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

项目总结 尽管免疫接种取得了无可否认的成功，但每年仍有200万婴儿死于感染。出生是最重要的 这是最可靠的卫生保健接触点，因此是确保广泛接种疫苗的理想时间点。 然而，新生儿免疫与成人不同，因为它在出生后会减弱，因此新生儿疫苗 反应通常会受到损害。在这方面，迫切需要开发新的新生儿疫苗，以 与一项缓慢、有风险、容易出错的事业约会。为这种努力提供分子基础，并加速 为了降低未来疫苗开发的风险，NIAID/NIH发起了人类免疫学项目 联盟，专注于应用无偏见的全球分子(OMIC)和免疫表型技术 询问人类免疫系统及其对免疫等挑战的反应。一个目标 我们关于识别新生儿疫苗免疫原性生物标志物的系统生物学建议的目的是 新生儿出生前7天血浆和白细胞蛋白质组的MAP变化 免疫：(A)不接种--即，将免疫推迟到第7天，以确定个体发育(随年龄变化)，(B) (C)卡介苗(卡介苗) 疫苗，已知可以改变乙肝病毒的作用，或(D)(乙肝卡介苗)。其他数据是通过使用新颖的方式生成的 使用相同研究参与者血液的体外免疫平台(项目3)。蛋白质组 基础状态和景观的变化将与转录组的变化相关(服务核心1)和 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、蛋白质翻译和与成功相关的途径 免疫接种。重债穷国核心/项目数据将通过一个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实现以下具体目标 在冈比亚(临床核心(CC)-站点1)和Papa新几内亚(CC-站点2)，和/或在Levy中生成 波士顿儿童医院实验室(项目3)： 特异性Aim1：研究新生儿血浆蛋白质组的基础状态、个体状态和疫苗诱导状态 在生命的头7天里。 特异性AIM2：鉴定基础、个体和疫苗诱导的白细胞蛋白质组 血样作为血浆样本。 特定的目标3。使用靶向技术验证乙肝病毒诱导的与免疫原性相关的蛋白质组特征 CC站点1和2的验证队列样品的LC/MS方法。 总体而言，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开创性的见解 与保护相关的蛋白质组签名，从而为未来新生儿疫苗的开发提供信息。

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.