Fcrl5 and T-bet define influenza-specific memory B cells that predict long-lived antibody responses

Early surrogates for long-lived immunity after inactivated influenza vaccination (IIV) are lacking. Antigen-specific memory B cells (Bmem) after IIV have been recently identified. We show that the antigen-specific Bmem compartment after IIV is heterogenous and comprises a clonotypically and transcriptionally distinct T-bethi subset that persists in circulation over time after vaccination and exclusively correlates with the long-lived antibody response. We demonstrate that this subset has an effector memory transcriptome and is epigenetically remodeled to facilitate intracellular immunoglobulin production. Finally, via clonal sharing, we show an enriched in vivo ontologic relationship between the secondary plasmablast response that develops after vaccine boost and the T-bethi fraction of the flu-specific Bmem response that forms after initial prime. Collectively, our data identify a novel biomarker of durable humoral immunity after influenza vaccination.