Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

Next-generation influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these do not block virus-receptor interactions and thus are predicted to provide protection via alternative mechanisms at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of respiratory disease (ERD). Our study describes ADE with two different functional MAbs that destabilized HA stem domain, increased influenza virus fusion kinetics, and led to enhanced lung pathology and ERD in a dose-dependent manner in a mice model. This study underlines careful preclinical evaluation of next-generation influenza vaccines or antibody-based therapeutics that do not block influenza virus receptor binding.