Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza infected mice, likely due at least in part to NA-mediated inhibition of FcgR dependent activation of innate immune cells by antibody bound to virions. FDA approved NA inhibitors enhance anti-stem based Fcg dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.