Development of a structure-based HCV vaccine using a virus-like particle platform

描述（由申请人提供）：丙型肝炎病毒（HCV）是一种主要的人类病原体，慢性感染全球2-3%的人口。在美国，它是最常见的血液传播疾病，大约有390万携带者。大多数感染HCV的患者进展为慢性疾病，肝硬化和肝细胞癌的风险增加。慢性丙型肝炎的标准治疗是用聚乙二醇化干扰素和利巴韦林联合治疗，辅以一种抗病毒化合物，使病毒NS3/4A蛋白酶失活。最近在联合治疗中纳入蛋白酶抑制剂已导致许多患者持续病毒反应率的改善，但某些因素可能限制治疗的总体成功。这些因素包括丙型肝炎病毒对这些抗病毒药物产生耐药性的可能性、它们的高成本以及宿主因素在治疗反应中的作用。的发展

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major human pathogen that chronically infects 2-3% of the global population. In the United States it is the most common blood-borne illness with approximately 3.9 million carriers. Most patients infected with HCV progress to chronic disease and are at increased risk of liver cirrhosis and hepatocellular carcinoma. The standard of care for chronic hepatitis C is combination therapy with pegylated interferon and ribavirin, supplemented with an antiviral compound that inactivates the viral NS3/4A protease. The recent inclusion of protease inhibitors in combination therapy has led to an improvement in sustained viral response rates in many patients, but certain factors may limit the overall success of treatment. These include potential of HCV to acquire resistance to these antivirals, their high cost and the role of host factors in response to therapy. The development of an effective vaccine to control the global HCV epidemic is therefore highly desirable. New evidence strongly suggests that neutralizing antibodies play a more protective role in viral clearance than previously appreciated. A caveat is that such protective antibody responses are isolate-specific given the high sequence diversity of HCV. A prophylactic or therapeutic vaccine against HCV would therefore have to target conserved epitopes in the natural HCV antigens. This proposal focuses on linear, highly conserved epitopes in the viral glycoproteins E1 and E2 targeted by broadly neutralizing antibodies IGH526 and HCV1, respectively. It outlines a novel strategy for presenting these epitopes on chimeric virus-like particles engineered to present specific structures on their surfaces as a highly immunogenic particulate array. This strategy offers a wide selection of properties needed to mimic the cognate epitopes of IGH526 and HCV1, including the ability to orient and expose key residues and structural features for antibody recognition, in order to re- elicit broad neutralization activity. Aim 1 outlines design, synthesis and characterization of VLPs displaying the highly conserved E1 and E2 epitopes and aim 2 investigates the immunogenic properties of the VLPs in mice. Their ability to induce antibodies that bind to full- length E1E2 heterodimer and their capacity to neutralize HCV particles will be evaluated. If successful, the work proposed could lead to a significant advance in HCV vaccine development.