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。这将导致鉴定指示疫苗诱导的抗体应答的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。 相关性（参见说明）：疫苗代表了免疫学的主要成功，但我们对有效的疫苗如何刺激保护性免疫反应知之甚少。我们的初步研究表明，三种市售疫苗以完全不同的方式改变血细胞组成和转录组，以诱导保护性免疫。我们提出了五个高度集成的项目，由七个核心的特征疫苗诱导的免疫系统改变使用系统生物学方法。 项目1：健康个体疫苗反应分析的系统生物学方法 项目负责人：Banchereau，J 项目1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。尽管它们取得了成功，但我们对有效的疫苗如何刺激保护性免疫反应知之甚少。可区分三类疫苗：i）高效疫苗，如黄热病、麻疹和天花; ii）在大多数人中产生保护性免疫力的良好疫苗，包括季节性流感（Flu）疫苗、乙型肝炎B和肺炎疫苗;以及iii）目前在很大程度上无效的疫苗，包括HIV-艾滋病、疟疾和丙型肝炎。我们推测，通过研究低反应人群，了解好疫苗在健康人群中的工作方式，并了解它们的缺点，将使我们能够解开疫苗接种的免疫学原理。最近的两个发展有望产生这样的理解：i）树突状细胞在诱导和调节免疫反应中的关键作用的认识和ii）系统生物学方法基础上的高通量分子分析技术的进展。我们假设，系统生物学分析将产生一个全面的看法与流感疫苗接种的有效反应相关的免疫改变。我们进一步假设有效的疫苗接种与抗原呈递细胞的早期激活有关。我们的目标是确定流感疫苗有效抗体反应的早期生物标志物。提出了四个目标来实现这一目标：目标1：建立健康受试者的基线免疫谱。目的2：建立健康人接种流感疫苗的免疫模式。目的3：鉴定DC亚群对流感疫苗接种应答的分子特征。目的4：鉴定活化的单核细胞对流感疫苗应答的分子特征。 相关性（见说明）：尽管疫苗取得了成功，但我们对有效疫苗如何刺激保护性免疫反应知之甚少。我们将研究流感疫苗如何产生有效的抗体反应。目标是确定有效疫苗引起的免疫反应，以便改进不那么有效的疫苗。为此，我们会为健康人士接种流感疫苗，并监察他们在接种疫苗后的免疫反应。

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. RELEVANCE (See instructions): Vaccines represent the major success of immunology and yet we understand little about how effective vaccines stimulate protective immune responses. Our preliminary studies indicate that three commercially available vaccines alter the blood cell composition and transcriptome in completely different ways to induce protective immunity. We propose five highly integrated projects supported by seven cores to characterize vaccine-induced immune system alterations using a systems biology approach. PROJECT 1: Systems Biology Approach to Analysis of Vaccine Response in Healthy Individuals Project Leader: Banchereau, J PROJECT 1 DESCRIPTION (provided by applicant): Vaccines represent the major success of immunology and have spared countless numbers of people from infections. Despite their success, we understand little about how effective vaccines stimulate protective immune responses. Three classes of vaccine can be distinguished: i) highly effective vaccines such as yellow fever, measles and smallpox; ii) good vaccines which yield protective immunity in a majority of people including seasonal Influenza (Flu) vaccines, hepatitis B and pneumovax; and iii) vaccines which are largely not effective at the current time including HIV-AIDS, malaria, and Hepatitis C. We surmise that understanding the modus operandi of good vaccines in healthy people and understanding their shortcomings by studying hypo-responsive people will permit us to unravel the immunological principles of vaccination. Two recent developments promise to yield such understanding: i) the appreciation of the crucial role of dendritic cells in inducing and tuning the immune responses and ii) advances in high-throughput molecular profiling technologies underlying systems biology approaches. We hypothesize that a systems biology analysis will yield a comprehensive view of the immune alterations associated with a potent response to flu vaccination. We further hypothesize that efficient vaccination is associated to the early activation of antigen presenting cells. Our goal is to identify early biomarkers of effective antibody responses to flu vaccination. Four aims are proposed to meet this goal: Aim 1: To establish the baseline immune profiles in healthy subjects. Aim 2: To establish the immune profiles of Flu vaccination in healthy subjects. Aim 3: To identify the molecular signatures of DC subset(s) in response to Flu vaccination. Aim 4: To identify the molecular signatures of activated monocytes in response to Flu vaccination. RELEVANCE (See instructions): Despite the success of vaccines, we understand little about how effective ones stimulate protective immune responses. We will study how the flu vaccine generates effective antibody responses. The goal is to identify the immune responses elicited by effective vaccines so that vaccines that aren't as effective can be improved. To do this, we will vaccinate healthy people with the flu vaccine and monitor their immune response following the vaccination.