Antibody Evasion Properties of SARS-CoV-2 Omicron Sublineages

Abstract

The identification of the Omicron variant (B.1.1.529.1 or BA.1) of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in Botswana in November 20211 immediately raised alarms due to the sheer number of mutations in the spike glycoprotein that could lead to striking antibody evasion. We2 and others3-6 recently reported results in this Journal confirming such a concern. Continuing surveillance of Omicron evolution has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K mutation (BA.1+R346K) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike mutations while lacking 13 spike mutations found in BA.1. We therefore extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.12,3,5,6. These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)7, which had retained appreciable activity against BA.1 and BA.1+R346K2-4,6 . This new finding shows that no presently approved or authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant.

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2

“…3). A recent study using in vitro neutralization assays reported that there were differences in the reactivity of several mAbs against these different Omicron sublineages 38 . These observations suggest that BA.2 are antigenically distinct from BA.1 and BA.1.1, which is consistent with the data performed convalescent hamster sera 3 .…”

“…In addition, S309 and REGN10987/REGN10933, which we previously showed were not effective against BA.1, reduced lung virus titers [mean reduction in viral titer = 2.7 and 2.2 log 10 (PFU/g), respectively], although the difference was not statistically signi cant between the REGN10987/REGN10933-and control mAb-treated groups. A recent study showed that the neutralizing activity of S309 against BA.2 is lower than that against BA.1 38 . The disparity between the in vitro and in vivo ndings may be due in part to the attenuated infectivity (~100fold lower levels) of BA.2 compared to BA.1 in hamster lungs (Fig.…”

A structural dynamic explanation for observed escape of SARS-CoV-2 BA.2 variant mutation S371L/F

“…SASA was computed in PyRosetta using SasaCalc() and a 10 Å probe. The epitope accessibility score was then plotted versus the escape values measured in Liu et al 9 or Iketani et al 10 for each mutation using Seaborn regplot(). Note that the raw reported fold-change in IC 50 was first converted to fold-change relative to wild-type (IC 50,mutant /IC 50,WT ) and then the natural logarithm was taken prior to plotting.…”

“… Antibody epitope accessibility in RBD up versus RBD down correlates with observed S371L/F escape. Escape ( y-axis ) measured by Liu et al 9 and Iketani et al 10 against S371L, S371F, K417N, or E484A for 11 antibodies with solved crystal structures is plotted versus RBD down epitope accessibility ( x-axis ). Class 1–4 antibodies are annotated by color as shown in the legend at right.…”

“…Additionally, REGN10987 (the largest outlier from the trend) features steric constraints on binding in the closed state resulting from clashes between the light chain and the adjacent RBD despite an epitope that is highly accessible. 10 against S371L, S371F, K417N, or E484A for 11 antibodies with solved crystal structures is plotted versus RBDdown epitope accessibility (xaxis). Class 1-4 antibodies are annotated by color as shown in the legend at right.…”