SARS-CoV-2 Mutates into New Antibody-Evading Variants by Selectively Deleting Small Bits of Its Genetic Sequence

In a recurring pattern of evolution, SARS-CoV-2 evades immune responses by selectively deleting small bits of its genetic sequence, according to new research.

Researchers from the University of Pittsburgh (Pittsburgh, PA, USA) investigated the scientific detective story starting with a single patient that unearthed how the SARS-CoV-2 virus mutates to create new variants, including the UK strain B.1.1.7, and escapes neutralizing antibodies. Since these deletions happen in a part of the sequence that encodes for the shape of the spike protein, the formerly neutralizing antibody cannot grab hold of the virus. And because the molecular "proofreader" that usually catches errors during SARS-CoV-2 replication is "blind" to fixing deletions, they become cemented into the variant's genetic material.

Since their research, the team has watched this pattern play out, as several variants of concern rapidly spread across the globe. The variants first identified in the UK and South Africa have these sequence deletions. The researchers first came across these neutralization-resistant deletions in a sample from an immunocompromised patient, who was infected with SARS-CoV-2 for 74 days before ultimately dying from COVID-19. That's a long time for the virus and immune system to play "cat and mouse," and gives ample opportunity to initiate the coevolutionary dance that results in these worrisome mutations in the viral genome that are occurring all over the world.

In order to confirm whether the deletions present in the viral sequences of this one patient might be part of a larger trend, the researchers pored through the database of SARS-CoV-2 sequences collected across the world since the virus first spilled over into humans. When the project started, in the summer of 2020, SARS-CoV-2 was thought to be relatively stable, but the more the team scrutinized the database, the more deletions they saw, and a pattern emerged. The deletions kept happening in the same spots in the sequence, spots where the virus can tolerate a change in shape without losing its ability to invade cells and make copies of itself.

Among the sequences that the team identified as having these deletions was the UK variant, or B.1.1.7, which hadn't taken off at that point of time, but was there in the datasets. The strain was still emerging, and no one knew then the significance that it would come to have. But the team’s analysis caught it in advance by looking for patterns in the genetic sequence. Reassuringly, the strain identified in the patient is still susceptible to neutralization by the swarm of antibodies present in convalescent plasma, demonstrating that mutational escape isn't all or nothing. And that's important to realize when it comes to designing tools to combat the virus. Although the study shows how SARS-CoV-2 is likely to escape the existing vaccines and therapeutics, it's impossible to know at this point exactly when that might happen.

"Going after the virus in multiple different ways is how we beat the shapeshifter," said study senior author Paul Duprex, Ph.D., director of the Center for Vaccine Research at the University of Pittsburgh. "Combinations of different antibodies, combinations of nanobodies with antibodies, different types of vaccines. If there's a crisis, we'll want to have those backups."

"How far these deletions erode protection is yet to be determined," said lead author Kevin McCarthy, Ph.D., assistant professor of molecular biology and molecular genetics at Pitt and an expert on influenza virus. "At some point, we're going to have to start reformulating vaccines, or at least entertain that idea."

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