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:10608110
- 负责人:
- 金额:$ 79.13万
- 依托单位:
- 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:
- 关键词:AccelerationAdoptionAffinityAntibodiesAntibody ResponseAntigensAntiviral AgentsAntiviral TherapyAttenuatedAutologousB cell differentiationB cell repertoireB-Lymphocyte SubsetsB-LymphocytesBiological AssayCD4 Positive T LymphocytesCanadaCell SeparationClinicalContractsDataDrug usageEgyptEpitopesEscape MutantExhibitsFlow CytometryGene Expression ProfileGenetic TranscriptionGlycoproteinsHelper-Inducer T-LymphocyteHepatitis CHepatitis C virusImmuneImmune responseImmunityImmunoglobulin-Secreting CellsIndividualInfectionInfection preventionInjecting drug userMediatingMemory B-LymphocyteMonoclonal AntibodiesMutationOutcomePeripheral Blood Mononuclear CellPhenotypePlasmaPlasma CellsPopulationPredispositionPrimary InfectionProliferatingPublic HealthResolutionSamplingSecondary toT memory cellVaccinationVaccine DesignVaccinesViralViral AntigensViremiaVirus Diseaseschronic infectioncohortexperiencelongitudinal analysisneutralizing antibodynew epidemicpolyclonal antibodypreventprogramsrecruitresponsesecondary infectionsingle-cell RNA sequencingstemtranscriptome sequencingvaccine strategy
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Arash Grakoui其他文献
Arash Grakoui的其他文献
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{{ truncateString('Arash Grakoui', 18)}}的其他基金
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10393614 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10393615 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10205764 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
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:
10393618 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10608105 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10205765 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10608106 - 财政年份:2021
- 资助金额:
$ 79.13万 - 项目类别:
Dynamics of antigen specific B and Tfh responses during acute and chronic HCV
急性和慢性 HCV 期间抗原特异性 B 和 Tfh 反应的动态
- 批准号:
10063938 - 财政年份:2017
- 资助金额:
$ 79.13万 - 项目类别:
Dynamics of antigen specific B and Tfh responses during acute and chronic HCV
急性和慢性 HCV 期间抗原特异性 B 和 Tfh 反应的动态
- 批准号:
10305612 - 财政年份:2017
- 资助金额:
$ 79.13万 - 项目类别:
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