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: 10205767
• 负责人: NAGLAA H. SHOUKRY
• 金额: $ 19.25万
• 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/10205767
• 关键词: Aftercare; Antibody Response; Antiviral Agents; Antiviral Therapy; B-Lymphocytes; Benchmarking; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Canada; Cells; Chemicals; Chronic; Chronic Hepatitis C; Chronic Phase; Coculture Techniques; Country; Defect; Developing Countries; Development; Egypt; Exhibits; Exposure to; Flow Cytometry; 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 of activation protein; Modeling; Molecular Profiling; North America; Pan Genus; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Production; Public Health; Quantitative Reverse Transcriptase PCR; RNA; Recovery; Resolution; Risk; Role; Sampling; 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; cohort; cytokine; enzyme linked immunospot assay; functional genomics; immune function; immunogenicity; marginalized population; memory CD4 T lymphocyte; neutralizing antibody; novel vaccines; opioid epidemic; pandemic disease; public health priorities; reconstitution; response; single-cell RNA sequencing; 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 抽象的 丙型肝炎病毒（HCV）是一种感染肝脏并通过受污染的血液传播的病毒。丙型肝炎病毒 感染仍然是一个公共卫生优先事项，也是全世界肝病的主要原因，特别是在发展中国家 埃及等国家。北美与阿片类药物相关的新发丙肝病毒感染也在增加 流行性。虽然新的抗病毒药物可以治愈 > 95% 的感染者，但许多人并不知道它们是 已感染并仍面临患肝病的风险，并且是新感染的活跃来源。此外， 如果个体再次接触病毒，成功的治疗并不能防止再次感染。因此，有一个 迫切需要能够预防这种病毒的疫苗。不幸的是，尽管我们了解 针对HCV的免疫反应，我们仍然没有有效的疫苗。唯一疫苗的最新结果 进入大规模（第二阶段）临床试验的候选药物并未对注射者显示出任何保护作用 有 HCV 感染风险的药物（注射吸毒者）。这意味着我们需要更好地了解免疫因素和 在能够自发清除病毒的患者群体中，细胞可以预防丙型肝炎病毒。这 该提案的总体目标是定义这些对于实现保护性免疫力至关重要的因素。 该特定项目（项目 1）的目的是描述白血细胞子集的作用和功能 一群吸毒者中被称为辅助 CD4 淋巴细胞的细胞，他们不断暴露于病毒，其中 有些能够多次清除，而另一些则不能。我们将找出那些清除者之间的差异 病毒反复感染，而那些不能感染的人。我们还将比较清除的个体的免疫反应 病毒自发地与治疗后清除病毒的人进行比较，以确定他们是否受到较少的保护 如果他们再次接触丙肝病毒。我们将使用两个独特的受试者队列，一个来自蒙特利尔的吸毒者队列， 加拿大和来自流行率最高的国家埃及的一组接受抗病毒治疗的受试者 丙肝病毒。该项目中获得的结果将补充项目 2，该项目将检查抗体 同一受试者对 HCV 的反应。我们将使用最新技术来检查免疫反应 功能和基因组水平，并识别参与的细胞途径和关键分子 保护性免疫反应的发展和维持。我们将尝试使用化合物 纠正那些无法清除病毒的人身上观察到的缺陷。这些化合物可以组合 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。