Tuberculosis Vaccine Strategy Using Salmonella Vectors

使用沙门氏菌载体的结核疫苗策略

• 批准号: 6364246
• 负责人: RICHARD K GROGER
• 金额: $ 10.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6364246
• 关键词: MHC class I antigen; Mycobacterium tuberculosis; Salmonella typhi; Salmonella vaccines; bacterial antigens; bacterial proteins; cellular immunity; cytotoxic T lymphocyte; drug delivery systems; drug screening /evaluation; enzyme linked immunosorbent assay; helper T lymphocyte; laboratory mouse; laboratory rabbit; live vaccine; microorganism antigen; peptide structure; recombinant proteins; transfection /expression vector; tuberculosis vaccines; vaccine development

The candidate is applying for a Career Development Award in order to gain additional training in vaccine research. He will work in Dr. Josephine Clark-Curtiss' lab, with Dr. Roy Curtiss serving as a co- mentor. The collaborative research environment of these laboratories should provide an ideal setting for the candidate to extend his previous research experience toward tuberculosis vaccine development. Several investigators in these laboratories are working on mycobacterial genetics and on the development of vaccines for other bacterial pathogens. During the award period the candidate will use a Salmonella live vaccine system to deliver specific mycobacterial polypeptide epitopes to the cytoplasm of antigen presenting cells, in order to stimulate an MHC class I-restricted CD8+ T cell response to these antigens. Growing evidence suggests a role for CD8+ T cells in natural immunity to tuberculosis. This hypothesis suggests that vaccine strategies designed to stimulate a CD8+ T cell response system may yield advances in tuberculosis vaccine technology. In addition, such advances may have implications for vaccines against other intracellular pathogens. The goals of this proposal are to: (1) test the ability of recombinant proteins based on SptP, or other proteins secreted and translocated by Salmonella, to stimulate a CD8+ T cell response to ESAT-6, (Z) test the ability of the elicited ESAT-6- specific T cells to kill intracellular mycobacteria, (3) test the ability of the recombinant SptP/ESAT-6-expressing, attenuated Salmonella typhimurium vaccine strain to protect mice from an aerosol challenge with a virulent Mycohac(erium (ttherculosis strain and (4) screen for additional mycobacterial antigens that could serve as alternative vaccine candidates in this antigen presentation system.

候选人正在申请职业发展奖，以便获得疫苗研究的额外培训。他将在约瑟芬·克拉克·科尔蒂斯（Josephine Clark-Curtiss）博士的实验室工作，罗伊·柯蒂斯（Roy Curtiss）博士担任合伙人。这些实验室的协作研究环境应该为候选人提供理想的环境，以将其先前的研究经验扩展到结核病疫苗的开发。这些实验室中的几名研究人员正在研究分枝杆菌遗传学以及其他细菌病原体的疫苗开发。在奖励期间，候选人将使用沙门氏菌活疫苗系统将特定的分枝杆菌多肽表位传递给抗原呈递细胞的细胞质，以刺激对这些抗原的MHC I限制的CD8+ T细胞反应。越来越多的证据表明，CD8+ T细胞对结核病的自然免疫发挥作用。该假设表明，旨在刺激CD8+ T细胞反应系统的疫苗策略可能会导致结核病疫苗技术的进展。此外，这种进步可能对其他细胞内病原体具有疫苗的影响。该建议的目标是：（1）测试基于SPTP的重组蛋白的能力，或者由沙门氏菌分泌和易位的其他蛋白质，以刺激CD8+ T细胞对ESAT-6的响应，（（Z）测试引起的ESAT-6-特异性T细胞的能力，以杀死ESAT-6-特异性T细胞的能力，以杀死杀死36的RECOBACTERSS（3）杀死3.3）的能力（3），3） - 3）。减弱的鼠伤寒沙门氏菌疫苗菌株可保护小鼠免受毒性MyCohAc（therculosis菌株和（4）筛查的其他分枝杆菌抗原，可以用作这种抗原介绍系统中的替代性疫苗候选者。