PROJECT 3: Quality of T Cell Responses Following DENV Natural Infections and Live-Attenuated Dengue Virus Vaccination

项目 3：DENV 自然感染和登革热病毒减毒活疫苗接种后 T 细胞反应的质量

• 批准号: 10244878
• 负责人: Daniela Weiskopf
• 金额: $ 27.44万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-29 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10244878
• 关键词: Address; Antibodies; Antibody Response; Antigen Targeting; Area; Attenuated; B-Lymphocytes; Biological; CD8-Positive T-Lymphocytes; CD8B1 gene; Characteristics; Childhood; Clinical; Clinical Virology; Cohort Studies; Complex; Country; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Disease Outcome; Epidemiology; Epitopes; Flavivirus; Hypersensitivity; Immunity; Immunology; Individual; Infection; Institutes; Link; Measures; Memory; Nicaragua; Nicaraguan; Nonstructural Protein; Outcome; Pathogenesis; Pattern; Pediatric Hospitals; Performance; Phenotype; Public Health; Recording of previous events; Reporting; Research; Role; Sampling; Serotyping; Shapes; Specificity; Statistical Models; T cell response; T memory cell; T-Lymphocyte; T-cell receptor repertoire; Testing; Time; Vaccination; Vaccine Design; Vaccines; Vertebral column; Virus Diseases; Work; Yellow fever virus; adaptive immunity; antigen-specific T cells; base; cohort; cross reactivity; cytokine; env Gene Products; experience; insight; interest; multiple myeloma M Protein; neutralizing antibody; predict clinical outcome; programs; prospective; response; seropositive; severe dengue; tool; transcriptomics; vaccination outcome; vaccine access; vaccine development; vaccine efficacy; vaccine evaluation; vector; viral transmission

PROJECT 3: Quality of T-Cell Responses Following DENV Natural Infections and Live-Attenuated Dengue Virus Vaccination (La Jolla Institute for Allergy and Immunology) SUMMARY The overall theme of the P01 is to study and reveal the role of adaptive immunity in the context of DENV infection and vaccination, in terms of shaping clinical and virological endpoints and outcomes. In Project 3, we will specifically address the central issue of the relation between quality of T cell responses and clinical outcomes as well as antibody quality and durability. Beyond accurately measuring magnitude and number of DENV-specific T cells, we will thoroughly define the quality of T cell responses. First, we will study the antigens targeted by DENV-specific T cells; for example, are envelope (E)-specific T cell responses more effective for helping B cells? Are non-structural (NS) protein-derived responses better for providing help for killing infected targets by CD8 T cells? Second, we will examine another important component of response quality, namely its cross-reactivity among DENV serotypes, or with the vectors used in vaccination. This issue is of relevance in the context of the suboptimal performance of the first licensed DENV vaccine (Dengvaxia®), which utilizes DENV-derived E proteins expressed in a yellow fever virus backbone, which lacks DENV NS proteins. Third, we will determine the CD4 and CD8 subsets elicited by infection and vaccination, in terms of which memory subsets drive responses, what their specific transcriptomic profiles are, to what degree effector responses are multi-specific, and how narrow or diverse the T cell receptor (TCR) repertoire of DENV-specific T cell is. This comprehensive analysis will allow to ask the questions: What drives quality? And how does quality influence outcomes? Our hypothesis is that the quality of T cell responses influences the clinical outcomes of infection and vaccination, either by direct effector functions of DENV-specific T cells, or indirectly, through modulation of the quantity and quality of B cell responses. This hypothesis will be tested by characterizing the quantity and quality of memory T cell responses prior to either symptomatic (DF or severe dengue disease) or inapparent DENV infection in samples distributed by Core C from the Pediatric Dengue Cohort Study in Nicaragua (Aim 1). We will also investigate the role of T cell help in relation to antibody quality and durability (Project 1). Further, we will utilize samples collected 12-18 month after Dengvaxia® vaccination in the Philippine cohort (Core C), and specifically focus on differences observed in DENV-seronegative versus -seropositive vaccinees prior to vaccination (Aim 2). In parallel, we will analyze samples from vaccinees who experience breakthrough DENV infections after vaccination. The variables considered to define “quality” will include: magnitude of antigen- specific T cell response, definition of the dominant antigenic targets, cross-reactivity with other serotypes, determination of memory and CD4/CD8 subsets, multi-specificity in terms of cytokine secretion, transcriptomic profiles, and TCR repertoire diversity. We will test which of these “quality” measures, either alone or in combination with other variables, best correlates with the clinical outcomes. These studies are closely linked with other projects in this P01, as Project 1 (natural infection) and Project 2 (vaccination) will use the same samples/sample sets to investigate the quality of humoral responses. Statistical modeling as well as integrated analyses across projects will be performed by Core B. Overall, our studies will establish correlates of protection from DENV disease based on quality of T cell responses, which will constitute important contributions to dengue vaccine development and evaluation.

项目3：DENV自然感染和活减毒后T细胞应答的质量 登革热病毒疫苗接种（拉霍亚过敏和免疫学研究所） 总结 P01的总体主题是研究和揭示适应性免疫在DENV感染和疫苗接种背景下在塑造临床和病毒学终点和结局方面的作用。在项目3中，我们将专门解决T细胞应答质量与临床结果以及抗体质量和耐久性之间关系的核心问题。除了准确测量DENV特异性T细胞的数量和数量之外，我们还将彻底定义T细胞反应的质量。首先，我们将研究靶向抗原， DENV特异性T细胞;例如，包膜（E）特异性T细胞应答是否对帮助B细胞更有效？ 非结构性（NS）蛋白源性应答是否更有助于通过CD 8 T细胞杀伤受感染的靶细胞 细胞？其次，我们将检查反应质量的另一个重要组成部分，即DENV血清型之间或与疫苗接种中使用的载体之间的交叉反应性。这一问题在《公约》的范围内具有相关性， 第一个获得许可的DENV疫苗（Dengvaxia®）的次优性能，该疫苗利用DENV衍生的E 在黄热病病毒骨架中表达的蛋白，其缺乏DENV NS蛋白。第三，我们将确定 由感染和疫苗接种引起的CD 4和CD 8亚群，就其记忆亚群而言， 反应，它们的特异性转录谱是什么，效应子反应的多特异性程度， 以及DENV特异性T细胞的T细胞受体（TCR）库有多窄或多多样。这一全面 分析将允许提出问题：什么驱动质量？质量如何影响结果？我们 假设T细胞应答的质量影响感染的临床结果， 疫苗接种，或者通过DENV特异性T细胞的直接效应子功能，或者间接地，通过调节 B细胞应答的数量和质量。这一假设将通过表征数量和质量来检验 记忆T细胞反应之前，无论是症状（DF或严重登革热疾病）或隐性登革病毒 尼加拉瓜儿童登革热队列研究核心C分发的样本中的感染（目标1）。我们 还将研究T细胞在抗体质量和持久性方面的作用（项目1）。此外，我们将 使用菲律宾队列（核心C）中Dengvaxia®疫苗接种后12-18个月收集的样本，以及 特别关注在接种前DENV血清阴性与血清阳性疫苗接种者中观察到的差异， 疫苗接种（目标2）。与此同时，我们将分析来自经历突破性DENV的疫苗接种者的样本， 接种疫苗后感染。被认为定义“质量”的变量将包括： 特异性T细胞应答，主要抗原靶点的定义，与其他血清型的交叉反应性， 记忆和CD 4/CD 8亚群的测定，细胞因子分泌方面的多特异性，转录组学 概况和TCR库多样性。我们将测试这些“质量”措施，无论是单独或在 与其他变量相结合，与临床结果最相关。这些研究与 本P01中的其他项目，如项目1（自然感染）和项目2（疫苗接种）将使用相同的 样本/样本集，以研究体液应答的质量。统计建模以及集成 跨项目分析将由核心B执行。总的来说，我们的研究将建立保护的相关性， 从登革病毒疾病的基础上的T细胞反应的质量，这将构成登革热的重要贡献 疫苗开发和评估。