If there is one coronavirus mutation that keeps scientists awake at night, it is E484K. The mutation was found in both the South African variant (B1351) and the Brazilian variant (P1), but not in the British variant (B117). This so-called ‘escape mutation’ has raised fears 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 mutates slowly, accumulating about two single-letter mutations per month in its genome. This rate of change is about half that of flu viruses. Early in the pandemic, few scientists were worried that the coronavirus would turn into something more dangerous. But in November 2020, that changed rapidly when the first ‘variant of concern’ was discovered. The newly discovered variant B117 has been associated with the huge increase in cases in South East England and London.
Receptor-binding domain
Although all mutations in emerging variants of coronavirus should be monitored, scientists are particularly interested in mutations that occur in the ear protein of the virus, specifically the portion of the receptor binding domain (RBD) of the ear protein. This part of the virus sticks to our cells and causes infection. Mutations in the RBD can help bind the virus more strongly to our cells, making them more contagious.
The immunity we develop against the coronavirus after vaccination or infection is mainly due to the development of antibodies that bind to the RBD. Mutations in this region can enable the virus to evade or partially escape these antibodies. This is why they are called ‘escape mutations’. E484K is such a mutation.
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The mutation name is derived from the position in the strand of RNA (the genetic code of the virus) (484). The letter E refers to the amino acid that was originally at this site (glutamic acid). And K refers to the amino acid that is now in place (lysine).
Several studies have shown that mutation E484K 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 focusing on different areas of the virus. How harmful it is to lose the effect of antibodies targeting this particular region will depend on how much our immune system is dependent on antibodies targeting this particular region.
Two studies, one in Seattle, the other in New York, examined it. In the Seattle study, which is a precursor (meaning it has yet to be peer-reviewed), scientists have the ability of antibodies from eight people who recovered from COVID to reverse the mutated form of the virus that infects 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% when the E484K mutated form was presented. And it is reduced in samples from one person if presented with another mutation at the same position. However, the neutralizing ability of samples from four people was not affected by the mutation.
In the New York study, scientists investigated the effect of a series of mutations on the ability of antibodies, collected in four people, to neutralize the virus. The researchers found that none of the antibodies were affected by the E484K mutation. Yet, two of the samples saw a decrease in neutralizing ability when challenged with mutations occurring at different positions in the vein protein. It emphasizes the uniqueness of the antibody response produced by different people.
Both of these laboratory studies used only a few samples collected from people who were naturally infected, as opposed to vaccinated, so the results may differ, as we know that immunity obtained through vaccination is generally more robust. Consequently, several research groups have recently released data, as pre-prints, that have identified the impact of this mutation on vaccine protection.
Effect on vaccines
One of these studies, published by scientists in New York, looked at antibodies of 15 people vaccinated with one of the two approved mRNA vaccines (those manufactured by Pfizer / BioNTech and Moderna). The second, published by scientists in Texas in collaboration with Pfizer, looked at antibodies of 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 efficacy of the vaccine against variants carrying the E484K mutation was slightly reduced for some people, it was still within an acceptable level. Decrease in antibody neutralizing ability is measured by ‘vouver change’. For example, the antibodies produced by a flu vaccine will have to see a fold decrease of more than 4 before scientists have to change the vaccine.
The Texas study reported a fold decrease of 1.48 in antibodies, and the New York study reported a decrease of between 1 and 3. However, the Cambridge study found that antibodies of three of the five people had a fold decrease of more than 4 when they were infected with a virus carrying the E484K mutation.
An important difference between the Cambridge and American studies is that the American 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 on the detection of this mutation in B117 should be of more concern to British health officials than the introduction and subsequent spread of the South African variant. However, it is worth noting that the above studies are based on very small sample numbers and that any conclusions should be drawn with caution.
Nevertheless, it emphasizes the importance of investigating the combined effect of multiple mutations as opposed to studying only individuals, as it is unlikely that any single mutation will lead to a complete escape from the natural or vaccine-derived immunity.