Antibodies are proteins produced by white blood cells that are the body’s first line of defense against invading pathogens, including viruses. They are highly specific, however, and usually respond to individual invaders one at a time.
Now, researchers at Vanderbilt University Medical Center have found a way to isolate and amplify a class of rare antibodies that can target a wide range of different viruses.
Their discovery, reported in the journal PLOS Pathogens, could help open the door to the development of effective vaccines and antibody therapies with an “exceptional breadth of pathogen coverage.”
“A fundamental characteristic of monoclonal antibodies is their typically exquisite target specificity, which makes them prime targets for therapeutic development for a wide range of diseases,” said Ivelin Georgiev, PhD, professor of Pathology, Microbiology and Immunology in the Vanderbilt Vaccine Center, and the paper’s corresponding author.
“Antibodies that can promiscuously recognize multiple targets are generally taboo since they can produce undesired off-target effects,” Georgiev said.
“However, recent evidence, further elucidated by our work here, has shown that an unappreciated class of antibodies exists that can have broad target recognition, even against unrelated viruses, while still exhibiting no off-target effects,” he said. “But looking for such rare antibody phenotypes is exceptionally challenging.”
The key to finding these antibodies is a technique developed in the Georgiev lab several years ago called LIBRA-seq — Linking B-cell Receptor to Antigen Specificity through sequencing.
Traditionally it has taken months to identify — from the billions of antibodies produced by white blood cells called B cells in response to an infection — antibodies that recognizes a surface protein marker, or antigen, carried by a specific virus or other pathogen.
LIBRA-seq enables researchers to map the unique sequence of amino acids that make up the reactive portion of an antibody and match it to the specificities of the antigen it targets simultaneously and in a high throughput way.
Using this technique, in 2021 the Georgiev lab discovered an “ultrapotent” monoclonal antibody that recognized multiple variants of SARS-CoV-2, the virus responsible for COVID-19.
More recently, they isolated several antibody candidates that target the human parainfluenza virus 3 (HPIV3), a leading cause of acute and potentially fatal respiratory illness, particularly among infants, the elderly and immunocompromised patients.
“Pathogens keep evolving, and we’re basically playing catch-up,” Georgiev said in 2021. “This is one way to proactively build a repertoire of potential therapeutics” against future outbreaks.
In 2023, the researchers reported the discovery of cross-reactive antibodies that simultaneously target the AIDS virus, HIV, and the hepatitis C virus (HCV).
Of the more than 1 million people in the United States who are living with HIV, one-fifth have been co-infected with HCV, which often is not detected until significant damage to the liver has occurred. The discovery of cross-reactive antibodies potentially could transform the treatment of HIV/HCV co-infection.
In the current study, glycan-targeting antibodies were isolated from an HIV-infected individual’s blood sample before the COVID-19 pandemic reached the United States in early 2020.
Glycans, a type of carbohydrate, are part of the antigenic “badge” that enables cells to interact with each other. Cross-reactive antibodies have been found in previous studies to recognize glycans embedded in the surface antigens of their targets.
Human cells also display glycans, and there is a concern that antibodies developed against viral glycans may attack normal tissue. The antibodies discovered by Georgiev and his colleagues, however, displayed “no measurable autoreactivity to human proteins.”
One of the antibodies, named 2526, recognized multiple viruses, including HIV, influenza and SARS-CoV-2.
While 2526 did not neutralize several strains of influenza or SARS-CoV-2 in laboratory tests and did not protect against influenza in an animal model, it may be possible, by genetically re-engineering the structure of the antibody, to increase its therapeutic potential, the researchers noted.
Also significant was the antibody’s recognition of the SARS-CoV-2 antigen, even though the COVID-19 virus was not circulating when the blood sample was collected. “This emphasizes the power of LIBRA-seq in identifying antibodies reactive against future circulating viruses, including pandemic viruses,” they concluded.
Matthew Vukovich, PhD, a postdoctoral researcher in the Georgiev lab, is the paper’s first author. Other VUMC co-authors are Andrea Shiakolas, PhD, Lindsay Bass, Alexandra Abu-Shmais, Sabina Leonard, Kathryn Gripenstraw, Ian Setliff, PhD, and Rachel Bonami, PhD.
The research was supported in part by National Institutes of Health grants R01AI152693, R01AI175245, U54AI170752, R01AI165147, T32AI112541, and T32AR059039.
