Variants of SARS-CoV-2 have caused waves of severe infections and deaths around the globe. The Omicron variant, in particular, displayed a remarkable ability to evade currently available vaccines. This has underscored the need for protection against mutations as a key to combating COVID-19.

Scientists concentrating their efforts on the study of SARS-CoV-2 variants in recent months have relied heavily on the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at the DOE’s Argonne National Laboratory. The APS allows researchers to examine crystals grown from the proteins of the virus at the atomic level in high resolution. (APS scientists do not work with the live virus.)

“We can’t do this work without the APS. It's as simple as that." — Gordon Joyce, Walter Reed Army Institute of Research and The Henry M. Jackson Foundation for the Advancement of Military Medicine

Two teams of researchers using the APS have published breakthrough studies on SARS-CoV-2 variants. The first, from the Walter Reed Army Institute of Research (WRAIR), advances the development of an antibody cocktail with wide protection, including against current variants of concern, which are known to spread more easily, cause more severe disease and escape the body’s immune response. The second, out of the University of Maryland, furthers the creation of a type of broad-spectrum vaccine effective against a wide swath of coronaviruses.

“We can’t do this work without the APS,” said Gordon Joyce, chief of structural biology in the Emerging Infectious Diseases branch at WRAIR and The Henry M. Jackson Foundation for the Advancement of Military Medicine. “It’s as simple as that.”

Joyce’s team leveraged the Northeast Collaborative Access Team beamline — 24-ID-E at the APS — to identify several potent neutralizing monoclonal antibodies. These synthesized copies of the immune system proteins people generate to fight off infection, typically administered to high-risk patients intravenously, can attack the coronavirus and prevent it from invading cells. Using a method called X-ray crystallography, the researchers aimed a high-energy X-ray beam at lab-generated crystals of various antibodies bound to a virus variant’s spike protein. They were then able to inspect the bonds at the atomic level and document those structures.

“This allows us, as soon as a sequence of a new variant is available, to go back to that structure we’ve determined and immediately, with a high degree of accuracy, say that, ‘Yes, this antibody will be knocked out by the new variant,’ or ‘No, this antibody will not be affected by the variant,’” Joyce said. For example, in the group’s paper, published in Nature Immunology, one of the antibodies studied was less effective against the Omicron variant, while another was effective against Omicron but displayed reduced activity against the Delta variant.

This research stands to benefit those at high risk, such as the elderly and the immunocompromised, who can receive antibodies as a preventative measure to help guard them from infection. “We don’t know what the next variant will be,” Joyce said. “But by having a collection of antibodies with broad activity, we’ll always have something in our arsenal that will be protective.”

The Maryland researchers, meanwhile, used the APS to look at a different front of the biological war against the virus: how our body’s T-cells recognize variants at the atomic level. The job of T-cells, in part, is to identify and destroy infected cells.

The group’s work, published in Nature Communications, could be integral to developing T-cell-based vaccines as an additional form of protection against variants of concern. The initial COVID-19 vaccines are B-cell-based vaccines, which work to raise an antibody response. T-cell-based vaccines, on the other hand, boost the virus-busting T-cell response to SARS-CoV-2.

Using X-ray crystallography at the APS’s General Medical Sciences and Cancer Institutes Structural Biology Facility at beamline 23-ID-B, the researchers determined the structures of several T-cell receptors bound to SARS-CoV-2 peptides, short chains of amino acids that make up part of the spike protein.

“What we found is that some of these variants are able to be recognized by T-cells while other variants are not,” explained Roy Mariuzza, a professor with the Institute for Bioscience and Biotechnology Research at the University of Maryland. That is useful, he said, because, “When you’re making a T-cell vaccine, you want to choose the peptides carefully. You want to include ones that do not vary much from one SARS-CoV-2 variant to the next.’”

Vaccines that boast broad coverage against SARS-CoV-2 could eventually lead to what is known as a “pan-coronavirus vaccine,” which would be effective against all coronaviruses, including SARS-CoV-1, Middle East Respiratory Syndrome (MERS) and others. 

In the meantime, the APS will continue to be at the center of the scientific fight against further SARS-CoV-2 mutations. Since the start of the pandemic, more than 21,000 hours have been devoted to COVID-19-related research at the facility. Incredibly, the time spent is not tailing off.

“Researchers are not giving up,” said Robert Fischetti, the life science advisor to the APS director and group leader in Argonne’s X-ray Science division. “This is very different from past outbreaks. During those, when it started to look like the virus was under control, funding started to dry up and many scientists stopped working on the problem. Whereas now, people are actively continuing to do research. We as a society have learned that this virus isn’t necessarily going away. There’s another variant or another novel virus that’s going to come back at some point, so continuing to do research is really important.”