Correlates of protective immunity to HCV and rational vaccine design

HCV 保护性免疫与合理疫苗设计的相关性

• 批准号: 10393614
• 负责人: Arash Grakoui
• 金额: $ 204.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393614
• 关键词: Acute Hepatitis C; Adolescent and Young Adult; Adoption; Antibody Response; Antigens; Antiviral Agents; Antiviral Therapy; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Chronic Hepatitis C; DNA; Direct Costs; Egypt; Engineering; Epidemic; Exposure to; Frequencies; Generations; Goals; Government; Hepatitis C; Hepatitis C virus; High Prevalence; Human; Immune response; Immunity; Individual; Infection; Injecting drug user; Knowledge; Liver; Longevity; Memory; Methods; Modality; Modeling; Modified Vaccinia Virus Ankara; Monitor; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Phenotype; Prevention; Primary Infection; Production; Proteins; Public Health; Regimen; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Signal Pathway; Signaling Molecule; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Time; Vaccine Design; Vaccines; Viral; Viral Proteins; Virus; base; chronic infection; cohort; cytotoxic CD8 T cells; design; high risk; human subject; memory CD4 T lymphocyte; neutralizing antibody; nonhuman primate; novel vaccines; prevent; programs; recruit; response; screening; stem; success; transcription factor; vaccination strategy; vaccine development; vaccine trial

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.

抽象的 即使最近采取了预防丙肝病毒感染的措施，预防丙肝病毒感染仍然是一个重要的公共卫生目标 高效的抗病毒疗法。重要的是，直接作用抗病毒药物（DAA）治疗不会 不能防止已成功治疗的患者再次感染。预防丙型肝炎病毒的疫苗 需要坚持不懈地阻止青少年和年轻人中新出现的感染流行病 注射获得筛查和治疗机会有限的药物。只有百分之二十五的急性 HCV 感染会自行消退。然而，决议确实大大降低了持续存在的风险 再次接触病毒后感染。记忆 CD4+ T 辅助细胞和 CD8+ 细胞毒性 T 细胞反应 有助于加速清除二次感染。然而，中和抗体的作用 再感染期间的情况不太清楚。重要的是，产生同等 T 细胞反应的疫苗未能 阻止天真的接受者的坚持率。在这里，我们将检验中心假设： 记忆 CD4+ T 细胞通过促进 HCV 特异性 B 细胞和产生有助于病毒清除的广泛中和抗体。 该提案的独特之处在于（i）使用来自蒙特利尔高水平队列的纵向样本 注射毒品的人面临风险。在 HCV 感染之前、期间和之后对参与者进行监测 然后，当他们第二次再次接触丙肝病毒后，再次进行随访 解决他们的原发感染。 (ii) 我们在埃及开罗组建了一个调查小组 将协助我们招募和治疗接受 DAA 治疗的受试者。埃及最高 世界范围内 HCV 感染流行情况。 2014年埃及政府做出DAA治疗 经济实惠，已有 250 万名受试者开始接受治疗。了解免疫反应 这两个队列将为我们提供宝贵的信息来开发有效的疫苗方案 这将模仿丙型肝炎病毒自然挑战期间产生的成功反应。 提出了三个高度互动的项目。项目 1（N. Shoukry，PI）将比较频率， HCV 再感染中 CD4+ T 细胞的广度、功能和表型要么消退，要么成为 执着的。项目 2（A. Grakoui，PI）将使用最先进的新技术来隔离和 表征 HCV 再感染期间和 DAA 治疗后的抗原特异性 B 细胞。项目3（R. Amara，PI）将开发疫苗方式来诱导 CD4+ T 辅助反应和强大的 使用 DNA、改良安卡拉牛痘 (MVA) 和 针对非人类灵长类动物中 HCV 蛋白的基于蛋白质的疫苗。