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: 9245976
• 负责人: Tobias R. Kollmann
• 金额: $ 13.26万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245976
• 关键词: Age; Algorithmic Analysis; Antibodies; Antibody titer measurement; Antigens; Attenuated; B-Lymphocytes; BCG Vaccine; Biological Assay; 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; Immunophenotyping; Infant; Infection; Lead; Life; Mediating; Medical; Modeling; Molecular; Neonatal; Newborn Infant; Outcome; Pathway interactions; Phenotype; Pilot Projects; Plasma; Population; Preparation; Procedures; Process; Proteomics; Publishing; Purines; Quality Control; 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; insight; neonatal hepatitis; novel; peripheral blood; phenotypic data; predictive marker; predictive signature; programs; protective efficacy; response; tool; transcriptomics; 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人的生命，但生命早期感染的风险仍然很高。 生命早期免疫需要更好地了解疫苗诱导的分子途径 保护相关性（CoP）系统生物学方法的保护和免疫原性。 应用于疫苗学的 OMIC（“OMIC”）为疫苗介导的保护提供了重要的见解，但 尚未应用于最年轻的儿童，尽管他们非常需要改善免疫接种。 乙型肝炎疫苗 (HBV) 从出生时开始就非常有效，可实现 90% 以上的 HBV 保护。 少数具有明确特征和可量化 CoP（抗乙型肝炎表面抗原）的疫苗 重要的是，虽然存在已确定的最低保护阈值（抗 HBs）。 > 10 mIU/ml)，所达到的绝对滴度与保护直接相关（滴度越高，浓度越高 保护效果越持久）。如此高的保护功效，再加上可量化的 CoP。 新生儿和婴儿群体中显着的反应变异性使 HBV 成为定义的理想模型 因此，我们的重债穷国提案重点关注成功新生儿免疫的机制。 使用 HBV 作为模型的“识别新生儿疫苗免疫原性生物标志物的系统生物学”。 为此，新生儿将接受无任何（延迟）、HBV、BCG 或（HBV + BCG）和外周血的免疫接种。 收集免疫前/后的血液用于转录组和蛋白质组分析，以确定途径 与 CoP 相关（“免疫状态作为新生儿疫苗免疫原性的预测因子”；PI） Tobias Kollmann；联合负责人 Ryan Brinkman）我们将分析 OMIC 询问的完全相同的样本 通过详细的免疫表型分析将衍生的 OMIC 特征转化为宿主免疫的方法 这不仅有助于对 OMIC 消息进行反卷积，还可以生成细粒度的信息。 确定预测新生儿后保护性免疫反应的生物标志物所需的详细视图 在目标 1 中，我们将通过高端流式细胞术测定血液样本中的细胞成分。 为此，我们收集了新生儿免疫前和免疫后的样本，并将其与疫苗结果相关联。 开发了一种新颖的自动化无监督门控平台，相当于无偏系统 生物学发现方法，但对于流式细胞术，我们将确定可溶性浓度。 免疫调节剂，包括血浆前和血浆中的细胞因子、趋化因子和嘌呤代谢酶 在目标 3 中，我们将开发新的工具来进一步研究免疫后的结果并与疫苗结果相关联。 高端免疫高级表型分析，并将其应用于此处生成的新生儿疫苗数据 总体而言，我们的努力将为与乙型肝炎相关的免疫表型提供重要见解。 保护性新生儿免疫，从而为未来早期生命疫苗的开发提供信息。