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Antibody Escape May Be Caused by Small, Recurrent Deletions in SARS-Spike CoV-2's Protein

New SARS-CoV-2 variants are making headlines and causing fear among others. The main concern is whether the vaccine's effectiveness would be harmed by changes in the virus's genome. In a repeated pattern of evolution, new research from the University of Pittsburgh School of Medicine indicates that SARS-CoV-2 can escape immune responses by selectively removing small bits of its genetic sequence.

This work is published in Science under title, “Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape.”

The deletions occur in genes that code for the spike protein's shape, preventing the previously neutralizing antibody from grabbing hold of the virus. Since the molecular "proofreader" that normally detects errors during SARS-CoV-2 replication is "blind" to deletions, they become embedded in the genetic material of the variant.

“You can't repair what isn't there,” study senior author Paul Duprex, PhD, director of the University of Pittsburgh's Center for Vaccine Research, said. “Once it's gone, it's gone for good, and if it's gone in a critical section of the virus that the antibody ‘sees,' it's gone for good.”

The researchers have been watching this trend play out over the past several months, as many different types of anxiety have spread rapidly across the world. These sequence deletions can be found in the variants first discovered in the United Kingdom and South Africa.

These neutralization-resistant deletions were first discovered by Duprex's team in a sample from an immunocompromised patient who had been infected with SARS-CoV-2 for 74 days before succumbing to COVID-19. That's a lot of time for the virus and immune system to play "cat and mouse," and it gives them plenty of chances to start the coevolutionary steps that leads to these alarming viral genome mutations all over the planet.

Then Duprex enlisted the aid of lead author Kevin McCarthy, PhD, an authority on influenza virus and a master of immune evasion, to see if the deletions found in the viral sequences of this one patient were part of a larger pattern.

McCarthy and his colleagues combed through a collection of SARS-CoV-2 sequences gathered from around the world after the virus first infected humans.

SARS-CoV-2 was thought to be relatively stable when the project began in the summer of 2020, but as McCarthy examined the database, he noticed further deletions, and a trend appeared. The deletions kept occurring in the same places in the series, places where the virus can withstand a shape shift without losing its ability to enter cells and replicate itself.

McCarthy, who recently started a structural virology lab at Pitt's Center for Vaccine Research, said, "Evolution was repeating itself." “We could forecast by looking at this trend. It was likely to happen again if it happened a few times.”

B.1.1.7 was one of the sequences McCarthy discovered to have these deletions. It was October 2020 at this stage, and B.1.1.7 had yet to take off. Even though it didn't have a tag, it was present in the datasets. The strain was still developing, and no one knew what impact it might have in the future. McCarthy's study, on the other hand, detected it ahead of time by searching for patterns in the genetic sequence.

Reassuringly, the strain found in this Pittsburgh patient can still be neutralized by the swarm of antibodies found in convalescent plasma, showing that mutational escape isn't all or nothing.

The shapeshifter can be defeated by attacking the virus in several forms, according to Duprex. “Vaccines that combine various antibodies, nanobodies with antibodies, and different types of vaccines. We'll need those backups in the event of a crisis.”

While this paper demonstrates how SARS-CoV-2 is likely to evade current vaccines and therapeutics, it is difficult to predict when this will occur. Can the COVID-19 vaccines already on the market provide enough security for another six months? Is it really a year? How about five years?

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