Pro-Apoptotic BCG as an HCV vaccine vector

作为 HCV 疫苗载体的促凋亡 BCG

• 批准号: 7936880
• 负责人: Spyros A Kalams
• 金额: $ 19.33万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936880
• 关键词: Antigens; Apoptotic; Attenuated; BCG Vaccine; Chronic; Clinic; Future; Genes; Genetic; Goals; HCV Vaccine; Hepatitis C; Hepatitis C virus; Human; Hybrids; Immune; Immune response; Infection Control; Interleukin-2; Liver Cirrhosis; Modification; Mouse Strains; Mus; Mycobacterium tuberculosis; Organism; Pan Genus; Parents; Peripheral Blood Mononuclear Cell; Primates; Production; Recombinants; Research Personnel; Safety; T-Lymphocyte; Testing; Transgenic Mice; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; citrate carrier; immunogenic; immunogenicity; improved; latent infection; migration; mouse model; novel; novel vaccines; pathogen; response; vector

DESCRIPTION (provided by applicant): Hepatitis C virus and Mycobacterium tuberculosis are each immensely successful pathogens, with the common thread between them that host cellular immune responses are extremely important in controlling infection. Our group has made novel genetic modifications to eliminate immune-evasive genes in the most commonly administered worldwide vaccine, BCG. The modified BCG vaccine, called "pro-apoptotic BCG", demonstrates potent immune responses in susceptible mouse strains. Compared to the parent BCG vaccine, the new vaccine elicits greater IL-2 production by T-cells during the primary response to vaccination and quicker recall responses during re-challenge. Our goal with this R21 application is to introduce HCV antigens into these modified BCG strains to develop a hybrid TB-HCV vaccine capable of eliciting potent cellular immune responses. We will 1) Construct recombinant pro-apoptotic BCG (rpaBCG) vaccines that express HCV antigens. 2) Verify recognition of vaccine-expressed HCV antigens by T cell clones and peripheral blood mononuclear cells previously isolated from chimpanzees with chronic or resolved HCV infection. 3) Evaluate immunogenicity of these vaccines in HLA Class I-transgenic mice. If successful, our future goals will include larger scale mouse studies, and small primate studies to evaluate the immunogenicity of vaccines with different HCV inserts. The advantage of pro-apoptotic BCG as a platform for antigen delivery is its ability to elicit stronger immune responses than BCG despite modifications which make it more attenuated, which should also improve upon an already good safety profile in humans. This proposal will take advantage of the unique expertise of each investigator. Our plan to express HCV antigens in a highly immunogenic and safe vector will facilitate the migration of this vaccine from the bench to the clinic. Project Narrative: Hepatitis C virus currently infects 170 million people worldwide, and is a leading cause of cirrhosis of the liver. Our goal is to incorporate Hepatitis C proteins in a modified version of a widely used and safe tuberculosis vaccine, which we call "pro-apoptotic BCG". Our modified BCG vaccine elicits better immune responses in a mouse model than the original BCG strain, and as a combined pro-apoptotic BCG-HCV vaccine could move quickly from testing in mice to humans.

描述（由申请人提供）：丙型肝炎病毒和结核分枝杆菌都是非常成功的病原体，它们之间的共同点是宿主细胞免疫反应对于控制感染极其重要。我们的团队进行了新颖的基因改造，以消除全球最常用的疫苗卡介苗中的免疫逃避基因。改良的卡介苗疫苗被称为“促凋亡卡介苗”，在易感小鼠品系中表现出强大的免疫反应。与母体 BCG 疫苗相比，新疫苗在疫苗接种的初次反应期间引发 T 细胞产生更多的 IL-2，并在再次攻击期间引发更快的回忆反应。我们的 R21 应用目标是将 HCV 抗原引入这些改良的 BCG 毒株中，以开发能够引发有效细胞免疫反应的混合 TB-HCV 疫苗。我们将 1) 构建表达 HCV 抗原的重组促凋亡卡介苗 (rpaBCG) 疫苗。 2) 验证先前从患有慢性或已解决的 HCV 感染的黑猩猩中分离出的 T 细胞克隆和外周血单核细胞对疫苗表达的 HCV 抗原的识别。 3) 评估这些疫苗在 HLA I 类转基因小鼠中的免疫原性。如果成功，我们未来的目标将包括更大规模的小鼠研究和小型灵长类动物研究，以评估具有不同 HCV 插入片段的疫苗的免疫原性。促凋亡卡介苗作为抗原递送平台的优势在于，尽管经过修饰使其更加弱化，但它能够引发比卡介苗更强的免疫反应，这也应该会改善人类本已良好的安全性。该提案将利用每位研究者的独特专业知识。我们计划在高免疫原性和安全的载体中表达 HCV 抗原，这将有助于该疫苗从实验室转移到临床。项目简介：丙型肝炎病毒目前感染全球 1.7 亿人，是导致肝硬化的主要原因。我们的目标是将丙型肝炎蛋白纳入广泛使用且安全的结核疫苗的改良版本中，我们将其称为“促凋亡卡介苗”。我们的改良 BCG 疫苗在小鼠模型中比原始 BCG 菌株能引发更好的免疫反应，并且作为一种促凋亡 BCG-HCV 联合疫苗，可以快速从小鼠测试转向人类测试。