Investigators Discover Unknown Achilles Heel of Influenza Virus

In a study funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, investigators detail the discovery of a new site of vulnerability on the hemagglutinin (HA) of influenza virus.

The new findings offer a potential new target for antibody-based therapeutics and influenza vaccines along the HA head domain of the influenza virus prone to antigenic drift and shift. In the study, published in the journal Cell, investigators describe the unexpected discovery of a naturally occurring human antibody called FluA-20, that recognizes a previously unknown area of vulnerability on the HA that is found in most influenza A viruses, essentially uncovering influenza’s Achilles heel.

In an interview with Contagion^®, Anthony S. Fauci, MD, director of NIAID, explained that the finding was surprising in a positive way. “There are a number of components of the influenza virus that are candidates for universal flu vaccine because they don’t change very much,” he said, noting that recent research has largely been directed at targeting the more stable stem of influenza’s HA, rather than the head. “However, what the investigators found was that they identified a monoclonal antibody that was able to reach into the trimer interface and wind up essentially disrupting the entire hemagglutinin, making it unable to bind to the cell. This was something that was not expected, that there would be such a vulnerable component to the hemagglutinin head that a single antibody would be able to disrupt the structural integrity of the trimer.”

According to the paper, the research team was led by investigators from The Scripps Research Institute and Vanderbilt University Medical Center. The investigators structurally characterized FluA-20 with H1 and H3 head domains to reveal a novel epitope in the HA trimer interface, after discovering the antibody in an individual who had received multiple flu vaccines and was enrolled in a different vaccine study.

In a mouse model, the team found that the antibody can reach into a part of the HA trimer molecule that was previously inaccessible. FluA-20 binds tightly to an area on the globular head of the HA protein that is accessible to antibody attack but only very briefly, thereby rapidly disrupting the integrity of HA protein trimers, preventing cell-to-cell spread of influenza virus in culture, and protecting mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes both prophylactically and therapeutically.

The surprising discovery offers new inroads for flu prevention and treatment research, as this region of the HA head remains largely similar between influenza strains. Although human trials for a universal flu vaccine continue, antibody-based therapies targeting that precise region of trimeric HA—as well as vaccines designed to elicit antibodies against the target—could be used in the future to target strains of both Group 1 and Group 2 influenza A viruses and may eliminate the need for annual seasonal influenza vaccination.

“Obviously that needs to be demonstrated. You’ve got to get the epitope in the right confirmation, you’ve got to present it to the body to be able make a response, and you’ve got to make sure the response is one that produces the same kind of antibody, but the fact that a human has already produced that antibody means that it’s feasible,” said Fauci when asked about the road ahead for research on FluA-20. “The beauty of it is that no matter how you got there, by luck or happenstance, now that you know what the epitope is you can focus the body’s immune response against that epitope.”