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

项目摘要 新生儿和婴儿有感染的风险，对疫苗的反应往往不太理想。重债穷国项目 3提议利用两项技术进步，为疫苗提供根本性的新见解- 与保护性免疫相关的诱导分子变化，并可能改变未来的新生儿疫苗 发展：1)能够测量全面分子特征的新“组学”技术， 免疫后的特定转录组学和蛋白质组学；以及2)人类体外发育 对免疫的特定年龄的先天和适应性免疫反应进行建模的系统。我们的初步数据 建议目前在出生时接种的疫苗，明胶佐剂乙肝疫苗(乙肝疫苗)和活的 减毒牛分枝杆菌卡介苗(BCG)，诱导年龄依赖性免疫和 这些不同的体内诱导的变化也可以在体外模拟。因此， 项目3的目标是描述在体外和体内对免疫的特定年龄的组学反应。 确定的队列以加深我们对疫苗诱导的预测疫苗的签名的理解 免疫原性，包括保护相关性(COP)，并加强未来的特定年龄疫苗 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 用全血试验研究疫苗诱导的与活体COP相关的分子通路 在体外；在特定的目标2，我们将表征疫苗诱导的与COP相关的分子通路。 利用人体微生理组织在体外构建HIPC项目3的活体将与 重债穷国的其他组成部分，包括项目-1(基因组整合)和-2(免疫表型)和数据 管理核心，定义和验证与新生儿疫苗免疫原性相关的签名。 这些研究将利用新的体外平台来定义、表征和剖析分子签名 与新生儿疫苗的免疫原性相对应，从而为未来早期生命疫苗的发展提供信息。 好了！

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. !