Chimeric SHIV VLP as an oral mucosal HIV vaccine

描述(由申请人提供)： 疫苗诱导粘膜HIV特异性免疫反应可能有助于有效控制这些部位的HIV或SIV复制。然而，目前还没有有效的HIV粘膜疫苗。本研究旨在确定有效的口服免疫原，确定最佳的简便有效的免疫途径，并揭示该疫苗能够诱导强大的粘膜免疫反应以保护其免受黏膜病毒攻击的作用机制。我们已经开发并鉴定了具有抗原提呈细胞(APC)成熟信号CD40L的嵌合CD40L/猴-人类免疫缺陷(CD40L/SIV)病毒样颗粒(VLP)。我们已经证明这种CD40L/Shiv嵌合VLP具有直接结合和激活口腔粘膜和局部引流淋巴结(LN)中的树突状细胞(DC)的能力。与已有的SHV VLP疫苗相比，CD40L/SHV VLP嵌合疫苗可通过口服粘膜下免疫途径诱导高达4倍的粘膜IgA应答和粘膜细胞毒性T淋巴细胞(CTL)应答。目前，没有一种VLP黏膜疫苗策略被证明在非人类灵长类动物模型中具有保护效果。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，即口腔黏膜下注射具有APC成熟信号CD40L/Shiv VLP的嵌合CD40L/Shiv VLP将直接结合和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系统和粘膜免疫，从而保护SIV SF162P3对恒河猴的攻击。为了验证我们的假设，我们提出了以下特定目标：目的1：确定mCD40L/Shiv VLP口服黏膜下免疫方案，并研究其在小鼠粘膜免疫反应中的特征；目的2：在非人类灵长类动物模型中，确定hCD40L/Shiv VLP口服黏膜疫苗对病理性SHIVSF162P3攻击的免疫原性和保护作用；以及目的3.破译hCD40L/Shiv VLP口服黏膜下免疫接种在小鼠和非人灵长类动物中诱导强烈粘膜免疫反应的机制。该项目代表了一种新的抗原和免疫途径的探索，目的是开发一种有效和安全的嵌合Shiv VLP口腔粘膜HIV疫苗。这项研究也将增加我们对口腔粘膜免疫的了解，这可能有助于未来的口腔粘膜疫苗设计。我们未来的目标是推动这一有希望的战略向前发展，以开发有效的预防艾滋病的口腔粘膜疫苗。

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.