Enhancing cytotoxic lymphocytes in a TB vaccine strategy

摘要：目前，卡介苗是世界范围内使用最广泛的抗结核疫苗。 结核病（TB）。然而，结核病仍然是感染性疾病最常见的死亡原因之一， 这种疾病在全球范围内强调了其有限的疗效。我们已经证明卡介苗的疫苗效力 如果通过不同的途径或剂量给药，事实上，静脉注射卡介苗 疫苗接种在结核病的非人灵长类动物模型中产生90%的保护，但这种方法 在人口规模上不切实际。与保护相关的功能包括 气道中存在CD 8和CD 4 T细胞以及肺驻留T细胞。在本提案中，我们 计划模仿这种免疫反应，并在现有的BCG疫苗的基础上进行改进， 我们称之为“增强的启动和拉动”我们建议使用N-803，一种IL-15激动剂，以增强 先天性CD 8细胞的频率，并增强高剂量皮内BCG的作用。这是 接着是一剂雾化的卡介苗，将疫苗诱导的免疫细胞拉到这些区域， 在肺中繁殖常驻T细胞。使用一个重现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和机器学习技术。免疫原 在接种前，将在疫苗组和对照组中检查血液和气道中的免疫细胞。 结核分枝杆菌感染（目的1）。感染后，我们将比较 疫苗方案预防感染和/或降低细菌负荷的能力， 对照组（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，肺和纵隔淋巴结的背景下， 接种组和对照组的细菌负荷。最后，机器学习技术将 可用于鉴定与以下情况下的保护相关的免疫参数： 疫苗。拟议的研究可能会揭示有关以下作用的重要信息： 先天性细胞毒性CD 8细胞及其在疫苗诱导保护中的作用和机制 募集粘膜免疫应答。我们还可以获得重要的见解，关键替代 结核病领域迫切需要的保护标志物。

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.