Deconvolution and reconstruction of immune histories to enhance infectious disease prevention and vaccination strategies and optimize surveillance efforts

项目摘要 传染病仍然是对人类健康的最大威胁之一。新的流行病随着 频率，因为方便旅行促进传播，环境变化改变了潜在的动态， 不可预测的方式。与此同时，疫苗越来越多地控制许多主要的人类病原体。然而， 这些进步的潜力只有通过准确测量和量化的手段才能充分实现， 从个体到全球人群，传染病的格局跨越许多病原体和规模， 并涵盖相关或不相关病原体之间的相互作用和潜在的非预期后果。 总的目标是连接分子生物学和计算工具的新发展， 从根本上改善传染病监测和研究。Aim 1将建立在先前报道的 噬菌体展示系统，并优化它的传染病监测。PADERNS（噬菌体展示抗体） 用于传染病和公共卫生的通过病原体表位分析的检测和谱分析 监测）将：能够对所有人类病原体，包括细菌， 寄生虫和蚊子媒介，同时从可获得的样品，即唾液和干血斑; 将区分与密切相关的病原体（即寨卡病毒和登革热）的暴露，并估计自 感染或接种疫苗。重要的是，它将被优化用于低资源环境， 现有技术的成本。目的2：通过Epi-TRACER（Epitope）的开发，提高流行病检测水平 基于通过综合表位识别的匿名样品的追踪）。Epi-TRACER将使用 PADERNS剧目从（1）提取和构建流行病学上强大的“虚拟纵向队列” 来自包含“隐藏”系列样本的横截面样本集（即80%的美国血液供应来自 重复捐赠者）。由于Epi-TRACER在PADERNS数据上运行，它将同时启用重建 以及对当前流行病的早期检测。目标3将阐明病原体暴露的生活史 跨年龄（从出生前到老年人）、时间、性别和地理区域：以前所未有的详细程度量化病原体 攻击率，疫苗对脱靶病原体的异源效应，并测量 抗体，包括母源性抗体，以改善疫苗接种和控制策略。 这些目标将通过涉及分子生物学的多学科方法来实现， 噬菌体展示系统，通过合作进行强大的纵向样本管理，以及至关重要的是， 建立数学和统计模型，将生物学与个人和群体水平联系起来 推论一旦完成，工具，方法和数据将提供给公共卫生机构和传染病管理机构。 疾病研究人员，开辟了一条道路，在检测或控制现有的和新的病原体的步骤变化。

PROJECT SUMMARY Infectious diseases remain among the greatest threats to human health. Novel epidemics occur with increasing frequency as ease of travel facilitates spread, and environmental changes alter underlying dynamics in unpredictable ways. At the same time, vaccines are increasingly controlling many major human pathogens. Yet, the potential of these advances can only be fully realized with a means to accurately measure and quantify the landscape of infectious diseases across many pathogens and scales, from the individual to the global population, and encompassing interactions and potential unintended consequences across related or unrelated pathogens. The overall objectives are to bridge novel developments in molecular biology and computational tools to fundamentally improve infectious disease surveillance and research. Aim 1 will build on a previously reported phage display system, and optimize it for infectious disease surveillance. PADERNS (Phage display for Antibody repertoire Detection and profiling via pathogen Epitope RecognitioN for infectious disease and public health Surveillance) will: enable serological surveillance for exposures to all human pathogens, including bacteria, parasites and mosquitos vectors, simultaneously, from accessible samples, i.e. saliva and dried blood spots; will discriminate exposures from closely related pathogens (i.e. Zika and Dengue) and estimate time since infection or vaccination. Importantly, it will be optimized for use in low resource settings and at a fraction of the cost of current technologies. Aim 2 will improve epidemic detection with development of Epi-TRACER (Epitope based TRacking of Anonymous samples via Comprehensive Epitope Recogntion). Epi-TRACER will use PADERNS repertoires from (1) to extract and construct epidemiologically powerful ‘virtual longitudinal cohorts’ from cross-sectional sample sets that contain ‘hidden’ serial samples (i.e. 80% of the US blood supply comes from repeat donors). Because Epi-TRACER runs on PADERNS data, it will simultaneously enable reconstruction of past, and early detection of current epidemics. Aim 3 will elucidate the life-histories of pathogen exposures across ages (pre-birth to elderly), time, genders and geographies to: quantify in unprecedented detail pathogen attack rates, heterologous effects of vaccines on off-target pathogens, and measure the longevity and waning of antibodies, including maternally derived antibodies, to improving vaccination and control strategies. These aims will be accomplished through a multi-disciplinary approach involving molecular biology and phage-display systems, robust longitudinal sample curation through collaborations, and, crucially, careful development of mathematical and statistical models to link the biology to individual and population level inference. Once complete, the tools, methods and data will be available to public health agencies and infectious disease researchers, opening the way to a step change in detection or control of existing and novel pathogens.