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Study shows new COVID target could improve vaccines

Apr. 1, 2021, 9:23 AM


by Bill Snyder

Despite an impressive vaccination effort that exceeds 2 million shots a day, rates of COVID-19 are again on the rise in several parts of the United States, as is the spread of highly transmissible variants of the virus.

Current vaccines and monoclonal antibody therapies may be insufficient to bring the pandemic fully under control because they target only one, highly mutable part of the COVID-19 virus, according to researchers at Vanderbilt University Medical Center and Washington University School of Medicine in St. Louis, Missouri.

Treatment and prevention may be more effective if multiple antigenic sites on the virus are targeted, they concluded in a paper published last week in the journal Cell.

“Our team found a new site of vulnerability on the virus spike protein that can be targeted by protective human antibodies. This gives new insights into how our vaccines are working,” said James Crowe Jr., MD, director of the Vanderbilt Vaccine Center.

Crowe, who is Ann Scott Carell Professor in the Departments of Pediatrics and Pathology, Microbiology and Immunology at VUMC, is the paper’s co-corresponding author with Washington University’s Larissa Thackray, PhD, and Michael Diamond, MD, PhD.

Most human monoclonal antibodies and vaccines that neutralize or prevent the replication of the COVID-19 virus, SARS-CoV-2, target the receptor binding domain (RBD) of the spike protein that enables the virus to bind to certain cells in the body.

But among human monoclonal antibodies isolated from people who had been infected by SARS-CoV-2, the researchers found several others that bound the N-terminal domain (NTD) of the spike protein adjacent to the RBD, and three of which were able to neutralize the virus.

Mechanistic studies conducted in the two most potently neutralizing monoclonal antibodies showed that they blocked a key step after SARS-CoV-2 attached to its target cell that was necessary for it to enter the cell and replicate.

The two monoclonal antibodies also protected mice against serious illness or death when given before or following infection by the virus.

Adding NTD-recognizing monoclonal antibodies to therapeutic antibody cocktails could minimize the selection of “escape variants” or development of resistance by emerging variants to current therapies that target only RBD, the researchers concluded.

Similarly, because current vaccines that include only RBD antigens lack the ability to induce NTD-reactive neutralizing antibodies, a vaccination approach that elicits a broader immune response may be more effective.

Others from VUMC who contributed to the research were Naveen Suryadevara, PhD, Pavlo Gilchuk, PhD, Elad Binshtein, PhD, Seth Zost, PhD, Rachel Nargi, Rachel Sutton, Elaine Chen, and Robert Carnahan, PhD.

The research at VUMC was supported by National Institutes of Health grants AI095202 and AI157155, and by the Defense Advanced Research Projects Agency of the US Department of Defense, the Dolly Parton COVID-19 Research Fund at Vanderbilt and the Mercatus Center “Fast Grants” program at George Mason University.

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