Enhancing cytotoxic lymphocytes in a TB vaccine strategy

摘要：卡介苗是目前世界上应用最广泛的疫苗。 结核病(TB)。然而，结核病仍然是最常见的传染病致死原因之一。 这种疾病在全球范围内凸显了其有限的效力。我们已经证明了卡介苗的疫苗功效 如果通过不同的途径或剂量给药，效果会有所改善。事实上，静脉注射卡介苗 在非人类灵长类结核病模型中，接种疫苗可获得90%的保护，但这种方法 在人口规模上进行是不切实际的。与保护相关的功能包括 CD8和CD4T细胞在呼吸道和肺内的存在。在这份提案中，我们 计划模拟这种免疫反应，并在战略上改进现有的卡介苗 我们称之为“增强型素数和拉力”。我们建议使用IL-15激动剂N-803来增强 提高先天CD8细胞的频率，增强高剂量、皮内卡介苗的作用。这是 然后是一剂雾化卡介苗，将疫苗诱导的免疫细胞拉入这些区域 在肺部繁殖常驻T细胞。使用重述人类结核病的动物模型，我们 将利用最先进的现代工具，如PET CT、大规模免疫分析 在转录和流式细胞术水平上，以及机器学习技术。免疫原性 疫苗组和对照组在接种疫苗前将检查血液和呼吸道中的免疫细胞 感染结核分支杆菌(目标1)。在感染之后，我们将比较 疫苗方案预防感染和/或降低细菌负荷的能力 控制(目标2)。我们将检查免疫反应(包括组织的存在 常驻T细胞)在肉芽肿、肺和纵隔淋巴结中 接种疫苗组和对照组的细菌负荷。最后，机器学习技术将 用于识别与保护相关的免疫参数 疫苗。拟议中的研究可能会揭示关于 天然细胞毒CD8细胞及其在疫苗诱导保护中的作用和机制 招募粘膜免疫反应。我们还可能获得对关键代理的重要见解 结核病领域迫切需要保护标志。

ABSTRACT: Currently BCG is the most widely administered vaccine worldwide against tuberculosis (TB). Yet, TB remains one of the most common causes of death from an infectious disease globally underscoring its limited efficacy. We have shown that BCG’s vaccine efficacy can be improved if administered by a different route or dose. In fact, intravenous BCG vaccination resulted in 90% protection in a non-human primate model of TB but this method is impractical to conduct on a population scale. Features associated with protection include the presence of CD8 and CD4 T cells in the airways and lung resident T cells. In this proposal we plan to mimic this immune response and improve upon the existing BCG vaccine in a strategy that we call “enhanced prime and pull”. We propose to use N-803, an IL-15 agonist, to enhance the frequency of innate CD8 cells and boost the effects of high dose, intradermal BCG. This is followed by a dose of aerosolized BCG to pull vaccine-induced immune cells into the areas and propagate resident T cells in the lungs. Using an animal model that recapitulates human TB, we will utilized state-of-the-art modern tools such as PET CT, large scale immunologic profiling both at a transcriptional and flow cytometric level and machine learning techniques. Immunogenicity in blood and airway immune cells will examined among vaccine and control groups prior to infection with Mycobacterium tuberculosis (Aim 1). After infection, we will then compare the ability of the vaccine regimen to prevent infection and/or lower bacterial burden compared to controls (Aim 2). We will examine the immune responses (including the presence of tissue resident T cells) in the granuloma, lungs and mediastinal lymph nodes in the context of bacterial burden among vaccinated and control groups. Lastly, machine learning techniques will be used to identify immune parameters that correlate with protection in the context of vaccines. The proposed studies are likely to reveal important information about the role of innate cytotoxic CD8 cell and their role in vaccine induced protection and mechanisms of recruiting mucosal immune responses. We may also gain important insights into key surrogate markers of protection sorely needed in the TB field.