Dissecting virus neutralizing determinants to guide HCV vaccine development

剖析病毒中和决定因素以指导 HCV 疫苗的开发

• 批准号: 9212766
• 负责人: Mansun Law
• 金额: $ 45.71万
• 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: 2014-03-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212766
• 关键词: Adjuvant; Adopted; Age-Years; Animal Hepatitis; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Antiviral Agents; Autologous; Awareness; B-Lymphocytes; Binding Sites; Biomimetics; Cause of Death; Chemicals; Chronic; Clinical; Clinical Trials; Complement 1q; Complex; Crystallization; Development; Diagnosis; Elements; Engineering; Epidemic; Epitopes; Genetic Variation; Genomics; Genotype; Glycoproteins; Goals; HCV Animal Models; HIV; Hepatitis C; Hepatitis C Antibodies; Hepatitis C Vaccine; Human; Immune Evasion; Immune system; Immunization; Immunize; Immunodominant Epitopes; Infection; Interferons; Lead; Liver; Liver Cirrhosis; Malignant neoplasm of liver; Masks; Modeling; Molecular Structure; Mus; Patients; Peptides; Pharmaceutical Preparations; Polysaccharides; Population; Proteins; Role; Structure; Symptoms; System; T-Lymphocyte Epitopes; Testing; Transgenic Mice; United States; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; X-Ray Crystallography; age group; base; chronic liver disease; clinical candidate; cost effective; crosslink; design; humanized mouse; improved; mouse model; neutralizing antibody; novel; peptidomimetics; public health relevance; receptor binding; vaccine candidate; vaccine development

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.

描述（由申请人提供）：丙型肝炎病毒（HCV）长期感染了2-3％的全球人群，使患者患有慢性肝病和肝癌。广泛有效的疫苗将是解决这一全球问题的成本效益。但是，HCV在遗传上是多种多样的，基于单个病毒菌株设计的疫苗不会有效地针对遗传多样的循环病毒。为了克服这一科学挑战， 候选疫苗必须针对病毒靶向保守区域。该应用的目的是确定中和表位的分子结构，以帮助有理由设计O免疫原子，这将集中于疫苗接种中对保守的表位的抗体反应。这种“表位疫苗”方法包括：（1）确定与相应的广泛中和抗体的复合物中HCV抗体表位的晶体结构； （2）将免疫原的设计和合成作为已知表位结构的仿生学； （3）在HCV感染的小动物模型中测试新型免疫原，以鉴定铅疫苗候选物。如果成功，该建议可能会导致新的HCV疫苗用于临床试验，并显着提高HCV和疫苗场。