Systems biological assessment of B cell responses to vaccination

摘要-项目3 项目3的重点是研究抗原特异的B细胞和浆细胞在两个及时的背景下的反应 和疫苗学的基本主题：(I)新冠肺炎疫苗的免疫学，以及(Ii)疫苗的影响 微生物区系对疫苗免疫反应的影响。新型冠状病毒引起的新冠肺炎大流行 SARS-CoV-2(CoV-2)以及为对抗这种病原体而开发的疫苗强调了需要 更好地了解人类的主要抗体反应。我们将使用一个系统的切割小组- 边缘体液免疫分析，以彻底表征两种CoV-2疫苗所产生的抗体， B细胞记忆和持续抗体所需的B细胞和浆细胞克隆群 效价。我们的重点将放在由脂质纳米粒mRNA引发的血清学、B细胞和浆细胞反应上 Pfizer-BioNTech疫苗(辉瑞-BioNTech)和基质M佐剂重组蛋白疫苗(Novavax)。将这些组合在一起 对这些疫苗的天然免疫(项目1)和T细胞(项目2)反应的研究分析应 强调与抗体反应的强度和持久性相关的细胞机制。罕见的严重 据报道，mrna疫苗出现了类过敏反应，特别是在有过敏史的个体中。 食物过敏，以及那些具有聚乙二醇特异性抗体的人。我们将研究潜在的 B细胞在这些类过敏反应中的作用，使用来自受影响的人的样本 接种SARS-COV-2mRNA疫苗。最后，我们将讨论微生物群对体液的作用 对疫苗的免疫，采用类似的血清学、记忆B细胞和浆细胞分析策略 在抗生素治疗后有或没有暂时消融微生物区系的参与者。特别的 在上述研究中，我们不仅将分析外周血B细胞和浆母细胞， 还可通过细针抽吸监测淋巴生发中心反应，并取骨样 在同一参与者的骨髓浆细胞中，全面研究体液免疫 在人类身上接种疫苗。 这些研究的综合影响可能在临床上具有重要的指导作用。 通过揭示B细胞和浆细胞的特异性、分化途径和 由新的SARS-CoV-2疫苗平台刺激的寿命，以及在阐明微生物组在 疫苗对新抗原的反应。

ABSTRACT – Project 3 The focus of Project 3 is to study antigen-specific B cell and plasma cell responses in the context of two timely and fundamental topics in vaccinology: (i) Immunology of COVID-19 vaccines, and (ii) the impact of the microbiota on immune responses to vaccination. The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 (CoV-2), and the vaccines developed to combat this pathogen, have underscored a need for greater understanding of primary antibody responses in humans. We will use a systematic panel of cutting- edge humoral immunity analyses to thoroughly characterize antibodies elicited by two CoV-2 vaccines, and the B cell and plasma cell clonal populations required for B cell memory and sustained antibody titers. Our focus will be on the serological, B cell and plasma cell responses elicited by a lipid nanoparticle mRNA vaccine (Pfizer-BioNTech), and a Matrix M-adjuvanted recombinant protein vaccine (Novavax). Combining these analyses with studies of innate immunity (Project 1) and T cell (Project 2) responses to these vaccines should highlight cellular mechanisms correlated with the strength and durability of antibody responses. Rare serious anaphylactoid adverse reactions have been reported for mRNA vaccines, particularly in individuals with a history of food allergy, and those with IgG antibodies specific for polyethylene glycol (PEG). We will examine potential B cell contributions to these anaphylactoid reactions, using specimens from affected individuals who received SARS-COV-2 mRNA vaccines. Finally, we will address the role of the microbiome on humoral immunity to vaccination, with a similar strategy of serological, memory B cell and plasma cell analyses in participants with or without temporarily ablated microbiota following antibiotic treatment. Of particular importance in the aforementioned studies, we will not only analyze peripheral blood B cells and plasmablasts, but also monitor lymph node germinal center reactions by fine-needle aspiration, and sample bone marrow plasma cells in the same participants, to comprehensively study humoral immunity to vaccination in humans. The combined impact of these investigations will likely be clinically significant in guiding the development of future vaccination strategies by uncovering the B cell and plasma cell specificities, differentiation pathways, and longevity stimulated by new SARS-CoV-2 vaccine platforms, and in clarifying the role of the microbiome in vaccine responses to novel antigens.