Most studies investigating the characteristics of emerging SARS-CoV-2 variants have been focusing on mutations in the spike proteins that affect viral infectivity, fusogenicity, and pathogenicity. However, few studies have addressed how naturally occurring mutations in the non-spike regions of the SARS-CoV-2 genome impact virological properties. In this study, we proved that multiple SARS-CoV-2 Omicron BA.2 mutations, one in the spike protein and another downstream of the spike gene, orchestrally characterize this variant, shedding light on the importance of Omicron BA.2 mutations out of the spike protein.

• Keywords
• BA.1, BA.2, COVID-19, Omicron, SARS-CoV-2, fusogenicity, growth capacity, immune resistance, pathogenicity,
• MeSH
• COVID-19 virology   MeSH
• Genome, Viral * genetics   MeSH
• Spike Glycoprotein, Coronavirus * genetics   MeSH
• Humans MeSH
• Mutation * MeSH
• SARS-CoV-2 * genetics   pathogenicity   physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Spike Glycoprotein, Coronavirus * MeSH
• spike protein, SARS-CoV-2 MeSH Browser

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

• MeSH
• COVID-19 * MeSH
• Phylogeny MeSH
• Spike Glycoprotein, Coronavirus genetics   MeSH
• Cricetinae MeSH
• Humans MeSH
• Recombination, Genetic MeSH
• SARS-CoV-2 genetics   MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Spike Glycoprotein, Coronavirus MeSH
• spike protein, SARS-CoV-2 MeSH Browser

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

• MeSH
• Biological Assay MeSH
• COVID-19 * MeSH
• Phylogeny MeSH
• Cricetinae MeSH
• Antibodies, Neutralizing MeSH
• Antibodies, Viral MeSH
• SARS-CoV-2 genetics   MeSH
• Amino Acid Substitution MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antibodies, Neutralizing MeSH
• Antibodies, Viral MeSH

• MeSH
• COVID-19 * MeSH
• Humans MeSH
• SARS-CoV-2 * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH