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

整体项目总结 丙型肝炎病毒(HCV)感染全球约7000万人，是肝细胞癌的主要原因 和肝功能衰竭。即使使用高效的丙型肝炎病毒治疗，最近的数据显示，80%的高收入国家 没有达到世卫组织消除丙型肝炎病毒的目标。在大多数国家，每年新增的 感染人数仍然高于通过治疗治愈的人数。丙型肝炎病毒疫苗应该是可能的，因为 25%的人通过有效的抗病毒T细胞和产生广泛的中和来解决原发感染 抗体(BNAbs)。最近，我们发现了反复接触丙型肝炎病毒并再次感染的人。 并控制多达六种不同的丙型肝炎病毒感染，通常是一种以上的丙型肝炎病毒基因型。到目前为止，有一位候选人 疫苗已经在高危人群中进行了测试。这种疫苗旨在诱导强大的T细胞 并由计划调查员评估健康志愿者的免疫原性和疗效 在预防丙型肝炎持续感染的高危人群中。虽然不能保护人们免受 与安慰剂相比，慢性感染、接种疫苗的参与者的平均丙型肝炎病毒RNA峰值显著降低 收件人。我们的主要假设是定义丙型肝炎病毒特异性T细胞和抗体介导的免疫 有效控制丙型肝炎病毒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 已解决感染和疫苗接种者的序列。这将为新药的设计和临床前评估提供信息 疫苗策略。在项目1中，将比较以下人群的CD4和CD8 T细胞反应 反复接触并自发控制丙型肝炎病毒和丙型肝炎病毒临床试验参与者，两者都是为了定义T细胞 与丙型肝炎病毒控制相关的属性，也是为了确定疫苗失败的原因。NAB也做出了贡献 要成功控制丙型肝炎病毒的重复暴露，并在几个项目中开展工作，将识别和测试新的 有可能诱导抗-丙型肝炎病毒bNAb的疫苗抗原和平台。约束性(项目2)和结构性 (项目3)合作选择的包膜蛋白(E2或E1E2)复合体中的bNAbs的研究 在项目2和4之间，将确定一组具有独特结构特征的潜在疫苗抗原 这有利于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)- 以疫苗为基础呈现这些E2或E1E2抗原并在小鼠身上进行测试。项目5将评估新的T细胞 病毒载体疫苗中的免疫原，与病毒载体E2或E1E2、NPs或VLP在小鼠中，旨在产生 抗E1E2抗体和项目1中定义的有效的、基因交叉反应的T细胞反应。 然后将在非人类灵长类动物身上测试两种最成功的候选疫苗。建议的一体化 研究将提供感染事件的准确分子描述和全面的特征 有效的丙型肝炎病毒免疫控制下的获得性免疫反应，并评估了新的候选疫苗 在临床前研究中，以确定最佳疫苗抗原和策略，以推进到未来的人体试验。

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.