Systems Analysis Vaccine Responses in Healthy and Hyporesponsive Humans

描述（由申请人提供）：疫苗代表了免疫学的重大成功，使无数人免于感染。尽管取得了这一成功，但我们对有效的疫苗如何刺激保护性免疫反应知之甚少。我们推测，了解疫苗在健康人群中的工作方式，并通过研究低反应人群来了解它们的缺点，将使我们能够解开疫苗接种的免疫学原理。将对三种疫苗进行详细研究：灭活流感疫苗和B型肝炎疫苗，使用明矾作为传统佐剂（Engerix）或使用CPGoliglitide（Heplisav）。我们推测，系统生物学方法将使我们能够全面了解与疫苗接种有效反应相关的免疫生物学。这将导致识别指示疫苗诱导的抗体反应质量的生物标志物特征。这反过来又将有助于合理设计和开发新的改进疫苗。我们对24名健康志愿者进行的初步研究表明，三种市售疫苗：Fluzone（流感），Pneumovax和Engerix以完全不同的方式改变血细胞组成和转录组。这些初步结果支持我们提出的策略。他们证明，不同的疫苗，这是能够诱导保护性体液反应，动员不同的免疫效应。我们提出了五个高度集成的项目，将由七个核心支持。我们的主要成果将包括：i）增加对疫苗诱导的树突状细胞、单核细胞和T滤泡辅助细胞中免疫系统改变的认识; ii）体液免疫应答的生物标志物; iii）预测疫苗免疫应答的离体测定; iv）评估疫苗活化细胞的工具; v）两种佐剂的系统生物学分析：明矾和CPG-寡核苷酸; vi）免疫系统改变的患者对疫苗的反应的系统生物学分析;和vii）用于评估疫苗免疫功效的免疫芯片或聚焦微阵列。

DESCRIPTION (provided by applicant): Vaccines represent the major success of immunology and have spared countless numbers of people from infections. Despite this success, we understand little about how effective vaccines stimulate protective immune responses. We surmise that understanding the modus operandi of vaccines in healthy people and understanding their shortcomings by studying hypo-responsive people will permit us to unravel the immunological principles of vaccination. Three vaccines will be studied in great detail: inactivated influenza vaccine and hepatitis B vaccine with either alum as the traditional adjuvant (Engerix) or with CPGoligonucleotide (Heplisav). We surmise that systems biology approaches will permit us to gain a comprehensive view of the immunobiology associated with a potent response to vaccination. This will lead to the identification of biomarker signatures indicative of the quality of vaccine-induced antibody responses. This, in turn, will facilitate the rational design and development of novel improved vaccines. Our preliminary studies performed with 24 healthy volunteers indicate that three commercially available vaccines: Fluzone (influenza), Pneumovax and Engerix alter the blood cell composition and transcriptome in completely different ways. These preliminary results support our proposed strategy. They demonstrate that the different vaccines, which are able to induce protective humoral responses, mobilize different immune effectors. We propose five highly integrated projects which will be supported by seven cores. Our key deliverables will include: i) Increased knowledge on vaccine-induced immune system alterations in dendritic cells, monocytes and T follicular helper cells; ii) Biomarkers of humoral immune responses; iii) An ex vivo assay for prediction of immune response to vaccination; iv) Tools to assess vaccine-activated cells; v) A systems biology analysis of two adjuvants: Alum and CPG-Oligonucleotides; vi) A systems biology analysis of the response to vaccine in patients with altered immune systems; and vii) An Immunochip, or focused microarray, for the assessment of vaccine immune efficacy.