Boerries Brandenburg, Wouter Koudstaal, Jaap Goudsmit, Vincent Klaren, Chan Tang, Miriam V. Bujny, Hans J. W. M. Korse, Ted Kwaks, Jason J. Otterstrom, Jarek Juraszek, Antoine M. van Oijen, Ronald Vogels, Robert H. E. Friesen

Human monoclonal antibodies have been identified which neutralize broad spectra of influenza A or B viruses. Here, we dissect the mechanisms by which such antibodies interfere with infectivity. We distinguish four mechanisms that link the conserved hemagglutinin (HA) epitopes of broadly neutralizing antibodies to critical processes in the viral life cycle. HA-stem binding antibodies can act intracellularly by blocking fusion between the viral and endosomal membranes and extracellularly by preventing the proteolytic activation of HA. HA-head binding antibodies prevent viral attachment and release. These insights into newly identified ways by which the human immune system can interfere with influenza virus infection may aid the development of novel universal vaccines and antivirals.