Epitope-targeted Vaccines for HIV-1 Prevention

用于预防 HIV-1 的表位靶向疫苗

• 批准号: 8789431
• 负责人: XIANGPENG KONG
• 金额: $ 213.52万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-23 至 2016-01-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789431
• 关键词: Administrative Coordination; Advanced Development; Animals; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Biochemical; Bioinformatics; Cameroon; Cellular Immunity; Collaborations; Complex; DNA; Data; Elements; Epitopes; Failure; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Human; Immune response; Immunization; Immunology; Indium; Individual; Infection; Influenza; Mediating; Methods; Modality; Modeling; Molecular Biology; Molecular Models; Monoclonal Antibodies; Neisseria; Oryctolagus cuniculus; Participant; Peptides; Pilot Projects; Positioning Attribute; Prevalence; Prevention; Production; Productivity; Program Research Project Grants; Proteins; Protocols documentation; Recombinants; Relative (related person); Scaffolding Protein; Scientist; Serum; Site; Specificity; Specimen; Structural Models; Structure; T-Lymphocyte; Testing; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Physiology; Virion; Virus; Wit; Work; antibody-dependent cell cytotoxicity; base; design; engineering design; env Gene Products; experience; immunogenic; immunogenicity; improved; molecular modeling; neutralizing antibody; nonhuman primate; novel; novel vaccines; pathogen; programs; protein B; research study; response; scaffold; scale up; simian human immunodeficiency virus; structural biology; success; tool; vaccine candidate; vaccine development; vaccinology; virology; virus envelope

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.

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。