Pro-Apoptotic BCG as an HCV vaccine vector

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应答在控制感染方面极其重要。我们的研究小组已经进行了新的遗传修饰，以消除全球最常用的疫苗BCG中的免疫逃避基因。被称为“促凋亡BCG”的改良BCG疫苗在易感小鼠品系中显示出有效的免疫应答。与亲本BCG疫苗相比，新疫苗在对疫苗接种的初次应答期间通过T细胞产生更大的IL-2，并且在再激发期间产生更快的回忆应答。我们的目标与此R21应用程序是引入HCV抗原到这些修改BCG菌株开发一个混合TB-HCV疫苗能够引发有效的细胞免疫反应。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个核细胞对疫苗表达的HCV抗原的识别，这些细胞以前从慢性或已消退的HCV感染的黑猩猩中分离。3)在HLA I类转基因小鼠中评价这些疫苗的免疫原性。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，以评估不同HCV插入物疫苗的免疫原性。促凋亡BCG作为抗原递送平台的优点是其引发比BCG更强的免疫应答的能力，尽管进行了使其更减毒的修饰，这也应该改善在人类中已经良好的安全性。这项建议将利用每一位调查员的独特专长。我们计划在一个高免疫原性和安全的载体中表达HCV抗原，这将促进这种疫苗从实验室到临床的迁移。丙型肝炎病毒目前感染全球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广泛使用的安全结核疫苗的改良版本中，我们称之为“促凋亡BCG”。我们的改良BCG疫苗在小鼠模型中比原始BCG菌株产生更好的免疫应答，并且作为促细胞凋亡的组合BCG-HCV疫苗可以迅速从小鼠试验转移到人类。

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.