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

使用类病毒颗粒平台开发基于结构的 HCV 疫苗

• 批准号: 8766102
• 负责人: Anette Schneemann
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766102
• 关键词: Antibodies; Antibody Formation; Antiviral Agents; Attention; B-Lymphocytes; Binding; Biological Assay; Blood; Chronic Disease; Chronic Hepatitis C; Cloning; Combined Modality Therapy; Cultured Cells; Development; Drug Formulations; Electron Microscopy; Engineering; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitopes; Escape Mutant; Genotype; Glycoproteins; Goals; HCV Vaccine; Hepatitis C; Hepatitis C virus; Housing; Human; Immune response; Immune system; Insect Viruses; Integration Host Factors; Interferons; Lead; Length; Liver Cirrhosis; Methods; Monoclonal Antibodies; Mus; Particulate; Patients; Peptide Hydrolases; Play; Population; Primary carcinoma of the liver cells; Property; Protease Inhibitor; Ribavirin; Risk; Role; Serum; Specificity; Structure; Surface; T cell response; Testing; United States; Vaccinated; Vaccine Antigen; Vaccines; Viral; Viral Antigens; Viral Drug Resistance; Virion; Virus; Virus-like particle; Work; anti-hepatitis C; base; cost; design; human subject; immunogenic; in vivo; neutralizing antibody; novel strategies; particle; pathogen; prevent; prophylactic; public health relevance; response; standard of care; success; synthetic peptide; therapeutic vaccine; vaccine development

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.

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，长期感染全球 2-3% 的人口。在美国，它是最常见的血液传播疾病，约有 390 万携带者。大多数感染 HCV 的患者会发展为慢性疾病，并且患肝硬化和肝细胞癌的风险增加。慢性丙型肝炎的护理标准是聚乙二醇干扰素和利巴韦林联合治疗，辅以灭活病毒 NS3/4A 蛋白酶的抗病毒化合物。最近将蛋白酶抑制剂纳入联合治疗中，许多患者的持续病毒缓解率得到改善，但某些因素可能会限制治疗的总体成功。其中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 因此，非常需要一种控制全球丙型肝炎病毒流行的有效疫苗。新证据强烈表明，中和抗体在病毒清除中发挥的保护作用比以前认为的更强。需要注意的是，鉴于 HCV 的高度序列多样性，这种保护性抗体反应是分离株特异性的。因此，针对 HCV 的预防性或治疗性疫苗必须针对天然 HCV 抗原中的保守表位。该提案重点关注广泛中和抗体 IGH526 和 HCV1 分别靶向的病毒糖蛋白 E1 和 E2 中的线性、高度保守的表位。它概述了一种新的策略，将这些表位呈现在嵌合病毒样颗粒上，这些颗粒被设计为在其表面呈现特定结构，作为高度免疫原性的颗粒阵列。该策略提供了模拟 IGH526 和 HCV1 的同源表位所需的多种特性，包括定向和暴露抗体识别的关键残基和结构特征的能力，以重新引发广泛的中和活性。目标 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，目标 2 研究了 VLP 在小鼠中的免疫原性特性。将评估它们诱导与全长E1E2异二聚体结合的抗体的能力以及它们中和HCV颗粒的能力。如果成功，拟议的工作可能会导致丙型肝炎疫苗开发取得重大进展。