Cooperative Center for the study of HCV antibody responses and vaccine antigens

 描述(申请人提供)：丙型肝炎病毒感染了近3%的世界人口，通常被称为一种沉默的流行病。它是导致肝硬变和癌症的主要原因，许多感染者直到肝脏功能障碍的迹象出现时才意识到感染。尽管最近在病毒治疗方面取得了重大进展，但还没有阻止病毒传播的疫苗。该项目的中心假设是，尽管病毒基因多样性，但诱导强大的广谱中和抗体反应的疫苗将有效地防止高危人群中的丙型肝炎病毒传播。项目1将研究在先前的第一阶段临床试验中接种了E1E2抗原的人和感染丙型肝炎病毒的人的抗体反应。同时，将研究临床前动物模型中接种E1E2抗原的抗体和B细胞反应，并将其与人类研究进行比较。这项研究项目将产生一套关于抗体、B细胞谱系和丙型肝炎病毒免疫表位的全面数据，以指导合理的疫苗设计工作。这个项目将由罗曼孙博士指导。项目2将利用最近的结构性 关于丙型肝炎病毒广泛中和表位的信息和计算蛋白质设计的进展，以开发针对表位的免疫原及其颗粒形式作为疫苗抗原，以诱导针对保守免疫表位的中和抗体反应。这个项目将由姜朱博士领导。这两个项目将利用法律实验室开发的抗体和病毒试剂，该实验室将由管理核心管理。督导人员亦会在他们的计划中互相协助，技能互补。罗博士将提供丙型肝炎病毒、病毒中和抗体和免疫动物模型方面的专业知识。朱博士将提供下一代B细胞谱系测序和免疫原设计方面的专业知识。管理核心还将负责所有行政职责，从而促进他们的沟通和工作效率 协调实验室和合作地点之间的研究活动，包括样品的组织、运输和储存。在来自内部和外部专家的宝贵建议的指导下，该团队的专业知识和努力的结合为加快发现有前途的丙型肝炎疫苗候选者提供了坚实的基础。

 DESCRIPTION (provided by applicant): HCV infects nearly 3% of the world population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and cancer, and many infected are not aware of the infection until signs of liver malfunction develop. Although significant progress has been made recently in virus treatment, there is no vaccine to stop virus transmission. The central hypothesis for this Program Project is that a vaccine inducing potent broadly neutralizing antibody responses will be effective in preventing HCV transmission in high risk population despite of the virus genetic diversity. Project 1 will study the antibody response in humans who have been vaccinated by the E1E2 antigen in a previous Phase 1 Clinical Trial, and in humans who have been infected by HCV. In parallel, antibody and B cell responses in preclinical animal models vaccinated with E1E2 antigens will be studied and compared to the human studies. This research project will produce a comprehensive set of data on the antibodies, B cell lineages, and HCV immune epitopes to guide rational vaccine design effort. This project will be directed by Dr. Mansun Law. Project 2 will capitalize on the recent structural information on HCV broadly neutralizing epitopes and advances in computational protein design to develop epitope-focused immunogens and their particle forms as vaccine antigens to elicit neutralizing antibody responses to the conserved immune epitopes. This project will be led by Dr. Jiang Zhu. The two projects will utilize antibody and viral reagents developed in the Law lab, which will be managed by an Admin Core. The PIs will also assist each other in their projects with their complementary skills. Dr. Law will provide expertise on HCV, virus neutralizing antibodies, and animal models for immunization. Dr. Zhu will provide expertise in next-generation sequencing of B cell repertoire and immunogen design. The Admin Core will facilitate their communication and productivity by taking care of all administrative duties as well as coordinating research activities including sample organization, shipment and storage between the labs and the collaborative sites. The combined expertise and effort of the team, guided by the valuable advice from internal and external experts, provide a solid foundation to accelerate the discovery of promising HCV vaccine candidates.