AbstractThe B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (B_m) cell subsets, including CD21⁺ resting, CD21^–CD27⁺ activated and CD21^–CD27^– B_m cells. The interrelatedness between these B_m cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific B_m cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21^– B_m cells 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 B_m cells were the major B_m cell 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 B_m cell clones could redifferentiate upon antigen rechallenge into other B_m cell subsets, including CD21^–CD27^– B_m cells, demonstrating that single B_m cell clones can adopt functionally different trajectories.