Targeting the "Dark Side" of Flu Virus Protein: New Antibodies' Hidden Weakness

Research led by scientists at the Vaccine Research Center, part of the National Institutes of Health (NIH), have found antibodies that target a challenging-to-identify area of the influenza virus. They've especially focused on what they describe as the neuraminidase (NA) protein head's "dark side." The new human antibodies they've discovered, represented in purple/pink and brown/beige in their illustration, are shown binding the influenza neuraminidase protein tetramer, displayed in varying shades of blue. The antibodies they've found target a common region of the NA protein present in numerous influenza viruses, including subtype H3N2. The discovery provides a promising new area for countermeasures against the virus. The research was recently published in the Immunity journal.

Millions of individuals worldwide are affected by the influenza virus annually, causing severe illness and even death. Vaccination can diminish the effects of the virus, although updated vaccines that provide protection against the virus's many strains and subtypes are needed each year due to the virus's rapid evolution. A wider protection against multiple influenza viruses would be ideal to prevent outbreaks of both new and recurrent flu strains without the necessity of annual vaccine changes or vaccinations.

An effective method to strengthen influenza countermeasures and vaccines is by identifying fresh targets on the conserved regions of the virus’s surface proteins. These conserved regions typically remain relatively unaltered across different virus strains. The NA is a influenza surface protein consisting of a globular head and a narrow stalk.

The NA head's underside contains a highly conserved region susceptible to antibody binding and virus inhibition due to its 'dark side', an area full of potent targets for antibodies, known as epitopes. This 'dark side' remains unaffected by common mutations seen in drug-resistant strains and is partially hidden, hence making it a relatively uncharted territory.

Having isolated human antibodies from the blood of two individuals who recovered from the influenza type A subtype H3N2, the researchers found that these antibodies targeted the NA's 'dark side.' In lab tests, these antibodies were seen to inhibit the propagation of subtype H2N2 viruses, which caused the pandemic flu in 1957-58, and H3N2 viruses found in humans, swine, and birds. They found that these antibodies also safeguarded mice from lethal infection by a subtype H3N2 virus, when administered either a day before or two days after the infection. This suggests that the antibody could be an effective preventive measure as well as a treatment for influenza.

After examining two of the antibodies' structure while connected to NA using advanced cryogenic electron microscopy techniques, they found that each antibody targets distinct, non-adjacent regions of the 'dark side', indicating various useful areas for countermeasure development.

The research findings imply that the unique, untapped epitopes of the NA's 'dark side' could aid in developing new vaccine and therapeutic strategies. They suggest that in conjunction with antivirals or other types of antibodies, antibodies targeting the NA's 'dark side' could be valuable in intervening against influenza, as they prove effective against influenza viruses with drug-resistant mutations. The researchers also concluded that these 'dark side' targets of the NA should be considered for inclusion in the next generation of broadly protective influenza vaccines.

The National Institute of Allergy and Infectious Diseases provided funding for this study.