Hemagglutinin stalk-binding antibodies enhance effectiveness of neuraminidase inhibitors against influenza via Fc-dependent effector functions

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next-generation universal influenza vaccines. Protection provided by hemagglutinin stalk-binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual’s titers of stalk-binding antibodies and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments. • NA inhibitors potentiate Fc-mediated activation of immune effector cells by bNAbs • bNab-NA inhibiter combination therapy is superior to either monotherapy • bNAb-NA inhibitor combination therapy is effective therapeutically and prophylactically • Pre-existing bNAb titers may predict effectiveness of NA inhibitor treatment Broadly neutralizing antibodies (bNAbs) that bind to the hemagglutinin stalk domain are an attractive therapeutic that protect against multiple strains of influenza virus. Here, Zhang et al. demonstrate that neuraminidase inhibitors cooperate with both monoclonal and polyclonal bNAbs to protect against influenza by potentiating Fc-dependent effector cell functions.