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: 10205546
• 负责人: Steven Foung
• 金额: $ 237.7万
• 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/10205546
• 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; 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; vaccine candidate; vaccine development; vaccine evaluation; 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 该U19项目的总体目标是开发HCV疫苗，以防止疾病进展 接种宿主中的病毒暴露。我们的总体方法是基于越来越多的数据的研究 接受初次HCV感染的患者表明这些个体的一部分会产生免疫 导致病毒清除和抗恢复会议免疫力的反应。这是自然发生的 保护性免疫学似乎包括急性期的早期和健壮的体液和细胞反应 感染。因此，早期的动力学，力量和质量（即两种体液的跨保护能力 和针对不断发展的HCV准特性多样性的细胞反应对于有效的清除至关重要 对潜水员HCV分离株/感染的重复暴露在高危个体中。那就成功的疫苗将 需要诱导疫苗接种宿主中的强大和耐用的自适应B和T细胞免疫回报。这个程序 旨在通过四个完成项目和科学核心来实现这一目标。项目1专注于 结构引导的方法开发免疫原，以增强广泛中和的诱导 抗体（BNAB），其中包括合并后导致协同病毒神经化的抗体。这个项目将 HCV包膜糖蛋白的结构分析和结构方面的结构分析广泛相互作用 BNAB和受体与HCV颗粒的结合。项目2将为T细胞设计HCV NS马赛克抗原 识别引起全球大多数感染的HCV基因型和亚型。镶嵌抗原是设计的 通过从数据库中获取的病毒基因组序列的重组来计算。项目3采用 评估短期和长期B和T细胞反应以及对疫苗接种的先天反应的系统方法 在项目1和3中制定的疫苗，并与强大的佐剂结合使用。这些研究 将以科学核心执行的非人类素数进行。行政核心将 提供成功实现我们为每个项目实现的目标所必需的运营支持 和整个程序。综上所述，这些项目和科学核心中提出的工作非常高 相互依存的将导致能够引起对HCV的保护性B和T细胞免疫的疫苗设计。 我们希望在该计划项目结束时，我们将有一种候选疫苗开始临床前研究 这将发展为I/II期临床试验。