Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity

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: 10265669
• 负责人: OFER LEVY
• 金额: $ 210.3万
• 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: 2020-05-07 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265669
• 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; 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.

项目摘要 早期免疫的改善需要更好地了解疫苗诱导的分子 保护性免疫原性作为保护的途径（COP）。系统疫苗学 采用测量分子变化（“ OMICS”）的技术为您提供了关键的见解 成人对疫苗接种的免疫应答，但尚未应用于最小的疫苗，dospite的需求 改善免疫。我们将在对乙型肝炎的新生儿免疫反应中应用强大的OMIC工具 疫苗接种（HBV）。 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％的保护），并且具有良好的COP（抗肝炎B 表面抗原抗体（抗HB））; b）抗HBS滴度与保护直接相关，即较高的抗 - HBS更好，更耐用的保护； c）拳头（新生儿）剂量后的抗HBS滴度与 最后一个滴度； d）抗HBS水平在受试者之间差异很大；这种受试者间的可变性启用 强大的系统疫苗学工具提取有意义的相关性； e）新生儿HBV响应是 对巴奇氏菌（BCG）（BCG）的共同给药敏感，它通常与HBV一起给予 扩展的免疫计划（EPI）；这提供了特征体内特征的独特机会 通过OMICS扰动。我们在冈比亚和巴布亚新几内亚选择的临床研究网站之一 世界上最有经验的新生儿疫苗学。在这里，新生儿将与 无需（延迟），HBV，BCG或（HBV + BCG）和外周血前/免疫后收集了用于 转录组和蛋白质组学分析以及免疫表型。项目1将开发和雇用 尖端，跨平台生物信息学工具，以识别与COP相关的途径。项目2，威尔 将公正的免疫表型分析分析工具应用于同一样品，并转化为免疫免疫 参数是计算机衍生的omics特征。在项目3中，将剖析关键分子信号 体外建立因果关系。我们已经优化了所有测定法以使用小血量和 在我们的快速入学率，严格控制的样本收集和 处理产生的可爱数据已经暗示了不同的疫苗诱导的反应。我们的跨平台 在包含培训和测试集的队列中与COP的验证和相关性以及验证 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（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（总体目的3） 完成此HIPC的输出。总体而言，我们的工作将确定疫苗诱导的分子途径钥匙 为了成功疫苗诱导的新生儿免疫反应，从而增强和加速疫苗 最需要的人的发展。