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

基本信息

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
项目类别：
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

项目摘要

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 HCV 再感染保护尽管最近采取了高度预防措施，但预防 HCV 感染仍然是一个重要的公共卫生目标。有效的抗病毒疗法。需要一种预防 HCV 持续存在的疫苗来阻止新出现的流行病易感人群。回想一下，对继发性病毒感染的反应自然会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解决者可能拥有抗原特异性 B 细胞，很容易被滤泡辅助 T (Tfh) 细胞激活并扩增 HCV 抗原暴露后迅速发生。然而，个体继发性 HCV 感染的治愈率较低尽管在治疗开始时出现了 HCV 特异性 CD4+ T 细胞的初始爆发，但 DAA 治愈了持续性 HCV 感染 DAA治疗。这两种情况之间的这种截然不同的回忆反应暗示了深刻的表型 DAA 处理组与 DAA 处理组之间抗原特异性记忆 T 细胞和 B 细胞反应的功能差异未经治疗、正在解决的个人。我们建议阐明自发抗体回忆反应的个体之间的差异解决原发感染，随后清除继发性 HCV 再感染 (SR/SR) 或发展持续感染（SR/CI）。我们还将这些反应与接受 DAA 治疗的个体的反应进行比较。治愈持续性 HCV 感染。我们将分析两个不同 HCV 队列的纵向样本受感染的个体进行这些研究。其中一组由注射吸毒者（PWID）组成，这些人是从加拿大蒙特利尔，原发性 HCV 感染自行痊愈，但出现不同程度的继发性再感染结果。另一组由来自埃及的个体组成，他们在以下情况下清除了持续性丙型肝炎病毒感染： DAA 治疗（HCV 治愈）。我们假设 SR/SR PWID 会加速和持续记忆 B 细胞反应可产生早期广泛中和抗体 (bNAb)，从而有助于更快地清除，而来自 SR/CI PWID 或 HCV 治愈个体的延迟抗体反应无法抑制病毒血症早期，促进病毒逃脱中和。我们提出以下目标：目标 1. 确定来自 B 细胞的大量和抗原特异性记忆 B 细胞的表型和转录谱再次感染但经历不同感染后遗症的主要解决者。目标 2. 通过对比 HCV 评估来自解析器的 HCV 特异性抗体的中和功效和广度再感染结果。目标 3. 确定 DAA 治疗个体感染病毒前后 B 细胞的表型和功能变化清除。