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 – 整体组成部分 该 U19 项目的总体目标是开发 HCV 疫苗，以预防疾病进展 已接种疫苗的宿主体内的病毒暴露。我们的总体方法基于来自以下领域的研究中不断增长的数据： 经历原发性 HCV 感染的患者表明这些个体中的一部分产生了免疫 导致病毒清除并赋予针对再次感染的免疫力的反应。这种自然发生的 保护性免疫似乎包括急性期的早期和强烈的体液和细胞反应 的感染。因此，早期的动力学、强度和质量（即两种体液的交叉保护能力） 以及针对不断进化的 HCV 准种多样性的细胞反应）对于有效清除至关重要 高危个体反复接触不同 HCV 分离株/感染的情况。因此，成功的疫苗将 需要在接种疫苗的宿主中诱导强大且持久的适应性 B 和 T 细胞免疫反应。本计划 旨在通过四个互补的项目和一个科学核心来实现这一目标。项目 1 重点关注 结构引导方法开发免疫原，增强广泛中和的诱导 抗体（bNAb），包括组合时可产生协同病毒中和作用的抗体。该项目将 与项目 4 就 HCV 包膜糖蛋白的结构分析和结构方面进行广泛互动 bNAb 和受体与 HCV 颗粒的结合。项目2将为T细胞设计HCV NS Mosaic抗原 识别导致全球大多数感染的 HCV 基因型和亚型。设计了嵌合抗原 通过从数据库检索的病毒基因组序列重组进行计算。项目 3 需要 评估短期和长期 B 细胞和 T 细胞反应以及对疫苗接种的先天反应的系统方法 使用项目 1 和 3 中配制的疫苗，并与强效佐剂组合。这些研究 将在非人类灵长类动物中进行，并在科学核心中执行。行政核心将 提供成功实现我们为每个项目设定的目标所需的运营支持 和程序作为一个整体。总而言之，这些项目提出的工作和科学核心具有很高的 相互依存，这将导致疫苗设计能够引发针对 HCV 的保护性 B 和 T 细胞免疫。 我们预计在该计划项目结束时，我们将拥有一种候选疫苗来开始临床前研究 将进入I/II期临床试验。