Newborn cohorts to discover and validate biomarkers of neonatal vaccine immunogenicity

项目总结 新生儿受到感染的影响很严重。免疫接种是预防疾病最有效的策略之一。 感染，但许多疫苗在早期生命中并不能发挥最佳效果。我们对领导机制的理解 对疫苗诱导的保护是早期生命非常有限的。这在一定程度上与样本量较小有关 在新生儿中，宿主对接种疫苗的反应因迅速的 变化的发育程序和母体抗体(MatAbbs)的存在。我们的人类免疫学 项目联盟(HIPC)团队开发了一种健壮的协议，允许系统的全部力量 疫苗学(转录组学、蛋白质组学、免疫图谱；统称为基因组学)与2ml一起应用 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的影响 状态以及MatAbbs。最后，我们开发了能够评估因果关系的体外平台 两性关系。我们已经在试点(扩展计划)中证明了这种综合方法的可行性 免疫联盟；EPIC)研究。我们现在提议用我们最先进的实验 和信息学管道，以表征疫苗诱导的新生儿分子通路与 乙肝疫苗(乙肝)的免疫原性。选择乙肝病毒作为模型，是因为它是唯一的新生儿 疫苗具有明确确立的、可量化的保护相关性(COP)。 临床核心(CC)的目标是定义这两个基本特征对乙肝病毒应答的影响 (免疫状态、抗体等)和联合接种卡介苗(BCG)。招生 在医学研究理事会(MRC)-冈比亚(CC-SITE)对新生儿进行培训和测试 1)之后将在巴布亚新几内亚的一个队列中验证关键签名(巴布亚新几内亚；CC-Site 2)。vt.给出 他们的长期和可靠的跟踪记录，这两个CC-地点特别适合进行这些 学习。在两个CCS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参加体内基因组学 乙肝病毒和卡介苗免疫后的体外反应；2)测量获得性免疫 对乙肝病毒的反应，使体内基因组签名和体外疫苗建模分析与 已建立的CoP；3)检测与疫苗诱导的新生儿和婴儿基因组疫苗有关的MatAbbs 签名和自适应响应；4)验证在不同的独立PNG中识别的关键签名 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 这将为优化早期生命免疫的疫苗配方的开发提供信息。

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.