Mucosal Immune-enhancing Delivery System for HIV vaccines

描述（由申请人提供）：尽管全世界有近4000万HIV感染者，每年有数百万新感染者，但HIV疫苗开发领域的深入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仍然是主要的感染途径。因此，在HIV进入的粘膜入口以及全身部位产生免疫应答将是有利的。在粘膜部位诱导免疫应答需要安全且有效的免疫增强递送系统和佐剂，其目前主要由于其毒性问题而不以许可形式存在。在本提案的I期，我们将在小鼠中测试一种新型安全制剂的有效性，该制剂被称为粘膜免疫增强递送系统（MIDS），用于HIV包膜蛋白的粘膜（鼻内）和全身（皮内）给药，目的是诱导FGT和全身组织的免疫力。具体目标将包括首先优化MIDS制剂和诱导上皮细胞和抗原呈递细胞（APC）中的体外先天性应答，然后通过抗原呈递、B和T细胞（包括调节性（Treg）、辅助性（TH）和细胞毒性（CTL））在小鼠中体内诱导粘膜和全身先天性和适应性应答。在第II阶段，我们将在雌性恒河猴中测试用具有HIVenv蛋白的MIDS免疫，然后用SHIV阴道内攻击的免疫原性和保护效力。公共卫生相关性：目前，没有获得许可的预防艾滋病毒感染的疫苗。该项目涉及设计一种新型，安全和有效的Muclidase免疫增强递送系统用于HIV疫苗开发，可以保护公众免受HIV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.