If there’s a coronavirus mutation that keeps scientists awake at night, it’s E484K. The mutation was found in the South African variant (B1351) and the Brazilian variant (P1), but not in the United Kingdom variant (B117). This so-called “escape mutation” has raised fears that Covid’s approved vaccines may not be as effective against these variants. The E484K mutation was also found in the UK variant – although in only 11 cases.
The coronavirus mutates slowly, accumulating about two single letter mutations per month in its genome. This rate of change is about half that of influenza viruses. At the beginning of the pandemic, few scientists feared that the coronavirus would turn into something more dangerous. But in November 2020, that changed quickly when the first “concern variant” was discovered. The newly discovered variant B117 has been associated with the large peak in cases in southeastern England and London.
Domain of connection to the receiver
While all mutations found in emerging variants of the coronavirus must be monitored, scientists are particularly interested in the mutations that occur in the virus’s spike protein, specifically in the section of the spike protein receptor-binding domain. This section of the virus clings to our cells and initiates the infection. Mutations in the receptor-binding domain can help the virus to bind more tightly to our cells, making it more infectious.
The immunity we develop to the coronavirus, after vaccination or infection, is largely due to the development of antibodies that bind to the receptor-binding domain. Mutations in this region can allow the virus to avoid or partially avoid these antibodies. This is the reason why they are called “escape mutations”. E484K is one of those mutations.
The name of the mutation comes from the position in the RNA chain (the genetic code of the virus) in which it occurs (484). The letter E refers to the amino acid that was originally at this location (glutamic acid). EK refers to the amino acid that is now at that location (lysine).
Several studies have shown that the E484K mutation prevents antibodies that target this position from binding to it. However, after an infection or vaccination, we do not produce antibodies that target only one area of the virus.
We produce a mixture of antibodies, each targeting different areas of the virus. How harmful it is to lose the effect of antibodies targeting that specific region will depend on how much our immune system depends on antibodies targeting that specific location.
Two studies, one in Seattle and the other in New York, have investigated this. In the Seattle study, which is a preprint (meaning it has not yet been peer-reviewed), scientists examined the ability of antibodies from eight people who recovered from Covid to prevent the mutant form of the virus from infecting cells. – in other words, to neutralize the virus.
In samples from three people, the ability of antibodies to neutralize the virus was reduced by up to 90% when presented with the mutated form E484K. And it was reduced in samples from one person when presented with a different mutation in the same position. However, the ability to neutralize samples from four people was not affected by the mutation.
In the New York study, scientists examined the effect of a series of mutations on the ability of antibodies, collected from four people, to neutralize the virus. The researchers found that none of the antibodies were affected by the E484K mutation.
However, two of the samples saw a reduction in neutralization capacity when challenged with mutations occurring at different positions in the spike protein. This highlights the uniqueness of the antibody response produced by different people.
Both laboratory studies used only a few samples collected from people who were naturally infected, rather than vaccinated, so the results may be different, as we know that the immunity obtained through vaccination is generally more robust. Consequently, several research groups have recently released data, such as preprints, examining the impact of this mutation on vaccine-induced protection.
Effect on vaccines
One such study, published by scientists in New York, looked at antibodies from 15 people vaccinated with one of two approved mRNA-based vaccines (those produced by Pfizer / BioNTech and Moderna).
The second, published by Texas scientists in collaboration with Pfizer, analyzed antibodies from 20 people vaccinated with the Pfizer / BioNTech vaccine. A third, launched by scientists in Cambridge, England, analyzed five people vaccinated with the Pfizer / BioNTech vaccine.
New York and Texas studies showed that while the vaccine’s effectiveness in protecting against variants carrying the E484K mutation was slightly reduced for some people, it was still within an acceptable level. Decreases in the neutralization capacity of antibodies are measured in “variation of times”. For example, the antibodies produced by a flu vaccine would need to be reduced more than four times before scientists had to change the vaccine.
The Texas study reported a 1.48 decrease in antibodies, and the New York study reported decreases one to three times. However, the Cambridge study found that the antibodies of three of the five people decreased more than 4 times when challenged with a virus carrying the E484K mutation.
A fundamental difference between the Cambridge and US studies is that the US studies used the South African variant, while the Cambridge study introduced the E484K mutation in the UK variant (B117) and used it in its tests. This may indicate that recent reports on the detection of this mutation in B117 should be of greater concern to UK health officials than the import and subsequent circulation of the South African variant.
It is important to remember, however, that the studies above are based on very small samples and any conclusions should be drawn with caution.
However, it highlights the importance of examining the combined effect of multiple mutations, as opposed to studying only individual ones, as any mutation is unlikely to lead to a complete escape of natural or vaccine-derived immunity.
Claire Crossan is a researcher in Virology at Glasgow Caledonian University.
This article first appeared in The Conversation.