Antibodies formed during primary immune responses suppress germinal center quality upon boosting

Abstract

Upon exposure to foreign antigens, germinal center (GC) responses result in the generation of high-affinity plasma cells and memory B cells, providing long-term protection against infection. Re-exposure to previously encountered antigens typically results in faster and higher affinity antibody responses due to rapid differentiation of memory B cells into antibody-secreting plasma cells. However, to generate antibodies against new epitopes, the generation of high-quality secondary, or ‘recall’, GCs is desired. Previous studies have shown that antigen-specific antibodies can suppress recall GC quality by blocking antigenic epitopes for naive B cells or promoting Fc-dependent antigen clearance. However, there is still a lot unknown about the effect of prior antigen exposure on recall GC quality and in particular the influence of pre-existing antibodies. By using prime-boost models for the influenza hemagglutinin protein, we show that B cells in recall GCs poorly bind to the immunogen. Recall GC quality could be improved by inhibiting the generation of antibody-producing plasma cells during primary immune responses, supporting the notion that antibody-mediated suppression is an important mechanism by which recall GC quality is reduced. Boosting with variant antigen partially overcomes antibody-mediated suppression, as seen by increased antigen-binding of GC B cells. Interestingly, when mice were immunized with SARS-CoV-2 Spike or hemagglutinin mRNA, recall GC B cells showed similar antigen-binding to primary GC B cells, indicating that mRNA vaccination induces recall GCs of higher quality than protein immunization. Lastly, we studied the contribution of recall GC B cells to serum antibody levels by using a novel ‘molecular fate-mapping’ approach, in which fate-mapping of immunoglobulin molecules in GC B cells allows us to differentiate between antibodies formed in primary and recall responses. We show that there is little contribution of recall GC B cells to antigen-specific antibody levels, even upon mRNA vaccination, while memory B cells from the primary response are potently engaged. In the future, these insights into the mechanisms governing recall GC quality can be used to improve booster vaccination strategies.