Dissecting virus neutralizing determinants to guide HCV vaccine development

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)慢性感染全球人口的2-3%，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问题的具有成本效益的手段。然而，丙型肝炎病毒的基因是多种多样的，基于单一病毒株设计的疫苗不能有效地对抗基因多样化的流行病毒。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。这项应用的目的是确定病毒中和表位的分子结构，以帮助合理设计免疫原，使抗体反应集中在疫苗接种中保守的表位。这种“表位疫苗”方法包括：(1)确定丙型肝炎病毒抗体表位与相应的广谱中和抗体的复合体的晶体结构；(2)设计和合成免疫原，作为已知表位结构的仿生学；(3)在丙型肝炎病毒感染的小动物模型中测试新型免疫原，以确定主要候选疫苗。如果成功，这项建议可能导致新的丙型肝炎疫苗候选临床试验，并显著推进丙型肝炎病毒和疫苗领域。

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.