Letter to the Editor from Masaki Imai, D.V.M., Ph.D., et al.

Three sublineages of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have serially transitioned into globally dominant forms — first BA.1, then BA.2, and then BA.5. As of October 2022, most circulating omicron variants belong to BA.5. However, the prevalence of BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant) is increasing rapidly in several countries, including the United States and India. BA.2 and BA.5 variants have been shown to have less sensitivity to certain monoclonal antibodies than previously circulating variants of concern.1-5 Notably, as compared with BA.5 and BA.2, BQ.1.1 and XBB carry additional substitutions in the receptor-binding domain of the spike (S) protein, which is the major target for vaccines and therapeutic monoclonal antibodies for coronavirus disease 2019 (Covid-19). These subvariants may, therefore, be more immune-evasive than BA.5 and BA.2.Figure 1.In Vitro Efficacy of Therapeutic Monoclonal Antibodies and Antiviral Drugs against Omicron Subvariants.

We assessed the efficacy of therapeutic monoclonal antibodies against omicron BQ.1.1 (hCoV-19/Japan/TY41-796/2022; TY41-796) and XBB (hCoV-19/Japan/TY41-795/2022; TY41-795), which were isolated from patients. The BQ.1.1 isolate had three more substitutions (R346T, K444T, and N460K) in its receptor-binding domain than a BA.5 (hCoV-19/Japan/TY41-702/2022) isolate (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The XBB isolate had nine more changes (G339H, R346T, L368I, V445P, G446S, N460K, F486S, F490S, and the wild-type amino acid at position 493) in its receptor-binding domain than a BA.2 (hCoV-19/Japan/UT-NCD1288-2N/2022) isolate (Fig. S1B). To examine the reactivity of monoclonal antibodies against these subvariants, we determined the 50% focus reduction neutralization test (FRNT50) titer of the monoclonal antibodies by using a live-virus neutralization assay. REGN10987 (marketed as imdevimab), REGN10933 (marketed as casirivimab), COV2-2196 (marketed as tixagevimab), COV2-2130 (marketed as cilgavimab), and S309 (the precursor of sotrovimab) did not neutralize the BQ.1.1 or XBB isolates even at the highest FRNT50 value (>50,000 ng per milliliter) tested (Figure 1A and Table S1). LY-CoV1404 (marketed as bebtelovimab), which effectively neutralizes1,3-5 omicron BA.1, BA.2, BA.4, and BA.5, had no efficacy against BQ.1.1 or XBB. Both combinations of monoclonal antibodies tested (i.e., imdevimab–casirivimab and tixagevimab–cilgavimab) failed to neutralize either BQ.1.1 or XBB. These results suggest that imdevimab–casirivimab, tixagevimab–cilgavimab, sotrovimab, and bebtelovimab may not be effective against BQ.1.1 or XBB in the clinical setting.

Link to article in The New England Journal of Medicine by Masaki Imai, D.V.M., Ph.D., et al.

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