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: 10323188
• 负责人: Hanno Steen
• 金额: $ 227.57万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323188
• 关键词: Adult; Age; Antibodies; Antibody Response; BCG Live; Biological Assay; Biological Markers; Birth; Blood; Blood Volume; Cause of Death; Cell Compartmentation; Cells; Characteristics; Child; Clinical Research; Complement; Complex; Data; Detection; Developing Countries; Development; Dose; Enrollment; Gambia; Gene Expression; Gene Proteins; Global Change; Health Benefit; Hepatitis; Hepatitis B Surface Antigens; Hepatitis B Vaccination; Hepatitis B Vaccines; Human; Immune; Immune response; Immunization; Immunization Programs; Immunize; In Vitro; Infant; Infection; Knowledge; Leukocytes; Life; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Neonatal; Newborn Infant; Output; Papua New Guinea; Pathway interactions; Pattern; Phenotype; Plasma; Procedures; Proteins; Proteome; Proteomics; Public Health; RNA; Sampling; Signal Transduction; Site; Surface Antigens; System; Systems Biology; Technology; Testing; Time; Training; Translating; Vaccination; Vaccines; Validation; Variant; Whole Blood; Work; anti-hepatitis B; bioinformatics tool; biological systems; cohort; experience; functional status; global health; immunogenicity; immunological status; improved; in silico; in vivo; insight; mortality; neonatal hepatitis; novel; novel strategies; peripheral blood; predictive marker; protective efficacy; response; sample collection; tool; transcriptomics; vaccine development; vaccine response; vaccine-induced immunity; vaccinology

PROJECT SUMMARY Improvement of early life immunization requires a better understanding of vaccine-induced molecular pathways that underlie protective immunogenicity as Correlates of Protection (CoP). Systems vaccinology employing technologies that measure molecular changes (“OMICs”) has provided critical insights into the adult immune response to vaccination, but has yet to be applied to the youngest, despite their need for improved immunization. We will apply powerful OMIC tools to the neonatal immune response to Hepatitis B vaccination (HBV). HBV is an ideal model to define mechanisms of successful neonatal immunization because: a) HBV is highly effective (>90% protection) and has a well-characterized CoP (anti-hepatitis B surface antigen antibody (anti-HBs)); b) anti-HBs titres directly correlate with protection, i.e. the higher anti- HBs the better and more durable protection; c) anti-HBs titers after the fist (neonatal) dose correlate with titers after the last; d) anti-HBs levels vary widely between subjects; such inter-subject variability enables powerful systems vaccinology tools to extract meaningful correlations; e) the neonatal HBV response is sensitive to co-administration of Bacille Calmette-Guérin (BCG), which is routinely given together with HBV in the Expanded Program of Immunization (EPI); this offers the unique opportunity to characterize this in vivo perturbation via OMICs. Our chosen clinical study sites in the Gambia and Papua New Guinea are amongst the world's most experienced with respect to neonatal vaccinology. Here, newborns will be immunized with nothing (delayed), HBV, BCG or (HBV + BCG) and peripheral blood pre-/post-immunization collected for transcriptomic and proteomic analysis as well as immune phenotyping. Project 1 will develop and employ cutting edge, cross-platform bioinformatics tools to identify pathways associated with CoP. Project 2, will apply unbiased immune phenotyping analysis tools to the same samples and translate to host immune parameters the in silico derived OMICs signatures. In Project 3 key molecular signals will be dissected in vitro to establish cause and effect. We have optimized all assays to work with small blood volumes and demonstrated feasibility in our pilot of rapid enrollment, stringently controlled sample collection and processing yielding cogent data that already hint at distinct vaccine-induced responses. Our cross-platform validation and correlation with CoP in a cohort containing training- and test-sets as well as a validation cohort, will identify biomarkers predicting neonatal vaccine immunogenicity i) pre-vaccination (Overall Aim 1) and ii) post-vaccination (Overall Aim 2). Delineation of the relevant mechanisms in vitro (Overall Aim 3) complements the output of this HIPC. Overall, our work will identify vaccine-induced molecular pathways key for successful vaccine-induced neonatal immune responses, thereby enhancing and accelerating vaccine development for those in greatest need.

项目概要 改善早期生命免疫需要更好地了解疫苗诱导的分子机制 作为保护相关性（CoP）的保护性免疫原性途径。 采用测量分子变化（“OMIC”）的技术为研究提供了重要的见解 成人对疫苗接种的免疫反应，但尚未应用于最年轻的人，尽管他们需要 我们将应用强大的 OMIC 工具来改善新生儿对乙型肝炎的免疫反应。 乙型肝炎疫苗（HBV）是定义成功新生儿免疫机制的理想模型。 因为：a) HBV 非常有效（>90% 保护）并且具有良好特征的 CoP（抗乙型肝炎） 表面抗原抗体（抗-HBs））；b）抗-HBs滴度与保护直接相关，即抗-HBs越高 HBs 更好、更持久的保护；c) 首次（新生儿）剂量后的抗 HBs 滴度与 d) 受试者之间的抗 HBs 水平差异很大； 强大的系统疫苗学工具可提取有意义的相关性；e) 新生儿 HBV 反应是 对卡介苗 (BCG) 联合用药敏感，卡介苗通常与 HBV 一起服用 扩大免疫计划（EPI）提供了在体内表征这一点的独特机会； 我们在冈比亚和巴布亚新几内亚选择的临床研究地点就在其中。 在这里，新生儿将接受世界上最有经验的新生儿疫苗接种。 没有（延迟）、乙肝病毒、卡介苗或（乙肝病毒+卡介苗）和免疫前/免疫后外周血收集 项目 1 将开发和应用转录组学和蛋白质组学分析以及免疫表型分析。 尖端的跨平台生物信息学工具将用于识别与 CoP 项目 2 相关的途径。 将无偏见的免疫表型分析工具应用于相同的样本并转化为宿主免疫 在项目 3 中，将对计算机衍生的 OMIC 特征进行剖析。 我们已经优化了所有测定法，以适用于小血量和 我们的快速入组试点的可行性，严格证明受控样本收集和 处理产生的令人信服的数据已经暗示了我们的跨平台疫苗引起的反应。 在包含训练集和测试集以及验证的队列中进行验证和与 CoP 的相关性 队列，将确定预测新生儿疫苗免疫原性的生物标志物 i) 疫苗接种前（总体目标 1） ii) 疫苗接种后（总体目标 2）体外相关机制的描述（总体目标 3）。 总体而言，我们的工作将确定疫苗诱导的关键分子途径。 成功地疫苗诱导的新生儿免疫反应，从而增强和加速疫苗 为最需要帮助的人提供发展。