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The B cell response to diferent pathogens uses tailored efector mechanisms and results in functionally specialized memory B (Bₘ) cell subsets, including CD21⁺ resting, CD21⁻CD27⁺ activated and CD21⁻CD27⁻Bₘ cells. The interrelatedness between these Bₘ cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specifc Bₘ cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21⁻Bₘ cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specifc immunization. At months 6 and 12 post-infection, CD21⁺ resting Bₘ cells were the major Bₘ 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 Bₘ cell clones could rediferentiate upon antigen rechallenge into other Bₘ cell subsets, including CD21⁻CD27⁻Bₘ cells, demonstrating that single Bₘ cell clones can adopt functionally diferent trajectories., Nature Immunology, 24 (6), ISSN:1529-2908, ISSN:1529-2916