Affinity maturation broadens influenza vaccine-induced antibody responses in humans [gex]

Influenza virus vaccination remains the best strategy for combating virus infection, but vaccine efficacy is highly variable. An ideal influenza vaccine must have two attributes: one, it should be capable of inducing broadly cross-reactive antibodies that can neutralize diverse influenza virus strains; and two, it must induce long-lived antibody responses to maintain protective immunity for extended periods. Germinal center (GC) reactions are the major sites where diversification and affinity maturation of B cells occur. Whether a persistent GC response could expand the breadth of responding B cell clones following influenza vaccination in humans remains unknown. Here, we show that influenza virus vaccine-specific GC B cells persist for over nine weeks post vaccination in two out of seven individuals. These late vaccine-specific GC B cells exhibited increased somatic hypermutation (SHM) of their B cell receptors compared to early vaccine-specific GC B cells. After re-immunization with seasonal influenza virus vaccine, individuals with a persistent GC engaged vaccine-specific plasmablasts (PBs) with higher SHM frequency. Tracking the maturation of three clonally related GC B cell lineages over time revealed that late GC B cells had receptors that recognized and neutralized heterologous influenza virus strains. Thus, SHM induced by persistent GCs can broaden the antibody response to influenza virus vaccination. This indicates that seasonal influenza virus vaccination in humans can induce broadly cross-reactive antibodies that target diverse influenza virus strains.