Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies

Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains. [Display omitted] •Flu virus infection induces many neuraminidase (NA)-reactive B cells and antibodies•NA antibodies have broad cross-reactivity and inhibit neuraminidase enzyme activity•Current flu vaccines poorly display key NA epitopes and do not produce NA antibodies•NA-reactive antibodies offer protection against lethal flu virus infection Current influenza vaccines predominantly produce antibodies targeting the viral hemagglutinin (HA). However, during natural infection, the body also produces antibodies targeting the viral neuraminidase (NA). These NA antibodies can provide robust and broad protection and could potentially be elicited prophylactically or via new vaccine strategies or used therapeutically.