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细胞介导的针对HCV再感染的保护 即使最近采用高度采用，预防HCV感染仍然是重要的公共卫生目标 有效的抗病毒疗法。需要一种防止HCV持续性的疫苗，以阻止新兴的流行病 易感人群。回忆对继发病毒感染的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。我们的发现表明自发解析器 可能具有抗原特异性B细胞，这些B细胞很容易被T卵泡辅助器（TFH）细胞激活并扩展 HCV抗原暴露后迅速。但是，个体的继发性HCV感染的分辨率很低 尽管在开始时最初爆发了HCV特异性的CD4+ T细胞，但DAA的持续性HCV感染了 DAA治疗。这两种情况之间的这种对比回忆反应暗示了深刻的表型 DAA处理与抗原特异性内存t和B细胞反应的功能差异 未经治疗的，解决的个人。 我们建议阐明自发的个体之间的抗体回忆反应的差异 解决原发性感染，然后清除其继发性HCV重新感染（SR/SR）或发展 持续感染（SR/CI）。我们还将将这些回应与经过DAA处理的个人的回应进行比较 治愈持续的HCV感染。我们将分析来自两个单独的HCV队列的纵向样品 感染这些研究的人。一个队列由注射毒品（PWID）的人组成 加拿大蒙特利尔，自发解决原发性HCV感染但有不同的次要感染 结果。其他队列由埃及的个人组成，他们清除了持续的HCV感染。 DAA治疗（HCV固化）。我们假设SR/SR PWID安装更加加速和持续 记忆B细胞反应产生早期，广泛中和抗体（BNAB）的响应，有助于更快 清除率，而SR/CI PWID或HCV固定个体的延迟抗体反应无法抑制病毒血症 早期，促进病毒脱离中和。我们提出以下目标： 目标1。确定来自大量和抗原特异性记忆B细胞的表型和转录曲线 重新感染但经历了发散感后遗症的原发性解析器。 AIM 2。评估与HCV对比的解析器中HCV特异性抗体的中和宽度 恢复结果。 AIM 3。确定病毒前后DAA处理个体B细胞的表型和功能变化 清除。