Targeting New Antibody Supersite Key to COVID-19 Immunity

Antibodies from recovered patients have been shown to recognize a lesser-known site on the SARS-CoV-2 virus and block infection in lab studies.

Scientists at the University of Washington School of Medicine (Seattle, WA, USA) as well as Humabs Biomed SA, a subsidiary of Vir Biotechnology (San Francisco, CA, USA) have learnt that a lesser-studied region on the SARS-CoV-2 virus is recognized by COVID-19 infection-fighting antibodies. These antibodies were identified in blood samples from previously infected patients, and were found to potently prevent the virus from infecting cells.

The coronavirus spike protein is the key that unlocks the door to the cell, and antibodies bind to the spike protein jamming this function. Much attention has been given to studying antibodies that target the receptor-binding domain on the coronavirus spike protein. The receptor-binding domain of the spike is responsible for triggering the merging of the virus with a host cell to achieve a takeover. However, some of the recovered patients’ antibodies blocked the coronavirus by binding to a different place on the virus spike – the N-terminal domain. These antibodies were as strong as those that bind to receptor-binding domain, a recent study shows.

Using electron cryo-microscopy (cryoEM) to map where these antibodies bound showed that all the antibodies that prevent infection bind a single place on the N-terminal domain. The research demonstrated that these antibodies protected Syrian hamsters from SARS-CoV-2, the coronavirus that causes COVID-19 in people. Additional recent findings indicate that the virus is slowly defying these antibodies people are acquiring. The virus is adapting to these antibodies by accumulating mutations that help the virus escape these antibodies, becoming so-called variants-of-concern. Some of these variants, such as those first detected in the UK and South Africa, contain mutations that appear to make the virus less vulnerable to the neutralizing power of the N-terminal domain antibodies.

The researchers believe that investigating these neutralization escape mechanisms is revealing some unconventional ways the N-terminal domain on the virus is acquiring antibody resistance, and why N-terminal domain variants warrant closer monitoring. The N-terminal domain antibodies in this study were derived from memory B cells, which are white blood cells that can persistently recognize a previously encountered pathogen and re-launch an immune response. N-terminal domain-specific antibodies likely act in concert with other antibodies to wage a multipronged uprising against the coronavirus. The N-terminal domain antibodies appear to inhibit virus-cell fusion. In conjunction, another part of the antibody, called a constant fragment, might also activate some of the body’s other approaches to eliminating the virus.

Continuing research on the N-terminal domain neutralizing antibodies may lead to improved therapeutic and preventive anti-viral drugs for COVID-19, as well as inform the design of new vaccines or the evaluation of current ones. For example, patients who have recovered from COVID-19 and later received a first dose of an mRNA vaccine might experience a boost in their N-terminal domain neutralizing antibodies. Also, a cocktail of antibodies that target different critical domains on the coronavirus might also be a promising approach to examine to see if it provides broad protection against variant strains.

Antiviral drugs, they explain, are expected to play a role in controlling disease during the ongoing pandemic. They are likely to be particularly helpful, according to the researchers, for unvaccinated individuals and for those who didn’t get a strong enough immune response from their vaccinations. Antivirals could also prove vital when immunity from previous infection or from vaccination wanes, or as mutant strains that break through the shield of vaccination emerge.

“This study shows that NTD-directed antibodies play an important role in the immune response to SARS-CoV-2 and they appear to contribute a key selective pressure for viral evolution and the emergence of variants,” said David Veesler, associate professor of Biochemistry at the University of Washington School of Medicine.

Related Links:
University of Washington School of Medicine
Vir Biotechnology