Researchers at the Polish Academy of Sciences in Warsaw have identified a substrain of the recently emerged B.1.1.7 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may confer resistance to antibody neutralization.
The SARS-CoV-2 virus is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that has now claimed the lives of more than 2.35 million people.
The substrain of the B.1.1.7 variant of concern (VOC) contains mutations that have previously been shown to compromise the binding of neutralizing antibodies.
Tomasz Lipniacki and colleagues say mutations in the receptor-binding domain (RBD) of the viral spike protein are of particular concern, especially those identified in the receptor-binding motif (RBM).
The spike protein is the surface structure the virus uses to bind to and infect cells by attaching to the host cell receptor angiotensin-converting enzyme 2 (ACE2).
The researchers say the mutations could eventually lead to “immune escape” strains that can reinfect convalescent individuals and reduce the efficacy of the vaccines currently being used in mass immunization efforts.
“Such mutants may hinder the efficiency of existing vaccines and expand in response to the increasing after‐infection or vaccine‐induced seroprevalence,” writes the team.
A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
The B.1.1.7 variant has spread rapidly since mid-October 2020
The B.1.1.7 variant has rapidly spread since mid-October 2020, and by January 2021, it constituted about 80% of all SARS-CoV-2 genomes sequenced in England.
The high transmissibility of this VOC may be expressed in terms of its replicative advantage – defined as the ratio of the VOC reproduction number to that of non-VOC strains.
To date, a number of studies have estimated the replicative advantage as lying somewhere between 1.47 and 2.24.
As is the case with all viral strains, the B.1.1.7 variant will continue to mutate, and given its significant replicative advantage, any mutations acquired are likely to spread globally.
“As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution,” say the researchers.
What did the current study involve?
Using the Global Initiative on Sharing Avian Influenza Data (GISAID) database, Lipniacki and colleagues estimated growth rates of the mutations that B.1.1.7 has acquired.
This revealed a substrain with an L18F substitution in the spike protein that is rapidly growing in the UK.
This leucine‐to‐phenylalanine substitution in residue 18 was first reported to have occurred in a VOC strain genome collected on December 4th, 2020.
As of February 5th, 2021, as many as 850 spikes L18F VOC genomes had been reported in England.
Based on data collected between December 7th, 2020 and January 17th, 2021, the researchers showed that the L18F substrain had spread exponentially in England. They estimated a replicative advantage of 1.70 relative to the remaining B.1.1.7 substrains.
RBM mutations are particularly concerning
Lipniacki and colleagues say that mutations in the RBD of the spike protein are particularly concerning, especially substitutions E484K and S494P found in the RBM.
Importantly, the LI8F mutation has expanded in the South African variant 501Y.V2 that contains the spike mutations E484K and N501Y. Studies have suggested that E484K may compromise the binding of class 2 neutralizing antibodies, while the A501V mutation compromises the binding of class 1 antibodies.
Furthermore, in a 2021 study published in Science, the S494P substitution was characterized as an escape mutation, along with six other escape residues in the RBM that included F490.
In the current study, Lipniacki and colleagues also identified F490S as a potential escape mutation.
What do the authors advise?
“These mutations may potentially lead to immune escape mutants, resulting in reinfection of convalescent individuals and lowering efficacy of current vaccines,” warn the researchers.
“Propagation of such mutations is facilitated by high replicative advantage of the VOC strain and potential selection due to the increasing number of convalescent or immunized individuals,” they add.
Correspondingly, a study published in 2021 showed that L18F substitution compromises the binding of neutralizing antibodies, suggesting that the replicative advantage of L18F mutants may be partly associated with the ability to infect seroprevalent individuals (who already have anti-SARS-CoV-2 antibodies).
“In turn, propagation of mutations in escape residues (L18, E484, F490S, or S494) on the VOC strain suggests an increasing selection pressure resulting from the growth of the seroprevalent fraction of the population of England,” says Lipniacki and colleagues.
“This trend can be enhanced by the ongoing English vaccination program, in which the relatively large time span between the first and second dose can be a contributing factor,” concludes the team.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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