Systems biological assessment of innate and adaptive immunity to vaccination

抽象-整体组件 在目前的提案中，我们将使用系统疫苗学方法来解决以下两个基本问题 疫苗学。第一个问题涉及新冠肺炎疫苗的免疫学，这种疫苗利用了新的平台 (信使核糖核酸)或佐剂(Novavax疫苗中使用的基质M)。第二个问题是与 微生物组对疫苗免疫的影响。关于第一个问题，尽管COVID发展迅速-- 19种疫苗，对它们诱导天生和 适应性反应。此外，本研究还对基因疫苗诱导的免疫应答的性质进行了初步探讨。 诸如患有严重过敏性疾病的人群尚不清楚。有趣的是，有报道称 在有特应性背景的个人中，对疫苗接种发生罕见但严重的过敏反应。因此，我们将 评估特应性BNT162b2疫苗与健康受试者的免疫力。在矩阵-M的情况下 对于诺华公司研发的重组新冠肺炎佐剂疫苗，目前尚缺乏了解。 皂苷类基质-M佐剂刺激的免疫机制。我们会分析收集到的样本 来自一项由Novavax赞助的南非临床试验。 提案的第二个主题是微生物群对免疫系统的影响。 在健康的成年人中接种疫苗。我们最近关于抗生素驱动的微生物区系消融的工作已经 强调了微生物群在调节免疫反应中的重要作用 季节性流感疫苗。然而，成人对季节性流感疫苗的免疫反应 代表召回反应，因为之前接触过流感。微生物群对细菌的影响 初级免疫反应，如对狂犬病疫苗接种的反应，尚不清楚。 这两个问题将在以下高度协作的项目和核心中得到解决：项目1(PI Pulendran)将利用一种多组学方法来定义驱动适应性免疫的先天反应 去接种疫苗。在这个项目中确定的特征将与抗原特异性T和B细胞相关联 项目2(Pi Davis)和项目3(Pi Boyd)分别评估了答复。项目2将深入演绎 疫苗接种后抗原特异性T细胞反应的动态分析。项目3(Pi Boyd；Co-I Nadeau)将对抗原特异性B细胞反应的动力学进行深入分析 接种疫苗。这三个项目将得到4个核心的协助。行政核心将支持 整个重债穷国-斯坦福中心的协调工作。临床核心(Pi Nadeau)将确保 所有研究中人类受试者招募和临床特征的标准化方法； 数据管理和分析核心(Pi Khatri)将提供生物信息学专业知识，而人类 免疫监测核心(PI Holden)将通过提供免疫监测分析来支持这些项目。

ABSTRACT – Overall Component In the current proposal we will use a systems vaccinology approach to address two fundamental issues in vaccinology. The first issue concerns the immunology of COVID-19 vaccines, which utilize novel platforms (mRNA) or adjuvants (Matrix M used in the Novavax vaccine). The second issue is related to the role of the microbiome on vaccine immunity. With respect to the first issue, despite the rapid development of COVID- 19 vaccines, there is a paucity of understanding about the mechanisms by which they induce innate and adaptive responses. Furthermore, the nature of the immune response induced by mRNA vaccines in special populations such as those with serious allergic disease is unknown. Interestingly, there have been reports of rare but severe allergic reactions to vaccination, in individuals with an atopic background. Therefore, we will assess immunity to the BNT162b2 vaccine atopic versus healthy subjects. In the case of the Matrix-M adjuvanted recombinant COVID-19 vaccine developed by Novavax, there is a paucity of understanding of immune mechanisms stimulated by the saponin-based Matrix-M adjuvant. We will analyze samples collected from a Novavax sponsored clinical trial in South Africa. The second theme of the proposal is focused on the impact of the microbiome on immunity to vaccination in healthy adults. Our recent work involving antibiotics driven ablation of the microbiota has highlighted an important role for the microbiome in modulating immune responses to vaccination with the seasonal influenza vaccine. However, the immune response against seasonal influenza vaccine in adults represents a recall response, because of prior exposure to influenza. The impact of the microbiome on a primary immune response, such as the response to rabies vaccination, is unknown. These two issues will be addressed in the following highly collaborative projects and cores: Project 1 (PI Pulendran) will utilize a multi-omics approach to define innate responses driving adaptive immunity immunity to vaccination. The signatures identified in this project will be correlated with antigen-specific T and B cell responses assessed in Projects 2 (PI Davis) and 3 (PI Boyd), respectively. Project 2 will perform an in-depth analysis of the dynamics of the antigen-specific T cell responses to vaccination. Project 3 (PI Boyd; Co-I Nadeau) will perform an in-depth analysis of the dynamics of the antigen-specific B cell responses to vaccination. The three projects will be assisted by 4 cores. The Administrative Core will support the coordination efforts across the HIPC-Stanford Center. The Clinical Core (PI Nadeau) will ensure a standardized approach in the recruitment and clinical characterization of human subjects in all studies; the Data Management and Analysis Core (PI Khatri) will provide bioinformatics expertise, and the Human Immune Monitoring Core (PI Holden) will support the projects by providing immune monitoring assays.