Omicron breakthrough infection drives cross-variant neutralization and memory B cell formation

Omicron is the evolutionarily most distinct SARS-CoV-2 variant (VOC) to date and displays multiple amino acid alterations located in neutralizing antibody sites of the spike (S) protein. We report here that Omicron breakthrough infection in BNT162b2 vaccinated individuals results in strong neutralizing activity not only against Omicron, but also broadly against previous SARS-CoV-2 VOCs and against SARS-CoV-1. We found that Omicron breakthrough infection mediates a robust B cell recall response, and primarily expands preformed memory B cells that recognize epitopes shared broadly by different variants, rather than inducing new B cells against strictly Omicron-specific epitopes. Our data suggest that, despite imprinting of the immune response by previous vaccination, the preformed B cell memory pool has sufficient plasticity for being refocused and quantitatively remodeled by exposure to heterologous S protein, thus allowing effective neutralization of variants that evade a previously established neutralizing antibody response. ### Competing Interest Statement U.S. and O.T. are management board members and employees at BioNTech SE. J.Q., A.M., N.S., B.G.L., S.L., K.K., A.W., P.A., M.B., A.F., O.O. and I.V. are employees at BioNTech SE. K.G., S.H. and S.C. are employees at University Hospital, Goethe University Frankfurt. U.G. is an employee at the Health Protection Authority, City of Frankfurt am Main. U.S., O.T. and A.M. are inventors on patents and patent applications related to RNA technology and COVID-19 vaccines. U.S., O.T., J.Q., A.M., N.S., B.G.L., S.L., K.K., A.W., P.A., M.B., A.F., O.O. and I.V. have securities from BioNTech SE. S.C. has received honorarium for serving on a clinical advisory board for BioNTech.