Structure and function analysis of an antibody recognizing all influenza A subtypesMore about Open Access at the Crick
Authors listNicole L Kallewaard Davide Corti Patrick J Collins Ursula Neu Josephine M McAuliffe Ebony Benjamin Leslie Wachter-Rosati Frances J Palmer-Hill Andy Q Yuan Philip Walker Matthias K Vorlaender Siro Bianchi Barbara Guarino Anna De Marco Fabrizia Vanzetta Gloria Agatic Mathilde Foglierini Debora Pinna Blanca Fernandez-Rodriguez Alexander Fruehwirth Chiara Silacci Roksana Ogrodowicz Stephen R Martin Federica Sallusto JoAnn A Suzich Antonio Lanzavecchia Qing Zhu Steve Gamblin John J Skehel
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Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross-reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.
Issue number 3