Proteomics Core: Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity

项目摘要 尽管免疫接种取得了不可否认的成功，但每年仍有200多万婴儿死于感染。出生是 这是最可靠的医疗保健接触点，因此是确保广泛免疫的理想时间点。 然而，新生儿免疫与成人不同，因为它在出生后减弱，使得新生儿疫苗 反应常常受到损害。在这种情况下，迫切需要开发新的新生儿疫苗， 约会一个缓慢的，有风险的和容易出错的事业。为这种努力提供分子基础， 为了降低未来疫苗开发的风险，NIAID/NIH启动了人类免疫学项目 专注于应用无偏、全局分子（OMIC）和免疫表型技术的联盟 询问人类免疫系统及其对免疫等挑战的反应。一个目标 我们关于系统生物学用于鉴定新生儿疫苗免疫原性生物标志物的建议之一是， 绘制新生儿血浆和白细胞蛋白质组在生命最初7天内的变化， 免疫接种（a）什么都没有-即，延迟免疫至第7天以确定个体发育（随年龄变化），（B） 具有明显保护作用的B型肝炎疫苗，（c）卡介苗 已知改变HBV作用的疫苗，或（d）（HBV + BCG）。通过采用新的 使用来自相同研究参与者的血液的体外免疫平台（项目3）。蛋白质组 基础状态和景观变化将与转录组的变化相关（服务核心1）， 免疫表型/状态（项目2）。项目1中的综合生物信息学分析将确定基础和 疫苗诱导的基因表达模式，蛋白质翻译，以及与成功 次免疫HIPC核心/项目数据将通过强大的数据管理核心进行共享/分析。 为了支持这些努力，蛋白质组学核心将利用收集的样本， 在冈比亚（临床核心（CC）-研究中心1）和巴布亚新几内亚（CC-研究中心2），和/或在Levy 波士顿儿童医院实验室（项目3）： 特定目标1：表征新生儿血浆蛋白质组的基础、个体发育和疫苗诱导状态 在生命的前七天。 特异性目标2：表征来自相同细胞的基础、个体发生和疫苗诱导的白细胞蛋白质组 血液样本作为血浆样本。 具体目标3。HBV诱导的蛋白质组特征与免疫原性相关，使用靶向 CC研究中心1和研究中心-2验证队列样品的LC/MS方法。 总的来说，我们的蛋白质组学核心将为疫苗诱导的血浆和白细胞提供突破性的见解 与保护相关的蛋白质组特征，从而为未来的新生儿疫苗开发提供信息。

PROJECT SUMMARY Despite the undeniable success of immunization, >2 million infants still die annually from infections. Birth is the most reliable point of healthcare contact and is thus an ideal time point to ensure widespread immunization. However, neonatal immunity is distinct from adult as it is attenuated after birth, such that neonatal vaccine responses are often impaired. In this context, there is an urgent need to develop new neonatal vaccines, to date a slow, risky and error-prone undertaking. To provide the molecular basis for such efforts and accelerate and de-risk future vaccine development, the NIAID/NIH has initiated the Human Immunology Project Consortium with a focus on applying unbiased, global molecular (OMIC) and immunophenotyping techniques to interrogate the human immune system and its response to challenges such as immunization. One objective of our proposal on systems biology for the identification of biomarkers of neonatal vaccine immunogenicity is to map changes in neonatal plasma and leukocyte proteomes across the first 7 days of life in response to immunization with (a) nothing – i.e., delayed immunization to Day 7 to define ontogeny (change with age), (b) Hepatitis B vaccine (HBV) for which there is a clear correlate of protection, (c) Bacille Calmette-Guérin (BCG) vaccine, known to modify HBV action, or (d) (HBV + BCG). Additional data are generated by employing novel in vitro immunization platforms employing blood from the same study participants (Project 3). The proteome basal state and landscape changes will be correlated with changes in the transcriptome (Service Core 1) and immune phenotype/status (Project 2). Integrative bioinformatic analysis in Project 1 will identify basal and vaccine-induced patterns of gene expression, protein translation, and pathways associated with successful immunization. HIPC Core/Project data will be shared/analyzed via a robust Data Management Core. To support these efforts, the Proteomics Core will pursue the following Specific Aims, using samples collected in The Gambia (Clinical Core (CC)-Site 1) and Papa New Guinea (CC-Site 2), and/or generated in the Levy Laboratory at Boston Children's Hospital (Project 3): Specific Aim1: Characterize the basal, ontogenic and vaccine-induced state of the neonatal plasma proteome across the first 7 days of life. Specific Aim2: Characterize the basal, ontogenic and vaccine-induced leukocyte proteome from the same blood sample as the plasma samples. Specific Aim3. Validate HBV-induced proteomic signatures correlating with immunogenicity using targeted LC/MS Approaches on samples from validation cohorts at CC Sites 1 and -2. Overall our Proteomics Core will provide groundbreaking insight into vaccine-induced plasma and leukocyte proteome signatures that correlate with protection thereby informing future neonatal vaccine development.