biostudies-literatureLei RKinship FoundationPasteur InstituteNCCIH NIH HHSNIAID NIH HHSNational Institutes of HealthNational Research Foundation of KoreaNIAIDMichelson Prize and Grants2621-2634.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC10655865biostudies-literatureUnknown56(11)There is growing appreciation for neuraminidase (NA) as an influenza vaccine target; however, its antigenicity remains poorly characterized. In this study, we isolated three broadly reactive N2 antibodies from the plasmablasts of a single vaccinee, including one that cross-reacts with NAs from seasonal H3N2 strains spanning five decades. Although these three antibodies have diverse germline usages, they recognize similar epitopes that are distant from the NA active site and instead involve the highly conserved underside of NA head domain. We also showed that all three antibodies confer prophylactic and therapeutic protection in vivo, due to both Fc effector functions and NA inhibition through steric hindrance. Additionally, the contribution of Fc effector functions to protection in vivo inImmunityLeveraging vaccination-induced protective antibodies to define conserved epitopes on influenza N2 neuraminidase.PMC10655865R01 AI16547575N93021C00014DP2 AT01196675N93019C00051U01 AI144616U01 AI141990U01 AI150747Schmitz AJTan TJCRivera-Cardona JTurner JSLiang WEllebedy AHWu NCScherm MJOuyang WOGraham CSMok CKPTeo CBrooke CBDai XKrammer FKim WLv HPresti RMLei RMou ZWang YfalseLeveraging vaccination-induced protective antibodies to define conserved epitopes on influenza N2 neuraminidase.There is growing appreciation for neuraminidase (NA) as an influenza vaccine target; however, its antigenicity remains poorly characterized. In this study, we isolated three broadly reactive N2 antibodies from the plasmablasts of a single vaccinee, including one that cross-reacts with NAs from seasonal H3N2 strains spanning five decades. Although these three antibodies have diverse germline usages, they recognize similar epitopes that are distant from the NA active site and instead involve the highly conserved underside of NA head domain. We also showed that all three antibodies confer prophylactic and therapeutic protection in vivo, due to both Fc effector functions and NA inhibition through steric hindrance. Additionally, the contribution of Fc effector functions to protection in vivo in2023-01-01T00:00:00Z2023 Nov2026-06-03T03:21:59.234Z2025-04-06T22:44:59.975ZS-EPMC106558653796753310.1016/j.immuni.2023.10.005