Mucosal Immune-enhancing Delivery System for HIV vaccines

描述(申请人提供)：尽管全世界每年有近4000万艾滋病毒感染者和数百万新感染者，但艾滋病毒疫苗开发领域的紧张研究尚未导致获得许可的预防性或治疗性疫苗。无论感染途径如何，艾滋病毒在感染的早期和晚期都会以胃肠道、呼吸道和泌尿生殖道的粘膜细胞为目标。通过女性生殖道传播艾滋病毒(FGT)仍然是感染的主要途径。因此，在HIV进入的这个粘膜入口以及全身部位产生免疫反应将是有利的。在粘膜部位诱导免疫反应需要安全有效的免疫增强递送系统和佐剂，目前这些系统和佐剂还没有获得许可，主要是因为它们的毒性问题。在这项建议的第一阶段，我们将在小鼠身上测试一种名为黏膜免疫增强递送系统(MIDS)的新的安全配方的有效性，该制剂用于粘膜(鼻腔内)和全身(真皮内)注射HIV包膜蛋白，目的是在FGT和全身组织中诱导免疫。具体目标将包括首先优化MIDS的配方并在体外诱导上皮细胞和抗原提呈细胞(APC)的先天性反应，然后在体内通过抗原提呈、B和T细胞，包括调节性(Treg)、辅助性(TH)和细胞毒性(CTL)诱导小鼠粘膜和全身的固有和适应性反应。在第二阶段，我们将测试带有HIVenv蛋白的MIDs免疫雌性猕猴的免疫原性和保护效果，然后用SHV阴道内攻击。与公共卫生相关：目前，没有获得许可的针对艾滋病毒感染的疫苗。该项目涉及为艾滋病毒疫苗开发设计一种新颖、安全和有效的粘膜免疫增强递送系统，以保护公众免受艾滋病毒的新感染。

DESCRIPTION (provided by applicant): Despite close to 40 million HIV-infected individuals worldwide and millions of new infections each year, intense research in the field of HIV vaccine development has not yet lead to a licensed prophylactic or therapeutic vaccine. Regardless of the route of infection, HIV targets mucosal cells of the gastrointestinal, respiratory and genitourinary tracts, at both early and late stages of infection. HIV transmission through the female genital tract (FGT) remains a major route of infection. Thus, generation of immune responses at this mucosal portal of HIV entry, as well as systemic sites would be advantageous. Induction of immune responses at mucosal sites requires safe and effective immune enhancing delivery systems and adjuvants, which currently do not exist in licensed form mainly due to their toxicity issues. In phase I of this proposal, we will test in mice the effectiveness of a novel and safe formulation designated mucosal immune enhancing delivery system (MIDS) for mucosal (intra-nasal) and systemic (intra-dermal) administration of an HIV-envelope protein with the goal of inducing immunity in both FGT and systemic tissues. The specific aims will include first optimization of the MIDS formulations and induction of in vitro innate responses in epithelial and antigen-presenting cells (APC), followed by in vivo induction in mice of mucosal and systemic innate and adaptive responses by antigen-presenting, B and T cells, including regulatory (Treg), helper (TH) and cytotoxic (CTL). In phase II, we will test the immunogenicity and protective efficacy of immunizations with MIDS with HIVenv proteins in female rhesus macaques followed by intra-vaginal challenge with SHIV. PUBLIC HEALTH RELEVANCE: Currently, there are no licensed vaccines against infections with HIV. This project pertains to designing a novel, safe and effective Mucosal Immune-enhancing Delivery System for HIV vaccine development that can protect the public against new infections with the HIV virus.