Correlates of protective immunity to HCV and rational vaccine design: Project 1

HCV 保护性免疫与合理疫苗设计的相关性：项目 1

• 批准号: 10608109
• 负责人: NAGLAA H. SHOUKRY
• 金额: $ 13.15万
• 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/10608109
• 关键词: Acceleration; Aftercare; Antibody Response; Antiviral Agents; Antiviral Therapy; B-Lymphocytes; Benchmarking; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Canada; Chemicals; Chronic; Chronic Hepatitis C; Chronic Phase; Clinical Trials; Coculture Techniques; Country; Cytoprotection; Defect; Developing Countries; Development; Egypt; Exhibits; Exposure to; Flow Cytometry; Genomics; Goals; Hepatitis C; Hepatitis C Prevalence; Hepatitis C virus; High Prevalence; Immune; Immune response; Immunity; Immunologic Factors; Individual; Infection; Injecting drug user; Interferon Type II; Kinetics; Knowledge; Leukocytes; Liver; Liver diseases; Maintenance; Measures; Mediating; Mediator; Modeling; Molecular Profiling; North America; Pan Genus; Pathway interactions; Patients; Phase; Phenotype; Predisposition; Production; Public Health; Quantitative Reverse Transcriptase PCR; RNA; Recovery; Resolution; Risk; Role; Sampling; Sorting; Source; Stains; T cell response; T memory cell; T-Cell Proliferation; T-Lymphocyte; T-cell receptor repertoire; Target Populations; Technology; Time; Vaccination; Vaccine Design; Vaccines; Viral; Virus; antiviral drug development; cohort; cytokine; enzyme linked immunospot assay; immune function; immunogenicity; marginalized population; memory CD4 T lymphocyte; neutralizing antibody; novel vaccines; opioid epidemic; pandemic disease; protective pathway; public health priorities; reconstitution; response; single-cell RNA sequencing; transmission process; vaccine candidate

Project 1: High resolution profiling of protective HCV-specific CD4 T cells Abstract Hepatitis C virus (HCV) is a virus that infects the liver and is transmitted through contaminated blood. HCV infection is still a public health priority and a major cause of liver disease worldwide, especially in developing countries like Egypt. New HCV infections are also on the rise in North America in association with the opioid epidemic. While new antiviral drugs can cure >95% of infected individuals, many do not know that they are infected and remain at risk of developing liver disease and an active source of new infections. Furthermore, successful treatment does not prevent reinfection if the individual is re-exposed to the virus. Hence, there is an urgent need for vaccines that can protect against this virus. Unfortunately, despite our knowledge about the immune response against HCV, we still do not have an effective vaccine. Recent results from the only vaccine candidate that made it into a large scale (Phase 2) clinical trial did not show any protection in people who inject drugs (PWID) at risk of HCV infection. This means that we need to understand better the immune factors and cells that protect against HCV in cohorts of patients who are able to clear the virus spontaneously. The overarching goal of this proposal t is to define these factors that are essential to achieve protective immunity. The aim of this specific project (Project 1) is to characterize the role and functions of a subset of white blood cells known as helper CD4 lymphocytes in a group of PWID who are constantly being exposed to the virus where some are able to clear it several times and others that cannot. We will identify the differences in those who clear the virus repeatedly and those who cannot. We will also compare the immune response in individuals who clear the virus spontaneously versus those who clear it post treatment to determine if they are less protected against HCV if they are re-exposed to it. We will use two unique cohorts of subjects, a PWID cohort from Montreal, Canada and a cohort of subjects undergoing antiviral therapy from Egypt, the country with the highest prevalence of HCV. The results obtained in this project will be complementary to Project 2 that will examine the antibody response to HCV in the same subjects. We will use the latest technology to examine the immune response at the functional and genomic level and identify cellular pathways and key molecules that are implicated in the development and maintenance of a protective immune response. We will attempt to use chemical compounds to correct the defects observed in those who are unable to clear the virus. Such compounds may be combined with different vaccine candidates, as described in project 3, to enhance their immunogenicity and protective capacity.

项目1：保护性HCV特异性CD4 T细胞的高分辨率分析 摘要 丙型肝炎病毒（HCV）是一种感染肝脏的病毒，通过受污染的血液传播。HCV 感染仍然是公共卫生的优先事项，也是世界范围内肝病的主要原因，特别是在发展中国家， 像埃及这样的国家新的HCV感染在北美也在增加，与阿片类药物有关 疫情虽然新的抗病毒药物可以治愈>95%的感染者，但许多人并不知道他们是 感染并保持发展为肝病的风险和新感染的活跃来源。此外，委员会认为， 如果个体再次暴露于病毒，成功的治疗不能防止再次感染。因此，有一个 我们迫切需要能够预防这种病毒的疫苗。不幸的是，尽管我们知道 针对HCV的免疫反应，我们仍然没有有效的疫苗。唯一一种疫苗的最新结果 进入大规模（2期）临床试验的候选药物在注射的人中没有显示出任何保护作用 有HCV感染风险的药物（PWID）。这意味着我们需要更好地了解免疫因素， 在能够自发清除病毒的患者队列中保护抗HCV的细胞。的 本提案的首要目标是确定这些对实现保护性免疫至关重要的因素。 这个特定项目（项目1）的目的是描述白色血液亚群的作用和功能 在一组PWID中被称为辅助CD4淋巴细胞的细胞不断暴露于病毒， 有些人能够清除它几次，而另一些人则不能。我们将找出那些明确的差异 病毒反复传播和那些不能传播的人我们还将比较那些清除了 病毒自发与那些谁清除它后治疗，以确定他们是否较少保护， 我们将使用两个独特的受试者队列，来自蒙特利尔的PWID队列， 加拿大和来自埃及（患病率最高的国家）接受抗病毒治疗的受试者队列 的HCV。本项目获得的结果将补充项目2，项目2将检查抗体 在相同的受试者中对HCV的应答。我们将使用最新的技术来检查免疫反应， 功能和基因组水平，并确定细胞途径和关键分子，涉及 保护性免疫反应的发展和维持。我们将尝试使用化学化合物 以纠正在那些无法清除病毒的人中观察到的缺陷。这样的化合物可以组合 如项目3所述，使用不同的候选疫苗，以增强其免疫原性和保护性 容量