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.

总结 信使RNA（mRNA）疫苗代表了诱导保护性免疫的强有力的疫苗方法， 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 2020年首次被批准用于人类使用，但人们对它的耐用性和机制知之甚少。 诱导由SARS-CoV-2 mRNA疫苗引起的免疫应答。在小鼠中，SARS的产生- 由mRNA疫苗驱动的CoV-2中和抗体（nAbs）与稳健的免疫应答的形成相关。 生发中心（GC）。GC是复杂的过程，在此过程中，抗原特异性B细胞产生高水平的 亲和Ab分泌细胞和记忆B细胞。GC反应受滤泡辅助性T细胞（Tfh）的严格调控 细胞，其也在SARS-CoV-2 mRNA疫苗接种期间有效产生。在这份申请中，我们 我们试图解决以下3个与SARS-CoV-2 mRNA疫苗相关的基本问题：1）如何持久 GC衍生的B细胞对SARS-CoV-2 mRNA疫苗在小鼠和人中的应答是否相同？2)哪些类型的 SARS-CoV-2 mRNA疫苗接种后抗原提呈细胞（APC）促进Tfh细胞分化？以及如何 这些APCs能感知这些mRNA疫苗吗？SARS-CoV-2 mRNA疫苗如何诱导GC B细胞 回应？总的来说，我们在这里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，并阐明SARS-CoV-2 mRNA疫苗确保强大的免疫应答的机制。 诱导Tfh和GC B细胞。在这里获得的知识将是重要的，以告知未来的提高 SARS-CoV-2 mRNA疫苗的策略，以及下一代疫苗的合理设计， 难以中和的病原体