PT - JOURNAL ARTICLE AU - Tortorici, M. Alejandra AU - Addetia, Amin AU - Seo, Albert J. AU - Brown, Jack AU - Sprouse, Kaitlin R. AU - Logue, Jenni AU - Clark, Erica AU - Franko, Nicholas AU - Chu, Helen AU - Veesler, David TI - Persistent immune imprinting after XBB.1.5 COVID vaccination in humans AID - 10.1101/2023.11.28.569129 DP - 2023 Jan 01 TA - bioRxiv PG - 2023.11.28.569129 4099 - http://biorxiv.org/content/early/2023/11/30/2023.11.28.569129.short 4100 - http://biorxiv.org/content/early/2023/11/30/2023.11.28.569129.full AB - Immune imprinting - also known as ‘original antigenic sin’ - describes how the first exposure to a virus shapes the immunological outcome of subsequent exposures to antigenically related strains. SARS-CoV-2 Omicron breakthrough infections and bivalent COVID-19 vaccination were shown to primarily recall cross-reactive memory B cells and antibodies induced by prior mRNA vaccination with the Wuhan-Hu-1 spike rather than priming naive B cells that recognize Omicron-specific epitopes. These findings underscored a strong immune imprinting resulting from repeated Wuhan-Hu-1 spike exposures. To understand if immune imprinting can be overcome, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID mRNA vaccine booster. Our data show that the XBB.1.5 booster elicits neutralizing antibody responses against current variants that are dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. These results indicate that immune imprinting persists even after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 spike booster mRNA vaccination, which will need to be considered to guide the design of future vaccine boosters.Competing Interest StatementThe authors have declared no competing interest.