Terminally Differentiated Influenza-Specific Effector Memory B Cells Circulate after Live Attenuated Influenza Vaccination

Live attenuated influenza vaccination (LAIV) is the only FDA approved mucosal vaccine. Easily assayed, circulating correlates of protection after LAIV are lacking. Using fluorochrome labeled hemagglutinin (HA) antigen, we previously identified a subset of HA-specific (HA ⁺ ) IgD ^neg memory B cells that circulate after inactivated intramuscular vaccination (IIV), express the master transcriptional regulator, T-bet, as well as effector memory genes and predict durable antibody (Ab) responses to IIV. Here we profile the circulating HA ⁺ IgD ^neg memory B cell response in a cohort of immunized patients who seroconvert after LAIV to identify which, if any, circulating HA ⁺ B cells predict antibody responses after LAIV. Although we report LAIV elicits circulating T-bet ⁺ HA ⁺ IgD ^neg B cells that are phenotypically similar to those we described after IIV, we find no correlation between the magnitude of these cells and systemic HA-IgG responses after LAIV. Supervised and unsupervised analyses demonstrate that unlike IIV, LAIV preferentially elicits circulating HA ⁺ IgD ^neg B cells that co-express <i>TBX21</i> and the terminal effector cell gene, <i>Zeb2</i> . Consistent with their terminal differentiation status, LAIV-elicited T-bet ⁺ cells cannot be recalled as short-lived antibody-secreting cells (ASCs) after systemic or mucosal antigen re-challenge. We conclude that the transcriptional profiles and functions of HA ⁺ IgD ^neg B cells vary by influenza vaccine platform.