Mechanisms of spontaneous and vaccine mediated hepatitis C virus control to direct rational development of a novel HCV vaccine

自发和疫苗介导的丙型肝炎病毒控制机制指导新型丙型肝炎疫苗的合理开发

基本信息

批准号：
10398147
负责人：
ANDREA L COX
金额：
$ 263.12万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398147
关键词：
Acute Acute Hepatitis C Adjuvant Animals Antibodies Antibody Response Antibody-mediated protection Antigens B cell repertoire B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cellular Immunity Cessation of life Characteristics Chronic Hepatitis C Clinical Cohort Studies Collaborations Complex Country Data Development Epitopes Event Evolution Exposure to Extinction (Psychology)Future Generations Genes Genetic Genotype Goals Gold Hepatitis C Hepatitis C Antibodies Hepatitis C Therapy Hepatitis C Vaccine Hepatitis C virus Human Humoral Immunities Immune Immune response Immunity Income Infection Infection Control Length Liver Failure Mediating Membrane Modeling Molecular Mus Participant Pathway interactions Patients Persons Phenotype Placebos Plasma Population Prevention Primary Infection Primary carcinoma of the liver cells Property Recovery Regimen Research Research Personnel Resolution Resources Risk Sequence Analysis Site Standardization Structure T cell response T-Lymphocyte Testing Time Translating Vaccinated Vaccination Vaccine Antigen Vaccinee Vaccines Viral Viral Antigens Viral Genome Viral Hepatitis Vaccines Viral Vector Viremia Virus Virus-like particle Work acute infection adaptive immune response anti-hepatitis C antigen test base chronic infection clinical trial participant cross reactivity design efficacy study efficacy trial env Gene Products genome sequencing healthy volunteer high risk high risk population human data immunogenicity memory CD4 T lymphocyte nanoparticle neutralizing antibody nonhuman primate novel novel vaccines pre-clinical assessment preclinical study prevent programs recruit repository response vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine failure vaccine immunogenicity vaccine platform vaccine strategy vaccine trial vector vaccine viral RNA virus envelope

项目摘要

Overall Project Summary Hepatitis C virus (HCV) infects ~70 million people worldwide and is a major cause of hepatocellular carcinoma and liver failure. Even with highly effective HCV treatment, recent data show that 80% of high-income countries are not on target to meet the WHO goals of elimination of HCV. In most countries, the annual number of new infections remains higher than the number cured by treatment. A vaccine for HCV should be possible because 25% of people resolve primary infection with effective anti-viral T cells and the generation of broadly neutralizing antibodies (bNAbs). Recently, we have identified people who are repeatedly exposed to HCV with reinfection and control of up to six distinct HCV infections, often of more than one HCV genotype. To date, one candidate vaccine has been tested in an at-risk human population. This vaccine was designed to induce robust T cell responses and was evaluated by proposal investigators for immunogenicity in healthy volunteers and for efficacy in the prevention of HCV persistence in people at high risk of HCV infection. Although not protective against chronic infection, vaccinated participants had significantly reduced mean peak HCV RNA compared to placebo recipients. Our overarching hypothesis is that defining HCV-specific T cell and antibody mediated immunity in effective control of HCV infection can be directly translated into more effective vaccine strategies. Therefore, we plan an integrated analysis of T cell and B-cell/Ab mediated immunity alongside an assessment of viral antigen sequences in resolved infection and vaccinees. This will inform the design and pre-clinical assessment of novel vaccine strategies. In Project 1, CD4 and CD8 T cell responses will be compared between people who are repeatedly exposed to and spontaneously control HCV and HCV clinical trial participants, both to define T cell properties associated with HCV control, but also to identify the reasons for vaccine failure. NAbs also contribute to successful control of repeated HCV exposure and work across several projects will identify and test novel vaccine antigens and platforms with potential to induce anti-HCV bNAbs. Binding (Project 2) and structural (Project 3) studies of bNAbs in complex with envelope proteins (E2 or E1E2) selected through a collaboration between projects 2 and 4 will identify a panel of potential vaccine antigens with unique structural characteristics that favor bNAb induction and maturation. Project 3 will develop nanoparticle (NP) and virus-like particle (VLP)- based vaccines to present these E2 or E1E2 antigens and test them in mice. Project 5 will assess new T cell immunogens in viral vectored vaccines, with viral vectored E2 or E1E2, NPs, or VLPs in mice, aiming to generate both anti-E1E2 antibodies and the effective, genotype cross-reactive T cell responses defined in Project 1. We will then test the two most successful vaccine candidates in non-human primates. The proposed integrative research will provide a precise molecular description of infection events and the comprehensive characterization of adaptive immune responses underlying effective HCV immune control, with new vaccine candidates assessed in pre-clinical studies to identify the best vaccine antigens and strategy to advance to future human trials.

项目总体概要丙型肝炎病毒 (HCV) 感染全球约 7000 万人，是导致肝细胞癌的主要原因和肝功能衰竭。即使采用高效的 HCV 治疗，最近的数据显示 80% 的高收入国家没有达到世界卫生组织消除丙肝病毒的目标。在大多数国家，每年新增加的数量感染人数仍然高于通过治疗治愈的人数。 HCV 疫苗应该是可能的，因为 25% 的人通过有效的抗病毒 T 细胞和广泛中和的产生来解决原发感染抗体（bNAb）。最近，我们发现反复接触 HCV 并出现再感染的人控制多达六种不同的 HCV 感染，通常有不止一种 HCV 基因型。迄今为止，一名候选人疫苗已在高危人群中进行了测试。该疫苗旨在诱导强大的 T 细胞反应并由提案研究人员评估健康志愿者的免疫原性和功效预防 HCV 感染高危人群的 HCV 持续存在。虽然不能起到防护作用慢性感染者中，与安慰剂相比，接种疫苗的参与者 HCV RNA 平均峰值显着降低收件人。我们的首要假设是，定义 HCV 特异性 T 细胞和抗体介导的免疫有效控制HCV感染可以直接转化为更有效的疫苗策略。因此，我们计划对 T 细胞和 B 细胞/抗体介导的免疫进行综合分析，同时评估病毒抗原已解决的感染和疫苗接种者的序列。这将为新型药物的设计和临床前评估提供信息疫苗策略。在项目 1 中，将比较以下人群之间的 CD4 和 CD8 T 细胞反应：反复接触并自发控制 HCV 和 HCV 临床试验参与者，两者均用于定义 T 细胞与 HCV 控制相关的特性，还可以确定疫苗失败的原因。 NAb 也有贡献为了成功控制重复的丙肝病毒暴露，跨多个项目的工作将识别和测试新的具有诱导抗 HCV bNAb 潜力的疫苗抗原和平台。绑定（项目 2）和结构（项目3）通过合作选择的bNAb与包膜蛋白（E2或E1E2）复合物的研究项目 2 和 4 之间将鉴定一组具有独特结构特征的潜在疫苗抗原有利于 bNAb 的诱导和成熟。项目3将开发纳米颗粒（NP）和病毒样颗粒（VLP）- 基于疫苗来呈现这些 E2 或 E1E2 抗原并在小鼠中进行测试。项目5将评估新的T细胞病毒载体疫苗中的免疫原，在小鼠体内使用病毒载体 E2 或 E1E2、NP 或 VLP，旨在产生抗 E1E2 抗体和项目 1 中定义的有效基因型交叉反应性 T 细胞反应。我们然后将在非人类灵长类动物中测试两种最成功的候选疫苗。拟议的综合研究将为感染事件提供精确的分子描述和全面的表征有效 HCV 免疫控制的适应性免疫反应，并对新候选疫苗进行了评估在临床前研究中确定最佳疫苗抗原和推进未来人体试验的策略。