Abstract
Coronavirus disease-2019 (COVID-19) pandemic gave the opportunity for various vaccine design strategies and their evaluation. However, the emergence of variants severely challenged the efficacy of the COVID-19 vaccines. The changes in the amino acid sequences and corresponding changes in the epitope topology of the variants could be the primary reasons for the loss of antibody binding affinity. The structural deviations in the epitopes may not be the same for all the variants resulting in differential efficacy of the same vaccine against different variants. In this study we performed an in silico evaluation of the strain-specific structural deviations in 15 variants of coronavirus in order to predict the antibody binding affinity and in turn estimate the success/failure of the current vaccines. The spike protein trimer homology models of 15 variants along with the wild type were prepared in close, open and semi-open conformations. The variant models were superposed onto the wild type model to calculate the C α root mean square deviations (RMSD) in their epitopes and ACE2 binding sites. Our results show that both the epitopes and the ACE2 binding sites of variants have RMSDs >35 Å suggesting that such large structural deviations in the epitopes are potentially responsible for the loss of binding affinities of the neutralizing antibodies that are generated in response to the current vaccine shots. Based on our analysis, we further prepared two hand-drawn clover leaf plots one for the main variants and the other for the omicron sub-variants summarizing all the structural deviations in the epitopes and ACE2 binding sites in open, closed and semi-open conformations. These plots serve as quick reference charts to predict the efficacy of current vaccines. For example, large structural deviations that are >20 Å can certainly lead to total loss of the antibody binding. Based on our findings in this study we propose alternative and improved strategies of future vaccine design for COVID-19.