The COVID-19 pandemic that emerged around December 2019 claimed millions of lives. For vaccine development, S protein on viral envelope that binds to ACE2 receptor on cells for entry was identified as vaccine candidate. S protein consists of Receptor Binding Motif (RBM) in the S1 subunit followed by the S2 subunit with an intermediate furin cleavage site. A stabilized version of S protein with 2 proline residues was used as antigen. Overall, most vaccines exhibited efficacy between 80 and 95%. However, being a RNA virus that is prone to mutations along with selection pressure on S protein and frequent use of convalescent plasma led to evolution of variants. These variants are responsible for multiple waves of infection observed globally. In our review, we discuss current data on vaccines and its efficacy in neutralizing SARS-CoV-2 from Wuhan and its variants. Further, our docked mutations observed in variants on the ACE2-S complex cryo-EM structure show that mostly the S1 domain is under selection pressure where major mutations occur in the N terminal domain (NTD), RBM and junction near S1-S2 subunit. Therefore, this review would be a reference for development of new candidate antigen(s) with better efficacy against variants.