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).

新型结核病减毒活疫苗的免疫原性研究 总结。 由结核分枝杆菌感染引起的结核病是一个全球性问题。 目前，这影响了大约三分之一的世界人口，并导致近1.4 每年有数百万人死亡。目前的结核病疫苗，卡介苗(BCG)，具有可变的 保护级别从0-80%不等。我们小组的早期研究发现了几个结核分枝杆菌 进一步发展成为结核病减毒活疫苗(LAV)候选的突变体。vbl.使用 一种严格的小鼠挑战气溶胶模型，用这些候选者进行免疫(M.TBMOSR，M. TBechA7)显著降低了小鼠组织中的结核分枝杆菌载量，使其无法检测到 具有产生强健的细胞介导免疫(CMI)的构建。更重要的是，它保护了 小鼠对北京分支结核分枝杆菌的挑战，目前的卡介苗显示 保护不足。然而，这些疫苗的长期保护性反应并没有 下定决心。该项目的主要假设是，基于MOSR的疫苗将诱导 更广泛和更强大的记忆T细胞反应，将更有效地对抗强毒结核分枝杆菌 临床分离，并将能够中和调节性T细胞的活性，在三个领域 BCG的表现非常糟糕。在这个项目中，我们将检验我们的假设并剖析保护性的 这一有希望的结核疫苗候选疫苗的免疫应答：A)评价其安全性和稳定性 结核分枝杆菌MosrechA7)。我们将构建一个双敲击突变体，在这里称为 MTBLAV(M.TBMOSRechA7)，并从基因组和转录组水平分析其稳定性。在……里面 此外，MTBLAV的安全性将在免疫活性(C57BL/6)和免疫缺陷病毒(C57BL/6)中进行检测。 受损(RAG-/-，干扰素-/-)小鼠(AIM I)。在该项目的第二个目标中；b)我们将剖析 MTBLAV诱导小鼠免疫应答的产生和维持。我们将分析 MTBLAV诱导的长期疫苗免疫和T细胞反应的研究进展 (MOSRECHA7)与使用卡介苗的小鼠结核病模型进行比较 结核分枝杆菌北京4619株强毒临床分离株。通过完成这些目标，我们将更好地描述 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 将进一步剖析与人类结核病更相关的其他结核病模型中产生的免疫力(例如 非人灵长类)。