3.4. Spike mutations and its role in emergence of antibody
escape phenotypes
The mutations at the antibody binding sites and their conservation
within the NTD or RBD raises the chances of escape from neutralizing
antibodies through naturally occurring spike mutations. Here, we found
several mutations in the antibody binding sites in either NTD or RBD
with at least one variation in either of the analyzed lineages (Alpha,
Beta, Gamma, Delta or Omicron). Notably, the Omicron variant (BA.1 and
BA.2) showed the highest mutations (20 aa and-18 aa respectively) at
different mAb binding epitopes (Figure 4A). These data are consistent
with the recent experimental evidence which suggests the decreased
neutralization efficacy of few monoclonal antibodies against the Omicron
variant [22]. Similarly, majority of the antibody binding epitopes
are highly mutated in different SARS-CoV-2 variants. The highest
mutations were found in the epitopes of highly neutralizing mAbs (4-10
aa changes) whereas, less neutralizing antibodies were not affected by
mutations in either of the variants. Interestingly, 5 out of 74 mAb
binding sites had no mutations in the SARS-CoV-2 variants, but these
mAbs have less neutralization potential, which predicts the chances of a
natural selection based on antibody neutralization of SARS-CoV-2 (Figure
4A). In addi-tion, analysis of the Kd (dissociation constant) and IC50
values of the mAbs suggest a strong binding affinity to wildtype spike
protein. However, the mAb binding affinity has decreased with respect to
the spike variants of SARS-CoV-2 and the IC50 values
have increased which shows the potential chances of escape from
neutralizing anti-bodies (Supplementary Table 2). The decrease in
affinity of mAbs towards the spike variants is clearly demonstrated by
the increased Kd and IC50 values of mAbs including the well
characterized REGN10933, LY-CoV555, LY-CoV016, and REGN10987. The data
suggest that consequences in host adaptation along with other factors
including im-mune pressure might trigger the chances of emergence of
antibody escape variants with increased tropism and transmissibility.