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: 10580073
• 负责人: JoAnne L. Flynn
• 金额: $ 77.35万
• 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/10580073
• 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; 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; PET/CT scan; Pathology; Population; Prevention; Proliferating; 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; biomarker identification; cell type; comparative efficacy; comparison control; cytotoxic; cytotoxicity; design; immunogenicity; improved; insight; intravenous administration; multidimensional data; mycobacterial; nonhuman primate; novel; novel vaccines; prevent; recruit; response; single-cell RNA sequencing; success; tool; translation to humans; translational potential; 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，卡介苗是世界上使用最广泛的疫苗