Inactivated SARS-CoV-2 Variant Omicron, Lineage XBB (USA/CA-Stanford-109_S21/2022)

Since late 2021, the SARS-CoV-2 Omicron variant has been the most concerning variant. As of December 2022, the newly emerged Omicron subvariants are undergoing convergent evolution, acquiring substitutions at the same residues in the spike (S) protein, such as R346, K444, L452, N460, and F486. For example, the Omicron BQ.1.1 variant, a descendant of Omicron BA.5 and increasingly circulating in Western countries since December 2022, possesses all of the convergent substitutions, such as R346T, K444T, L452R, N460K, and F486V. L452R, N460K, and R346T enhance the binding affinity of the SARS-CoV-2 S protein to human angiotensin-converting enzyme 2 (ACE2), the viral infection receptor, while R346T12,13, K444T13, and F486V contribute to evasion of antiviral humoral immunity induced by vaccination and natural infection with SARS-CoV-2. Similar to observations in BA.5 and BA.2.75, in Omicron subvariants (including BQ.1.1), combinations of S protein substitutions were frequently observed that: (1) evaded antiviral humoral immunity at the expense of reduced ACE2 binding affinity; (2) compensated for the decreased affinity associated with immune evasion substitutions (e.g., L452R and N460K) at the expense of enhanced ACE2 binding affinity.

In addition to the diversification and subsequent convergent evolution of emerging Omicron subtypes (such as BQ.1.1), a recombinant variant named XBB has recently emerged. The Omicron XBB variant likely originated from the recombination of two BA.2 descendants: BJ.1 and BM.1.1.1, a descendant of BA.2.75. While the BQ.1 lineage gradually became dominant in Europe, XBB has become dominant in India and Singapore and spread to multiple countries in December 2022. On October 28, 2022, the World Health Organization (WHO) designated XBB as an Omicron subtype under surveillance. XBB.1 is the variant most resistant to BA.2/5 breakthrough infection serotypes to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of the spike protein, and each region of the recombinant spike protein confers immune evasion and enhances fusogenicity. XBB is the first observed SARS-CoV-2 variant whose fitness is enhanced by recombination rather than substitution.