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: 10205768
• 负责人: Arash Grakoui
• 金额: $ 73.75万
• 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/10205768
• 关键词: 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; Clinical; Contracts; Data; Drug usage; Egypt; Epidemic; 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; Injecting drug user; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mutation; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Plasma Cells; Population; Prevention; Primary Infection; Public Health; Resolution; Sampling; Secondary to; T memory cell; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Viremia; Virus Diseases; chronic infection; cohort; experience; neutralizing antibody; polyclonal antibody; prevent; programs; recruit; response; secondary infection; single-cell RNA sequencing; stem; transcriptome sequencing

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HCV再感染保护作用 预防HCV感染仍然是一个重要的公共卫生目标，即使最近采用了高度 有效的抗病毒治疗。需要一种预防HCV持续存在的疫苗来阻止一种新的流行病， 易感人群。对继发性病毒感染的回忆反应自然地模仿保护性免疫 与针对病毒抗原的疫苗接种相关的机制。我们的研究结果表明，自发消退 可能具有抗原特异性B细胞，其容易被T滤泡辅助（Tfh）细胞激活并扩增 HCV抗原暴露后迅速死亡。然而，继发性HCV感染的解决是低的个人 通过DAA治愈了持续的HCV感染，尽管在治疗开始时HCV特异性CD 4 + T细胞的初始爆发， DAA治疗。这两种情景之间的这种对比回忆反应暗示了深刻的表型 和抗原特异性记忆T和B细胞应答的功能差异， 未治疗的正在康复的患者 我们建议阐明抗体回忆反应的个体之间的差异，自发 解决原发性感染，随后清除继发性HCV再感染（SR/SR）或发展为 持续感染（SR/CI）。我们还将这些反应与DAA治疗的个体进行比较， 治愈持续性HCV感染。我们将分析两个独立的HCV队列的纵向样本， 受感染的人进行这些研究。一个队列由从以下地区招募的注射毒品者（PWID）组成： 蒙特利尔，加拿大，自发解决原发性HCV感染，但有不同的继发性再感染 结果。另一个队列由来自埃及的个体组成，这些个体在以下治疗后清除了持续性HCV感染。 DAA治疗（HCV治愈）。我们假设SR/SR PWID安装一个更加速和持续的 记忆B细胞反应，产生早期广泛中和抗体（bNAb），有助于更快地 清除，而来自SR/CI PWID或HCV治愈个体的延迟抗体应答不能抑制病毒血症 早期，促进病毒逃避中和。我们提出以下目标： 目标1.确定来自以下的本体和抗原特异性记忆B细胞的表型和转录谱： 再次感染但出现不同感染后遗症的原发性消退者。 目标2.评价与对照HCV的消退者中HCV特异性抗体的中和效力和广度 再感染结果。 目标3.确定病毒感染前后DAA处理个体的B细胞的表型和功能变化 间隙