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Immune correlates of protection against hepacivirus persistence.

抵抗肝炎病毒持久性的免疫相关性。

基本信息

批准号：
10594475
负责人：
Amit Kapoor
金额：
$ 61.48万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594475
关键词：
Acceleration Address Adenovirus Vector Adenoviruses Adjuvant Animal Model Animals Antigens Antiviral Agents B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell surface Cellular Immunity Chronic Communication Data Dissection Epitope Mapping Escape Mutant Failure Future Genetic Variation Goals Hepatitis C Hepatitis C Vaccine Hepatitis C virus Hepatitis C-Like Viruses Human Human papillomavirus 16 E1 protein Humoral Immunities Immune Immunity Immunocompetent Individual Infection Knowledge Mediating Modeling Mus Nature Nonstructural Protein Outcome Pan Genus Paper Phenotype Play Proteins RNA Virus Infections RNA vaccine Rattus Reporting Rodent Role Stains Structural Protein T-Cell Depletion T-Lymphocyte T-Lymphocyte Epitopes Testing Vaccinated Vaccination Vaccines Variant Viral Virus Virus Diseases cell killing chronic infection cytokine env Gene Products experimental study in vivo innovation insight neutralizing antibody novel prevent single-cell RNA sequencing transcriptome vaccination strategy vaccine development vaccine failure vaccine trial vaccine-induced immunity

项目摘要

Abstract Although direct acting antivirals can cure Hepatitis C virus (HCV) infection, a vaccine is necessary to stop new infections, and to prevent re-infections in the cured individuals. Studies in humans and chimpanzees suggest that both T cells and neutralizing antibodies (nAb) can play an important role in the clearance of HCV infection. However, further progress on HCV vaccine development has been stymied by a lack of animal models. Notably, the nature, breadth, and relative contribution of humoral and cellular immunity in determining the outcomes of HCV infection remain poorly understood. We recently showed that a rat hepacivirus (HCV-like virus), RHV, shares the hallmarks of HCV infection and immunity. A majority of fully-immunocompetent rats develop lifelong viral persistence, and thus rats are appropriate models for “proof-of-concept” vaccination studies to prevent HCV- like viral persistence, the desired goal of HCV vaccines. We further validated this model by determining that like reported from HCV studies in chimpanzees, rats vaccinated using an Adenovirus expressing RHV non-structural (NS) proteins develop partial protection against persistence of a homologous RHV strain (Nature communications, PMC6405742). Interestingly, we observed that the vaccinated rats that cleared a homologous virus developed more efficient and broader immunity for homologous and heterologous viruses, and T cell escape variants. These results suggest that the short- term viral infection either enhances T cell immunity or generates nAbs, or both, to confer effective immunity against heterologous viruses. Most importantly, these results are promising for defining the nature of immunity that confers effective protection against persistent infection of genetically diverse viruses, like HCV variants. The overall goal of this project is to define the immune correlates of protection against hepacivirus persistence. Specific aim-1 is to define the T cell correlates of protection against hepacivirus persistence. Our hypothesis is that the nature and breadth of virus-specific T cells determines the fate of hepacivirus infections. Specific aim-2 is to study the role of envelope proteins (E1/E2) induced immunity and importance of nAbs in virus clearance. Our hypothesis is that a vaccination approach using a combination of NS and E1E2 vaccines will increase the immunity against viral persistence. Specific Aim- 3 is to define the breadth of vaccine induced immunity, and to identify the viral determinants of vaccine failure. Our hypothesis is that vaccination can prevent persistence of genetically diverse viruses that share only a few T cell epitopes. The proposed dissection of vaccine and short-term viral infection conferred immunity is necessary to understand the relative contributions of T and B cells in hepacivirus clearance, and this knowledge can help in conceptualizing an effective vaccination strategy for HCV. Finally, the proposed characterization of T and B cell immunity in this unique model of life-long persistent RNA virus infection will pave the way for testing of newer vaccination approaches (like RNA vaccines) to prevent chronic virus infection.

抽象的虽然直接作用的抗病毒药物可以治愈丙型肝炎病毒 (HCV) 感染，但仍需要疫苗来阻止新的丙型肝炎病毒感染。感染，并防止治愈者再次感染。对人类和黑猩猩的研究表明 T细胞和中和抗体（nAb）都可以在清除HCV感染中发挥重要作用。然而，由于缺乏动物模型，丙型肝炎疫苗开发的进一步进展受到阻碍。尤其，体液和细胞免疫的性质、广度和相对贡献在决定结果中 HCV 感染的机制仍知之甚少。我们最近证明了一种大鼠肝炎病毒（HCV 样病毒）， RHV 具有 HCV 感染和免疫的特征。大多数具有完全免疫功能的大鼠发育病毒终生持续存在，因此大鼠是“概念验证”疫苗接种研究的合适模型防止丙型肝炎样病毒持续存在，这是丙型肝炎疫苗的预期目标。我们通过以下方式进一步验证了该模型确定与黑猩猩 HCV 研究报告一样，使用腺病毒接种的大鼠表达 RHV 非结构 (NS) 蛋白可形成部分保护，防止病毒持续存在同源 RHV 毒株（《自然通讯》，PMC6405742）。有趣的是，我们观察到清除同源病毒的接种疫苗的老鼠产生了更有效和更广泛的免疫力同源和异源病毒，以及 T 细胞逃逸变体。这些结果表明，短期长期病毒感染要么增强 T 细胞免疫力，要么产生 nAb，或两者兼而有之，以赋予有效的免疫力对抗异源病毒。最重要的是，这些结果有望定义免疫力，可有效防止 HCV 等遗传多样性病毒的持续感染变种。该项目的总体目标是确定预防肝炎病毒的免疫相关性坚持。具体目标 1 是确定 T 细胞与预防肝炎病毒持久性的相关性。我们的假设是，病毒特异性 T 细胞的性质和广度决定了肝炎病毒的命运感染。具体目标2是研究包膜蛋白（E1/E2）诱导免疫的作用和重要性 nAbs 在病毒清除中的作用。我们的假设是，结合使用 NS 和 NS 的疫苗接种方法 E1E2 疫苗将增强针对病毒持续存在的免疫力。具体目标 - 3 是定义范围疫苗诱导免疫力，并确定疫苗失败的病毒决定因素。我们的假设是疫苗接种可以防止仅共享少数 T 细胞表位的遗传多样性病毒的持续存在。这建议解剖疫苗和短期病毒感染赋予的免疫力，有必要了解 T 细胞和 B 细胞在肝炎病毒清除中的相对贡献，这些知识可以帮助制定有效的 HCV 疫苗接种策略。最后，提出了 T 和 B 的表征这种终生持续性RNA病毒感染的独特模型中的细胞免疫将为测试新病毒铺平道路预防慢性病毒感染的疫苗接种方法（如 RNA 疫苗）。