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

蛋白质组学核心：识别新生儿疫苗免疫原性生物标志物的系统生物学

• 批准号: 10063824
• 负责人: Hanno Steen
• 金额: $ 11.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-27 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063824
• 关键词: Achievement; Address; Adjuvant; Adult; Age; Attenuated; Australia; BCG Live; BCG Vaccine; Bioinformatics; Biological Markers; Biological Models; Birth; Blood; Blood specimen; Boston; Childhood; Clinical; Collaborations; Data; Development; Ensure; Future; Gambia; Gene Expression Profile; Geography; Goals; Growth; Healthcare; Hepatitis B Vaccines; Human; Immune; Immune system; Immunization; Immunization Programs; Immunology; Immunophenotyping; Impairment; In Vitro; Individual; Infant; Infection; Institutes; International; Isotope Labeling; Laboratories; Leukocytes; Life; Maps; Measures; Medical Research; Methods; Modeling; Modern Medicine; Molecular; Molecular Profiling; National Institute of Allergy and Infectious Disease; Neonatal; New Guinea; Newborn Infant; Outcome; Papua New Guinea; Participant; Pediatric Hospitals; Phase; Phenotype; Plasma; Population; Protein Translation Pathway; Proteins; Proteome; Proteomics; Risk; Sampling; Services; Site; Systems Biology; Techniques; Time; United States National Institutes of Health; Vaccine Adjuvant; Vaccine Design; Vaccines; Validation; adaptive immune response; aluminum sulfate; base; biomarker identification; biomarker signature; candidate marker; cohort; data integration; data management; immunogenicity; in vitro Model; in vivo; innovation; insight; interest; liquid chromatography mass spectrometry; neonatal immunity; novel; novel vaccines; proteomic signature; response; success; synergism; transcriptome; transcriptomics; vaccine development; vaccine response; vaccinology

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.

项目概要 尽管免疫接种取得了不可否认的成功，但每年仍有超过 200 万婴儿死于感染。出生是 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，新生儿的免疫力与成人不同，出生后免疫力减弱，因此新生儿疫苗 反应常常受到损害。在此背景下，迫切需要开发新的新生儿疫苗， 约会是一项缓慢、危险且容易出错的事情。为此类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 启动了人类免疫学项目 专注于应用公正的全局分子 (OMIC) 和免疫表型分析技术的联盟 询问人类免疫系统及其对免疫等挑战的反应。一个目标 我们关于鉴定新生儿疫苗免疫原性生物标志物的系统生物学提案的目的是 绘制出生后 7 天新生儿血浆和白细胞蛋白质组的变化图 (a) 不进行任何免疫——即延迟至第 7 天进行免疫以确定个体发育（随年龄变化），(b) 乙型肝炎疫苗 (HBV) 具有明显的保护相关性，(c) 卡介苗 (BCG) 已知可改变 HBV 作用的疫苗，或 (d) (HBV + BCG)。通过采用新颖的方法生成附加数据 使用来自同一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）和 免疫表型/状态（项目 2）。项目 1 中的综合生物信息分析将确定基础和 疫苗诱导的基因表达模式、蛋白质翻译以及与成功相关的途径 免疫接种。重债穷国核心/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实现以下具体目标 冈比亚（临床核心 (CC)-站点 1）和巴巴新几内亚（CC-站点 2），和/或在 Levy 中生成 波士顿儿童医院实验室（项目 3）： 具体目标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 生命的最初 7 天。 具体目标2：表征来自同一细胞的基础、个体发育和疫苗诱导的白细胞蛋白质组 血液样品作为血浆样品。 具体目标3。使用靶向验证 HBV 诱导的与免疫原性相关的蛋白质组特征 对来自 CC 站点 1 和 -2 的验证队列的样品进行 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。