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）感染全世界约7000万人，是肝细胞癌的主要原因 和肝衰竭。即使有高效的HCV治疗，最近的数据显示，80%的高收入国家 没有达到WHO消除HCV的目标。在大多数国家， 感染人数仍然高于治疗治愈人数。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性感染。 抗体（bNAb）。最近，我们发现反复暴露于HCV并再次感染的人 以及控制多达六种不同的HCV感染，通常是一种以上的HCV基因型。迄今为止，一名候选人 疫苗已经在高危人群中进行了测试。该疫苗旨在诱导强大的T细胞 应答，并由建议研究者评价健康志愿者的免疫原性和疗效 在HCV感染高危人群中预防HCV持续存在。虽然不能防止 与安慰剂组相比，接种疫苗的受试者的HCV RNA平均峰值显著降低 受惠人士我们的首要假设是，定义HCV特异性T细胞和抗体介导的免疫， HCV感染的有效控制可以直接转化为更有效的疫苗策略。所以我们 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。 疫苗战略。在项目1中，CD 4和CD 8 T细胞反应将在以下人群之间进行比较： 反复暴露于并自发控制HCV和HCV临床试验参与者，均定义T细胞 与HCV控制相关的性质，而且还可以确定疫苗失败的原因。NAB也做出了贡献 为了成功控制反复的HCV暴露，几个项目的工作将确定和测试新的 疫苗抗原和具有诱导抗HCV bNAb潜力的平台。装订（项目2）和结构 （项目3）通过合作选择的与包膜蛋白（E2或E1 E2）复合的bNAb研究 在项目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E1 E2抗原并在小鼠中测试它们。项目5将评估新的T细胞 病毒载体疫苗中的免疫原，在小鼠中使用病毒载体E2或E1 E2、NP或VLP，旨在产生 抗E1 E2抗体和项目1中定义的有效的基因型交叉反应性T细胞应答。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。建议的综合 研究将提供感染事件的精确分子描述和全面表征 适应性免疫应答是有效的HCV免疫控制的基础， 临床前研究，以确定最佳疫苗抗原和战略，以推进未来的人体试验。