If there’s one coronavirus mutation that’s keeping scientists up at night, it’s E484K. The mutation was found in both the South African variant (B1351) and the Brazilian variant (P1), but not in the UK variant (B117). This so-called “escape mutation” raised concerns that the approved Covid vaccines may not be as effective against these variants. The E484K mutation has now also been found in the British variant – albeit in only 11 cases.
The coronavirus is slow to mutate, accumulating about two one-letter mutations per month in its genome. This rate of change is about half that of flu viruses. At the beginning of the pandemic, few scientists were concerned that the coronavirus would turn into something more dangerous. But that changed quickly in November 2020 when the first “variant of concern” was discovered. The newly discovered variant B117 has been linked to the massive spike in cases in South East England and London.
Receptor binding domain
While all mutations found in emerging variants of coronavirus should be monitored, scientists are particularly interested in mutations that occur in the virus’s spike protein, particularly the receptor binding domain portion of the spike protein. This part of the virus attaches to our cells and causes infection. Mutations in the receptor binding domain can cause the virus to bind better to our cells, making it more contagious.
The immunity that we develop against 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 allow the virus to avoid or partially avoid these antibodies. This is why they are called “escape mutations.” E484K is one such mutation.
The mutation name comes from the position in the RNA (the genetic code of the virus) string where it occurs (484). The letter E refers to the amino acid that was originally in this location (glutamic acid). And K refers to the amino acid now in that location (lysine).
Several studies have shown that mutation E484K stops the binding of antibodies targeting this site. 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 parts of the virus. How harmful it is to lose the effect of antibodies targeting this one specific region depends on how much our immune system is dependent on antibodies targeting this specific site.
Two studies, one in Seattle and the other in New York, have investigated this. In the Seattle study, which is a preprint (meaning it is not yet to be peer reviewed), scientists examined the ability of antibodies from eight people who had recovered from Covid to stop the mutated form of the virus infecting cells – in other words, to neutralize the virus.
In samples from three of the humans, the ability of the antibodies to neutralize the virus was reduced by up to 90% upon presentation of the mutated E484K form. And it was reduced in samples from one person when presented in the same position with a different mutation. However, the neutralization ability of samples from four humans 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.
Still, two of the samples saw a reduction in their neutralization ability 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 differ, as we know that the immunity gained through vaccination is generally more robust. As a result, several research groups have recently released data, as preprints, examining the impact of this mutation on vaccine-induced protection.
Effect on vaccines
One of these studies, 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 scientists in Texas in collaboration with Pfizer, looked at antibodies from 20 people vaccinated with the Pfizer / BioNTech vaccine. A third, released by scientists in Cambridge, England, looked at five people vaccinated with the Pfizer / BioNTech vaccine.
Both the New York and Texas studies showed that although the vaccine’s effectiveness in protecting against variants with the E484K mutation was slightly reduced for some people, it was still within acceptable levels. Decrease in the ability to neutralize antibodies is measured in “fold change”. For example, the antibodies produced by a flu vaccine would have to see a fold decrease of more than four before scientists would have to change the vaccine.
The Texas study reported a 1.48-fold decrease in antibodies, and the New York study reported a one to three-fold decrease. However, the Cambridge study found that antibodies from three out of five people had a multiple decrease of more than four when exposed to a virus carrying the E484K mutation.
An important difference between the Cambridge and the US studies is that the US studies used the South African variant, while the Cambridge study introduced the E484K mutation in the British variant (B117) and used it in their tests. This may indicate that the recent reports of the detection of this mutation in B117 should be of more concern to UK health officials than the importation and subsequent circulation of the South African variant.
However, keep in mind that the above studies are based on very small sample numbers and that any conclusions should be drawn with caution.
Nonetheless, it stresses the importance of examining the combined effect of multiple mutations rather than studying individual mutations alone, as a single mutation is unlikely to result in complete escape from natural or vaccine-derived immunity.
Claire Crossan is a Research Fellow, Virology at Glasgow Caledonian University.
This article first appeared in The Conversation.