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How SARS-CoV-2 Is Mutating And Escaping Immune System Detection

Johannes Van Zijl

Johannes Van Zijl

Johannes has a MSci in Neuroscience from King’s College London and serves as the Managing Director at IFLScience.

Managing Director


SARS-CoV-2 virus illustration. Image Credit: CROCOTHERY/ 

All viruses mutate over time, it is a common occurrence in nature. This is no different for SARS-CoV-2, the virus that causes COVID-19. SARS-CoV-2 has had thousands of mutations since the original sequence of the virus was first identified over a year ago. Most of the time, these mutations don't change the behavior of the virus, and they are thought of as "passenger" mutations the virus carries with it as it continues to spread. 

However, once in a while, some of the mutations turn out to beneficial to the virus. Depending on where they occur, it may help the virus to become more infectious and spread more rapidly, or it could help the virus evade the immune system better by making it less detectable. Various new variants of SARS-CoV-2 have recently been described, and many raised alarm bells due to the fact that the virus started to behave differently from the original variants, seemingly becoming more transmissible and/or less detectable. 


Now, new research from the University of Pittsburgh School of Medicine has shown that SARS-CoV-2 may be selectively deleting fragments of the genetic sequence that codes for an important part of the virus, the spike protein on its surface. The spike protein is used by the virus to latch onto cells to infect them, and this is also the part of the virus that is targeted by antibodies, allowing the immune system to detect the virus and remove it. 

“You can’t fix what’s not there,” said study senior author Paul Duprex, PhD, director of the Center for Vaccine Research at the University of Pittsburgh in a statement. “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.” 

The study, published in the journal Science, shows how the small deletions of fragments in the genetic code responsible for the structure of the spike protein are causing it to become more resistant to neutralizing antibodies. This results in a form of adaptive evolution, as the proofreading mechanism in the virus that should normally detect these mistakes during replication and fix them is not catching the fragment deletions, which results in a permanent change to the SARS-CoV-2 sequence, and this is altering the virus evolution and behavior. 

Multiple antibodies (green and red) bind SARS-CoV-2 spike protein within cells (blue)

Multiple antibodies (green and red) bind SARS-CoV-2 spike protein within cells (blue) when there are no deletions (LEFT). Spike protein deletions stop neutralizing antibody from binding (absence of green) but other antibodies (red) still attach very well (RIGHT). Recurrent deletion generates variants that escape from neutralization. Image Credit: Kevin McCarthy and Paul Duprex

The Duprex research group first came across this fragment deletion in the SARS-CoV-2 sequence while studying an immunocompromised patient who had the infection for 74 days before passing away. As the press release described it, this was a sufficient amount of time for the immune system of the patient and the virus to play "cat and mouse" and may have resulted in the evolution of the new deletion fragment they had detected, which may or may not have occurred in other variants around the world. 
Therefore, Duprex decided to team up with the lead author of the study, Dr Kevin McCarthy, an expert in influenza viruses (that are really good at evading the immune system) to collaborate and to further investigate the deletion mutation they had detected in the immunocompromised patient, and to see if it may be a more common occurrence. 
McCarthy's team scoured through a global database that contains a catalog of the SARS-CoV-2 mutations since it was first detected in humans. Looking at this data, the researchers noticed that at the start of the pandemic in 2020, the virus sequence was quite stable. However, as time proceeded, more and more changes seemed to have occurred in the same part of the virus – a part that can alter its shape but does not necessarily change the ability of the virus to infect cells or to replicate.
Using this approach, they had in fact detected the UK variant back in October 2020 before it was officially recognized, without knowing the significance of the variant. McCarthy's team detected it by looking at the genetic sequence alone. “Evolution was repeating itself,” said  McCarthy, “By looking at this pattern, we could forecast. If it happened a few times, it was likely to happen again.” Now, we do have various similar variants around the globe that carry this deletion sequence in the spike protein, something they had predicted. 
The researchers stressed, in a reassuring way, that the mutated virus in the immunocompromised patient Duprex detected was still capable of being neutralized by other antibodies present in convalescent plasma. This suggests it is not an all or nothing evasion event, it just stresses the point that the virus is changing, and more approaches should be considered to tackle the virus as a whole.  
“Going after the virus in multiple different ways is how we beat the shapeshifter,” Duprex reiterated. “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.”

Furthermore, more research needs to done to understand just how the South African and UK variants might be able to evade different antibodies, so that vaccine strategies could be informed of how to make changes in the future to tackle the virus most effectively. 
“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.”  McCarthy concluded. 

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