Enhancing cytotoxic lymphocytes in a TB vaccine strategy

在结核病疫苗策略中增强细胞毒性淋巴细胞

• 批准号: 10462928
• 负责人: JoAnne L. Flynn
• 金额: $ 77.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-25 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462928
• 关键词: Acute Disease; Aerosols; Agonist; Animal Model; Animals; Area; B-Lymphocytes; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bioinformatics; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cause of Death; Cells; Cessation of life; Communicable Diseases; Control Groups; Data; Data Set; Disease; Dose; Frequencies; Genetic Transcription; Granuloma; HIV; Human; Immune; Immune response; Immunologic Markers; Immunologics; Immunology; Industry Collaboration; Infection; Infection prevention; Interleukin-15; Intravenous; Lung; Lung diseases; Lymphocyte; Macaca mulatta; Machine Learning; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediastinal lymph node group; Mediating; Methods; Microbiology; Modeling; Modernization; Monitor; Mucosal Immune Responses; Mycobacterium tuberculosis; Myeloid Cells; Outcome; Pathology; Population; Positron-Emission Tomography; Prevention; Pulmonary Inflammation; Randomized; Regimen; Research; Role; Route; SIV; Scourge; Site; Surrogate Markers; T-Lymphocyte; Techniques; Testing; Tissues; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Virulent; X-Ray Computed Tomography; acute infection; aerosolized; cell type; comparative efficacy; cytotoxic; cytotoxicity; design; immunogenicity; improved; insight; multidimensional data; mycobacterial; nonhuman primate; novel; novel vaccines; prevent; recruit; response; single-cell RNA sequencing; success; tool; translation to humans; vaccination outcome; vaccination protocol; vaccine efficacy; vaccine strategy; vaccine-induced immunity

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.

摘要：目前BCG是全球管理最广泛的疫苗 结核病（TB）。然而，结核病仍然是感染性的最常见死亡原因之一 全球疾病强调其有限的效率。我们已经证明了BCG的疫苗效率 如果通过不同的路线或剂量给药，可以改进。实际上，静脉注射BCG 疫苗接种在非人类的TB私人模型中导致90％的保护，但此方法是 不切实际地进行人口规模。与保护相关的功能包括 气道和肺居民T细胞中存在CD8和CD4 T细胞。在这个建议中，我们 计划模仿这种免疫反应并在策略中改善现有的BCG疫苗 我们称之为“增强的质量和拉力”。我们建议使用IL-15激动剂N-803来增强 先天CD8细胞的频率，并增加了高剂量，皮内BCG的影响。这是 然后是剂量的雾化BCG，将疫苗诱导的免疫细胞拉到该区域， 传播居民T细胞中的T细胞。使用概括人类结核的动物模型，我们 将使用最先进的现代工具，例如PET CT，大规模免疫分析 在转录和流式细胞仪和机器学习技术下。免疫原性 在血液和气道免疫细胞中，将在疫苗和对照组中检查 结核分枝杆菌感染（AIM 1）。感染后，我们将比较 与疫苗方案相比 控件（AIM 2）。我们将检查免疫调子（包括组织的存在 在肉芽肿，肺和纵隔淋巴结中的常驻T细胞） 接种疫苗和对照组之间的细菌燃烧。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。拟议的研究可能揭示有关有关作用的重要信息 先天的细胞毒性CD8细胞及其在疫苗诱导的保护和机制中的作用 招募粘膜免疫反应。我们也可能会获得对主要代理的重要见解 在结核病领域需要保护的标记。