Correlates of protective immunity to HCV and rational vaccine design

摘要 预防丙型肝炎病毒感染仍然是一个重要的公共卫生目标，即使最近通过了 高效的抗病毒疗法。重要的是，用直接作用抗病毒药物(DAA)治疗确实 不能防止那些成功接受治疗的人再次感染。预防丙型肝炎的疫苗 需要持之以恒地遏制青少年和年轻人中新出现的感染流行病 注射筛查和治疗机会有限的药物。只有25%的急性 丙型肝炎病毒感染会自发消退。然而，解决方案确实大大降低了持续存在的风险 在再次暴露于病毒时感染。记忆性CD4T辅助细胞和CD8细胞毒性T细胞反应 有助于加速清除第二次感染。然而，中和抗体的作用 再感染的时间还不是很清楚。重要的是，产生等同T细胞反应的疫苗未能 挫败天真接受者的持久率。在这里，我们将检验中心假设 记忆性CD4T细胞通过促进病毒的扩增而显著影响丙型肝炎病毒的再感染结局 丙型肝炎病毒特异的B细胞和产生有助于病毒清除的广谱中和抗体。 这项建议的独特之处在于：(I)使用来自蒙特利尔高铁队列的纵向样本。 冒着注射毒品的人的风险。参与者在感染丙型肝炎病毒之前、期间和之后接受监测，并 然后，当他们第二次接触丙型肝炎病毒时，随后再次跟随 解决他们的原发感染。(2)我们在埃及开罗组建了一个调查小组，他们 将帮助我们招募和治疗接受DAA治疗的受试者。埃及拥有最高的 世界上丙型肝炎病毒感染的流行情况。2014年，埃及政府进行了DAA治疗 负担得起的250万受试者已经开始治疗。了解患者的免疫反应 这两个群体将为我们提供有价值的信息来开发有效的疫苗方案。 这将模仿在与丙型肝炎病毒的自然挑战中产生的成功反应。 提出了三个高度互动的项目。项目1(N.Shoukry，PI)将比较频率， 丙型肝炎病毒再感染患者中CD4T细胞的宽度、功能和表型 坚持不懈。项目2(A.Grakoui，PI)将使用最新的技术来隔离和 丙型肝炎病毒再感染和DAA治疗后抗原特异性B细胞的特征。项目3(R. Amara，PI)将开发疫苗模式，以诱导CD4T辅助反应和强大的 用DNA、改良安卡拉痘苗病毒(MVA)和日本血吸虫疫苗在血液和肝脏中产生抗原特异性抗体 非人灵长类动物中丙型肝炎病毒蛋白的蛋白质疫苗。

Abstract Prevention of HCV infection remains an important public health objective even with the recent adoption of highly effective antiviral therapies. Importantly, treatment with direct acting antivirals (DAAs) does not prevent reinfection in those who have successfully been treated. A vaccine to prevent HCV persistence is needed to stem an emerging epidemic of infection in adolescents and young adults who inject drugs that have limited access to screening and treatment. Only twenty five percent of acute HCV infections resolve spontaneously. Resolution does, however, sharply reduce the risk of persistent infection upon re-exposure to the virus. Memory CD4+ T helper and CD8+ cytotoxic T cell responses contribute to accelerated clearance of a second infection. However, the role of neutralizing antibodies during reinfection is less clear. Importantly, vaccines to generate an equivalent T cell response failed to thwart off the rate of persistence in naïve recipients. Here, we will test the central hypothesis that memory CD4+ T cells contribute significantly to HCV reinfection outcome by promoting expansion of HCV-specific B cells and production of broadly neutralizing antibodies that contribute to viral clearance. Unique features of this proposal are (i) the use of longitudinal samples from the Montreal cohort of high- risk people who inject drugs. Participants are monitored prior to, during, and after HCV infection and then subsequently followed again when they have been re-exposed to HCV a second time after resolving their primary infection. (ii) We have assembled a team of investigators in Cairo, Egypt who will assist us with recruiting and treating subjects undergoing DAA treatment. Egypt has the highest prevalence of HCV infection in the world. In 2014, Egypt's government has made DAA treatment affordable and 2.5 million subjects have started treatment. Understanding the immune responses in these two cohorts will provide us with valuable information to develop an efficacious vaccine regimen that would emulate the successful responses generated during a natural challenge with HCV. Three highly interactive Projects are proposed. Project 1 (N. Shoukry, PI) will compare the frequency, breadth, function, and phenotype of CD4+ T cells in HCV reinfections that either resolve or become persistent. Project 2 (A. Grakoui, PI) will use new state of the art technology to isolate and characterize antigen-specific B cells during HCV reinfection and post DAA treatment. Project 3 (R. Amara, PI) will develop vaccine modalities to induce both a CD4+ T helper response and a robust antigen-specific antibody response in blood and liver using DNA, modified vaccinia Ankara (MVA) and protein-based vaccines against HCV proteins in non-human primates.