To assess the extent of immune escape of the SARS-CoV-2 Omicron variant, we first mapped its mutations on the RBD and compared these regions with the binding epitopes of some previously reported antibodies (Lu et al., 2021; Yu et al., 2020; Figure S1). According to the spatial overlapping of antibody epitopes and viral mutations, the RBD-targeting antibodies can be grouped into three types: those that bind to the RBM, those that bind the cryptic epitopes hidden or partially hidden inside the trimeric interface, and antibodies that bind to lateral surface epitopes outside the trimeric interface (Figure 1A). This classification was comparable to a study of a large panel of SARS-CoV-2 antibodies, which classified epitopes into RBM, inner face, and outer face (Hastie et al., 2021), corresponding to our groups of RBM, cryptic epitopes, and lateral surface epitopes. Evidently, more mutations were involved in the epitopes of apex RBM-binding antibodies than the other two clusters (Figure 1B). To confirm this finding, we measured the binding and neutralization titer of plasma collected from 7 vaccine recipients who received three doses of inactivated SARS-CoV-2 vaccine. The average median binding titer (ED50) of serum declined by 12.8-fold for Omicron RBD, while the neutralizing potency (average median neutralizing titer, ID50) decreased by 5.1-fold against Omicron pseudovirus (Figures 1C, S2A, and S2B). Interestingly, we found that some vaccinees had high binding and neutralizing antibody titers against the wild-type (WT) SARS-CoV-2 but relatively low neutralization titers against the Omicron variant. To understand the underlying mechanism, we performed epitope binning by saturating the RBM of the SARS-CoV-2 RBD with ACE2, and then loaded plasma to allow the binding of non-RBM antibodies (Figures 1D, S2C, and S2D). The Spearman’s rank correlation test was applied to measure the potential relationship between ID50 with RBM- or non-RBM-binding antibodies. This analysis revealed a high correlation between the binding of non-RBM a