Correlates of protective immunity to HCV and rational vaccine design: Project 2

HCV 保护性免疫与合理疫苗设计的相关性：项目 2

• 批准号: 10608110
• 负责人: Arash Grakoui
• 金额: $ 79.13万
• 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/10608110
• 关键词: Acceleration; Adoption; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; Antiviral Therapy; Attenuated; Autologous; B cell differentiation; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Canada; Cell Separation; Clinical; Contracts; Data; Drug usage; Egypt; Epitopes; Escape Mutant; Exhibits; Flow Cytometry; Gene Expression Profile; Genetic Transcription; Glycoproteins; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C virus; Immune; Immune response; Immunity; Immunoglobulin-Secreting Cells; Individual; Infection; Infection prevention; Injecting drug user; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mutation; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Plasma Cells; Population; Predisposition; Primary Infection; Proliferating; Public Health; Resolution; Sampling; Secondary to; T memory cell; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Viremia; Virus Diseases; chronic infection; cohort; experience; longitudinal analysis; neutralizing antibody; new epidemic; polyclonal antibody; prevent; programs; recruit; response; secondary infection; single-cell RNA sequencing; stem; transcriptome sequencing; vaccine strategy

Project 2. B Cell-Mediated Protection Against HCV Reinfection Prevention of HCV infection remains an important public health objective even with the recent adoption of highly effective antiviral therapies. A vaccine to prevent HCV persistence is needed to stem an emerging epidemic in susceptible populations. Recall responses to secondary viral infections naturally emulate the protective immune mechanisms associated with vaccination against viral antigens. Our findings suggest that spontaneous resolvers may possess antigen-specific B cells that become readily activated by T follicular helper (Tfh) cells and expand rapidly following HCV antigenic exposure. However, resolution of secondary HCV infection is low in individuals cured of persistent HCV infection by DAAs, despite an initial burst of HCV-specific CD4+ T cells at the start of DAA treatment. Such contrasting recall responses between these two scenarios implicate profound phenotypic and functional differences in antigen-specific memory T and B cell responses between DAA-treated versus untreated, resolving individuals. We propose to elucidate the differences in antibody recall responses between individuals who spontaneously resolve primary infection and subsequently either clear their secondary HCV reinfection (SR/SR) or develop persistent infection (SR/CI). We will also compare these responses to those of DAA-treated individuals who are cured of persistent HCV infection. We will analyze longitudinal samples from two separate cohorts of HCV infected individuals for these studies. One cohort consists of people who inject drugs (PWIDs) recruited from Montreal, Canada, who spontaneously resolve primary HCV infection but have different secondary reinfection outcomes. The other cohort consists of individuals from Egypt who cleared persistent HCV infection following DAA treatment (HCV-cured). We hypothesize that SR/SR PWID mount a more accelerated and sustained memory B cell response that produces early, broadly neutralizing antibodies (bNAbs) that contribute to faster clearance, while delayed antibody responses from SR/CI PWID or HCV-cured individuals fail to suppress viremia early, facilitating viral escape from neutralization. We propose the following aims: Aim 1. Determine the phenotypic and transcriptional profiles of bulk and antigen-specific memory B cells from primary resolvers who were reinfected but experienced divergent infection sequelae. Aim 2. Evaluate neutralizing efficacy and breadth of HCV-specific antibodies from resolvers with contrasting HCV reinfection outcomes. Aim 3. Determine phenotypic and functional changes in B cells of DAA-treated individuals before and after viral clearance.

项目2.B细胞介导的抗丙型肝炎病毒再感染保护作用 预防丙型肝炎病毒感染仍然是一个重要的公共卫生目标，即使最近通过了高度的 有效的抗病毒疗法。需要一种预防丙型肝炎持续存在的疫苗，以遏制#年出现的疫情。 易感人群。对二次病毒感染的回忆反应自然模仿保护性免疫 与病毒抗原疫苗接种相关的机制。我们的研究结果表明，自发解决者 可能具有抗原特异的B细胞，容易被T滤泡辅助细胞(TFH)激活并扩张 在丙型肝炎病毒抗原暴露后迅速死亡。然而，在个体中，继发性丙型肝炎病毒感染的解决率很低。 DAA治愈了持续的丙型肝炎病毒感染，尽管在开始时出现了丙型肝炎病毒特异性的CD4+T细胞 DAA治疗。这两种情景之间的这种不同的回忆反应蕴含着深刻的表型 DAA治疗组和对照组在抗原特异性记忆T和B细胞反应中的功能差异 未经治疗，意志消沉的个体。 我们建议阐明不同个体之间抗体回忆反应的差异。 解决初次感染，随后清除他们的继发性丙型肝炎病毒再感染(SR/SR)或发展为 持续感染(SR/CI)。我们还将比较这些反应与接受DAA治疗的患者的反应 治愈了持续性的丙型肝炎病毒感染。我们将分析来自两个不同的丙型肝炎病毒队列的纵向样本 用于这些研究的感染者。一个队列由注射毒品(PWID)的人组成，这些人是从 加拿大蒙特利尔，自发解决初次丙型肝炎病毒感染，但有不同的继发再感染 结果。另一组由来自埃及的个人组成，他们在以下情况下清除了持续的丙型肝炎病毒感染 DAA治疗(丙型肝炎病毒治愈)。我们假设SR/SR PWID会更快、更持久地 记忆B细胞反应，产生早期、广谱中和抗体(BNAbs)，有助于更快 清除，而来自SR/CI PWID或丙型肝炎治愈患者的延迟抗体反应未能抑制病毒血症 早期，促进病毒逃脱中和。我们提出以下目标： 目的1.测定中国人外周血中大量和抗原特异性记忆B细胞的表型和转录水平。 再次感染但有不同感染后遗症的主要解决者。 目的2.评估来自与对照丙型肝炎病毒对照的解决者的丙型肝炎病毒特异性抗体的中和效果和广度 再感染结果。 目的3.检测DAA治疗前后个体B细胞表型和功能的变化 通行证。