Pro-Apoptotic BCG as an HCV vaccine vector

作为 HCV 疫苗载体的促凋亡 BCG

• 批准号: 7386674
• 负责人: Spyros A Kalams
• 金额: $ 24.56万
• 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/7386674
• 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，其中宿主细胞免疫反应在控制感染中非常重要。我们的小组进行了新的遗传修饰，以消除最常见的全球疫苗BCG中的免疫渗透基因。改良的BCG疫苗称为“ pro凋亡BCG”，在易感小鼠菌株中表现出有效的免疫反应。与母体BCG疫苗相比，新的疫苗在对疫苗接种的主要反应过程中引起了T细胞产生的IL-2，并在重新挑战期间更快的回忆反应。我们使用此R21应用的目标是将HCV抗原引入这些改良的BCG菌株中，以开发能够引起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BCG（RPABCG）疫苗。 2）验证T细胞克隆和外周血单核细胞以前从慢性或分辨HCV感染中分离出的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HLA I类转基因小鼠中这些疫苗的免疫原性。如果成功，我们的未来目标将包括大规模的小鼠研究和小型灵长类研究，以评估不同HCV插入物的疫苗的免疫原性。促凋亡BCG作为抗原递送平台的优势在于，尽管修改使其更加衰减，但它与BCG相比具有比BCG更强的免疫反应的能力，这也应该改善人类已经良好的安全性。该提案将利用每个调查员的独特专业知识。我们在高度免疫原性和安全载体中表达HCV抗原的计划将促进该疫苗从长凳迁移到诊所。项目叙述：乙型肝炎病毒目前在全球感染了1.7亿人，是肝硬化的主要原因。我们的目标是将丙型肝炎蛋白纳入一种经过改良的，安全的结核病疫苗的改良版本中，我们称之为“促凋亡BCG”。与原始BCG菌株相比，我们修饰的BCG疫苗在小鼠模型中引起的免疫反应更好，并且作为组合的促凋亡BCG-HCV疫苗，可以从小鼠的测试迅速移动到人类。