When researchers cultivate the SARS-CoV-2 virus with minimal human antibodies, it develops three mutations, including E484K, which enables it to escape immune responses within just 90 days. This specific mutation occurs in the spike protein, changing the amino acid at position 484 from glutamic acid (E) to lysine (K).

“The experiment wasn’t specifically designed to succeed,” stated Jason S. McLellan, an associate professor of virology and co-author of the study that artificially evolved SARS-CoV-2 in a laboratory setting. The team was surprised to find that just 1 to 3 mutations could render the virus entirely resistant to neutralization by antibodies.

Supporting this pre-print study is another that highlights the significance of the E484K mutation in allowing SARS-CoV-2 to evade human antibodies. In laboratory conditions, antibodies were found to be ten times less effective against the virus with this mutation.

Fortunately, the study also indicated no signs of antibody evasion from the N501Y mutation, another variant linked to increased infectivity, which aligns with existing data.

The true concern may arise when these mutations, along with newer variants, proliferate among human populations.

21st January 2021 update: A more recent pre-print has revealed that the 501Y.V2 variant — containing K417N, N501Y, and E484K mutations — identified in South Africa has the ability to evade antibodies from individuals previously infected with SARS-CoV-2. The researchers concluded, “These findings underscore the potential for reinfection with variants that differ antigenically and may indicate reduced efficacy of current spike-based vaccines.”

The E484K variant was first discovered in South Africa at the end of December 2020 and has since spread to at least twelve other nations. While it does not seem to lead to more severe cases of Covid-19, there are concerns regarding its impact on vaccine effectiveness.

Ravindra Gupta, a microbiology professor with expertise in HIV drug resistance at the University of Cambridge, emphasized that the E484K mutation is “the most alarming of all,” surpassing the well-known N501Y variant from the UK.

Currently, there is no data indicating the prevalence of the E484K variant. Although it poses significant risks concerning immune evasion, it does not appear to enhance the virus's infectivity or transmissibility like the D614G and N501Y mutations. The real concern will likely emerge when these mutations, along with others yet to be discovered, circulate widely among the human population.

It has been nearly a year since the Covid-19 pandemic was declared in March 2020. Given the extensive spread of SARS-CoV-2, the virus has replicated numerous times, allowing ample opportunity for mutations. Therefore, the emergence of the E484K variant is not surprising. Thankfully, the virus's relatively low mutation rate has prevented more severe mutations thus far.

The first global case of reinfection occurred in August 2020, linked to the D614G mutation. In December 2020, the first reinfection case involving the N501Y mutation was reported in London. Now, Brazil has recorded two instances of reinfection involving the E484K variant.

In one pre-print study, researchers described a 45-year-old woman with no underlying health conditions who recovered from Covid-19 in May 2020 but tested positive again in October 2020, experiencing more severe symptoms upon reinfection. Genetic analysis revealed that the reinfection was due to the E484K mutant. The authors stated, “We document the first case of reinfection from a genetically distinct SARS-CoV-2 lineage presenting the E484K spike mutation in Brazil, a variant associated with evasion of neutralizing antibodies.”

Another preliminary report focused on a 37-year-old female healthcare worker in Brazil, also without underlying health issues, who contracted SARS-CoV-2 twice — once in June and again in October — with the first infection lacking the E484K mutation. Fortunately, both infections were mild, and she recovered.

Indeed, immunity developed from mild infections, as seen in the two E484K reinfection cases, may not provide lasting protection.

These reinfection cases illustrate that the E484K variant can bypass the immunity that follows infection with SARS-CoV-2 lacking the E484K mutation. This raises the question of whether the E484K variant could also evade current Covid-19 vaccines.

Experts largely believe the answer is no, although some reduction in vaccine efficacy is possible. However, there's currently no solid evidence indicating that Covid-19 vaccines are ineffective against this mutation. Thus, it remains a theoretical concern that the E484K mutation — which can evade antibodies in lab conditions and cause reinfections — might diminish vaccine effectiveness.

As with any evolutionary process, such as antibiotic resistance, this change is gradual. The likelihood of sudden and complete vaccine resistance is low. “Over time, it may chip away at vaccine efficacy, but we’re not going to face a crisis overnight,” explained Paul Bieniasz, a virology professor at Rockefeller University.

Returning to the subject of the E484K reinfection cases, the studies did not assess existing immunity levels. It’s possible that the individuals’ immunity had diminished, making them more vulnerable to reinfection. Mild infections do not always result in enduring immunity. Even if immunity were still robust, vaccines tend to induce stronger responses targeting specific viral regions compared to natural infections.

Summary

The E484K mutation, first identified in South Africa, enables SARS-CoV-2 to evade human antibodies, at least in laboratory settings. Experts have issued warnings regarding the potential for this mutation to contribute to vaccine resistance, labeling it the “most concerning” mutation currently. The E484K mutation not only allows for immune evasion but also has been linked to reinfection cases. Consequently, vaccines remain crucial, as reliance solely on immunity from natural infections is inadequate. While vaccine resistance may develop, it will not occur abruptly, as evolution is a gradual process. Furthermore, the Covid-19 mRNA vaccines stimulate T-cell immunity in addition to antibody production, suggesting that the E484K variant will not entirely escape vaccine-induced protection.