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Immunogenicity of A Novel Live Attenuated Tuberculosis Vaccine

新型结核病减毒活疫苗的免疫原性

基本信息

批准号：
9750621
负责人：
ADEL M TALAAT
金额：
$ 18.49万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-25 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750621
关键词：
Address Adult Aerosols Affect Area Attenuated Attenuated Live Virus Vaccine BCG Live BCG Vaccine Biological Assay Birth CD4 Positive T Lymphocytes Cellular Immunity Cessation of life Child Clinical Defect Developed Countries Developing Countries Development Disease Future Generations Genetic Genetic Variation Genomics Genus Mycobacterium Health Human Immune Immune response Immunity Immunization Infection Interferons Lung Maintenance Mediating Modeling Monitor Mus Mycobacterium bovis Mycobacterium tuberculosis Nature Parents Phenotype Population Primary Infection Production Public Health Pulmonary Tuberculosis Regulatory T-Lymphocyte Research Resistance Safety Schools Site T cell response T memory cell Testing Time Tissues Tuberculosis Tuberculosis Vaccines United States National Institutes of Health Vaccinated Vaccines Virulent attenuation authority base immunogenicity in vivo memory CD4 T lymphocyte mouse model mutant nonhuman primate novel novel vaccines prevent protective efficacy reactivation from latency response transcriptome vaccine candidate vaccine efficacy vaccine response vaccine safety

项目摘要

Immunogenicity of A Novel Live Attenuated Tuberculosis Vaccine. Summary. Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tb), is a global problem that currently affects approximately one-third of the world’s population and results in nearly 1.4 million deaths each year. The current tuberculosis vaccine, M. bovis BCG (BCG), has variable protection levels ranging from 0-80%. Earlier research from our group has identified several M. tb mutants that were further developed into live attenuated vaccine (LAV) candidates against TB. Using a stringent aerosol model of murine challenge, immunization with these candidates (M. tbmosR, M. tbechA7) significantly reduced the M. tb load in murine tissues to undetectable levels for one of the constructs with the production of robust cell mediated immunity (CMI). More importantly, it protected mice against challenge with the Beijing clade of M. tb isolates where the current BCG vaccine shows insufficient protection. However, the long-term protective responses of these vaccines have not been determined. The overarching hypothesis of this project is that mosR-based vaccines will induce a broader and more potent memory T-cell response, will be more effective against highly virulent M. tb clinical isolates, and will be able to counteract the activity of regulatory T cells, three areas in which BCG performs very poorly. In this project, we will test our hypothesis and dissect the protective immune responses for this promising TB vaccine candidate by; A) Evaluating the safety and stability of MTBLAV (M. tbmosRechA7). We will construct a double knock mutant dubbed here as MTBLAV (M. tbmosRechA7) and assay its stability on both genomics and transcriptome levels. In addition, the safety of MTBLAV will be assayed in both immune-competent (C57BL/6) and immune- compromised (Rag-/-, IFN-/-) mice (Aim I). In the Second Aim of the project; B) We will dissect the generation and maintenance of immune responses induced by MTBLAV in mice. We will analyze the development of long-term vaccine immunity and T-cell responses elicited by the MTBLAV (mosRechA7) compared to BCG using the murine model of TB following aerosol challenge with virulent clinical isolate of M. tb Beijing 4619. By completing these aims, we will better characterize and understand the ability of this novel vaccine to protect against tuberculosis. In future project, we will further dissect the generated immunity in other TB models, more relevant to human TB (such as non-human primates).

一种新型结核病减毒活疫苗的免疫原性