(417a) Two Complementary Memory B Cell Processes Generate Antibody Protection Against the Same or Variant Viruses

We study an important question in immunology: how are memory B cells recalled upon re-exposure to the same or variant antigens? B cells and their antibody products help protect humans from diverse pathogens. Upon infection or vaccination, B cells undergo a Darwinian evolutionary process in germinal centers (GCs) called affinity maturation. During this process, the B cell receptor (later secreted as antibodies) undergoes rapid mutation and selection based off the receptor’s ability to bind to a pathogen. This process produces memory B cells poised to respond to future pathogens and plasma cells that secrete the B cell receptor as antibodies. We developed a physics-based computational model incorporating 1) the kinetics of antigen capture, 2) selectivity of T cells, 3) differing affinity between B cell receptors and variants and 4) other relevant biological features to study how memory B cells are recalled upon re-infection or a booster vaccination. We find that prime and secondary GCs generate a diverse pool of B cells, some with low antigen affinity and some with high affinity. Upon re-exposure to the same or similar antigen, memory B cells that enter secondary GCs can undergo mutation and selection to generate even higher affinity B cells, albeit slowly. Meanwhile, upon re-exposure to the same antigen, affinity-dependent selective expansion of available memory B cells outside GCs (EGCs) results in a rapid antibody response comprised of the best available B cells. The EGC response behaves similarly toward a variant antigen, selecting cross-reactive B cells from the diverse pool generated in the prime GC to provide the best possible antibody response while new secondary GCs slowly generate a tailored response for the new variant. The EGC also generates high antibody titers that cause the GC to increase B cell diversity. Our results were validated with data from humans vaccinated with two doses of the same antigen (COVID-19 vaccine). Based on a simple evolutionary model, we suggest that the complementary roles of EGC and GC processes evolved in response to exposure to evolving pathogen families.