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: 10221106
• 负责人: OFER LEVY
• 金额: $ 11.11万
• 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: 2020-08-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221106
• 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.

项目总结