Researchers at Vanderbilt University Medical Center and the Scripps Research Institute in La Jolla, California, have discovered a “hidden target” on the surface of the hypervariable influenza A virus that could lead to better ways to prevent and treat the flu.
Because influenza A viruses such as H1N1 and H3N2 mutate continuously, vaccines sometimes provide variable or incomplete protection and must be updated annually. Poor matches can lead to severe flu seasons as in 2017-2018, when an estimated 80,000 people in the United States died from flu-related complications.
A receptor binding site on the surface of the influenza virus enables it to infect cells in the body. Located on the “head” of the globular hemagglutinin (HA) glycoprotein, this binding site is targeted by neutralizing antibodies. But because it mutates rapidly, influenza is often able to evade immune detection.
That’s why the discovery by VUMC and Scripps researchers of a broadly protective, naturally occurring human antibody is so exciting.
Isolated from a donor with an extensive influenza vaccination history, the antibody, called FluA-20, protected mice from four flu strains that cause disease in humans, the researchers reported this week in the journal Cell.
The antibody’s effectiveness results from its ability to expose and latch onto a previously “hidden” surface near the viral binding site that is strongly conserved (with little variation) among diverse subtypes of influenza, including bird flus with pandemic potential.
“We were surprised and excited to find this new site of vulnerability on the surface of influenza, which we were able to identify by making hundreds of different antibodies from immune subjects,” said James Crowe Jr., MD, director of the Vanderbilt Vaccine Center.
Exposing and targeting this buried protein sequence could lead to broader, more effective and longer lasting vaccines and treatments. “The human body’s own natural response for flu is teaching us the way forward toward a universal flu vaccine,” Crowe said.
Crowe, who is the Ann Scott Carell Professor in Pediatrics and Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine, led the research team with Ian Wilson, DPhil, chair of the Department of Integrative Structural and Computational Biology at Scripps.
The research was supported in part by National Institutes of Health grants AI117905, AI127371 and AI097092 from the National Institute of Allergy and Infectious Diseases, GM103393 from the National Institute of General Medical Sciences and TR002243 from the National Center for Advancing Translational Sciences.