Tuberculosis Vaccine Strategy Using Salmonella Vectors

使用沙门氏菌载体的结核疫苗策略

• 批准号: 6650845
• 负责人: RICHARD K GROGER
• 金额: $ 11.22万
• 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 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650845
• 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; vaccine evaluation

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，以便获得疫苗研究方面的额外培训。他将在约瑟芬·克拉克-柯蒂斯博士的实验室工作，罗伊·柯蒂斯博士担任共同导师。这些实验室的合作研究环境应该为候选人提供一个理想的环境，让他将之前的研究经验扩展到结核病疫苗开发。这些实验室的几名研究人员正在研究分枝杆菌遗传学，并开发针对其他细菌病原体的疫苗。在获奖期间，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输送到抗原呈递细胞的细胞质中，以刺激MHC I类限制性CD8+T细胞对这些抗原的反应。越来越多的证据表明，CD8+T细胞在对结核病的自然免疫中发挥了作用。这一假设表明，旨在刺激CD8+T细胞反应系统的疫苗策略可能会带来结核病疫苗技术的进步。此外，这些进展可能会对针对其他细胞内病原体的疫苗产生影响。这项建议的目标是：(1)测试基于SptP的重组蛋白或沙门氏菌分泌和移位的其他蛋白刺激CD8+T细胞对ESAT-6做出反应的能力；(Z)测试被诱导的ESAT-6特异性T细胞杀死细胞内分枝杆菌的能力；(3)测试表达SptP/ESAT-6的重组鼠伤寒沙门氏菌疫苗株对小鼠免受强毒Mycohac(Er)的攻击的能力；以及(4)筛选可作为该抗原提呈系统中替代疫苗的替代疫苗的分枝杆菌抗原。

项目成果

Antibody-based protection against HIV infection by vectored immunoprophylaxis.

• DOI: 10.1038/nature10660
• 发表时间: 2011-11-30
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Balazs, Alejandro B.;Chen, Joyce;Hong, Christin M.;Rao, Dinesh S.;Yang, Lili;Baltimore, David
• 通讯作者: Baltimore, David