Immunologic and Metabolic Profiles of T cells that control diverse HCV infections

控制多种 HCV 感染的 T 细胞的免疫学和代谢特征

基本信息

批准号：
10398150
负责人：
ANDREA L COX
金额：
$ 81.41万
依托单位：
JOHNS HOPKINS 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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398150
关键词：
Acute Antibody Response Antigens Assessment tool B-Lymphocytes CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Characteristics Chronic Hepatitis C Data Development Disease Outcome Failure Flow Cytometry General Hospitals Generations Genetic Transcription Genotype Goals Gold Hepatitis C Hepatitis C Vaccine Hepatitis C virus Human Immune Immune response Immunity Immunologics Infection Infection Control Libraries Massachusetts Measures Mediating Memory Metabolic Mus Outcome Pan Genus Patients Peripheral Blood Mononuclear Cell Persons Phenotype Placebos Population Primary Infection Property RNA Recovery Regimen Risk Role Specimen T cell receptor repertoire sequencing T cell response T memory cell T-Lymphocyte Testing Time Transcriptional Regulation Universities Vaccination Vaccine Design Vaccines Variant Viral Viremia Virus acute infection base chronic infection cohort efficacy trial healthy volunteer high dimensionality high risk immunogenicity memory CD4 T lymphocyte metabolic abnormality assessment metabolic profile nonhuman primate novel patient population prevent programs prophylactic response single-cell RNA sequencing vaccine candidate vaccine response vaccine strategy

项目摘要

HCV Vaccine Program Project 1 Summary Evidence from chimpanzee and human studies support critical roles for CD4 and CD8 T lymphocyte responses in the control HCV infection, yet defining the correlates of protective HCV immunity has been challenging. Identifying CD4 and CD8 T cell memory that protects against infection from multiple different HCV genotypes and subtypes is a cornerstone in prophylactic HCV vaccine design. Our groups at Johns Hopkins University and Massachusetts General Hospital have contributed many key findings to the current understanding of HCV- specific T cell immunity, based on the combination of large and well documented patient cohorts with robust and sensitive experimental tools for the assessment of both CD8 and CD4 responses targeting HCV. We will build on this expertise and employ newly developed approaches to study the metabolism and transcriptional landscape of HCV-specific CD4 and CD8 T cells in order to assess T cell immunity in unique patient cohorts. We previously demonstrated that clearance occurs more often in reinfection than in primary infection, with reduced peak and duration of viremia associated with broadened T cell responses vs. initial infection of the same person. This suggests induction of memory that protects against infection from multiple different HCV genotypes and subtypes - a central goal of prophylactic HCV vaccine design. Using a population of patients who have cleared as many as six distinct HCV infections, we plan to better define the specific correlates of T cell mediated protection from chronic HCV infection. In addition, we will leverage access to research specimens from the only prophylactic HCV vaccine regiment tested in an at-risk human population. This regimen, consisting of a ChAd3NS prime followed by an MVA-NS boost, did not protect against chronic infection, but did induce T cells specific for vaccine NS antigens and suppressed geometric mean peak HCV RNA vs. placebo recipients. Specimens from this trial provide a unique opportunity to study the effect of vaccine- induced T cells on incident HCV infection, allowing us to further validate T cell properties associated with control of HCV, but also to identify the reasons for failure of this potent T cell based vaccine. Specifically, we propose: Aim 1: To define the critical characteristics of HCV-specific CD8 T-cell responses in spontaneous recovery from repeated HCV infection as determinants of protective immunity. Aim 2 To determine if specific CD8 T cell characteristics are associated with vaccine induced suppression of peak viremia in subsequent HCV infection. Aim 3: To define effective CD4 T cell responses in acute infection and HCV-specific CD4 memory T cells in patients with multiple episodes of successfully controlled HCV infection. Aim 4: To characterize the HCV-specific CD4 memory T cell population post vaccination and its response after HCV exposure. We build on our combined extensive expertise in studying both CD8 and CD4 T cell responses in order to define the effector and memory T cell responses that control diverse HCV infections, defining goals for T cell induction in HCV vaccines to be tested in Projects 3 (non-human primates) and 5 (mice) and, ultimately, in humans.

HCV疫苗计划项目1摘要黑猩猩和人类研究的证据支持CD4和CD8 T淋巴细胞反应的关键作用在控制HCV感染中，但是定义保护性HCV免疫的相关性是具有挑战性的。识别CD4和CD8 T细胞存储器，以防止感染免受多种不同的HCV基因型亚型是预防性HCV疫苗设计中的基石。我们在约翰霍普金斯大学的小组马萨诸塞州综合医院为当前对HCV-的理解做出了许多关键发现。特定的T细胞免疫，基于大型且文献良好的患者同类群体的组合敏感的实验工具，用于评估针对HCV的CD8和CD4响应。我们将以这种专业知识为基础，并采用新开发的方法来研究新陈代谢和 HCV特异性CD4和CD8 T细胞的转录景观，以评估独特的T细胞免疫力病人队列。我们以前证明，间隙在重新感染中的发生频率比原发性更频繁感染，峰值和病毒血症持续时间与T细胞反应有关同一人的感染。这表明诱导记忆，可预防多个感染不同的HCV基因型和亚型 - 预防性HCV疫苗设计的核心目标。使用人口在清除多达六种不同HCV感染的患者中，我们计划更好地定义特定 T细胞介导的保护免受慢性HCV感染的相关性。此外，我们将利用访问权限研究标本来自在高危人口中测试的唯一预防性HCV疫苗团。该方案由Chad3ns Prime组成，然后是MVA-NS的提升，没有预防慢性感染，但确实诱导了针对疫苗NS抗原的T细胞，并抑制了几何峰值HCV RNA与安慰剂接受者。该试验的标本提供了一个独特的机会来研究疫苗的影响。引起的T细胞在入射HCV感染中，使我们能够进一步验证与对照相关的T细胞特性 HCV的含量，但也确定了该有效T细胞疫苗失败的原因。具体来说，我们建议：目标1：定义从自发回收中HCV特异性CD8 T细胞反应的关键特征重复的HCV感染是保护性免疫的决定因素。目标2确定特定的CD8 T细胞是否特征与疫苗在随后的HCV感染中诱导的峰值病毒血症抑制有关。目标3：在急性感染和HCV特异性CD4记忆T细胞中定义有效的CD4 T细胞反应多次发作成功控制的HCV感染的患者。目标4：特征特定于HCV 疫苗接种后CD4记忆T细胞种群及其HCV暴露后其反应。我们基于研究CD8和CD4 T细胞反应的综合专业知识，以定义控制多种HCV感染的效应子和记忆T细胞反应，定义了T细胞诱导的目标在项目3（非人类灵长类动物）和5（小鼠）中进行测试的HCV疫苗中，最终在人类中进行了测试。