The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (Bm) cell subsets, including CD21+resting, CD21–CD27+activated and CD21–CD27–Bmcells. The interrelatedness between these Bmcell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific Bmcell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21–Bmcells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21+resting Bmcells were the major Bmcell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated Bmcell clones could redifferentiate upon antigen rechallenge into other Bmcell subsets, including CD21–CD27–Bmcells, demonstrating that single Bmcell clones can adopt functionally different trajectories.