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性B细胞和浆细胞反应的背景下，两个及时 和疫苗学的基本主题：（i）COVID-19疫苗的免疫学，以及（ii） 微生物群对疫苗接种免疫反应的影响。由新型冠状病毒引起的COVID-19大流行 SARS-CoV-2（CoV-2）和为对抗这种病原体而开发的疫苗强调了以下需求： 更好地理解人类的初级抗体反应。我们会用系统的切割- 边缘体液免疫分析以彻底表征两种CoV-2疫苗引起的抗体， 以及B细胞记忆和持续抗体所需的B细胞和浆细胞克隆群 滴度我们的重点将是血清学，B细胞和浆细胞反应引起的脂质纳米颗粒mRNA 疫苗（Pfizer-BioNTech）和基质M佐剂化重组蛋白疫苗（Novavax）。组合这些 对这些疫苗的先天免疫（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 mRNA疫苗已经报告了过敏样不良反应，特别是在有过敏史的个体中 食物过敏的患者，以及那些对聚乙二醇（PEG）有特异性IgG抗体的患者。我们将研究潜在的 B细胞对这些过敏样反应的贡献，使用受影响个体的样本， 接受SARS-COV-2 mRNA疫苗。最后，我们将讨论微生物组在体液免疫中的作用。 免疫接种，血清学，记忆B细胞和浆细胞分析的类似策略 在抗生素治疗后有或没有暂时消除微生物群的参与者中。特别 重要性在上述研究中，我们将不仅分析外周血B细胞和浆母细胞， 还可以通过细针穿刺监测淋巴结生发中心反应， 骨髓浆细胞，以全面研究体液免疫， 人类的疫苗。 这些研究的综合影响可能在指导开发 通过揭示B细胞和浆细胞的特异性、分化途径和 新的SARS-CoV-2疫苗平台刺激的寿命，以及阐明微生物组在 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.