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

摘要-整体组件 该U19项目的总体目标是开发HCV疫苗，以预防感染后的疾病进展。 接种疫苗宿主的病毒暴露。我们的总体方法是基于来自以下研究的越来越多的数据， 经历原发性HCV感染的患者表明这些个体的一个子集产生免疫应答， 导致病毒清除并赋予针对再感染的免疫力的应答。这种天然存在的 保护性免疫似乎包括急性期早期和强有力的体液和细胞反应 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 以及针对进化中的HCV准种的多样性的细胞应答）对于有效清除是至关重要的 在高危人群中反复暴露于不同的HCV分离株/感染。因此，成功的疫苗将 需要在接种的宿主中诱导稳健和持久的适应性B和T细胞免疫应答。这个程序 旨在通过四个互补项目和一个科学核心来实现这一目标。项目1侧重于 结构导向的方法来开发一种免疫原， 抗体（bNAb），包括组合时的那些抗体，导致协同病毒中和。该项目将 在HCV包膜糖蛋白的结构分析和结构方面与项目4有广泛的互动 bNAb和受体与HCV颗粒的结合。项目2将设计用于T细胞的HCV NS镶嵌抗原 识别导致全球大多数感染的HCV基因型和亚型。嵌合抗原被设计成 通过从数据库检索的病毒基因组序列的重组计算。项目3需要一个 评价短期和长期B和T细胞应答以及对疫苗接种的先天应答的系统方法 与项目1和项目3中配制的疫苗以及与强效佐剂组合。这些研究 将在非人类灵长类动物身上进行，并将在科学核心中执行。行政核心将 为成功实现我们为每个项目制定的目标提供必要的业务支持 和整个计划。综上所述，这些项目中提出的工作和科学核心是高度相关的， 这将导致能够引发针对HCV的保护性B和T细胞免疫的疫苗设计。 我们希望在这个项目结束时，我们将有一个候选疫苗开始临床前研究 将进入I/II期临床试验。

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.