Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection

Individuals that receive a 3 rd mRNA vaccine dose show enhanced protection against severe COVID19 but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a 3 rd or 4 th antigenic exposure by Delta or Omicron BA.1 infection, respectively. A 3 rd exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a 3 rd mRNA vaccine dose. A 4 th antigenic exposure with Omicron BA.1 infection increased variant specific plasma antibody and memory B cell responses. However, the 4 th exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a 3 rd mRNA vaccine dose. In conclusion, a 3 rd antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a 4 th antigenic exposure with Omicron BA.1 is limited to increased strain specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.