Immunogenicity of A Novel Live Attenuated Tuberculosis Vaccine

新型结核病减毒活疫苗的免疫原性

• 批准号: 9624984
• 负责人: ADEL M TALAAT
• 金额: $ 21.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/9624984
• 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

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).

新型活结核病疫苗的免疫原性。 概括。 结核病（TB）是由结核分枝杆菌（M. TB）引起的，是一个全球问题 目前，这影响了世界人口的大约三分之一，并导致接近1.4 每年有百万人死亡。当前的结核病疫苗M. Bovis BCG（BCG）具有可变的 保护水平范围为0-80％。我们小组的较早研究已经确定了几个M. TB 进一步发展为针对结核病的活疫苗（LAV）候选的突变体。使用 严格的鼠挑战气溶胶模型，这些候选者的免疫接种（M.tbmosr，M。 tbecha7）显着降低了鼠组织中的M. TB负荷为一个无法检测到的水平 构造具有鲁棒细胞介导的免疫（CMI）的构建体。更重要的是，它受到保护 M. TB分离株的北京进化枝反对挑战的小鼠，当前BCG疫苗显示 保护不足。但是，这些疫苗的长期保护反应尚未 决定。该项目的总体假设是，基于MOSR的疫苗将诱导 对于高毒力M. 临床分离株，并且能够抵消调节性T细胞的活性，这三个区域 BCG的性能非常差。在这个项目中，我们将检验我们的假设并剖析受保护的 对这种承诺结核病疫苗候选者的免疫反应； a）评估安全性和稳定性 mtblav（M。tbmosrecha7）。我们将在这里构建一个被称为配音的双敲突变体 mtblav（M。tbmosrecha7）并在基因组学和转录组水平上测定其稳定性。在 此外，MTBLAV的安全性将在免疫能力（C57BL/6）和免疫 - 受损（抹布 - / - ，ifn-/ - ）小鼠（AIM I）。在项目的第二个目标中； b）我们将剖析 MTBLAV在小鼠中引起的免疫反应的产生和维持。我们将分析 MTBLAV引起的长期疫苗免疫和T细胞反应的发展 （ -mosrecha7）与BCG使用TB的鼠模型在气溶胶挑战之后使用的鼠模型 北京M. TB M. 并了解这种新型疫苗预防结核病的能力。在未来的项目中，我们 将进一步剖析其他结核病模型中产生的免疫力，与人类结核更相关（例如 非人类隐私）。