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

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.