Immune status as a predictor of neonatal vaccine immunogenicity

免疫状态作为新生儿疫苗免疫原性的预测因子

• 批准号: 10063828
• 负责人: Tobias R. Kollmann
• 金额: $ 31.93万
• 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/10063828
• 关键词: Age; Algorithmic Analysis; Antibodies; Antibody titer measurement; Antigens; Attenuated; B-Lymphocytes; BCG Live; BCG Vaccine; Biological Markers; Birth; Blood; Blood specimen; Cells; Cessation of life; Clinical; Complement; Coupled; Data; Data Set; Development; Elderly; Enrollment; Enzymes; Flow Cytometry; Future; Gene Expression Profile; Hepatitis B Vaccines; Human; Immune; Immune response; Immunization; Immunize; Immunologic Markers; Immunomodulators; Immunophenotyping; Infant; Infection; Lead; Life; Mediating; Medical; Modeling; Molecular; Neonatal; Newborn Infant; Pathway interactions; Phenotype; Pilot Projects; Plasma; Population; Preparation; Procedures; Process; Proteomics; Publishing; Purines; Risk; Sampling; Sampling Studies; Ships; Site; Standardization; Surface Antigens; System; Systems Biology; Time; Translating; Vaccination; Vaccines; Whole Blood; Work; anti-hepatitis B; base; chemokine; cytokine; experience; immunogenicity; immunological status; improved; infection risk; insight; multiplex assay; neonatal hepatitis; novel; peripheral blood; phenotypic data; predictive marker; predictive signature; programs; protective efficacy; response; tool; transcriptomics; vaccination outcome; vaccine development; vaccine response; vaccinology

PROJECT 2 - SUMMARY Vaccines save millions of lives each year but the risk of infection remains high early in life. Improvement of early life immunization requires a better understanding of vaccine-induced molecular pathways that underlie protection and immunogenicity in the form of Correlates of Protection (CoP). Systems biology approaches (“OMICs”) applied to vaccinology have provided critical insights into vaccine-mediated protection, but have not yet been applied to the youngest, despite their great need for improved immunization. Immunization with Hepatitis B vaccine (HBV) starting at birth is highly effective resulting in protection of > 90%. HBV is one of the few vaccines that has a well characterized and quantifiable CoP (anti-Hep B surface antigen antigen (anti-HBs) antibody levels). Importantly, while there is an established minimal protective threshold (anti-HBs > 10 mIU/ml), the absolute titer reached correlates directly with protection (the higher the titer, the higher and the more durable the protection). Such high protective efficacy, coupled with a quantifiable CoP yet significant response-variability in the neonatal and infant population makes HBV an ideal model to define mechanisms underlying successful neonatal immunization. Accordingly, our HIPC proposal, focuses on ’Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity’ using HBV as the model. To this end, newborns will be immunized with nothing (delayed), HBV, BCG or (HBV + BCG) and peripheral blood pre-/post-immunization collected for transcriptomic and proteomic analyses to identify pathways associated with CoP. In our Project 2 (“Immune status as a predictor of neonatal vaccine immunogenicity’; PI Tobias Kollmann; Co-Lead Ryan Brinkman) we will analyze the exact same samples interrogated by OMIC approaches via detailed immune phenotyping to translate the derived OMICs signatures to host immune parameters. This will not only help to de-convolute the OMIC message, but generate the fine-granular detailed view necessary to identify biomarkers predicting a protective immune response following neonatal HBV vaccination. In Aim 1 we will determine cell composition in blood samples by high-end flow cytometry in pre- and post immunization samples from newborns and correlate with vaccine outcome. To this end we have developed a novel automated unsupervised gating platform that is the equivalent of unbiased systems biology discovery approaches but for flow cytometry. In Aim 2 we will determine the concentration of soluble immune modulators including cytokines, chemokines, and purine metabolizing enzymes in plasma pre- and post- immunization and correlate with vaccine outcome. In Aim 3 we will develop novel tools to further advance high-end immune phenotyping, and apply them to the data generated here on the newborn vaccine response to HBV. Overall our efforts will provide key insight into immunophenotypes associated with protective neonatal immunization thereby informing future development of early life vaccines.

项目2-摘要 疫苗每年挽救数百万生命，但感染的风险在生命的早期仍然很高。改进 早期的免疫需要更好地了解疫苗诱导的分子途径 保护和免疫原性的保护形式（COP）。系统生物学方法 （“ OMICS”）适用于疫苗已为疫苗介导的保护提供了关键的见解，但已有 尚未适用于最年轻的，dospite他们对改善免疫的巨大需求。免疫 肝炎B疫苗（HBV）从出生开始是非常有效的，导致> 90％的保护。 HBV是之一 具有良好特征和可量化COP的少数疫苗（抗HEP B表面抗原抗原 （抗HBS）抗体水平）。重要的是，虽然存在建立的最小保护阈值（反HB） > 10 miU/ml），绝对滴度达到的绝对滴度与保护直接相关（滴度越高，较高和 保护越耐用）。如此高的保护效率，再加上可量化的COP 在新生儿和婴儿种群中的重大响应可定性性使HBV成为定义的理想模型 成功的新生儿免疫的基础机制。根据我们的HIPC提议，专注于 使用HBV作为模型，“系统生物学鉴定新生儿疫苗免疫原性的生物标志物”。到 这一末端，新生儿将无需（延迟），HBV，BCG或（HBV + BCG）和外围物进行免疫接种。 对转录组和蛋白质组学分析收集的血液前/免疫后，以识别途径 与COP相关。在我们的项目2中（“免疫状态为新生儿疫苗免疫原性的预测指标”； PI 托比亚斯·科尔曼（Tobias Kollmann）；共同领导的瑞安·布林克曼 通过详细的免疫表型来转化派生的OMICS特征以托管免疫 参数。这不仅有助于解散imic信息，还可以产生细粒 确定生物标志物预测新生儿后受保护的免疫反应所需的详细观点 HBV疫苗接种。在AIM 1中，我们将通过高端流式细胞术确定血液样本中的细胞组成 来自新生儿的免疫样品和后后的免疫样本与疫苗结局相关。为此，我们 已经开发了一种新型的自动化的无监督的门控平台，相当于无偏系统 生物学发现方法，但用于流式细胞仪。在AIM 2中，我们将确定固体的浓度 免疫调节剂，包括细胞因子，趋化因子和等离子体前和血浆中的纯代谢酶 免疫后并与疫苗结局相关。在AIM 3中，我们将开发新的工具来进一步 提前高端免疫表型，并将其应用于此处在新生儿疫苗上产生的数据 对HBV的响应。总体而言，我们的努力将为与与之相关的免疫表型提供关键的见解 保护性新生儿免疫，从而告知未来早期生命疫苗的发展。