If there’s one coronavirus mutation that keeps 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 British variant (B117). This so-called “escape mutation” raised concerns that the approved COVID vaccines against these variants might not be as effective. The E484K mutation hasnow found in the UKVariants too – albeit in only 11 cases.
The coronavirus is slowly mutating and accumulating two single letter mutations per month in its genome. This rate of change is about half that of flu viruses. At the start of the pandemic, few scientists feared that the coronavirus would mutate into something more dangerous. However, this changed quickly in November 2020 when the first “worrying variant” was discovered. The newly discovered variant B117 was associated with the large increase in cases in south-east England and in London.
Receptor binding domain
While any mutations found in emerging variants of the coronavirus should be monitored, scientists are particularly interested in mutations that occur in the spike protein of the virus, particularly in the receptor binding domain (RBD) portion of the spike protein. This section of the virus attaches to our cells and causes infection. Mutations in the RBD can help the virus bind tighter to our cells and become more infectious.
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 allow the virus to evade these antibodies or partially. This is why they are called “escape mutations”. E484K is one such mutation.
The mutation name comes from the position in the RNA chain (the genetic code of the virus) where it occurs (484). The letter E refers to the amino acid that was originally at this point (glutamic acid). And K refers to the amino acid that’s now in that place (lysine).
Several studies have shown that the E484K mutation prevents antibodies that target this position from binding. However, after infection or vaccination, we do not produce antibodies that target only one area of the virus. We produce a mix of antibodies, each targeting different areas of the virus. How harmful it is to lose the effectiveness of antibodies targeting that particular region depends on how much our immune system relies on antibodies targeting that particular site.
Two studies, one in Seattle, the other in new Yorkinvestigated this. In the Seattle study, which is a preprint (meaning it has not yet been peer reviewed), the scientists looked at the ability of antibodies from eight people who had recovered from COVID to mutate Stop the form of the virus-infecting cells – in other words, neutralize the virus.
In samples from three subjects, the ability of the antibodies to neutralize the virus was reduced by up to 90% when presented with the mutated E484K form. And it was reduced in samples from one person when another mutation was presented in the same position. The ability to neutralize samples from four people was not influenced by the mutation.
In the New York study, scientists looked at the effect of a number 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 showed a decrease in neutralization ability when confronted with mutations that occurred at different positions in the spike protein. This highlights the uniqueness of the antibody response generated by different people.
In both laboratory studies, only a few samples were used from people who, unlike those who had been vaccinated, were naturally infected. Hence, results may differ as we know that immunity gained from vaccination is generally more robust. As a result, several research groups recently published data as preprints investigating the effects of this mutation on vaccine-induced protection.
Effect on vaccines
One of those studies published by scientists in New Yorkexamined antibodies from 15 people who were vaccinated with either of the two approved mRNA-based vaccines (manufactured by Pfizer / BioNTech and Moderna). The second, published by scientists in Texas In collaboration with Pfizer, antibodies were tested from 20 people who were vaccinated with the Pfizer / BioNTech vaccine. A third, published by Scientist in Cambridge, England,looked at five people vaccinated with the Pfizer / BioNTech vaccine.
Both the New York and Texas studies showed that the vaccine’s effectiveness in protecting against variants that carry the E484K mutation was slightly reduced for some people, but was still at acceptable levels. The decrease in the ability to neutralize antibodies is measured in “fold change”. For example, the antibodies produced by an influenza vaccine would have to decrease more than four times before scientists would have to change the vaccine.
The Texas study reported a fold decrease in antibodies by 1.48, and the New York study reported a fold decrease between 1 and 3. However, the Cambridge study found that three of the five people decreased antibodies a fold more than 4 when exposed to a virus carrying the E484K mutation.
A key 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 into the UK variant (B117) and used it in their tests has been. This could suggest that the recent reports of the detection of this mutation in B117 should be of greater concern to UK health authorities than the import and subsequent distribution of the South African variant. It should be noted, however, that the above studies are based on very small sample numbers and that conclusions should be drawn with caution.
Nonetheless, it emphasizes the importance of studying the combined effects of multiple mutations rather than just examining individual ones it’s unlikely that any single mutation would lead to a complete escape from natural or vaccine-derived immunity.