Broadly reactive human monoclonal antibodies targeting influenza a nucleoprotein lack protective activity in vivo.

The antibody response to influenza virus infection targets numerous viral proteins, with those specific for the hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins being the most extensively studied. Antibodies to HA and NA function as independent immune correlates of protection and form the basis of most vaccine approaches. In contrast, the contribution of antibodies to other viral proteins such as the nucleoprotein (NP) remains unclear, and existing studies have reached conflicting conclusions. In this work, we examined three human monoclonal NP antibodies isolated from plasmablasts of two individuals naturally infected with influenza A virus (IAV) during the 2018-2019 influenza season. These antibodies showed strong binding to NP across a broad range of IAV strains, yet none were able to limit weight loss or mortality when delivered prophylactically to mice. Further characterization demonstrated that the antibodies did not neutralize infection, and although they bound to the surface of infected MDCK cells, they did not induce cellular antiviral responses. While the broad cross-reactivity of these monoclonal antibodies is attractive for next-generation vaccine design, strategies that aim to elicit similar responses must either enhance their antiviral potency or clarify their role in modulating viral replication and disease.