Researchers at the National Institutes of Health have identified antibodies targeting a hard-to-spot region of the influenza virus. Their study in mice sheds light on the unexplored “dark side” of the neuraminidase (NA) protein head, that is common among many influenza viruses, including H3N2 subtype viruses, and could be a new target for countermeasures.

The findings are published in Immunity in an article titled, “Protective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase.”

“Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats,” the researchers wrote. “Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice.”

One way to improve influenza vaccines and other countermeasures is to identify new targets on the virus’s surface proteins in “conserved” regions—portions that tend to be relatively unchanged between different strains of the virus. Influenza NA is a surface protein containing a globular head portion and a narrow stalk portion. The underside of the NA head contains a highly conserved region with targets for antibodies—known as epitopes—that make it vulnerable to antibody binding and inhibition of the virus, as well as not being impacted by mutations common in drug-resistant strains. This region is termed the “dark side” due to its partially hidden location and relatively unexplored characteristics.

The researchers isolated human antibodies that target the NA dark side from the blood of two people who had recovered from influenza type A subtype H3N2, a major subtype of seasonal flu viruses.

In lab tests, the antibodies inhibited propagation of viruses from subtype H2N2. The antibodies also protected mice from lethal infection by a subtype H3N2 virus when given to the animals either one day before or two days after infection, showing that the antibody may treat and prevent influenza in this model.

The scientists analyzed the structure of two of the antibodies while bound to NA using cryogenic electron microscopy. Each antibody targeted different, nonoverlapping regions of the dark side.

These findings show that the NA dark side has unique, previously untapped epitopes that could be applied to the development of new vaccine and therapeutic strategies. Targeting the NA dark side may be useful in combination with antivirals or other types of antibodies for interventions against influenza.

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