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，并且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聚乙二醇干扰素和利巴韦林的联合治疗，并补充一种灭活病毒NS 3/4A蛋白酶的抗病毒化合物。最近在联合治疗中加入蛋白酶抑制剂，使许多患者的持续病毒应答率得到改善，但某些因素可能限制治疗的总体成功。这些因素包括HCV获得对这些抗病毒药物的耐药性的可能性、它们的高成本以及宿主因素在对治疗的反应中的作用。的发展 因此，非常需要一种控制全球HCV流行的有效疫苗。新的证据有力地表明，中和抗体在病毒清除中发挥的保护作用比以前认识到的更大。需要注意的是，鉴于HCV的高序列多样性，这种保护性抗体应答是分离株特异性的。因此，针对HCV的预防性或治疗性疫苗必须靶向天然HCV抗原中的保守表位。该建议的重点是线性，高度保守的抗原决定簇的病毒糖蛋白E1和E2的广泛中和抗体IGH 526和HCV 1，分别为目标。它概述了一种新的策略，提出这些表位的嵌合病毒样颗粒工程目前在其表面上的特定结构作为一个高度免疫原性的颗粒阵列。该策略提供了模拟IGH 526和HCV 1的同源表位所需的广泛选择的性质，包括定向和暴露关键残基和结构特征以用于抗体识别的能力，以重新引发广泛的中和活性。目的1概述了展示高度保守的E1和E2表位的VLP的设计、合成和表征，目的2研究了VLP在小鼠中的免疫原性。将评价它们诱导结合全长E1 E2异二聚体的抗体的能力和它们中和HCV颗粒的能力。如果成功的话，这项工作可能会导致HCV疫苗开发的重大进展。

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.