Project 3: Immunologic Determinants of Outcome in Dengue Virus Infection and Vaccination

项目总结/摘要 项目3的总体目标是确定由以下因素诱导的免疫记忆的要素： 自然DENV感染和疫苗接种与后续DENV暴露的结果相关。 免疫记忆对疫苗的有效性很重要。许多DENV感染发生在以下情况下： 预先存在的免疫记忆，其后果可能是有益的（降低的风险， 感染和/或疾病）或病理性（感染和/或疾病的风险增加）; 区分这些结果的特征将促进登革热疫苗的开发， 实施.我们小组以前的研究已经开始确定 登革病毒感染免疫记忆和临床结果。拟议的研究将解决差距问题 了解这些关联的机制和DENV特异性的 免疫记忆我们假设记忆T和B淋巴细胞的特定群体 由特异性和表型定义的基因决定感染的结果，并且随着时间的推移而变化， 记忆淋巴细胞群与DENV感染和疾病的随时间变化的风险相关。 这些假设将使用来自泰国队列研究的血液样本进行检验， 黄热病-登革热嵌合体III期试验中一组独特参与者的观察 菲律宾宿务的疫苗接种者，他们每年都进行血液收集和积极监测， 急性登革热病约5年。项目3的具体目标是：1）确定 感染前血液样本中的记忆T和B细胞群与 随后的DENV感染; 2）定义DENV的频率，特异性和功能的变化- 特异性T细胞和B细胞群体在自然感染后随时间变化及其与事件的关系 DENV感染;和3）定义DENV特异性T细胞的频率，特异性和功能的变化， 细胞和B细胞群体随接种后时间的变化及其与DENV感染风险的相关性 和疾病 项目3的重点是DENV特异性免疫记忆及其与临床的相关性。 结果直接涉及本计划项目的总体目标。项目3中开发的试验 将扩大到项目1和2的研究组群，反之亦然。项目3将利用核心A， 核心B用于数据管理和统计分析，核心C用于处理 临床标本、诊断检测以及抗体特异性和功能测定。的结果 这些研究将有助于提高对先前疫苗试验结果的理解，并指导 评估现有候选疫苗。

Project Summary/Abstract The overall objective of Project 3 is to identify the elements of immunological memory induced by natural DENV infection and vaccination that correlate with outcome upon subsequent DENV exposure. Immunological memory is important to vaccine efficacy. Many DENV infections occur in the context of pre-existing immunological memory, and the consequences can be either beneficial (reduced risk of infection and/or disease) or pathological (increased risk of infection and/or disease); defining the characteristics that distinguish these outcomes will advance dengue vaccine development and implementation. Previous studies by our group have begun to identify associations between immunological memory and clinical outcomes of DENV infection. The proposed studies will address gaps in knowledge regarding the mechanisms of these associations and the kinetics of DENV-specific immunological memory. We hypothesize that specific populations of memory T and B lymphocytes defined by specificity and phenotype determine the outcome of infection, and that changes over time in populations of memory lymphocytes correlate with the time-varying risk of DENV infection and disease. These hypotheses will be tested using blood samples from Thai cohort studies as well as extended observation of a unique cohort of participants in the phase III trial of the chimeric yellow fever-dengue vaccine in Cebu, the Philippines, who have had annual blood collections and active surveillance for acute dengue illnesses for ~5 years. The Specific Aims to be addressed in Project 3 are to: 1) define the memory T and B cell populations in pre-infection blood samples that are associated with the outcome of subsequent DENV infection; 2) define the changes in frequency, specificity, and function of DENV- specific T cell and B cell populations over time after natural infection and their associations with incident DENV infections; and 3) define the changes in frequency, specificity, and function of DENV-specific T cell and B cell populations over time after vaccination and their associations with risk of DENV infection and disease. Project 3’s focus on DENV-specific immunological memory and its correlations with clinical outcome directly address the overall objectives of this Program Project. Assays developed in Project 3 will be extended to the study cohorts of Projects 1 and 2, and vice versa. Project 3 will utilize Core A for project administration, Core B for data management and statistical analysis, and Core C for processing of clinical specimens, diagnostic testing, and assays of antibody specificity and function. The results of these studies will be useful to improve understanding of previous vaccine trial results and to guide the evaluation of current vaccine candidates.