Tunable Immune Imprinting of Memory B Cells to SARS-CoV-2 Variants 2255300

Abstract Introduction Immune imprinting, historically termed “original antigenic sin”, biases memory B cell (MBC) recall toward cross-reactive epitopes of ancestral strains, limiting vaccine adaptability to rapidly evolving variants. Whether immune imprinting is a fixed outcome of antigen exposure or can be modulated by host immune factors remains unclear. Chronic inflammatory and immunosuppressive conditions in systemic lupus erythematosus (SLE) patients affect antibody-secreting cell formation during MBC recall responses, but whether these host-intrinsic conditions can modulate MBC epitope targeting and immune imprinting in response to an antigenically distant variant remains unknown. Methods We recruited tightly time-matched cohorts of healthy individuals and SLE patients who had received three doses of ancestral inactivated vaccine and subsequently experienced synchronized Omicron BA.5/BF.7 breakthrough infection. We characterized their MBC responses through monoclonal antibody (mAb) epitope mapping, deep mutational scanning (DMS), spectral flow cytometry, and antigen-linked single-cell multi-omics. Results Healthy individuals displayed strong immune imprinting, characterized by robust recall of high-affinity cross-reactive MBCs. In contrast, SLE patients exhibited markedly reduced imprinting, with DMS revealing enhanced recognition of variant-specific neutralizing epitopes. Antigen-linked single-cell profiling showed attenuated MBC recall in SLE, associated with reduced MBC reactivation, diminished BCR signaling, and heightened inflammatory signatures. Concurrently, naïve and IgM MBCs were recruited and matured into variant-specific IgG MBCs, accompanied by a decline in early self- and polyreactivity. Conclusion Our findings demonstrate that immune imprinting in MBCs is plastic, and modulation of inflammatory and B cell activation signaling can rebalance recall versus de novo responses to promote variant-adaptable immunity. Funding Source National Natural Science Foundation of China Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)