COVID’s latest twist: New XBB variant gains strength through recombination, outsmarting immunity and amplifying fusogenicity

May 19, 2023 Abraham Smith

In a study recently published in the journal nature communicationResearchers are studying the virological characteristics of the XBB variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Learn: Virological properties of the SARS-CoV-2 XBB variant derived from the recombination of two omicron subvariants. Image Source: Kichigin / Shutterstock.com

What is the XBB variant?

In December 2022, SARS-CoV-2 omicron subvariants underwent convergent evolution, with substitutions occurring at the same spike (S) protein residues. XBB, a new recombinant variant, has since emerged in parallel with the diversification and convergent evolution of novel omicron subvariants such as BQ.1.1.

The Omicron XBB variant is believed to have arisen from the combination of two progeny of BA.2, BJ.1 and BM.1.1.1, a progeny of BA.2.75. Previous studies have described the virological properties of BQ.1; However, the properties of XBB remain unclear.

About the study

In the present study, researchers examine the virological characteristics of the SARS-CoV-2 subvariant Omicron

Convalescent sera were obtained from fully vaccinated individuals infected with SARS-CoV-2 BA.2 and BA.5 infections. In addition, four dose vaccine sera were obtained from subjects who received bivalent vaccine BA.1, monovalent vaccine and bivalent vaccine BA.5. Virus sequences were confirmed by viral ribonucleic acid (RNA) sequencing analysis.

About 100 random sequences were retrieved from each of the Omicron subvariants BA.1, BA.2, BA.4, and BA.5, as well as 20 random sequences from BQ.1.1, BA.2.75, BJ.1, and BM .1.1.1 to determine the To determine the overall relationship of BJ.1 and BM.1.1.1, the XBB parent lines, to other Omicron variants. These sequences were compared to the reference genome of SARS-CoV-2 Wuhan-Hu-1 and converted into a multiple sequence alignment.

The epidemic dynamics associated with viral lineages were analyzed using viral genomic surveillance data from the Global Initiative on Sharing All Influenza Data (GISAID) database. In addition, the researchers estimated the relative effective reproduction number (R_e) for XBB-related lineages in India, epidemic frequencies of XBB and BQ.1 in each country, and country-specific and global R_eValues of the BQ.1 and XBB lines in the countries where these variants were the predominant circulating strains.

Results

A single recombination breakpoint at genome position 22,920 was identified by a robust recombination assessment of the aligned sequence set that was unique to all XBB sequences and matched the Wuhan-Hu-1 reference genome. The data set showed no recombination in the BJ.1 and BM.1 sequences.

The most recent common ancestor (tMRCA) of the XBB clade was present in July 2022.; However, the tMRCA of BJ.1 and

XBB.1 showed a 30-fold resistance to breakthrough sera of BA.2 infection. Likewise, the substitutions V83A, Q183E, Y144del, L368I, R346T, F486S, V445P and F490S were significantly resistant to BA.2 infection sera.

While single substitutions have little impact on immune resistance, multiple substitutions within the XBB.1 S-protein act together to create resistance to the humoral immunity induced by breakthrough BA.2 infection. BA.2.75 showed significant resistance to BA.5 infection sera compared to BA.2. In addition, XBB.1 was associated with significant resistance to breakthrough sera of BA.5 infection.

The XBB.1S receptor binding domain (RBD) had lower binding affinity to the human ACE2 receptor compared to the original BA.2S RBD. The R346T substitution in both XBB.1 and BQ.1.1 increased the binding affinity of BA.2 S RBD to ACE2. The improved binding affinity of XBB.1S RBD over BA.2S RBD was due to three specific substitutions in the RBD, including L368I, R346T, and N460K.

The XBB.1 pseudovirus was 7.6-fold more infectious than the BA.2 pseudovirus because this viral RBD underwent a marked increase in pseudovirus infectivity due to two substitutions of R346T and L368I.

Y144del and G252V, both N-terminal domain (NTD) substitutions, significantly reduced pseudovirus infectivity. In comparison, the V83A substitutions in NTD significantly increased pseudovirus infectivity.

Conclusions

XBB exhibits superior fitness and resistance to antiviral humoral immunity induced by breakthrough infections of earlier Omicron variants. Therefore, local SARS-CoV-2 variants with higher fitness are likely to spread globally, similar to what has been observed in XBB. These results underscore the importance of continued viral genome surveillance to continually assess the risk of new SARS-CoV-2 variants.

Magazine reference:

Tamura T, Ito J, Uriu K, et al. (2023). Virological properties of the SARS-CoV-2 XBB variant derived from the recombination of two omicron subvariants. nature communication, 14(1), 1-20. doi:10.1038/s41467-023-38435-3

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in pharmaceutical sciences and she holds a bachelor’s degree in pharmacy. Her educational background allowed her to develop an interest in anatomical and physiological sciences. Her college project work on “The Manifestations and Causes of Sickle Cell Anemia” laid the foundation for a lifelong fascination with human pathophysiology.

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