Vaccines to Induce Functional Antibodies Targeting the V2 Loop

诱导针对 V2 环的功能性抗体的疫苗

• 批准号: 8307160
• 负责人: Susan B Zolla-Pazner
• 金额: $ 62.31万
• 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/8307160
• 关键词: Accounting; Advanced Development; Antibodies; Antibody Formation; Antigens; Bioinformatics; CD8B1 gene; Cameroon; Cells; Chimeric Proteins; Cleaved cell; Clinical Trials; DNA; Data; Epitopes; Evolution; Failure; Glycoproteins; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immune response; Individual; Influenza; Instruction; Literature; Mediating; Meningitis; Methods; Molecular Models; Neisseria; Oryctolagus cuniculus; Pattern; Peptides; Pilot Projects; Plasma; Prevalence; Prevention; Probability; Production; Protein Engineering; Reagent; Recombinants; Regimen; Relative (related person); Reporting; Research; Scaffolding Protein; Serum; Site; Specificity; Specimen; Structure; Surface; T cell response; T-Lymphocyte; Testing; Ursidae Family; Vaccine Clinical Trial; Vaccine Design; Vaccines; Variant; Viral Physiology; Virion; Virus; antibody-dependent cell cytotoxicity; base; design; flexibility; gp160; immunogenic; immunogenicity; in vivo; innovation; molecular modeling; nonhuman primate; novel; pandemic disease; pathogen; scaffold; success; vaccine candidate; vaccine development; virus envelope

The various forms of the HIV-1 envelope (Env) glycoproteins do not serve as ideal immunogens because they poorly induce Abs (Abs) with broad anti-viral functions, and the Ab response lasts <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 gpl 20. 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 with 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 anti-viral activities that mediate protection.

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<6个月。到 为了克服这些限制，表位支架免疫原可用于将抗体反应集中在 Env 上的脆弱站点；然而，HIV表位支架免疫原的设计充满了 许多失败。尽管如此，候选表位支架疫苗已经成功开发出来 抗流感和奈瑟菌，我们和其他人已经成功设计了几种 V3 支架和 V3 具有明显抗原性和免疫原性的肽免疫原，导致 HIV-1 的诱导 跨分支中和抗体。在这个项目中，我们建议将免疫反应集中在 V2 gpl 20 的区域。直到最近，该区域作为疫苗开发的目标实际上还被忽视， 但其作为疫苗靶标的重要性最近得到了数据的支持，表明抗 V2 抗体可以 高度交叉反应，显示中和活性，捕获病毒颗粒，并阻断 gp120/a4p7 相互作用。 对将 V2 作为疫苗设计有前途的抗原的支持也来自于以下方面的试点研究： RV144临床疫苗试验的标本。对于这个项目，我们将应用我们开发的平台 从生成V3支架免疫原到生成用于加强的V2支架免疫原 DNA Env 引发后的 Ab 反应。对于目标 1.1，我们将为支架构建 V2 插入件 基于人 V2 多克隆和单克隆抗体 (mAb) 的精细特异性的免疫原，以及 生物信息学和分子建模数据。在目标 1.2 中，我们将评估抗- 具有不同特异性的 V2 抗体，并阐明它们与感染 HIV 分支的不同之处。对于目标 1.3， 我们将选择并表征来自非分支 B 感染供体的新人类 V2 特异性单克隆抗体 喀麦隆感染了诱导最广泛和功能最广泛的抗 V2 抗体的进化枝。最后，之后 根据目标 1.2 和 1.3 的结果，选择与最广泛、最有效的反应的 V2 支架蛋白 和多功能抗V2多克隆抗体和单克隆抗体，我们将在目标1.4中测试所选V2的免疫原性 用 Env DNA 引发后，在兔子和非人灵长类动物中支架增强免疫原。这 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 Abs 介导保护的跨进化枝抗病毒活性。