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 摘要来自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控制 HCV 感染，但定义保护性 HCV 免疫的相关性一直具有挑战性。识别可防止多种不同 HCV 基因型感染的 CD4 和 CD8 T 细胞记忆和亚型是预防性 HCV 疫苗设计的基石。我们在约翰·霍普金斯大学的团队和马萨诸塞州总医院为当前对 HCV 的理解贡献了许多重要发现特异性 T 细胞免疫，基于大量且有据可查的患者队列与稳健和可靠的组合用于评估针对 HCV 的 CD8 和 CD4 反应的敏感实验工具。我们将利用这一专业知识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 细胞免疫患者队列。我们之前证明，再感染时的清除率比原发性感染时的清除率更高。感染，与初始相比，与扩大的 T 细胞反应相关的病毒血症峰值和持续时间减少同一个人感染。这表明记忆的诱导可以防止多种感染不同的 HCV 基因型和亚型 - 预防性 HCV 疫苗设计的中心目标。使用人口在已清除多达六种不同 HCV 感染的患者中，我们计划更好地定义具体的 T 细胞介导的慢性 HCV 感染保护的相关性。此外，我们将利用访问研究样本取自在高危人群中进行测试的唯一预防性 HCV 疫苗组。该方案由 ChAd3NS 初免和 MVA-NS 加强组成，不能预防慢性感染，但确实诱导了对疫苗 NS 抗原具有特异性的 T 细胞，并抑制了 HCV 几何平均峰值 RNA 与安慰剂接受者。该试验的样本提供了研究疫苗效果的独特机会在 HCV 感染事件中诱导 T 细胞，使我们能够进一步验证与对照相关的 T 细胞特性 HCV 的研究，同时也确定了这种基于 T 细胞的有效疫苗失败的原因。具体来说，我们建议：目标 1：确定 HCV 特异性 CD8 T 细胞反应在自发恢复过程中的关键特征反复感染 HCV 作为保护性免疫的决定因素。目标 2 确定特定 CD8 T 细胞是否这些特征与疫苗诱导的随后 HCV 感染中病毒血症峰值的抑制有关。目标 3：确定急性感染中有效的 CD4 T 细胞反应和 HCV 特异性 CD4 记忆 T 细胞成功控制 HCV 感染多次发作的患者。目标 4：表征 HCV 特异性接种疫苗后的 CD4 记忆 T 细胞群及其在 HCV 暴露后的反应。我们结合广泛的专业知识，研究 CD8 和 CD4 T 细胞反应，以确定控制不同 HCV 感染的效应和记忆 T 细胞反应，确定 T 细胞诱导的目标 HCV 疫苗将在项目 3（非人类灵长类动物）和项目 5（小鼠）中进行测试，并最终在人类中进行测试。