Human anti-N1 monoclonal antibodies elicited by pandemic H1N1 virus infection broadly inhibit HxN1 viruses in vitro and in vivo

Neuraminidase (NA) is one of the two influenza virus surface glycoproteins, and antibodies that target it are an independent correlate of protection. However, our current understanding of NA antigenicity is incomplete. Here, we describe human monoclonal antibodies (mAbs) from a patient with a pandemic H1N1 virus infection in 2009. Two mAbs exhibited broad reactivity and inhibited NA enzyme activity of seasonal H1N1 viruses circulating before and after 2009, as well as viruses with avian or swine N1s. The mAbs provided robust protection from lethal challenge with human H1N1 and avian H5N1 viruses in mice, and both target an epitope on the lateral face of NA. In summary, we identified two broadly protective NA antibodies that share a novel epitope, inhibited NA activity, and provide protection against virus challenge in mice. Our work reaffirms that NA should be included as a target in future broadly protective or universal influenza virus vaccines. [Display omitted] •Discovery of human monoclonal antibodies broadly reactive to influenza virus neuraminidase•Potent NA enzyme inhibition against human, avian, and swine HxN1 influenza viruses•Conserved epitopes identified on the lateral side of N1 neuraminidase by cryo-EM•Robust protection against lethal influenza H1N1 and H5N1 virus challenge in mice Optimizing neuraminidase antigenicity is essential for improving influenza vaccines. Hansen et al. isolated human monoclonal antibodies with broad enzyme inhibition activity against human, avian, and swine N1 neuraminidase that provided robust protection in vivo. Cryo-EM revealed highly conserved sites on the lateral face of neuraminidase, distal to the active site.