Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Abstract

The BQ and XBB subvariants of SARS-CoV-2 Omicron are now rapidly expanding, possibly due to altered antibody evasion properties deriving from their additional spike mutations. Here, we report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals boosted with a WA1/BA.5 bivalent mRNA vaccine. Titers against BQ and XBB subvariants were lower by 13- to 81-fold and 66- to 155-fold, respectively, far beyond what had been observed to date. Monoclonal antibodies capable of neutralizing the original Omicron variant were largely inactive against these new subvariants, and the responsible individual spike mutations were identified. These subvariants were found to have similar ACE2-binding affinities as their predecessors. Together, our findings indicate that BQ and XBB subvariants present serious threats to current COVID-19 vaccines, render inactive all authorized antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.

Keywords: BQ.1; BQ.1.1; COVID-19; SARS-CoV-2; XBB; XBB.1; antibody evasion; mRNA vaccine; neutralizing monoclonal antibody; receptor binding affinity.

Graphical abstract

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. 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 2

Serum neutralization of Omicron subvariants BQ.1, BQ.1.1, XBB, and XBB.1 (A) Neutralization of pseudotyped D614G and Omicron subvariants by sera from five different clinical cohorts, with their clinical information summarized in Table S1. The limit of detection is 100 (dotted line). Error bars represent geometric mean ± geometric SD. Values above the symbols denote the geometric mean ID₅₀ values, and values beneath the symbols denote the numbers of samples that lost neutralization activity. Values on the lower left show the sample size (n) for each group. The fold reduction in geometric mean ID₅₀ value for each variant compared to D614G is also shown above the symbols. Comparisons were made by two-tailed Wilcoxon matched-pairs signed-rank tests. ^∗∗∗p < 0.001; ^∗∗∗∗p < 0.0001. (B) Antigenic map based on the serum neutralization data from (A). Virus positions are represented by closed circles whereas serum positions are shown as open squares. Sera are colored by group. Both axes represent antigenic distance with one antigenic distance unit (AU) in any direction corresponding to a 2-fold change in neutralization ID₅₀ titer. See also Table S1 and Figure S3.

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.

Figure S2

Pseudovirus neutralization IC₅₀ values for mAbs against BQ and XBB subvariants and point mutants, related to Figure 3 Pseudovirus neutralization IC₅₀ values for mAbs against D614G, Omicron subvariants, and point mutants of BQ.1, BQ.1.1, XBB, and XBB.1 in the background of BA.4/5 or BA.2. See also Figure 3.

Figure 4

Structural analysis of mutational effects on binding of mAbs (A–F) Modeling of how (A) Q183E affects mAb C1520 neutralization, and how (B) and (C) K444T, (D) and (E) V445P, and (F) F490S affect RBD class 3 mAbs. Interactions are shown as yellow dotted lines and clashes are indicated as red asterisks.

Figure 5

Receptor binding affinities of Omicron subvariant spikes Each spike was produced and purified as prefusion-stabilized trimers, and their binding to human ACE2 was measured by SPR.

Figure S3

Antigenic map of BQ and XBB subvariants in relation to SARS-CoV-2 variants and sarbecoviruses, related to Figure 2 Antigenic map of BQ.1, BQ.1.1, XBB, and XBB.1 in relation to sarbecoviruses. See also Figure 2.