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Harnessing B cells for TB vaccine development to improve therapy of TB and TB-HIV coinfection

利用 B 细胞开发结核病疫苗，以改善结核病和结核病-艾滋病毒合并感染的治疗

基本信息

批准号：
10441411
负责人：
Martin Alfons Gengenbacher
金额：
$ 129.44万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441411
关键词：
Adult Animal Model Animals Apoptosis Area Attenuated Attenuated Vaccines Autophagocytosis B-Cell Development B-Lymphocyte Subsets B-Lymphocytes BCG Live BCG Vaccine Blood Blood Circulation Cells Childhood Clinical Complement Containment Data Development Drug resistance Exposure to Face Flow Cytometry Frequencies Genes Genetic Genetic Engineering HIV HIV therapy HIV/TB Human Immunodeficient Mouse Immunologics Immunophenotyping Individual Infection Infection prevention Ligands Longevity Lung Measures Memory Modeling Monitor Mus Mycobacterium bovis Mycobacterium tuberculosis Organ Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Pre-Clinical Model Recombinants Recurrence Regimen Relapse Research Role Route Safety T cell response T-Lymphocyte Testing Therapeutic Time Treatment Efficacy Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccine Research Vaccines Virus Diseases adaptive immunity antiretroviral therapy chemotherapy child protection co-infection cohort cytokine experimental study genetic resistance genetic vaccination immunogenic immunogenicity immunoregulation improved infected B cell innovation knock-down macrophage mouse model mutant mycobacterial next generation novel pathogen prevent prophylactic protective efficacy rBCG reactivation from latency receptor response safety assessment therapeutic vaccine tuberculosis drugs tuberculosis treatment vaccine candidate vaccine development vaccine evaluation

项目摘要

Abstract Current tuberculosis (TB) control in the presence or absence of human immunodeficiency virus (HIV) infection is suboptimal: Bacillus Calmette-Guérin (BCG), the sole TB vaccine in clinical use, provides only limited protection during childhood and multi-drug chemotherapy faces challenges due to the alarming spread of drug resistance. An integrated approach combining chemotherapy with a therapeutic vaccine given after exposure to Mycobacterium tuberculosis (Mtb) could be a way forward. TB vaccine research mostly focused on prophylactic candidates aiming to prevent infection. Therapeutic TB vaccines with novel mechanisms of action are needed (i) to complement existing chemotherapy and prevent relapse thereafter, and (ii) to cure latent TB infection (LTBI) or prevent reactivation. T lymphocytes are critical for the control of TB infection and the specific T cell response elicited by a vaccine has been used as a key correlate of immunogenicity. In contrast, B cells are understudied in all areas of TB research. Using a deep immunophenotyping approach, our preliminary data in mice suggest that TB infection leads to dramatic changes in the landscape of B cell subpopulations. We identified a novel B cell subset with marginal zone (MZ) phenotype that was activated, had a memory phenotype and expressed receptors recognizing the human cytokines A Proliferation-Inducing Ligand, APRIL, and B cell Activating Factor, BAFF, critical for B cell development and survival. Functional studies indicated that murine MZ B cells contributed to Mtb containment in mice. Surprisingly, these B cells expressed a panel of Th1 cytokines, well studied in T cells, suggesting a possible role in the first line of defense against TB infection. We found that MZ B cells were depleted in blood of TB patients and TB/HIV coinfected people. Our hypothesis is that MZ B cells can be restored by antitubercular therapy and harnessed for TB vaccine development. To test this, we genetically engineered BCG to express the human cytokines APRIL and BAFF that stimulate development and longevity of BAFF receptor- and APRIL receptor-expressing B cells, including MZ B cells. We will determine the safety, immunogenicity and prophylactic efficacy in mice. The therapeutic efficacy will be evaluated in two novel innovative mouse models that allow us to determine the capacity of cytokine expression in BCG strains to prevent relapse after drug treatment and to reduce the reactivation frequency of paucibacillary TB mimicking aspect of LTBI in humans. We will determine the frequency of MZ B cells in peripheral blood mononuclear cells (PBMC) from people having LTBI and TB, across HIV status, including antitubercular and antiretroviral therapy. We will stimulate PBMC of the same cohorts with cytokine-expressing BCG strains to study the immunological consequences and to demonstrate, in principle, the feasibility of these vaccines during therapy of TB, HIV and TB/HIV coinfection. We will monitor the global landscapes of T cells and B cells by high parameter flow cytometry to define immunological correlates of TB infection and vaccine protection. Our proposal will determine whether B cells can be harnessed by cytokine-secreting B cell-targeting BCG vaccines for TB vaccine development.

摘要