The ‘Most Worrying’ Coronavirus E484K Mutant Has Arrived

E484K (in South Africa) mutation evades human antibodies and causes reinfections, but the situation is still manageable.

Shin Jie Yong
Jan 15 · 6 min read
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hen immunologists culture the novel coronavirus — SARS-CoV-2 — in the presence of low amounts of human antibodies, it gained three mutations that endowed it with antibody evasion abilities within 90 days. One of the mutations is E484K in the SARS-CoV-2 spike protein, where amino acid at position 484 mutated from glutamic acid (E) to lysine (K).

“The experiment wasn’t necessarily supposed to work,” said Jason S. McLellan, an associate professor specializing in virology and co-author of the study (released as pre-print) that artificially evolved SARS-CoV-2 in the lab. The immunologists were surprised because as little as 1–3 mutations could make the coronavirus “completely resistant [to antibody] neutralization.”

This pre-print study is further supported by another pre-print that did a mutational screening study, and found that the E484K mutation is the most crucial in helping SARS-CoV-2 escape human antibodies. As a result, the antibodies were 10-times less effective at neutralizing SARS-CoV-2 with E484K mutation, at least in cultured cells in the lab.

Notably, a relief is that this pre-print study found no evidence of antibody evasion from the N501Y mutation — another important emerging SARS-CoV-2 mutant with increased infectivity—consistent with existing evidence.

The real alarm would probably begin when these all mutations, plus newer unknown ones, come together and propagate among human populations.

21th Jan 2021 update: A more recent pre-print also found that the 501Y.V2 variant or strain — containing K417N, N501Y, and E484K mutations — in South Africa escaped antibodies isolated from persons previously infected with SARS-CoV-2. “These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines,” the authors concluded.

The E484K mutation has arrived

SARS-CoV-2 with the E484K mutation was first detected in South Africa in late December 2020. It has now spread to at least 12 other countries. While it does not appear to cause a more severe Covid-19, scientists are concerned that E484K would undermine vaccine effectiveness.

Ravindra Gupta, professor of microbiology specializing in HIV drug resistance at the University of Cambridge, said that it’s this E484K mutation “the most worrying of all,” not the infamous N501Y mutant in the U.K.

However, presently, no data indicate how prevalent the E484K mutant is. While this mutant may be the most worrisome in terms of immune evasion, at least we can be glad that the E484K mutation doesn’t up the virus’s infectivity and transmissibility like the D614G and N501Y mutations. The real alarm would probably begin when these all mutations, plus newer unknown ones, come together and propagate among human populations.

It’s nearly a year into the Covid-19 pandemic declared in March 2020. Given the pandemic scale, SARS-CoV-2 has already replicated numerous times. With each viral replication comes the chance of mutation. So, it’s not surprising that the E484K mutation has arrived. Maybe we can be thankful that SARS-CoV-2 has a low mutation rate and genetic diversity; otherwise, we might see more disastrous mutations now.

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E484K mutation and reinfection

The first global reinfection case occurred in August 2020 due to the D614G mutation. Recently, in December 2020, we encounter the first reinfection case from SARS-CoV-2 with the N501Y mutation in London. Now, another reinfection has happened with the E484K mutant in Brazil — twice.

In a pre-print, researchers documented a 45-year-old female with no medical comorbidities. In May 2020, she got Covid-19 and recovered with ease. However, in October 2020, she tested positive for SARS-CoV-2 again and developed more severe Covid-19 than the first infection. Researchers then analyzed the SARS-CoV-2 genomes isolated from her clinical samples, and found that the E484K mutant caused the reinfection. The authors conclude, “We report the first case of reinfection from genetically distinct SARS-CoV-2 lineage presenting the E484K spike mutation in Brazil, a variant associated with escape from neutralizing antibodies.”

In another preliminary report, another group of researchers described a 37-year-old woman healthcare worker in Brazil. She also had no comorbidities and contracted SARS-CoV-2 on two separate occasions — in June and October — from SARS-CoV-2 without and with the E484K mutation. But this time, both the first and re-infection produced mild Covid-19, and she recovered.

Indeed, immunity generated from mild infection — as was with the two E484K reinfections cases — may not always be long-lasting.

These reinfection cases show that the E484K mutant can escape pre-existing immunity attained from SARS-CoV-2 without the E484K mutation. Does that mean the E484K mutant would also escape our current Covid-19 vaccines?

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E484K mutation and vaccines

Experts believe the answer is no, although vaccine efficacy might decrease a little. It’s a ‘might’ because there’s no concrete evidence of Covid-19 vaccine resistance now. So, it’s a theoretical extrapolation that the E484K mutation — which evades antibodies in lab-cultured cells and causes reinfections — might lower vaccine efficacy.

As with any other forms of evolution — like antibiotic resistance — the process is gradual. Instantaneous 100% vaccine resistance is improbable. “It’s going to be, over time, likely chipping away at vaccine efficacy, but we’re not going to fall off a cliff tomorrow,” said Paul Bieniasz, a virology professor at the Rockefeller University.

Maybe we can be thankful that SARS-CoV-2 has a low mutation rate and genetic diversity; otherwise, we might see more disastrous mutations now.

Plus, there’s more to immunity than antibodies secreted by B-cells. T-cells is arguably the kingpin of our adaptive immune system: cytotoxic T-cells that kill abnormal cells (e.g., virus-infected or cancerous cells), and helper T-cells that enhance overall immune activities, including B-cell antibodies. Fortunately, the Covid-19 mRNA vaccine does elicit T-cell immunity. So, if SARS-CoV-2 with the E484K mutation evades antibodies, T-cells can help.

Coming back to the E484K reinfection cases, the studies did not measure existing immunity. So, it’s possible that their immunity has waned, making them susceptible to reinfections. Indeed, immunity generated from mild infection — as was with the two E484K reinfection cases —may not always be long-lasting. Even if their immunity were still intact, vaccines are more useful as they can be designed to target key viral regions to elicit more specific and robust immunity than natural infections can.

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Short abstract

The E484K mutation (in South Africa) helps SARS-CoV-2 evade human antibodies, at least in lab-cultured cells. Experts have raised warnings about E484K mutation contributing to vaccine resistance, calling it the ‘most worrying’ mutation now. Indeed, the E484K mutation not only evades antibodies but is capable of causing reinfections. So, vaccines are even more important now since we cannot solely rely on immunity acquired from natural infections. Although vaccine resistance is possible, it won’t develop overnight as evolution is gradual. Plus, the Covid-19 mRNA vaccine also induces T-cell immunity in addition to antibodies, which means the E484K mutant won’t be able to escape vaccine-induced immunity completely.

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

Shin Jie Yong

Written by

Freelance medical writer | Neurobiology MSc postgrad in Malaysia | 2x published academic author | 100+ articles on coronavirus | contact: shinjieyong@gmail.com

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

Shin Jie Yong

Written by

Freelance medical writer | Neurobiology MSc postgrad in Malaysia | 2x published academic author | 100+ articles on coronavirus | contact: shinjieyong@gmail.com

Microbial Instincts

Decoding the microbial angle to health and the microbial world.

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