A Novel Th17-inducing Mucosal Vaccine for Tuberculosis

项目摘要/摘要 结核分枝杆菌(Mtb)潜伏感染着世界四分之一的人口，导致 约1000万人罹患肺结核，每年导致约160万人死亡。这个 目前可用的结核疫苗，牛分枝杆菌卡介苗(BCG)，显示出不同的效果。此外, 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，辅助性T细胞17型(Th17)产生 细胞因子白介素17(IL-17)是介导疫苗诱导保护的主要效应细胞 针对结核分枝杆菌。此外，粘膜疫苗可诱导更好的粘膜免疫，并赋予优势 与系统免疫路线相比，对结核病的保护。尽管有能力 实验性黏膜佐剂诱导保护性Th17反应并提供疫苗诱导 在保护方面，人类使用的诱导Th17的粘膜结核疫苗的开发缓慢。因此， 迫切需要找到安全有效的可诱发肺部的粘膜结核疫苗。 粘膜Th17反应并了解其作用机制(S)。纳米乳液(NE)是 用抗原配制的水包油乳状液。新佐剂在人体内安全且耐受性良好 当作为流感疫苗使用时，志愿者，并在 单次黏膜接种。在最新发表的数据中，我们发现去甲肾上腺素和结核杆菌的粘膜递送 抗原(NE-TB疫苗)可以控制结核分枝杆菌，并与减少#年的结核病疾病有关 老鼠。这项提案的总体目标是描述和优化保护性免疫 从而使开发一种新的、安全、有效的、 首创的Th17诱导的结核粘膜疫苗。因此，我们提出了以下具体目标。在……里面 具体目标1，利用小鼠结核病模型，我们将确定Prime-Boost策略和抗原 增强免疫原性并改善疫苗诱导的NE-TB保护作用的组合 疫苗，超过卡介苗接种提供的保护。在特定目标2中，使用鼠标 结核病模型，我们将评估表现最好的优质强化新城疫疫苗策略的效果 针对不同的结核分枝杆菌菌株，在遗传多样性的宿主中，以及预先暴露在环境中 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 在感染结核分枝杆菌的非人灵长类动物(NHP)中进行NE-TB疫苗的研究，并确定保护的相关因素。 这项拨款中提议的工作将确定作用机制(S)，并验证一种新的第一 一种诱导Th17的粘膜NE-TB候选疫苗将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.