Newborn cohorts to discover and validate biomarkers of neonatal vaccine immunogenicity

项目摘要 新生儿受感染的影响很大。免疫接种是预防艾滋病的最有效策略之一。 感染，但许多疫苗在生命早期并不发挥最佳作用。我们对导致 对疫苗诱导的保护作用在生命早期是非常有限的。这在一定程度上与样品体积小有关 可获得的，以及新生儿中宿主对疫苗接种的反应因快速免疫应答而复杂化的事实。 改变发育程序和母体抗体（MatAb）的存在。我们的人类免疫学 项目联盟（HIPC）团队开发了一个强大的协议，允许系统的全部力量 疫苗学（转录组学、蛋白质组学、免疫分析;统称为OMIC），适用于<2 ml 鲜血我们还开发了信息学工具来破译快速变化的宿主免疫系统的影响， 状态以及MatAbs。最后，我们开发了能够评估因果关系的体外平台， 关系。我们已经在一个试点项目中证明了这种综合方法的可行性（扩大的 免疫联盟; EPIC）研究。我们现在建议使用我们最先进的实验 和信息学管道来表征新生儿中疫苗诱导的分子途径， B型肝炎疫苗（HBV）免疫原性。选择HBV作为模型，因为它是唯一的新生儿 疫苗具有明确的、可量化的保护相关性（CoP）。 临床核心（CC）的目标是确定两种基础特征对HBV应答的影响 （免疫状态、MatAb等）和卡介苗（BCG）联合给药。招生 在冈比亚医学研究理事会（MRC）（CC-中心）， 1)随后将在巴布亚新几内亚（PNG; CC中心2）的一个队列中验证关键签名。给定 由于这两个CC站点长期以来的良好记录，它们特别适合开展这些活动 问题研究在两个CC中，我们将使用相同的疫苗、临床和实验室方案和试剂。我们 通过4个具体目标来实现这一点：1）招募定义明确的冈比亚新生儿队列进行体内OMIC 用HBV ± BCG免疫后的分析和体外应答; 2）测量适应性免疫 的应答，使得体内OMIC特征和体外疫苗建模测定与 建立CoP; 3）测量与疫苗诱导的新生儿和婴儿OMIC疫苗相关的MatAb 签名和自适应响应; 4）在不同的独立PNG中识别的私钥签名 新生儿队列。总体而言，拟议的CC将能够表征和验证疫苗诱导的OMIC 签名和评估其预测CoP的潜力。这些研究将最终确定机制 这将为开发针对生命早期免疫的最佳疫苗配方提供信息。

PROJECT SUMMARY Newborns are severely affected by infection. Immunization is one of the most effective strategies to prevent infection but many vaccines do not work optimally in early life. Our understanding of the mechanisms leading to vaccine-induced protection is early life is very limited. This relates in part to the small sample volumes obtainable, and the fact that the host response to vaccination in the newborn is complicated by a rapidly shifting developmental program and presence of maternal antibodies (MatAbs). Our Human Immunology Project Consortium (HIPC) team has developed a robust protocol that allows the full force of systems vaccinology (transcriptomics, proteomics, immune profiling; collectively called OMIC) to be applied with < 2ml of blood. We also have developed the informatics tools to decipher the impact of rapidly changing host immune status as well as MatAbs. Lastly, we developed in vitro platforms that enable assessment of cause-effect relationships. We have proven the feasibility of this comprehensive approach in a pilot (Expanded Program on Immunization Consortium; EPIC) study. We are now proposing to employ our state-of-the-art experimental and informatics pipeline to characterize vaccine-induced molecular pathways in newborns correlating with hepatitis B vaccine (HBV) immunogenicity. HBV was chosen as the model, because it is the only newborn vaccine with a clearly established, quantifiable correlate of protection (CoP). The goal of the Clinical Core (CC) is to define the impact on HBV responses of both basal characteristics (immune status, MatAbs, etc) and of co-administration of Bacille Calmette-Guérin (BCG) vaccine. Enrollment of newborns for a training- and test-set of samples at the Medical Research Council (MRC)-Gambia (CC-Site 1) will be followed by validation of key signatures in a cohort in Papua New Guinea (PNG; CC-Site 2). Given their longstanding and proven track records, both CC-Sites are particularly well suited to conduct these studies. Across both CCs, we will use identical vaccines, clinical and laboratory protocols and reagents. We approach this via 4 Specific Aims: 1) Enroll well-defined cohorts of Gambian newborns for in vivo OMIC profiling and in vitro responses following immunization with HBV ± BCG; 2) Measure adaptive immune responses to HBV, enabling correlation of in vivo OMIC signatures and in vitro vaccine modeling assays with established CoP; 3) Measure MatAbs in relation to vaccine-induced neonatal and infant OMIC vaccine signatures and adaptive responses; 4) Validate key signatures identified in a distinct independent PNG newborn cohort. Overall, the proposed CC will enable characterization and validation of vaccine-induced OMIC signatures and assessment of their potential to predict CoP. These studies will ultimately define mechanisms that will inform development of vaccine formulations optimized for early life immunization.