Identification of the distribution of the novel B.1.1.523 SARS-CoV-2

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In their most recent study, researchers from Lithuania reported the occurrence of a novel variant of coronavirus 2 (SARS-CoV-2) of severe acute respiratory syndrome B.1.1.523, which contains a number of mutations associated with immune defense, including deletion 156_158del, substitution E484K and S494P in the spike (S) protein.

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

The team performed an analysis to assess the origin of the newly discovered variant and to predict potential epidemiological impacts and risks. A preliminary phylogenetic analysis showed that this variant has a unique lineage of virus that could have originated in Russia.

A pre-print version of the research paper is available on the site medRxiv* Server while the article is being peer reviewed.

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

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

Genome sequencing played a critical role in developing the SARS-CoV-2 vaccine, as well as in understanding viral evolution. Sequencing is used as a tool for epidemiological infection management in many countries. As a result, a large data set of SARS-CoV-2 genomes was collected in the GISAID database, comprising more than 3.7 million sequenced genomes from around the world.

May 2021, the World Health Organization (WHO) proposed names for global SARS-CoV-2 Variants of Concern (VOC) and Variants of Interest (VOI), which, in addition to the scientific nomenclature, should be used in communication about variants to the public. There are currently five SARS-CoV-2 VOCs in circulation: Alpha, Beta, Gamma, Delta and, more recently, Omnicron.

Mutation overview in the B.1.1.523 line.  Several other mutations were observed in the spike protein sequence of the B1.1.523 variant, including E156V, F306L, D614G, E780A, D839V, and T1027I.
Mutation overview in the B.1.1.523 line. Several other mutations were 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 Lithuanian national sequencing results from national sequencing efforts coordinated by the National Laboratory for Public Health Surveillance. The sequences used for the comparative analyzes were downloaded from GISAID.

The distribution of the cases of the lineage B.1.1.523 to the countries at different points in time.  The time
The distribution of the cases of the lineage B.1.1.523 to the countries at different points in time. The time “0” indicates the date of the earliest ancestry sequence that was uploaded to the GISAID database. Only sequences that have the typical set of S mutations were taken into account (E484K, S494P, 156_158del). Only the cases corresponding to the top 12 countries with the highest detection rate are included in the underlying data. The top 12 countries correspond to 93% of all cases.

The parentage mapping tool Pangolin 3.1.11 was used to assign the most likely parentage to all sequences. A phylogenetic analysis of the full genomes was performed to elucidate the potential origin of the parentage and transmission cluster.

The S protein-based phylogeny was based on the S protein sequences extracted from GISAID and aligned with the COVID-19 reference sequence. 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 by PANGO as B.1, has been identified that contains several S-protein mutations associated with immune escape. The variant received the new trunk name B.1.1.523 (https://github.com/cov-lineages/pango-designation/issues/69).

Escape effects of the mutations E484, S494P 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.  The ΔΔΔG indicates the minimal difference between the ΔΔG of the double mutation and one of the two single point mutations.  The greater the value - the greater the synergy (A).  The structure of the antibody and receptor binding domains of the S-protein complex that was most strongly influenced by the S494P mutation (PDB ID: 7KN5) (B).
Escape effects of the mutations E484, S494P and their combination. The ΔΔG values ​​show a relative increase in the binding energy compared to the wild-type structure, as derived from the FoldX calculations. The ΔΔΔG indicates the minimum difference between the ΔΔG of the double mutation and one of the two single point mutations. The greater the value – the greater the synergy (A). The structure of the antibody and receptor binding domains of the S protein complex was most clearly influenced by the S494P mutation (PDB ID: 7KN5) (B).

At the time this study was completed, the total number of cases with the novel variant in over 32 countries was 598. It is likely that the rapid increase in the spread of the Delta variant may have reduced the rise in the B.1.1.523 ancestry, however, the spread of the novel SARS-CoV-2 lineage has not stopped and has even started to increase.

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

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

An enormous growth of B.1.1.523 can currently be observed in Germany. Interestingly, the transmission of this line has decreased in Russia, where it was most expected to increase. Various strategic diagnostic approaches could explain this in the Russian Federation, where the tests are carried out on sources that are not selected at random. Alternatively, this could be explained by the steep rise in the delta variant in Russia, which started a month earlier than 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 on the β-hairpin antigen supersite, which is in the same region as that for the delta variant (E156G and 157-158del). The E484K mutation was detected in the beta variant (B.1.351) and VUM Zeta (B.1.1.28). The mutation contributes to the evasion of the SARS-CoV-2 immune system, which is reflected in a significant reduction in the neutralization of the recovery serum. In addition, the S494P mutation is associated with a 3-5-fold reduced SARS-CoV-2 neutralization in sera. However, this mutation was not as strong as E484K when neutralized.

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

The maximum likelihood (ML) tree showed several interesting properties of B.1.1.523. The base of the lines leading to the B.1.1.523 sequences with a full set of expected S protein mutations branches into sequence clusters with the triple S: 156_158del deletion. The sequences with the additional substitutions at positions S: 484 and S: 494 continue to appear in evolution. However, no clear indication of the sequential introduction of the mutations S: E484K, S: S494P to form the B.1.1.523 line was found.

The team uses molecular modeling to show that the triple del156-158 deletion could decrease the interaction in at least one monoclonal antibody. Combined with other immune escape enhancing mutations in RBD, this could lead to a highly resistant variant against immunity.

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

This variant needs to be carefully monitored and investigated to look for new mutations that could cause even more damage in the Covid-19 pandemic, ”the team concludes.

*Important NOTE

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


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