENV）糖蛋白并不是理想的免疫原子，因为它们具有广泛的抗病毒功能诱导ABS（ABS），AB反应持续不到6个月。为了克服这些局限性，可以使用表位 - 律免疫将AB反应集中在Env上的脆弱部位上；但是，艾滋病毒表位 - 律师免疫的设计充满了许多失败。然而，候选候选者的表位型疫苗已经成功地针对流感和奈瑟氏菌，我们和其他人成功地设计了几种V3-Scaffold和V3肽免疫原子，具有可证明的抗原性和免疫原性，从而导致HIV-1交叉抗体中性中性中性中性化中性腹肌诱导。在这个项目中，我们建议将免疫反应集中在GPL20的V2区域上。直到最近，该区域实际上被视为疫苗发育的靶标，但其作为疫苗目标的重要性最近得到了数据的支持，该数据表明抗V2 ABS可以高度交叉反应，显示中和表现出中和活性，捕获病毒颗粒和阻塞GP120/A4P7相互作用。 支持V2作为疫苗设计的有前途的抗原的支持也来自RV144临床疫苗试验的试点研究。对于该项目，我们将应用我们开发的平台来生成V3-Scaffold免疫原，以生产V2-Scaffold免疫原，用于在使用DNA Env启动后用于增强AB反应。对于AIM 1.1，我们将基于人V2多克隆和单克隆ABS（mAb）以及生物信息学和分子建模数据的良好特异性构建脚手架免疫原子的V2插入物。在AIM 1.2中，我们将评估不同特异性的抗V2 ABS的患病率和功能，并阐明这些抗感染HIV进化枝的差异。对于AIM 1.3，我们将选择并表征源自喀麦隆的非脱落B感染供体的新型人类V2特异性mAb，这些供体被摄制最宽，功能性最广泛的抗V2 ABS感染的进化枝感染。最后，在选择了V2-Scaffold蛋白之后，从AIM 1.2和1.3的结果中，对最广泛，最有效和多功能的抗V2多克隆和mAb的反应，我们将在AIM 1.4中测试AEM 1.4，测试所选V2支架的免疫原性，在Rabbits和Non-Human and Non-Human and Not-Human and Native inding Enving dna中促进免疫力。该项目的最终目的是在兔子和非人类灵长类动物中诱导Antl-V2 ABS，这些兔子和非人类灵长类动物展示了介导保护的跨层抗病毒活性。 相关性：需要新的概念来开发有效的HIV疫苗。该项目的目标是设计新的艾滋病毒表位 - 损伤疫苗，该疫苗将把宿主免疫反应集中在病毒信封糖蛋白的V2环上的脆弱部位上。该项目将提供重要的数据，以推动开发更有效的HIV疫苗。