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: 10593174
• 负责人: Steven Foung
• 金额: $ 247.96万
• 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/10593174
• 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; 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; Innate Immune Response; Kinetics; Lead; Lipid A; Liposomes; Liver; Macaca; Masks; Modeling; Modification; Molecular Conformation; Monitor; 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; United States; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Viral Vector; Virion; Virus; Work; adaptive immune response; aluminum sulfate; cost; design; draining lymph node; fitness; flexibility; immunogenic; immunogenicity; improved; infection rate; molecular modeling; mosaic; neutralizing antibody; nonhuman primate; novel; preclinical study; prevent; programs; receptor; receptor binding; response; stem; synergism; tissue resident memory T cell; 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 我们的总体方法是基于越来越多的研究数据。 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感染的免疫力的反应，这是自然发生的。 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 检查感染的早期动力学、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 因此，成功的疫苗将减少高危人群反复接触不同 HCV 分离株/感染的风险。 需要在疫苗宿主中诱导强大且持久的适应性 B 和 T 细胞免疫反应。 旨在通过四个互补的项目来实现这一目标，其中一个科学核心项目 1 侧重于一个。 结构引导方法开发免疫原，增强广泛中和的诱导 抗体（bNAb），包括组合后产生协同病毒中和作用的抗体。 主要与项目 4 互动，涉及 HCV 包膜糖蛋白的结构分析和结构方面 项目 2 将为 T 细胞设计 HCV NS Mosaic 抗原。 设计了识别导致全球大多数感染的 HCV 基因型和亚型。 项目 3 通过计算重组从数据库中检索到的病毒​​基因组序列。 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。 将在非人类灵长类动物中进行，并将在科学核心中执行。 提供成功实现我们为每个项目制定的目标所需的运营支持 总的来说，这些项目提出的工作和科学核心都很高。 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。