“In this study, we identified mutations acquired by Omicron before its outbreak, and tested whether the molecular spectrum of these mutations was consistent with the cellular environment of human hosts… The molecular spectrum of mutations acquired by the progenitor of Omicron…
The molecular spectrum of mutations acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but resembled the spectra associated with virus evolution in a mouse cellular environment”
Image by Cmdragon – Own work, CC BY-SA 4.0
Pre-outbreak Omicron mutations in the spike protein significantly overlap with mutations in mouse-adapted SARS-CoV-2.
The molecular docking-based predictions suggested that the RBD of Omicron exhibited higher binding affinity for mouse ACE2 than that of RBD encoded in the reference SARS-CoV-2 genome, further suggesting an evolutionary history in mice (Fig. 5B). And as expected, the mutations detected in the RBD of the other four VOCs of SARS-CoV-2 as well as those of variants isolated from chronically infected human patients showed no apparent changes in their binding affinity for mouse ACE2 compared with the reference RBD.
“Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2.”
Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb 1 , retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab 2 , S2X259 3 and S2H97 4 , neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.