A Novel Th17-inducing Mucosal Vaccine for Tuberculosis

项目总结/摘要 结核分枝杆菌（Mtb）潜伏感染世界四分之一的人口， 肺结核（TB）每年约有1000万人，导致约160万人死亡。的 目前可用的TB疫苗牛分枝杆菌BCG（BCG）显示出可变的效力。此外，本发明还提供了一种方法， 最近出现了多药耐药（MDR）Mtb菌株。因此，对新结核病的需求很大 疫苗。我们最近的工作表明，产生免疫应答的辅助性T细胞17型（Th 17）细胞， 细胞因子白细胞介素-17（IL-17）是介导疫苗诱导的保护的主要效应细胞 针对结核病。此外，粘膜疫苗诱导更好的粘膜免疫，并赋予上级 与系统性免疫途径相比，尽管有能力 实验性粘膜佐剂诱导保护性Th 17应答并赋予疫苗诱导的 由于结核病的免疫保护作用，用于人类使用的Th 17诱导粘膜结核病疫苗的开发缓慢。因此，我们认为， 迫切需要确定安全有效的粘膜结核疫苗， 粘膜Th 17反应并了解其作用机制。纳米乳液（NE）是 用抗原配制的水包油乳剂。NE佐剂在人体中安全且耐受性良好 志愿者当用作流感疫苗，并引发全身和粘膜免疫后， 单次粘膜接种。在新发表的数据中，我们表明NE的粘膜递送沿着Mtb 抗原（NE-TB疫苗）可以赋予Mtb控制，并与结核病的减少有关， 小鼠该提案的总体目标是表征和优化保护性免疫 因此能够开发一种新的、安全的、有效的， 第一种Th 17诱导结核病粘膜疫苗。因此，我们提出以下具体目标。在 具体目标1：利用小鼠结核病模型，确定初免-加强免疫策略和抗原 增强免疫原性并改善疫苗诱导的NE-TB保护的组合 疫苗，以超过卡介苗接种提供的保护。在Specific Aim 2中，使用鼠标 结核病模型，我们将评估表现最好的初免-加强NE-TB疫苗策略的有效性 针对不同的Mtb菌株，在遗传多样性宿主中以及在预先暴露于环境中时， 分枝杆菌在具体目标3中，我们将进行临床前开发和概念验证测试 NE-TB疫苗在感染Mtb的非人灵长类动物（NHP）中的作用，并确定保护的相关性。 这项资助中提出的工作将确定作用机制，并验证一种新的 类Th 17诱导的粘膜NE-TB先导候选疫苗，在不久的将来用于人类。

PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (Mtb) latently infects one-fourth of the world's population, causing pulmonary tuberculosis (TB) in ~10 million people and resulting in ~1.6 million deaths each year. The currently available TB vaccine, Mycobacterium bovis BCG (BCG), shows variable efficacy. In addition, multi-drug resistant (MDR) Mtb strains have recently emerged. Thus, there is a great need for new TB vaccines. Our recent work has demonstrated that T helper type 17 (Th17) cells which produce the cytokine interleukin-17 (IL-17), are a primary effector cell mediating vaccine-induced protection against Mtb. Additionally, mucosal vaccines induce better mucosal immunity and confer superior protection against TB, when compared to systemic routes of immunization. Despite the ability of experimental mucosal adjuvants to induce protective Th17 responses and confer vaccine-induced protection, development of Th17-inducing mucosal TB vaccines for human use is slow. Therefore, there is an urgent need to identify safe and effective mucosal TB vaccines that can induce lung mucosal Th17 responses and understand their mechanism(s) of action. Nanoemulsions (NE) are oil-in-water emulsions formulated with antigen. NE adjuvant was safe and well-tolerated in human volunteers when used as a flu vaccine, and elicited both systemic and mucosal immunity following a single mucosal vaccination. In new published data, we show that mucosal delivery of NE along with Mtb antigens (NE-TB vaccine) can confer Mtb control, and is associated with decreased TB disease in mice. The overall goal of this proposal is to characterize and optimize the protective immune responses induced by NE-TB vaccine thus enabling development of a novel, safe, effective, first-of-kind Th17-inducing TB mucosal vaccine. Thus, we propose the following Specific Aims. In Specific Aim 1, using mouse model of TB, we will identify the prime-boost strategy and the antigen combination that enhances immunogenicity, and improves vaccine-induced protection of NE-TB vaccines, to exceed protection afforded by BCG vaccination. In Specific Aim 2, using the mouse model of TB, we will evaluate the efficacy of the best performing prime-boost NE-TB vaccine strategy against different Mtb strains, in genetically diverse hosts and upon pre-exposure to environmental mycobacteria. In Specific Aim 3, we will carry out preclinical development and proof-of-concept testing of NE-TB vaccines in non-human primates (NHP) infected with Mtb and identify correlates of protection. The work proposed in this grant will determine the mechanism(s) of action, and validate a novel first-of- kind Th17-inducing mucosal NE-TB lead candidate vaccine for use in humans in the near future.