Dissecting virus neutralizing determinants to guide HCV vaccine development

描述（由申请人提供）：丙型肝炎病毒（HCV）慢性感染全球2-3%的人口，使患者易患慢性肝病和肝癌。一种广泛有效的疫苗将是解决这一全球性问题的一种具有成本效益的手段。然而，HCV在遗传上是多样的，基于单一病毒株设计的疫苗将不能有效地对抗遗传多样性的循环病毒。为了克服这一科学挑战， 候选疫苗必须针对病毒上的保守区域。本申请的目的是确定病毒中和表位的分子结构，以帮助免疫原的合理设计，这将在疫苗接种中集中针对保守表位的抗体应答。这种“表位疫苗”方法包括：（1）确定与相应的广泛中和抗体复合的HCV抗体表位的晶体结构;（2）设计和合成作为已知表位结构的仿生物的免疫原;（3）在HCV感染的小动物模型中测试新型免疫原以鉴定先导疫苗候选物。如果成功的话，这一提议将为临床试验带来新的HCV候选疫苗，并大大推动HCV和疫苗领域的发展。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. A broadly effective vaccine will be a cost- effective mean to solve this global problem. However, HCV is genetically varied and vaccines designed based on a single viral strain will not be effectively against genetically diverse circulating viruses. To overcome this scientific challenge, the vaccine candidates must target conserved regions on the virus. The goal of this application is to determine the molecular structure of virus neutralizing epitopes to aid the rational design o immunogens, that will focus antibody responses to the conserved epitopes in vaccination. This "epitope vaccine" approach include: (1) Determination of crystal structures of HCV antibody epitopes in complex with the corresponding broadly neutralizing antibodies; (2) Design and synthesis of immunogens as biomimetics of the known epitope structures; (3) Testing of the novel immunogens in a small animal model of HCV infection to identify lead vaccine candidates. If successful, this proposal can result in novel HCV vaccine candidates for clinical trials, and also significantly advance the HCV and vaccine fields.