Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies

Abstract

Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariant BQ.1.1 became predominant in many countries in December 2022. The subvariants carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lose antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remaine weakly active. BQ.1.1 is also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals are low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increases these titers, which remains about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increases more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitates their spread in immunized populations and raises concerns about the efficacy of most available mAbs.

Fig. 1. Improved detection of infectious Omicron BA.1 in nasopharyngeal swabs using IGROV-1 cells.

A retrospective series of 135 RT+qPCR+ nasopharyngeal swabs from COVID-19 patients, harboring Delta (n = 53) or Omicron BA.1 (n = 82) variants was collected. a Viral RNA loads, measured by RT-qPCR. The samples were ranked from high to low viral RNA load (low to high Ct). Viral titers were measured in Vero-TMPRSS2 (b) and IGROV-1 cells (c). Delta and Omicron BA.1-positive samples are depicted in the left and right panels, respectively. d Comparison of infectious titers for Delta and BA.1 samples in IGROV-1 cells (left panel). e Percentage of samples harboring detectable infectious Delta (middle panel) or BA.1 virus (right panel) using Vero and IGROV-1 cells. A two-sided Chi-square test was performed ****p < 0.0001. Source data are provided as a Source Data file.

Fig. 2. Mutations present in the spike proteins of Omicron subvariants.

NTD, N-terminal domain; RBD, receptor binding domain; RBM, receptor binding motif; SD1, subdomain 1; SD2, subdomain 2; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2. The BA.1 and BA.2 mutations are relative to the ancestral Wuhan sequence, the BA.2.75.2 mutations are relative to BA.2, the BA.4.6 and BQ.1.1 relative to BA.4/BA.5. Data are adapted from.

Fig. 3. Neutralization activity of therapeutic monoclonal antibodies against BQ.1.1, BA.2.75.2, and BA.4.6.

a. Neutralization curves of monoclonal antibodies. Dose–response analysis of the neutralization by the indicated antibodies or their clinical combinations. Evusheld: Cilgavimab and Tixagevimab. Ronapreve: Casirivimab and Imdevimab. Data are mean ± s.d. of n = 2 independent experiments. b IC50 values in ng/ mL for each antibody against the indicated viral strains. *ED50 against BA.2 and BA.5 are from. Source data are provided as a Source Data file.

Fig. 4. Sensitivity of SARS-CoV-2 D614G and Omicron subvariants to sera from vaccinated, or infected-then-vaccinated individuals.

Neutralization titers of the sera against the indicated viral variants are expressed as ED50. a. Neutralizing activity of sera from individuals vaccinated with 3 doses of Pfizer vaccine. Sera were sampled at 1 month (left panel; n = 18) and 4 months (right panel; n = 10) after the third dose. b Neutralizing activity of sera from Pfizer-vaccinated recipients after BA.1/BA.2 breakthrough infection. Sera were sampled about 3 months (left panel; n = 16) and 8 months (right panel; n = 13) after the breakthrough. c Neutralizing activity of sera from Pfizer-vaccinated recipients after BA.5 breakthrough infection. Sera were sampled about 2 months after the breakthrough (n = 15). The dotted line indicates the limit of detection (ED50 = 30). Black lines represent the median values. Two-sided Friedman test with Dunn’s test for multiple comparisons was performed between each viral strain at the different time points; *p < 0.05; **p < 0.001; ***p < 0.0001; ****p < 0.0001. 1 month post-third dose: D614G versus BA.2.75.2, P < 0.0001; D614G versus BQ.1.1, P < 0.0001; D614G versus BA.4.6, P < 0.0001; BA.1 versus BA.2.75.2, P < 0.0001; BA.1 versus BQ.1.1, P = 0.0005; BA.5 versus BA.2.75.2, P < 0.0001; BA.5 versus BQ.1.1, P = 0.0033. 4 months post-third dose: D614G versus BA.5, P = 0.0152; D614G versus BA.2.75.2, P < 0.0001; D614G versus BQ.1.1, P = 0.0003; D614G versus BA.4.6, P = 0.0025; BA.1 versus BA.2.75.2, P = 0.0123. 3 months post-breakthrough BA.1/2: D614G versus BA.5, P = 0.0034; D614G versus BA.2.75.2, P < 0.0001; D614G versus BQ.1.1, P < 0.0001; D614G versus BA.4.6, P = 0.0071; BA.1 versus BA.2.75.2, P < 0.0001; BA.1 versus BQ.1.1, P < 0.0001. 8 months post-breakthrough BA.1/2: D614G versus BA.5, P = 0.0024; D614G versus BA.2.75.2, P < 0.0001; D614G versus BQ.1.1, P < 0.0001; D614G versus BA.4.6, P = 0.0173; BA.1 versus BA.2.75.2, P < 0.0001; BA.1 versus BQ.1.1, P < 0.0001. 2 months post-breakthrough BA.5: D614G versus BA.1, P = 0.0192; D614G versus BA.2.75.2, P < 0.0001; D614G versus BQ.1.1, P = 0.0009; BA.5 versus BA.2.75.2, P < 0.0001; BA.2.75.2 versus B.4.6, P = 0.0002. Source data are provided as a Source Data file.