Systems Analysis Vaccine Responses in Healthy and Hyporesponsive Humans

描述(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地刺激保护性免疫反应知之甚少。我们推测，了解健康人接种疫苗的方式，并通过研究低反应者了解它们的缺点，将使我们能够揭开疫苗接种的免疫学原理。将对三种疫苗进行非常详细的研究：灭活流感疫苗和乙肝疫苗，使用明矾作为传统佐剂(Engerix)或使用CPGoligonNP(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的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记物签名。这反过来将促进新型改良疫苗的合理设计和开发。我们对24名健康志愿者进行的初步研究表明，三种商用疫苗：流感、肺炎和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，能够诱导保护性体液反应的不同疫苗动员了不同的免疫效应器。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)增加关于疫苗诱导的树突状细胞、单核细胞和T滤泡辅助细胞免疫系统改变的知识；ii)体液免疫反应的生物标记物；iii)用于预测疫苗接种的免疫反应的体外试验；iv)评估疫苗激活细胞的工具；v)对两种佐剂：明矾和CpG寡核苷酸的系统生物学分析；vi)免疫系统改变患者对疫苗反应的系统生物学分析；以及vii)用于评估疫苗免疫效力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.