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: 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
• 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

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).

新型结核病减毒活疫苗的免疫原性。 概括。 结核病 (TB) 由结核分枝杆菌 (M. tb) 感染引起，是一个全球性问题 目前影响着世界上大约三分之一的人口，并导致近 1.4 每年有数百万人死亡。目前的结核疫苗，牛分枝杆菌卡介苗（BCG），具有可变性 保护水平范围为0-80%。我们小组的早期研究已经确定了几种结核分枝杆菌 突变体被进一步开发成针对结核病的减毒活疫苗（LAV）候选物。使用 小鼠攻击的严格气溶胶模型，用这些候选物进行免疫（M. tbmosR，M. tbechA7) 显着地将小鼠组织中的结核分枝杆菌负荷降低至无法检测到的水平，其中一种 构建产生强大的细胞介导的免疫（CMI）。更重要的是，它保护了 小鼠对抗结核分枝杆菌北京分支的攻击，目前的卡介苗疫苗显示 保护不足。然而，这些疫苗的长期保护反应尚未得到证实。 决定。该项目的总体假设是基于 mosR 的疫苗将诱导 更广泛、更有效的记忆 T 细胞反应，将更有效地对抗高毒力结核分枝杆菌 临床分离，并将能够抵消调节性 T 细胞的活性，这三个领域 BCG 的表现非常差。在这个项目中，我们将检验我们的假设并剖析保护性因素 这种有前途的结核病候选疫苗的免疫反应是： A) 评估安全性和稳定性 MTBLAV (M. tbmosRechA7)。我们将构建一个双敲击突变体，此处称为 MTBLAV (M. tbmosRechA7) 并测定其在基因组学和转录组水平上的稳定性。在 此外，MTBLAV 的安全性将在免疫功能正常 (C57BL/6) 和免疫- 受损（Rag-/-、IFN-/-）小鼠（目标 I）。在该项目的第二个目标中； B）我们将剖析 MTBLAV 在小鼠体内诱导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) 与使用 TB 小鼠模型进行气溶胶攻击后的 BCG 进行比较 M. tb 北京 4619 的强毒临床分离株。通过完成这些目标，我们将更好地表征 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，与人类结核病更相关（例如 非人类灵长类动物）。