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

• 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
• 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

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.

总体项目摘要 丙型肝炎病毒（HCV）在全球感染了约7000万人，是肝细胞癌的主要原因 和肝衰竭。即使进行了高效的HCV处理，最近的数据表明，有80％的高收入国家 不符合目标消除HCV的目标。在大多数国家 /地区，年度新数量 感染仍然高于治疗固化的数量。 HCV的疫苗应该是可能的，因为 25％的人通过有效的抗病毒T细胞解决原发性感染，并产生广泛中和 抗体（BNABS）。最近，我们确定了一再接触HCV的人 并控制多达六种不同的HCV感染，通常具有多种HCV基因型。迄今为止，一个候选人 疫苗已在高危人口中进行了测试。该疫苗旨在诱导强大的T细胞 反应，并由建议研究人员评估健康志愿者的免疫原性和功效 在预防HCV持久性的人群中，患有HCV感染的高风险。虽然不保护 与安慰剂相比 收件人。我们的总体假设是定义HCV特异性T细胞和抗体介导的免疫力 HCV感染的有效控制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/AB介导的免疫的综合分析，并评估病毒抗原 分辨感染和疫苗的序列。这将为新颖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CD4和CD8 T细胞响应 反复接触并自发控制HCV和HCV临床试验参与者，都定义T细胞 与HCV控制相关的属性，也可以确定疫苗衰竭的原因。 NABS也有贡献 为了成功控制重复的HCV暴露和在几个项目中的工作，将识别和测试新颖 疫苗抗原和具有诱导抗HCV BNAB的平台。绑定（项目2）和结构 （项目3）通过协作选择的包膜蛋白（E2或E1E2）进行复杂的BNAB研究 项目2至4之间将确定具有独特结构特征的潜在疫苗抗原面板 这种有利于BNAB诱导和成熟。项目3将开发纳米颗粒（NP）和病毒样粒子（VLP） - 基于疫苗以呈现这些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 病毒矢量疫苗的免疫原子，含有病毒矢量的E2或E1E2，NP或VLP的疫苗，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T细胞反应。 然后，将测试非人类灵长类动物中两种最成功的疫苗候选物。提出的综合效应 研究将为感染事件和全面表征提供精确的分子描述 有效HCV免疫控制的基础自适应免疫反应，并评估了新的候选疫苗 在临床前研究中，确定最佳的疫苗抗原和策略，以促进未来的人类试验。