The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to rage due to emergence of the Omicron variant and its descendant subvariants.1,2,3,4,5,6,7,8,9,10 Although the BA.5 subvariant is globally dominant at this time (Figure 1A), a diverse array of Omicron sublineages have arisen and are competing in the so-called “variant soup”.11 It has become apparent that four new subvariants are rapidly gaining ground on BA.5, raising the specter of yet another wave of infections in the coming months. BQ.1 and BQ.1.1 were first identified in Nigeria in early July and then expanded dramatically in Europe and North America, now accounting for 67%, 35%, and 47% of cases in France, the United Kingdom, and the United States, respectively (Figure 1A). XBB and XBB.1 were first identified in India in mid-August and quickly became predominant in India, Singapore, and other regions in Asia (Figure 1A). BQ.1 and BQ.1.1 evolved from BA.5, whereas XBB and XBB.1 resulted from a recombination between two BA.2 lineages, BJ.1 and BA.2.75 (Figure 1B). These two sublineages are continuing to evolve and diversify, with an ever-increasing complexity of spike mutations. However, the spike protein of the predominant BQ.1 subvariant harbors the K444T and N460K mutations in addition to those found in BA.5, with BQ.1.1 having an additional R346T mutation (Figures 1C and S1). Strikingly, the spike of the predominant XBB subvariant has 14 mutations in addition to those found in BA.2, including 5 in the N-terminal domain (NTD) and 9 in the receptor-binding domain (RBD), whereas XBB.1 has an additional G252V mutation (Figures 1C and S1). The rapid rise of these subvariants and their extensive array of spike mutations are reminiscent of the appearance of the first Omicron variant last year, thus raising concerns that they may further compromise the efficacy of current COVID-19 vaccines and monoclonal antibody (mAb) therapeutics. We now report findings that indicate that such concerns are, sadly, justified, especially so for the XBB and XBB.1 subvariants.

Figure 1. The rise of SARS-CoV-2 Omicron BQ.1, BQ.1.1, XBB, and XBB.1 subvariants

(A) Frequencies of Omicron subvariants from the Global Initiative on Sharing All Influenza Data (GISAID). Variants were designated according to their Pango dynamic lineage classification.12 Minor sublineages of each subvariant were grouped together with their parental variant. The values in the upper left corner of each box denote the cumulative number of sequences for all circulating viruses in the denoted time period.

(B) Unrooted phylogenetic tree of Omicron subvariants along with other main SARS-CoV-2 variants. The scale bar indicates the genetic distance.

(C) Key spike mutations found in XBB and XBB.1 in the background of BA.2 and in BQ.1 and BQ.1.1 in the background of BA.4/5. Del, deletion. The positions of these mutations on the spike trimer are shown in Figure S1.

Figure S1. Key spike mutations of BQ and XBB subvariants, related to Figure 1

(A and B) Key mutations of BQ.1 and BQ.1.1 in the context of BA.4/5 (A), and key mutations of XBB and XBB.1 in the context of BA.2 (B).

See also Figure 1.

Figure 3. Resistance of Omicron subvariants to monoclonal antibody neutralization

(A) Footprints of NTD- and RBD-directed antibodies tested are outlined, and mutations within BQ.1, BQ.1.1, XBB, and XBB.1 are highlighted in red.

(B) The fold changes in neutralization IC50 values of BQ.1, BQ.1.1, XBB, XBB.1, and the individual mutants compared with BA.4/5 or BA.2, with resistance colored red and sensitization colored green. The raw IC50 values are shown in Figure S2.

See also Figure S2.

Therefore, it is alarming that these newly emerged subvariants could further compromise the efficacy of current COVID-19 vaccines and result in a surge of breakthrough infections as well as re-infections. However, it is important to emphasize that although infections may now be more likely, COVID-19 vaccines have been shown to remain effective at preventing hospitalization and severe disease even against Omicron35,36,37,38 as well as possibly reducing the risk of post-acute sequelae of COVID-19 (PASC or long COVID).39,40,41

Lastly, we found that the spikes of BQ and XBB subvariants have similar binding affinities to hACE2 as the spikes of their predecessors (Figure 5), suggesting that the recently observed growth advantage for these novel subvariants is likely due to some other factors. Foremost may be their extreme antibody evasion properties, especially considering the extensive herd immunity built up in the population over the last three years from infections and vaccinations. BQ.1, BQ.1.1, XBB, and XBB.1 subvariants exhibit far greater antibody resistance than earlier variants, and they may fuel yet another surge of COVID-19 infections. We have collectively chased after SARS-CoV-2 variants for over two years, and yet, the virus continues to evolve and evade. This continuing challenge highlights the importance of developing vaccine and mAb approaches that protect broadly and anticipate the antigenic trajectory of SARS-CoV-2.