Corona: Are there threats of escape mutations in the virus? – What the new virus variants reveal about the adaptation and resistance development of SARS-CoV-2

Dynamic adaptation: Several mutations of the coronavirus cause concern – not only because of their increased infectivity. Some of these variants also carry mutations that could indicate an incipient “flight” from our immune response. It is still unclear whether SARS-CoV-2 could become immune to the new vaccines in the foreseeable future. After all, two out of four cold coronaviruses seem to form such escape mutations more frequently, as a study shows.

Since the beginning of the Corona-Pandemie SARS-CoV-2 has always changed slightly. Some of these mutations are today globally dominant, others have run away again, like the one made in mink Cluster-5-Mutation. Most, however, had little influence on the infectivity and severity of the course of Covid-19.

New variants with concentrated mutations

But in the last few weeks several coronavirus variants have been discovered that are of concern to medical professionals. The British is one of them Variant B.1.1.7, a virus line that appeared in South Africa and a variant that was detected in Brazil in January 2021. What they have in common is that they have several mutations, some of which apparently increase the infectivity of the virus.

Most antibodies and vaccines target the SARS-CoV-2 spike protein. © Emanresucamit / CC-by-sa 4.0

These concentrated mutations also raise another, crucial question: How great is the risk that the coronavirus will develop so-called escape mutations? Researchers call “escape mutation” gene changes that enable a virus to undermine its host’s immune response. This usually happens when the viral protein structures, to which the antibodies and defense cells of the immune system attach, change.

As a result of such mutations, the Immune protection become weakened or even ineffective after a disease or after a vaccination.

E484 mutation weakens the immune response …

Researchers led by Allison Greaney from the University of Washington in Seattle recently investigated which of the mutations that have already been detected at least hinder the human immune response. They used cell cultures to test how different mutations affect the binding of antibodies from the blood serum of recovered Covid 19 patients – and what this means for neutralizing the coronavirus.

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The result: “The place where mutations have the greatest effect on antibody binding and neutralization is unfortunately E484 – the place where several current coronavirus variants carry a mutation,” report the researchers. This E484 mutation lies in the receptor-binding region of the virus and is present in the South African and Brazilian mutants of SARS-CoV-2. In the experiments this mutation reduced the effect of the antibody sera ten-fold.

“The variants with this E484K mutation occurring in South Africa and Brazil will therefore have a significantly reduced susceptibility to the polyclonal serum antibodies of some patients,” write Greaney and her team.

… but not with all

But what does this mean for the course of the pandemic and our immune protection? Greaney and her colleagues emphasize that their results do not mean that vaccines or our natural immune response to SARS-CoV-2 are now ten times less effective. Because most people produce antibodies not just against one part of the viral protein, but against several different ones.

There are also individual differences in the antibody composition: “The neutralizing effect of several serum samples was reduced tenfold, but there were also some samples that were hardly affected by the E484 mutation,” they report. The antibody population in these was therefore diverse enough to switch off the virus by attacking other sites.

Infection favors escape mutations

However: The results clearly show that the coronavirus has already formed the first escape adaptations to our immune system. Virologists assume that such escape mutations mainly arise where the population is at least partially immunized against the virus. Because then the mutants in particular prevail, and they can still spread. Scientists then speak of an antigen drift or antigen evolution.

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It is therefore probably no coincidence that the E484K mutation developed and spread mainly in Brazil and South Africa: Because SARS-CoV-2 is rampant there, especially in the slums, the degree of infection in the population is sometimes 40 to 50 percent . “Under these conditions, the selection pressure favors virus mutants that can spread despite this immunity,” explains Andrew Pollard from Oxford University in the specialist magazine BMJ.

This is also confirmed by reports of re-infections in Brazil: There, apparently, some people have already been infected with the new coronavirus mutant who can be shown to have had an earlier infection.

OC43
Cold coronavirus of the type OC43. © CDC / Erskine Palmer

What the cold coronaviruses tell us

But how big is the risk that SARS-CoV-2 may soon develop even more effective escape mutations? Kathryn Kistler and Trevor Bedford from the Fred Hutchinson Cancer Research Center in Seattle wanted to find out by examining the four known cold coronaviruses. These viruses – OC43, 229E, NL63, and HKU1 – have been around in the human population for decades.

“Some of these coronaviruses can infect people multiple times, but it is unclear to what extent this is due to an antigen adaptation,” the researchers explain. “We therefore wanted to investigate whether these SARS-CoV-2-related coronaviruses have developed adaptations against our immune system.” To do this, they compared hundreds of genetic sequences of the four cold coronaviruses that have been created over the course of over 50 years.

Antigen adaptation at two out of four

“If the coronaviruses go through an antigen drift, then we would have to see adapting mutations in the spike protein and in particular in the S1 domain of this protein,” explain Kistler and Bedford. In fact, this is the case with two of the four cold viruses: the beta coronavirus OC43, which is more closely related to SARS-CoV-2, and the alphacoronavirus 229E. They developed an average of 0.3 to 0.5 such single mutations per year – about half as many as some influenza viruses.

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The researchers found no evidence of an antigen drift in the cold virus NBL63. For the beta coronavirus HKU1, which is also more closely related to SARS-CoV-2, the findings were inconclusive – too little data are available so far. “It is possible that a more complete genetic time series from HKU1 will change the results,” the scientists said. “We now have evidence that at least two out of four seasonal coronaviruses have developed adaptations to the spike protein.”

And SARS-CoV-2?

But what does this mean for SARS-CoV-2? It seems clear that at least some of the coronaviruses that are already circulating in humans develop escape mutations relatively quickly. That is also the reason why you can contract these viruses several times in your life and catch a cold. Because this antigen drift has not yet been clearly demonstrated in HKU1, it remains open for the time being whether all alphacoronaviruses – and thus also SARS-CoV-2 – may have this ability.

“But if SARS-CoV-2 develops in a similar way to the closely related OC43, then the vaccines against Covid-19 may have to be adapted more frequently – similar to the flu vaccines,” said Kistler and Bedford. (BioRxiv Preprint, 2021; doi: 10.1101/2020.12.31.425021; eLife, 2021; doi: 10.7554 / eLife.64509)

Quelle: BMJ, Science, BioRxiV, MedRxiV, eLife

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