In vitro modeling to characterize mechanisms of neonatal vaccine induced immune responses

项目摘要 新生儿和幼儿有感染的风险，对疫苗的反应往往不是最佳。重债穷国项目 3建议利用两项技术进步，为疫苗提供基本的新见解- 诱导与保护性免疫相关的分子变化，并可能改变未来的新生儿疫苗 开发：1）能够测量全面分子特征的新型“OMIC”技术， 特别是转录组学和蛋白质组学，免疫接种后;和2）体外开发人 系统来模拟针对免疫的年龄特异性先天性和适应性免疫应答。我们的初步数据 表明目前在出生时接种疫苗、含明矾佐剂的B型肝炎疫苗（HBV）和肝脏 减毒牛分枝杆菌，称为卡介苗（BCG），诱导年龄依赖性免疫， OMIC反应，并且这些不同的体内诱导的变化也可以在体外建模。因此，委员会认为， 项目3的目标是表征年龄特异性OMIC对体外和体内免疫的应答， 定义队列，以加深我们对疫苗诱导特征的理解， 免疫原性，包括保护相关物（CoP），并增强未来年龄特异性疫苗 发展我们将通过以下具体目标实现这一目标：在具体目标1中，我们将 采用全血测定法在体内表征疫苗诱导的与CoP相关的分子途径 在体外;在具体目标2中，我们将表征疫苗诱导的与CoP相关的分子途径， HIPC项目3将协同使用体外人微生理组织构建体， 重债穷国倡议的其他组成部分，包括项目-1（OMIC整合）和项目-2（免疫表型分析）以及数据 管理核心是定义和验证与新生儿疫苗免疫原性相关的特征。 这些研究将利用新的体外平台来定义，表征和剖析分子特征 这与新生儿疫苗的免疫原性相对应，从而为未来的早期生命疫苗开发提供信息。 !

Project Summary Newborns and young infants are at risk of infection and often respond sub-optimally to vaccines. HIPC Project 3 proposes to leverage two technological advances that will provide fundamental new insights into vaccine- induced molecular changes associated with protective immunity and may transform future neonatal vaccine development: 1) novel “OMIC” technologies capable of measuring comprehensive molecular signatures, in particular transcriptomics and proteomics, following immunization; and 2) the development of human in vitro systems to model age-specific innate and adaptive immune responses to immunization. Our preliminary data suggest that vaccines currently given at birth, the Alum-adjuvanted hepatitis B vaccine (HBV) and the live attenuated Mycobacterium bovis named Bacille Calmette-Guérin (BCG), induce age-dependent immune and OMIC responses, and that these distinct in vivo-induced changes can also be modeled in vitro. Accordingly, the goal of Project 3 is to characterize age-specific OMIC responses to immunization in vitro and in vivo in well- defined cohorts to deepen our understanding of vaccine-induced signatures that predict vaccine immunogenicity, including correlates of protection (CoP), and enhance future age-specific vaccine development. We will achieve this goal by pursuing the following Specific Aims: in Specific Aim 1, we will characterize vaccine-induced molecular pathways correlating with CoP in vivo employing whole blood assays in vitro; and in Specific Aim 2, we will characterize vaccine-induced molecular pathways correlating with CoP in vivo employing human microphysiologic tissue constructs in vitro HIPC Project 3 will work in synergy with the other HIPC components, including Projects-1 (OMIC integration) and -2 (Immunophenotyping) and the Data Management Core to define and validate signatures that correlate with neonatal vaccine immunogenicity. These studies will leverage novel in vitro platforms to define, characterize and dissect molecular signatures corresponding to newborn vaccine immunogenicity, thereby informing future early life vaccine development. !