Omicron-included mutation-induced changes in epitopes of SARS-CoV-2 spike protein and effectiveness assessments of current antibodies

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading globally and continues to rage, posing a serious threat to human health and life quality. Antibody therapy and vaccines both have shown great efficacy in the prevention and treatment of COVID-19, whose development progress and adaptation range have attracted wide attention. However, with the emergence of variant strains of SARS-CoV-2, the neutralization activity of therapeutic or vaccine-induced antibodies may be reduced, requiring long-term virus monitoring and drug upgrade in response to its evolution. In this paper, conformational changes including continuous epitopes (CPs), discontinuous epitopes (DPs) and recognition interfaces of the three representative SARS-CoV-2 spike protein (SP) mutants (i.e., the Delta (B.1.617.2), Mu (B.1.621) and Omicron (B.1.1.529) strains), were analyzed to evaluate the effectiveness of current mainstream antibodies. The results showed that the conformation of SP wild type (WT) and mutants both remained stable, while the local antigenic epitopes underwent significant changes. Sufficient flexibility of SP CPs is critical for effective antibody recognition. The DPs of Delta, Mu and Omicron variants have showed stronger binding to human angiotensin converting enzyme-2 (hACE2) than WT; the possible drug resistance mechanisms of antibodies against three different epitopes (i.e., NTD_DP, RBD1_DP and RBD2_DP) were also proposed, respectively; the RBD2 of Delta, NTD of Mu, NTD and RBD2 of Omicron are deserve more attention in the subsequent design of next-generation vaccines. The simulation results not only revealed structural characteristics of SP antigenic epitopes, but also provided guidance for antibody modification, vaccine design and effectiveness evaluation.

Keywords: Antibody; Drug resistance; Epitopes; SARS-CoV-2; Spike protein.

Fig. 1

Distribution and treatment strategies of COVID-19. a Schematic overview of the SARS-CoV-2 spike protein trimer; b cumulative distribution of confirmed COVID-19 cases worldwide by region (The darker the red, the more people are infected with COVID-19, the darker the blue, the less people are infected); c measures to deal with COVID-19; d a time line of SARS-CoV-2 variants with treatments in blue, vaccines under Emergency Use Authorization (EUA) in red and expectations in green

Fig. 2

a Free energy landscapes of the WT, Delta, Mu, Omicron systems, b the corresponding conformational cluster analyses as well as c the number of clusters over simulations time. The darker the color in FEL diagram, the lower the conformational free energy

Fig. 3

Continuous epitopes analysis of SP. a In SP complexes with antibody, the depth of red color indicates the occurrence probability in the interaction residues between SP and antibodies; b the possible CPs with occurrence probability over 35% from structural biology statistics; c the prediction result with BepiPred-2.0 are colored in blue, the statistical data form RCSB PDB are colored in red, and the overlapped part is the final determined CPs (CP1-CP7)

Fig. 4

The SASA analyses of the WT, Delta, Mu and Omicron systems. a SASA changes at the overall and residual levels; b domain-specific SASA for DPs in the NTD, RBD1 and RBD2 subdomains

Fig. 5

The up and down conformations of RBD. a Three parameters are used to describe the relative position of RBD and S2 in SP: the distance (Dist_1) between Q493-L1034 Ca atoms, the angle (Angle_A) among Q493-K986-L1034 Ca atoms, the dihedral angle (Dihedral) among Q493-F543-V576-K986 Ca atoms; b structural superimposition from the snapshots at 10, 50 and 90 ns in the four systems; c the changes of the three parameters over time