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Just What we Need: A Hybrid COVID Virus

Researcher inserting syringe in test tube
Paul Rothlauf, a visiting scientist at Washington University School of Medicine in St. Louis, works with a lab-made virus that infects cells and interacts with antibodies just like the COVID-19 virus, but lacks the ability to cause severe disease. Matt Miller

While another version of the SARS-CoV-2 virus might seem like the last thing the world needs right now, the germ whipped up by scientists at the Washington University School of Medicine can, in fact, greatly expand the search for vaccines and treatments for COVID-19.

Biosafety

When scientists work with SARS-CoV-2, the virus that causes COVID-19, they need to do so in a facility that has a biosafety level of three (BSL-3). This is a lab with specialized precautions, equipment, and training protocols in place so that researchers can work with airborne pathogens that, when inhaled, can cause severe disease. 

Because SARS-CoV-2 certainly fits this category, the number of labs where it can be studied has been limited. So the WSU researchers set out to develop a safer virus that can be worked with in much more plentiful BSL-2 labs, but one that is still close enough to SARS-CoV-2 for meaningful research.

“One of the problems in evaluating neutralizing antibodies is that a lot of these tests require a BSL-3 facility, and most clinical labs and companies don’t have BSL-3 facilities,” said Diamond, professor of molecular microbiology, pathology, and immunology. “With this surrogate virus, you can take serum, plasma, or antibodies and do high-throughput analyses at BSL-2 levels, which every lab has, without a risk of getting infected. And we know that it correlates almost perfectly with the data we get from bona fide infectious SARS-CoV-2.”

Dressing up a Mild Virus

To create their surrogate virus, the researchers began with the vesicular stomatitis virus (VSV), which generally affects horses, cows, pigs, and occasionally humans, but only causes a mild flu-like illness that clears within three to five days. VSV has been used for years in virology labs because of its mild effects and the fact that it can be genetically manipulated relatively easily.

To make VSV look like the SARS virus, the researchers swapped out its surface-protein gene, replacing it with the one from SARS-CoV-2. This caused the hybrid virus to grow the telltale spikes seen on the more deadly virus. These spikes were enough to trick the immune system into thinking the hybrid virus was SARS-CoV-2, as evidenced by the way purified antibodies attacked it–- in precisely the same way they did in patients with COVID-19. 

 “Humans certainly develop antibodies against other SARS-CoV-2 proteins, but it’s the antibodies against (the spikes) that seem to be most important for protection,” Whelan said. “So as long as a virus has the spike protein, it looks to the human immune system like SARS-CoV-2, for all intents and purposes.”

Big Demand

In testing, the antibodies that prevented SARS-CoV-2 from penetrating cells were also effective against the hybrid, while those that didn’t work on the first virus didn’t work on the second. The study, which has been published in Cell Host & Microbe, caused the hybrid germ to be in significant demand by labs around the world, according to co-senior author Sean Whelan, head of the Department of Molecular Microbiology.

“I’ve never had this many requests for a scientific material in such a short period of time,” he said. “We’ve distributed the virus to researchers in Argentina, Brazil, Mexico, Canada, and, of course, all over the US. We have requests pending from the UK and Germany. Even before we published, people heard that we were working on this and started requesting the material.”