Chimeric SHIV VLP as an oral mucosal HIV vaccine

嵌合 SHIV VLP 作为口腔粘膜 HIV 疫苗

• 批准号: 8698306
• 负责人: Qizhi C. Yao
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698306
• 关键词: Acquired Immunodeficiency Syndrome; Address; Antigen-Presenting Cells; Antigens; Antiviral Agents; Area; Attention; Attenuated; Binding; CD4 Positive T Lymphocytes; CD40 Ligand; Cell Maturation; Cells; Data; Dendritic Cells; Development; Disease; Future; General Population; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Immunization; Immunoglobulin A; Immunologic Deficiency Syndromes; Injection of therapeutic agent; Knowledge; Life; Macaca mulatta; Methods; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Neuraxis; Oral; Oral mucous membrane structure; Patient Care; Patients; Population; Regimen; Reporting; Research; Research Personnel; Route; SIV; Science; Services; Signal Transduction; Site; T-Cell Depletion; TNFSF5 gene; Technology; Testing; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Vagina; Veterans; Viral; Virion; Virus; Virus-like particle; base; cytotoxic; disability; frontier; gastrointestinal; immunogenic; immunogenicity; improved; innovation; lymph nodes; mucosal vaccination; mucosal vaccine; nonhuman primate; novel; prevent; protective effect; protective efficacy; response; simian human immunodeficiency virus; transmission process; vaccine delivery; vaccine development

DESCRIPTION (provided by applicant): Induction of mucosal HIV-specific immune responses by vaccines may facilitate effective control of HIV or SIV replication at these sites. However, there is no effective HIV mucosal vaccine yet. This proposal is intend to identify effective orally administered immunogen, determine the optimal easy and effective immunization route, and uncover the mechanism of action whereby this vaccine can induce potent mucosal immune responses to protect from mucosal viral challenge. We have developed and characterized chimeric CD40 ligand/simian-human immunodeficiency (CD40L/SHIV) virus-like particles (VLPs) which possess the antigen presenting cell (APC) maturation signal CD40L. We have shown that this chimeric CD40L/SHIV VLPs has the ability to directly bind and activate dendritic cells (DC) in oral mucosa and local draining lymph nodes (LN). Compared with the already potent SHIV VLP vaccine, the chimeric CD40L/SHIV VLPs can induce as much as 4-fold higher mucosal IgA response and mucosal cytotoxic T lymphcytes (CTL) response via an oral sub-mucosal immunization route. At present, none of the VLP mucosal vaccine strategies have been shown to enact protective efficacy in nonhuman primate models. Based on these exciting preliminary data, we have developed our central hypothesis that oral submucosal injection of chimeric CD40L/SHIV VLPs, which possess the APC maturation signal CD40L, will directly bind and activate DCs in oral mucosa and local draining lymph nodes (LN), thereby initiating strong and effective systemic and mucosal immunity that will protect SHIV SF162P3 challenge in rhesus macaques. To test our hypothesis, we propose the following specific aims: Aim 1: Determine the optimal mCD40L/SHIV VLP oral sub-mucosal immunization regimen and characterizing mucosal immune responses in mice; Aim 2: Determine the immunogenicity and protective effect of hCD40L/SHIV VLP oral mucosal vaccination from pathological SHIVSF162P3 challenge in a non-human primate model; and Aim 3. Decipher the mechanism whereby hCD40L/SHIV VLP oral submucosal vaccination induces strong mucosal immune responses in mice and in non-human primates. The proposed project represents exploration of a novel antigen and immunization route for the purpose of developing an effective and safe chimeric SHIV VLP oral mucosal HIV vaccine. This study will also increase our understanding of oral mucosal immunity, which may contribute to future oral mucosal vaccine design. Our future goal is to move this promising strategy forward for an effective oral mucosal vaccine development for preventing AIDS.

描述（由申请人提供）： 通过疫苗诱导粘膜 HIV 特异性免疫反应可能有助于有效控制 HIV 或 SIV 在这些部位的复制。然而，目前还没有有效的HIV粘膜疫苗。该提案旨在鉴定有效的口服免疫原，确定最佳的简单有效的免疫途径，并揭示该疫苗可诱导有效的粘膜免疫反应以防止粘膜病毒攻击的作用机制。我们开发并表征了嵌合 CD40 配体/猿人免疫缺陷 (CD40L/SHIV) 病毒样颗粒 (VLP)，其具有抗原呈递细胞 (APC) 成熟信号 CD40L。我们已经证明，这种嵌合 CD40L/SHIV VLP 能够直接结合并激活口腔粘膜和局部引流淋巴结 (LN) 中的树突状细胞 (DC)。与已经有效的SHIV VLP疫苗相比，嵌合CD40L/SHIV VLP可以通过口腔粘膜下免疫途径诱导高达4倍的粘膜IgA反应和粘膜细胞毒性T淋巴细胞（CTL）反应。目前，没有一种 VLP 粘膜疫苗策略已被证明能够在非人灵长类动物模型中发挥保护作用。基于这些令人兴奋的初步数据，我们提出了我们的中心假设，即口腔粘膜下注射具有APC成熟信号CD40L的嵌合CD40L/SHIV VLP，将直接结合并激活口腔粘膜和局部引流淋巴结（LN）中的DC，从而启动强大而有效的全身和粘膜免疫，保护恒河猴中的 SHIV SF162P3 攻击。为了检验我们的假设，我们提出以下具体目标： 目标 1：确定最佳 mCD40L/SHIV VLP 口腔粘膜下免疫方案并表征小鼠粘膜免疫反应；目标2：在非人灵长类动物模型中通过病理性SHIVSF162P3攻击确定hCD40L/SHIV VLP口腔粘膜疫苗的免疫原性和保护作用；目标 3. 破译 hCD40L/SHIV VLP 口腔粘膜下疫苗接种在小鼠和非人类灵长类动物中诱导强烈粘膜免疫反应的机制。拟议的项目代表了对新抗原和免疫途径的探索，旨在开发有效且安全的嵌合SHIV VLP口腔粘膜HIV疫苗。这项研究还将增加我们对口腔粘膜免疫的了解，这可能有助于未来口腔粘膜疫苗的设计。我们未来的目标是推动这一有前途的战略，开发有效的口腔粘膜疫苗来预防艾滋病。