Epsilon variant alterations facilitate immune escape from COVID-19

The Epsilon coronavirus variant, which emerged in California in May 2020, has been causing concern due to its ability to evade specific monoclonal antibodies used in clinics and reduce the effectiveness of antibodies from vaccinated individuals. A recent study, led by scientists from the University of Washington, Vir Biotechnology, and other institutions, has shed light on the variant's unique neutralization-escape strategy.

Published as a First Release paper in Science, the study was conducted by a team of scientists including Matthew McCallum, Alexandra C. Walls, Jessica Bassi, Anna de Marco, and Alex Chen. The research was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Pew Biomedical Scholars Award, and other funding bodies.

The Epsilon variant relies on an indirect and unusual neutralization-escape strategy. The variant's spike protein has three mutations that dampen the neutralizing potency of antibodies induced by current vaccines or past COVID infections. Two of these mutations affect the N-terminal domain on the spike glycoprotein, causing a remodeling of a part of the coronavirus N-terminal domain. This remodeling results in a total loss of neutralization by 10 out of 10 antibodies tested specific to the N-terminal domain in the spike glycoprotein.

Furthermore, the mutation in the receptor binding domain on the spike glycoprotein of the Epsilon variant reduced the neutralizing activity of 14 out of 34 neutralizing antibodies specific to that domain, including clinical stage antibodies. This finding indicates that the Epsilon variant can evade specific monoclonal antibodies used in clinics and reduce the effectiveness of antibodies from the plasma of vaccinated people.

By summer of 2020, the Epsilon variant had diverged into its B.1.427/B.1.429 lineages. The shift in the signal peptide cleavage site in the NTD antigenic supersite, and the formation of a new disulphide bond due to the mutations, are key factors contributing to the variant's immune evasion strategy.

The neutralizing potency of plasma against the Epsilon variant of concern was reduced about 2 to 3.5 fold in the study. This finding underscores the importance of understanding the mechanisms of immune evasion, such as the one found in the Epsilon variant, in countering the ongoing pandemic.

The study was led by David Veesler's lab in the Department of Biochemistry at the University of Washington in Seattle and by Luca Piccoli and Davide Corti of Vir Biotechnology. Other scientists involved included researchers from institutions such as the University of Washington, Fred Hutchinson Cancer Research Center, and Imperial College London, among various international collaborators.

The findings of the study suggest that uncovering mechanisms of immune evasion, such as this newfound mechanism based on signal peptide modification, is as important as variant surveillance through RNA sequencing in countering the ongoing pandemic. Together, such efforts could help to successfully counter the ongoing pandemic.

The DOI for this study published in Science is 10.1126/science.abi7994.

The Veesler lab and its collaborators have been exploring the molecular conformation and infection mechanics of SARS-like coronaviruses for several years. COVID cases from the Epsilon variant increased quickly and it soon became widespread in the United States, and has now been reported in at least 34 other countries. The study's findings underscore the need for continued vigilance and research into emerging coronavirus variants and their immune evasion strategies.