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，但我们对疫苗如何有效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运作方式，并通过研究低反应人群了解其缺点，将使我们能够解开疫苗接种的免疫学原理。将详细研究三种疫苗：以明矾作为传统佐剂（Engerix）或以cpgolignucleotide （Heplisav）为佐剂的灭活疫苗和乙型肝炎疫苗。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抗体反应质量的生物标志物特征。反过来，这将有助于合理设计和开发新的改良疫苗。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战略。他们证明，不同的疫苗，能够诱导保护性体液反应，调动不同的免疫效应器。我们提出了五个高度整合的项目，这些项目将得到七个核心的支持。我们的主要成果将包括：i)增加对树突状细胞、单核细胞和T滤泡辅助细胞中疫苗诱导的免疫系统改变的了解；ii)体液免疫反应的生物标志物；iii)预测疫苗接种免疫反应的离体试验；iv)评估疫苗活化细胞的工具；v)明矾和cpg -寡核苷酸两种佐剂的系统生物学分析；免疫系统改变患者对疫苗反应的系统生物学分析；免疫芯片或聚焦微阵列，用于评估疫苗免疫功效。

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.