A vaccine design to induce protective B and T cell immunity against hepatitis C virus

诱导针对丙型肝炎病毒的保护性 B 和 T 细胞免疫的疫苗设计

• 批准号: 10409757
• 负责人: Steven Foung
• 金额: $ 249.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409757
• 关键词: Acute; Address; Adjuvant; Agonist; Amino Acids; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Biopsy; Blood; Bone Marrow; CD8-Positive T-Lymphocytes; CD81 gene; Centers for Disease Control and Prevention (U.S.); Complex; Data; Databases; Development; Disease Progression; Engineering; Epitope Mapping; Epitopes; Exposure to; Frequencies; Genetic Recombination; Genotype; Glycoproteins; Goals; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Home; Immune response; Immunity; Immunization; Immunologic Memory; Individual; Infection; Kinetics; Lead; Lipid A; Liposomes; Liver; Macaca; Masks; Modeling; Modification; Molecular Conformation; Monitor; Mosaicism; Mus; Mutate; Mutation; Pan Genus; Patients; Persons; Phase; Phase I/II Clinical Trial; Polysaccharides; Probability; Property; QS21; Recombinants; Resolution; Risk; Sampling; Saponins; Series; Structure; Surface; System; T cell response; T memory cell; T-Lymphocyte; TLR4 gene; Tissues; United States; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Viral Vector; Virion; Virus; Work; adaptive immune response; aluminum sulfate; base; cost; design; draining lymph node; fitness; flexibility; immunogenic; immunogenicity; improved; infection rate; molecular modeling; neutralizing antibody; nonhuman primate; novel; preclinical study; prevent; programs; receptor; receptor binding; response; stem; synergism; vaccination strategy; vaccine candidate; vaccine development; vaccine evaluation; vaccine response; viral genomics

ABSTRACT – OVERALL COMPONENT The overall goal of this U19 project is the development of an HCV vaccine to prevent disease progression after virus exposure in a vaccinated host. Our overall approach is based on a growing body of data from studies in patients undergoing primary HCV infections indicating that a subset of these individuals generates immune responses that result in viral clearance and conferring immunity against reinfection. This naturally occurring protective immunity appears to include early and robust humoral and cellular responses during the acute phase of infection. Consequently, the early kinetics, strength, and quality (i.e., cross-protective capacity of both humoral and cellular responses against the diversity of the evolving HCV quasispecies) are critical for efficient clearance of repeated exposures to diverse HCV isolates/infections in at-risk individuals. Thus, a successful vaccine will need to induce robust and durable adaptive B and T cell immune responses in the vaccinated host. This Program is designed to achieve this goal by four complementary Projects and a Scientific Core. Project 1 focuses on a structure-guided approach to develop an immunogen that enhances the induction of broadly neutralizing antibodies (bNAbs) including those when combined lead to synergistic virus neutralization. This project will interact extensively with Project 4 on structural analysis of HCV envelop glycoproteins and on structural aspects of bNAbs and receptor binding to HCV particles. Project 2 will design HCV NS Mosaic antigens for T cell recognition of HCV genotypes and subtypes that cause most infections globally. Mosaic antigens are designed computationally by recombination of viral genomic sequences retrieved from databases. Project 3 takes a systems approach to evaluate short- and long-term B and T cell responses and innate responses to vaccination with vaccines that are formulated in Projects 1 and 3, and in combination with powerful adjuvants. These studies will be undertaken in non-human primates that will be executed in a Scientific Core. The Administrative Core will provide the operational support necessary to successfully achieved the goals we have laid out for each project and program as a whole. Taken together, the work proposed in these projects and scientific core are highly interdependent that will lead to a vaccine design capable to elicit protective B and T cell immunity against HCV. We expect that at the end of this program project, we will have a candidate vaccine to begin pre-clinical studies that will progress to Phase I/II clinical trial.

摘要-整体组件