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.

抽象-整体组件 这个U19项目的总体目标是开发一种丙型肝炎疫苗，以防止疾病在 在接种疫苗的宿主中接触病毒。我们的总体方法基于越来越多的来自 接受原发丙型肝炎病毒感染的患者表明这些人中的一部分产生免疫 导致病毒清除和对再次感染产生免疫力的反应。这是自然发生的 保护性免疫似乎包括在急性期早期和强烈的体液和细胞反应。 感染的可能性。因此，早期的动力学、强度和质量(即体液和体液的交叉保护能力 和针对进化中的丙型肝炎病毒准种多样性的细胞反应)是有效清除的关键 高危个体反复暴露于不同的丙型肝炎病毒分离株/感染的风险。因此，一种成功的疫苗将 需要在接种疫苗的宿主中诱导强大和持久的适应性B和T细胞免疫反应。本计划 旨在通过四个相辅相成的项目和一个科学核心实现这一目标。项目1的重点是 结构导向法开发可增强广谱中和诱导的免疫原 抗体(BNAbs)，包括当它们结合在一起时，会导致协同病毒中和。这个项目将 就丙型肝炎病毒包膜糖蛋白的结构分析和结构方面与项目4广泛互动 与丙型肝炎病毒颗粒结合的bNAbs和受体。项目2将为T细胞设计丙型肝炎病毒NS马赛克抗原 识别导致全球大多数感染的丙型肝炎病毒基因型和亚型。马赛克抗原被设计成 通过从数据库中检索到的病毒基因组序列的重组来计算。项目3需要一个 评估接种疫苗的短期和长期B和T细胞反应及先天反应的系统方法 使用项目1和项目3中配制的疫苗，并结合强大的佐剂。这些研究 将在非人类灵长类动物身上进行，将在科学核心中被处决。行政核心意志 为成功实现我们为每个项目制定的目标提供必要的运营支持 并作为一个整体进行编程。综上所述，这些项目中提出的工作和科学核心是高度 这将导致一种能够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。 我们希望在这个计划项目结束时，我们将有一种候选疫苗开始临床前研究 这将进入I/II期临床试验。