Therapeutic vaccination to augment stringent response-specific T-cell immunity to MTB persisters

治疗性疫苗接种可增强对 MTB 持续者的严格反应特异性 T 细胞免疫

• 批准号: 10341182
• 负责人: Petros C Karakousis
• 金额: $ 74.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341182
• 关键词: Adjuvant; Adoptive Cell Transfers; Aerosols; Animal Model; Animals; Antibiotics; Antibody titer measurement; Antigens; Antitubercular Agents; Archives; Bacteria; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cause of Death; Cellular Immunity; Clinical; Collaborations; Communicable Diseases; DNA; DNA Vaccines; Dendritic Cells; Development; Dinucleoside Phosphates; Dose; Drug resistance in tuberculosis; Emission-Computed Tomography; Enzyme-Linked Immunosorbent Assay; Enzymes; Flow Cytometry; Goals; Gold; Growth; HIV; HIV Infections; Histologic; Homeostasis; Human; Immune response; Immunity; Immunize; Immunology; In Vitro; Individual; Interferon Type I; International; Intramuscular; Longitudinal cohort; Lung; Macaca mulatta; Measures; Microbiology; Modeling; Molecular Biology; Monitor; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Nature; Pathway interactions; Patients; Pattern; Periodicity; Persons; Pharmaceutical Preparations; Physiological; Plasmids; Positron-Emission Tomography; Pre-Clinical Model; Pulmonary Inflammation; Pulmonary Tuberculosis; Regimen; Relapse; Reporting; Research Personnel; Resistance; Role; Sampling; South Africa; South African; Stains; Stimulator of Interferon Genes; Stress; Subunit Vaccines; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccine Therapy; X-Ray Computed Tomography; antibiotic tolerance; antigen-specific T cells; cell type; chemokine; cytokine; diagnostic tool; immunogenicity; improved; interest; isoniazid; mouse model; novel; novel diagnostics; novel strategies; novel vaccines; prevent; primary endpoint; protective efficacy; response; translational potential; treatment duration; tuberculosis treatment; vaccination strategy; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine platform; vaccine strategy

Mycobacterium tuberculosis (Mtb) is the leading infectious disease-related cause of death among people living with HIV worldwide. Shorter tuberculosis (TB) treatment regimens are needed to achieve global TB elimination. The protracted nature of the current 6-month TB treatment course reflects the unique ability of a subpopulation of “persister” bacteria to remain in a growth-limited, antibiotic-tolerant state through various adaptive strategies, including induction of the stringent response. The key stringent response enzyme RelMtb is essential for long-term Mtb survival under physiologically relevant stresses in vitro and in animal lungs. Recently, we have generated a therapeutic relMtb DNA vaccine, which induces RelMtb-specific cellular immunity, and significantly augments the activity of the first-line drug isoniazid against active TB in mice. We also have developed a novel vaccination strategy involving fusion of the antigen of interest with the immature dendritic cell (iDC)-targeting chemokine MIP3α, which significantly enhances antigen-specific T-cell responses. In the current proposal, we will determine if this iDC-targeting strategy, as well as a promising new adjuvant approach involving the use of cyclic dinucleotides to activate the stimulator of interferon genes (STING) pathway, enhance the immunogenicity of our relMtb DNA vaccine. The ideal vaccine platform will be used to test the novel hypothesis that enhanced cellular immunity against RelMtb potentiates the activity of the first- line anti-TB regimen and accelerates cure in the standard murine model of TB. Since HIV infection is associated with disturbed T-cell homeostasis, including depletion of CD4+ T cells and persistent expansion of CD8+ T cells, we will characterize the contribution of each of these cell types to the therapeutic efficacy of the relMtb DNA vaccine in mice. In order to transition our findings to the clinical setting, we will next test the immunogenicity of this vaccination strategy in rhesus macaques, which develop immune response patterns most analogous to those of humans. Finally, leveraging archived clinical samples available through the RePORT South Africa longitudinal cohort of HIV-infected and uninfected patients with pulmonary TB receiving first-line anti-tubercular treatment, we will measure RelMtb-specific T-cell responses during TB therapy. This proposal represents a unique collaboration between Investigators with significant expertise in microbiology, molecular biology, immunology, DNA vaccines, and animal models. Our findings are expected to have far- reaching implications for the development of novel adjunctive therapies for shortening the duration of treatment for drug-susceptible and drug-resistant TB, as well as novel diagnostic tools for confirming the adequacy of TB treatment in HIV-infected and uninfected individuals.

结核分枝杆菌 (Mtb) 是人类与传染病相关的主要死亡原因 全世界艾滋病毒感染者需要更短的结核病 (TB) 治疗方案才能实现全球结核病防治目标。 当前 6 个月的结核病治疗过程的长期性反映了治疗的独特能力。 “持久性”细菌亚群通过各种方式保持生长受限、抗生素耐受状态 适应性策略，包括诱导严格反应关键的严格反应酶 RelMtb。 对于 Mtb 在体外和动物肺部的生理相关应激下的长期生存至关重要。 最近，我们生产了一种治疗性 relMtb DNA 疫苗，它可以诱导 RelMtb 特异性细胞免疫， 并显着增强一线药物异烟肼对抗小鼠活动性结核病的活性。 开发了一种新的疫苗接种策略，涉及将感兴趣的抗原与未成熟的树突融合 细胞 (iDC) 靶向趋化因子 MIP3α，可显着增强抗原特异性 T 细胞反应。 目前的提案，我们将确定这种 iDC 靶向策略以及一种有前途的新佐剂 涉及使用环状二核苷酸来激活干扰素基因刺激剂（STING）的方法 途径，增强我们的 relMtb DNA 疫苗的免疫原性，将用于理想的疫苗平台。 测试新的假设，即增强针对 RelMtb 的细胞免疫会增强第一个的活性 线抗结核治疗方案并加速结核病标准小鼠模型的治愈，因为艾滋病毒感染是 与 T 细胞稳态紊乱有关，包括 CD4+ T 细胞的耗竭和 CD4+ T 细胞的持续扩张 CD8+ T 细胞，我们将描述每种细胞类型对治疗功效的贡献 relMtb DNA 疫苗在小鼠中的应用 为了将我们的发现转化为临床环境，我们接下来将测试该疫苗。 这种疫苗接种策略在恒河猴中的免疫原性，可形成免疫反应模式 最后，利用通过可用的存档临床样本。 报告南非艾滋病毒感染者和未感染者肺结核接受纵向队列 作为一线抗结核治疗，我们将在结核病治疗期间测量 RelMtb 特异性 T 细胞反应。 该提案代表了具有微生物学丰富专业知识的研究人员之间的独特合作， 我们的研究结果有望对分子生物学、免疫学、DNA 疫苗和动物模型产生深远影响。 对开发新型辅助疗法以缩短持续时间的影响 药物敏感和耐药结核病的治疗，以及用于确认结核病的新型诊断工具 HIV 感染者和未感染者的结核病治疗是否充分。