RT Journal Article SR Electronic T1 Persistent immune imprinting after XBB.1.5 COVID vaccination in humans JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.11.28.569129 DO 10.1101/2023.11.28.569129 A1 Tortorici, M. Alejandra A1 Addetia, Amin A1 Seo, Albert J. A1 Brown, Jack A1 Sprouse, Kaitlin R. A1 Logue, Jenni A1 Clark, Erica A1 Franko, Nicholas A1 Chu, Helen A1 Veesler, David YR 2023 UL http://biorxiv.org/content/early/2023/11/30/2023.11.28.569129.abstract 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.