Regulation of germinal center responses by SARS-CoV-2 messenger RNA vaccines

SARS-CoV-2 信使 RNA 疫苗对生发中心反应的调节

• 批准号: 10569579
• 负责人: Michela Locci
• 金额: $ 66.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569579
• 关键词: 2019-nCoV; Address; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antibody-Producing Cells; Antigen Presentation; Antigen-Presenting Cells; Antigens; Applications Grants; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; COVID-19 vaccine; Cell Differentiation process; Cell Shape; Complex; Dendritic Cells; Encapsulated; Endowment; Ensure; Epitopes; Event; FDA Emergency Use Authorization; Fostering; Future; Generations; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunoglobulin-Secreting Cells; Individual; Infection; Knowledge acquisition; Label; Length; Licensing; Longevity; Mediating; Membrane; Memory B-Lymphocyte; Messenger RNA; Molecular Conformation; Mus; Names; Nature; Nucleosides; Pathway interactions; Plasma Cells; Process; Proteins; RNA vaccination; RNA vaccine; Race; Reaction; Regulation; SARS-CoV-2 infection; Secondary Immunization; Speed; Structure of germinal center of lymph node; Technology; Testing; Time; Toll-like receptors; Vaccination; Vaccine Design; Vaccines; cell type; cytokine; innovation; lipid nanoparticle; mouse model; neutralizing antibody; novel vaccines; pandemic disease; pathogen; programs; rational design; response; secondary lymphoid organ; vaccine development; vaccine distribution; vaccine platform

SUMMARY Messenger RNA (mRNA) vaccines represent a powerful vaccine approach for the induction of protective immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since this vaccine platform was approved for human use in 2020 for the first time, little is known about the durability and mechanisms of induction of the immune responses elicited by SARS-CoV-2 mRNA vaccines. In mice, the generation of SARS- CoV-2 neutralizing antibodies (nAbs) driven by mRNA vaccines is associated with the formation of robust germinal centers (GCs). GCs are sophisticated processes during which antigen-specific B cells give rise to high- affinity Ab-secreting cells and memory B cells. The GC reaction is tightly regulated by T follicular helper (Tfh) cells, which are also efficiently generated during SARS-CoV-2 mRNA vaccination. In this grant proposal, we seek to address the following 3 fundamental questions related to SARS-CoV-2 mRNA vaccines: 1) How durable are the GC-derived B cell responses to SARS-CoV-2 mRNA vaccines in mice and humans?; 2) What types of antigen presenting cells (APCs) promote Tfh cell differentiation in SARS-CoV-2 mRNA vaccination? And how do these APCs sense these mRNA vaccines?; and 3) How do SARS-CoV-2 mRNA vaccines induce GC B cell responses? Overall, the studies that we propose here will allow us to determine the longevity of GC-derived B cell responses and to shed light on the mechanisms by which SARS-CoV-2 mRNA vaccines ensure a powerful elicitation of Tfh and GC B cells. The knowledge acquired here will be important to inform future boosting strategies for SARS-CoV-2 mRNA vaccination, as well as the rational design of next generation vaccines for difficult-to-neutralize pathogens.

概括 信使RNA（mRNA）疫苗代表了一种强大的疫苗方法，用于诱导保护性免疫 针对严重急性呼吸综合征冠状病毒2（SARS-COV-2）的反应。由于这个疫苗平台 在2020年被批准用于人类使用，对耐用性和机制知之甚少 SARS-COV-2 mRNA疫苗引起的免疫反应的诱导。在小鼠中，sars的产生 由mRNA疫苗驱动的中和抗体中和抗体（NABS）与稳健的形成有关 生发中心（GCS）。 GC是复杂的过程，在此过程中，抗原特异性B细胞产生高 亲和力分泌细胞和记忆B细胞。 GC反应由T卵泡辅助器（TFH）严格调节 细胞，在SARS-COV-2 mRNA疫苗接种期间也有效产生。在这个赠款建议中，我们 寻求解决以下3个与SARS-COV-2 mRNA疫苗有关的基本问题：1） GC衍生的B细胞对小鼠和人类中SARS-COV-2 mRNA疫苗的反应是吗？ 2）什么类型的 抗原呈递细胞（APC）促进SARS-COV-2 mRNA疫苗接种中的TFH细胞分化？以及如何 这些APC是否感觉到这些mRNA疫苗？ 3）SARS-COV-2 mRNA疫苗如何诱导GC B细胞 回答？总体而言，我们在这里提出的研究将使我们能够确定GC衍生B的寿命 细胞反应并阐明SARS-COV-2 mRNA疫苗的机制确保强大 诱导TFH和GC B细胞。在这里获得的知识对于告知未来提升非常重要 SARS-COV-2 mRNA疫苗接种的策略，以及下一代疫苗的合理设计 难以中和病原体。