SARS-CoV-2 Evolution: University of Pittsburgh Study Highlights How SARS-CoV-2 Antigenic Evolution Evades Immune Responses

SARS-CoV-2 Evolution: Researchers from the University of Pittsburgh School of Medicine in a new study found that in a recurring pattern of evolution, the SARS-CoV-2 coronavirus evades immune responses by selectively deleting small bits of its genetic sequence.


 
According to the study abstract, “Zoonotic pandemics, like that caused by SARS-CoV-2, can follow the spillover of animal viruses into highly susceptible human populations. Their descendants have adapted to the human host and evolved to evade immune pressure. Coronaviruses acquire substitutions more slowly than other RNA viruses, due to a proofreading polymerase. In the spike glycoprotein, the study team finds recurrent deletions overcome this slow substitution rate. Deletion variants arise in diverse genetic and geographic backgrounds, transmit efficiently, and are present in novel lineages, including those of current global concern. They frequently occupy recurrent deletion regions (RDRs), which map to defined antibody epitopes. Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.
 
The study findings were published in the peer reviewed journal: Science
https://science.sciencemag.org/content/early/2021/02/02/science.abf6950
 
The study team noted that since these deletions happen in a part of the sequence that encodes for the shape of the spike protein, the formerly neutralizing antibody can't 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.
 
Study senior author Dr Paul Duprex, Ph.D., director of the Center for Vaccine Research at the University of Pittsburgh told Thailand Medical News, "You can't fix what's not there. Once it's gone, it's gone, and if it's gone in an important part of the virus that the antibody 'sees,' then it's gone for good."
 
From the time the study was submitted as a preprint in November, the study team watched this pattern play out, as several variants of concern rapidly spread across the globe. The variants first identified in the United Kingdom and South Africa have these sequence deletions.
 
The study team 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.
 
Importantly 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.
 
The study team then enlisted the help of lead author Dr Kevin McCarthy, Ph.D., assistant professor of molecular biology and molecular genetics at University of Pittsburgh and an expert on influenza virus-;a master of immune evasion-;to see whether the deletions present in the viral sequences of this one patient might be part of a larger trend.
 
Dr McCarthy and his team pored through the database of SARS-CoV-2 sequences collected across the world since the virus first spilled over into humans.
 
Initially when the project started, in the summer of 2020, SARS-CoV-2 was thought to be relatively stable, but the more McCarthy scrutinized the database, the more deletions he saw, and a pattern emerged.
 
These 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.
 
Dr McCarthy, who recently started up a structural virology lab at Pitt's Center for Vaccine Research said, "Evolution was repeating itself. By looking at this pattern, we could forecast. If it happened a few times, it was likely to happen again."
 
Interestingly among the sequences Dr McCarthy identified as having these deletions was the so-called "U.K. variant"-;or to use its proper name, B.1.1.7.
 
Importantly by this point, it was October 2020, and B.1.1.7 hadn't taken off yet. In fact, it didn't even have a name, but it was there in the datasets. The strain was still emerging, and no one knew then the significance that it would come to have. But Dr McCarthy's analysis caught it in advance by looking for patterns in the genetic sequence.
 
However reassuringly, the strain identified in this Pittsburgh 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.
 
Dr Duprex commented, "Going after the virus in multiple different ways is how we beat the shapeshifter. 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."
 
Though this study findings show 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. Will the COVID-19 vaccines on the market today continue to offer a high level of protection for another six months? A year? Five years?
 
Dr McCarthy added, “How far these deletions erode protection is yet to be determined. At some point, we're going to have to start reformulating vaccines, or at least entertain that idea."
 
Defining recurrent, convergent, patterns of adaptation can provide predictive potential. From viral sequences, the study team identifed a pattern of deletions, contextualize their outcomes in protein structure and antibody epitope(s), and characterize their functional impact on antigenicity. During evaluation of this manuscript, multiple lineages with altered antigenicity and perhaps increased transmissibility have emerged and spread.
 
Significantly these variants of global concern are RDR variants and include Mink Cluster 5 Δ69-70, B.1.1.7 Δ69-70 and Δ144/145 and B.1.351 Δ242-244. https://www.who.int/csr/don/06-november-2020-mink-associated-sars-cov2-denmark/en/
 
https://www.biorxiv.org/content/10.1101/2020.12.14.422555v3.abstract
 
https://www.medrxiv.org/content/10.1101/2020.12.21.20248640v1.full
 
The study team’s analysis preceded the description of these lineages. The team had demonstrated that identical/similar recurrent deletions that alter positions 144/145 and 243-244 in the S glycoprotein disrupt binding of antibody 4A8, which defines an immunodominant epitope within the NTD.
 
Their  survey for deletion variants captured the first representative of what would become the B.1.1.7 lineage. These real-world outcomes demonstrate the predictive potential of this and like approaches and show the need to monitor viral evolution carefully and continually.
 
The study team concluded, “Additional circulating RDR variants have gone virtually unnoticed. Are they intermediates on a pathway of immune evasion? That remains to be determined. However, deletions and substitutions within major NTD and RBD epitopes will likely continue to contribute to that process as they have already in current variants of concern. The progression of adaptations in immunocompromised patients and concerning SARS-CoV-2 variants alike remain to be resolved. Their evolution has thus far converged. Recurrence of adaptations in single patients and on global scales underscores the need to track and monitor deletion variants.”
 
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