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

基本信息

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
项目类别：
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

项目摘要

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) 疫苗代表了诱导保护性免疫的强大疫苗方法针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的反应。自从这个疫苗平台于 2020 年首次被批准用于人类，但对其耐久性和机制知之甚少诱导 SARS-CoV-2 mRNA 疫苗引起的免疫反应。在小鼠中，SARS- 由 mRNA 疫苗驱动的 CoV-2 中和抗体 (nAb) 与强效抗体的形成有关生发中心（GC）。 GC 是复杂的过程，在此过程中抗原特异性 B 细胞产生高亲和力抗体分泌细胞和记忆B细胞。 GC 反应受到滤泡辅助 T (Tfh) 的严格调控细胞，这些细胞也在 SARS-CoV-2 mRNA 疫苗接种过程中有效生成。在这项拨款提案中，我们寻求解决以下与 SARS-CoV-2 mRNA 疫苗相关的 3 个基本问题： 1) 持久性如何小鼠和人类中 GC 衍生的 B 细胞对 SARS-CoV-2 mRNA 疫苗有反应吗？ 2）有哪些类型抗原呈递细胞 (APC) 在 SARS-CoV-2 mRNA 疫苗接种中促进 Tfh 细胞分化？以及如何这些 APC 能感知这些 mRNA 疫苗吗？ 3) SARS-CoV-2 mRNA 疫苗如何诱导 GC B 细胞回应？总体而言，我们在此提出的研究将使我们能够确定 GC 衍生的 B 的寿命细胞反应并揭示 SARS-CoV-2 mRNA 疫苗确保强大功效的机制 Tfh 和 GC B 细胞的诱导。在这里获得的知识对于未来的提升非常重要 SARS-CoV-2 mRNA 疫苗接种策略，以及下一代疫苗的合理设计难以中和的病原体。