Sat. Jan 22nd, 2022

In their recent study, researchers from Lithuania reported the emergence of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of line B.1.1.523 containing a set of mutations associated with immune escape, including deletion 156_158del, substitution E484K and S494P in Spike (S) protein.

The new SARS-CoV-2 variant lineage B.1.1.523 was added to the list of variants under the World Health Organization Monitoring Section (VUM) on 14 July 2021.

The team conducted an analysis to evaluate the origin of the newly discovered variant as well as predict potential epidemiological impacts and risks. Preliminary phylogenetic analysis indicated that this variant has a distinct viral lineage that may have originated in Russia.

A pre-printed version of the research paper is available at medRxiv* server while the article is undergoing peer review.

Study: Determination of international distribution of novel B.1.1.523 SARS-CoV-2 lineage.  Image credit: NIAID
Study: Determination of international distribution of novel B.1.1.523 SARS-CoV-2 lineage. Image credit: NIAID

The ever-growing list of SARS-CoV-2 genomic sequences

Genome sequencing has played a crucial role in the development of SARS-CoV-2 vaccines, as well as the understanding of viral development. In many countries, sequencing is used as a tool for epidemiological management of infection. As a result, a large dataset of SARS-CoV-2 genomes has been collected in the GISAID database, which includes more than 3.7 million sequenced genomes from around the world.

As of May 31, 2021, the World Health Organization (WHO) has proposed designations for global SARS-CoV-2 variants of concern (VOC) and variants of interest (VOI) to be used in conjunction with the scientific nomenclature in communicating variants to the public. There are currently five SARS-CoV-2 VOCs: Alpha, Beta, Gamma, Delta and more recently Omnicron circulating worldwide.

Mutation overview in B.1.1.523 genus.  Several other mutations have been observed in the spike protein sequence of the B1.1.523 variant, including E156V, F306L, D614G, E780A, D839V and T1027I.
Mutation overview in B.1.1.523 genus. Several other mutations have been observed in the spike protein sequence of the B1.1.523 variant, including E156V, F306L, D614G, E780A, D839V and T1027I.

What did the researchers do?

The study was conducted as part of a routine analysis of the Lithuanian national sequencing results from national sequencing efforts coordinated by the National Public Health Surveillance Laboratory. Sequences used for the comparative analyzes were downloaded from GISAID.

The distribution of cases of the genus B.1.1.523 across countries at different times.  The time
The distribution of cases of the genus B.1.1.523 across countries at different times. Time “0” indicates the date of the earliest lineage sequence uploaded to the GISAID database. Only sequences having the typical set of S mutations were considered (E484K, S494P, 156_158del). Only those cases corresponding to the top 12 countries with the most widespread detection rate are included in the underlying data. The 12 best countries correspond to the 93% of all cases.

Lineage assignment tool pangolin 3.1.11 was used to assign the most probable lineage to all sequences. Phylogenetic analysis of full genomes was performed to elucidate the potential origin of the lineage and transmission cluster.

The S-protein-based phylogeny was based on the S-protein sequences extracted from GISAID and adjusted to the reference COVID-19 sequence. The recombination detection was performed using either genomic or protein sequence corresponding to the S protein.

What did the researchers find out?

A new SARS-CoV-2 variant, classified as B.1 by PANGO, was identified containing multiple S protein mutations associated with immune escape. The variant was assigned the new movie name B.1.1.523 (https://github.com/cov-lineages/pango-designation/issues/69).

Escape effects of E484, S494P mutations and their combination.  The ΔΔG values ​​indicate relative increase in binding energy compared to the wild-type structure as derived from the FoldX calculations.  ΔΔΔG indicates the minimum difference between ΔΔG of the double mutation and any of the two single point mutations.  The great value - the great synergy (A).  The structure of the antibody and the receptor binding domain of the S-protein complex, which was most significantly affected by the S494P mutation (PDB ID: 7KN5) (B).
Escape effects of the E484, the S494P mutations and their combination. The ΔΔG values ​​indicate a relative increase in binding energy compared to the wild-type structure as derived from the FoldX calculations. ΔΔΔG indicates the minimum difference between ΔΔG of the double mutation and any of the two single point mutations. The great value – the great synergy (A). The structure of the antibody and receptor binding domain of the S-protein complex was most significantly affected by the S494P mutation (PDB ID: 7KN5) (B).

At the time of completion of this study, the total number of cases with the new variant had reached 598 in over 32 countries. It is likely that the rapid increase in the circulation of the Delta variant could have reduced the increase in the B.1.1.523 genus, but the spread of the new SARS-CoV-2 genus did not cease and has even begun to increase.

“Presence and spread of SARS-CoV-2 B.1.1.523 lineage is evident regardless of the rapid spread of the delta variant,” the team emphasizes.

According to analysis, B1.1.523 originated in the Russian Federation and spread across European countries. The sequenced clothes peaked at week 25 and then subsided. A total of 95 transmission clusters have been identified. The peak of the B.1.1.523 transmission intensity was around April – May 2021. The most numerous transmission clusters were detected for the most recent common ancestor (MRCA) originating from Germany and Russia.

Currently, a huge growth of B.1.1.523 can be observed in Germany. Interestingly, the transmission of this lineage has decreased in Russia, where it was most expected to increase. Various diagnostic strategy approaches could explain this in the Russian Federation, where the test is performed on non-randomly selected sources. Alternatively, this can be explained by the steep rise in the Delta variant in Russia, which started a month earlier than in Europe / Germany.

The B.1.1.523 line has three or more mutations that characterize SARS-CoV-2 VOCs, including S: 156-158 del, S: E484K, and S: S494P. S: 156-158 deletion at β-hairpin antigen supersite located in the same region as that of the Delta variant (E156G and 157-158del). E484K mutation has been detected in Beta variant (B.1.351) and VUM Zeta (B.1.1.28). The mutation contributes to SARS-CoV-2 immune system degradation, as evidenced by a significant reduction in convalescent serum neutralization. In addition, S494P mutation is related to 3-5-fold reduced SARS-CoV-2 neutralization in sera. However, this mutation was not as potent upon neutralization as E484K.

The team warns that with a combination of 158del, E484K and S494P mutations, the B1.1.523 lineage should remain on the epidemiologists’ observation list as one of the most worrying SARS-CoV-2 genera.

The Maximum Probability Tree (ML) revealed several interesting properties of B.1.1.523. The base of the lines leading to the B.1.1.523 sequences with a complete set of expected S protein mutations branches into clusters of sequences with the triple S: 156_158del deletion. The sequences with the additional substitutions at S: 484 and S: 494 positions appear further in evolution. However, no clear indication was found for the sequential introduction of the mutations S: E484K, S: S494P to form the B.1.1.523 line.

The team shows by molecular modeling that the triple deletion del156-158 could reduce interaction in at least one monoclonal antibody. When combined with other immunoscape-enhancing mutations in RBD, this may result in a highly resistant variant of immunity.

The Delta variant also has sequence changes at the S protein residues 156-158, which may induce immune escape and recombination with the B.1.1.523 variant, or the de novo introduction of the N484K and S494P mutations could make the Delta variant even more dangerous.

This variant needs to be carefully observed and studied to keep an eye out for new mutations that could cause even more damage in the Covid-19 pandemic, ”the team concludes.

*Important message

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered essential, guide clinical practice / health-related behavior or be treated as established information.

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