@article {Kaku2022.04.01.486726, author = {Chengzi I. Kaku and Alan J. Bergeron and Clas Ahlm and Johan Normark and Mrunal Sakharkar and Mattias N. E. Forsell and Laura M. Walker}, title = {Recall of pre-existing cross-reactive B cell memory following Omicron breakthrough infection}, elocation-id = {2022.04.01.486726}, year = {2022}, doi = {10.1101/2022.04.01.486726}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Understanding immune responses following SARS-CoV-2 breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses following Omicron/BA.1 infection in mRNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation (SHM) and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells (MBCs). BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit toward the receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 variants of concern (VOCs). Together, these findings provide fundamental insights into the role of pre-existing immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.One sentence summary BA.1 breakthrough infection activates pre-existing memory B cells with broad activity against SARS-CoV-2 variants.Competing Interest StatementC.I.K., M.S., and L.M.W. are employees of Adimab, LLC, and may hold shares in Adimab, LLC. L.M.W. is an employee of Adagio Therapeutics, Inc., and holds shares in Adagio Therapeutics, Inc. A.J.B., J.N., C.A., and M.N.E.F. declare no competing interests.}, URL = {https://www.biorxiv.org/content/early/2022/04/01/2022.04.01.486726}, eprint = {https://www.biorxiv.org/content/early/2022/04/01/2022.04.01.486726.full.pdf}, journal = {bioRxiv} }