Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) seriously threatens public health and safety. Genetic variants determine the expression of SARS-CoV-2 structural proteins, which are associated with enhanced transmissibility, enhanced virulence, and immune escape. Vaccination is encouraged as a public health intervention, and different types of vaccines are used worldwide. However, new variants continue to emerge, especially the Omicron complex, and the neutralizing antibody responses are diminished significantly. In this review, we outlined the uniqueness of SARS-CoV-2 from three perspectives. First, we described the detailed structure of the spike (S) protein, which is highly susceptible to mutations and contributes to the distinct infection cycle of the virus. Second, we systematically summarized the immunoglobulin G epitopes of SARS-CoV-2 and highlighted the central role of the nonconserved regions of the S protein in adaptive immune escape. Third, we provided an overview of the vaccines targeting the S protein and discussed the impact of the nonconserved regions on vaccine effectiveness. The characterization and identification of the structure and genomic organization of SARS-CoV-2 will help elucidate its mechanisms of viral mutation and infection and provide a basis for the selection of optimal treatments. The leaps in advancements regarding improved diagnosis, targeted vaccines and therapeutic remedies provide sound evidence showing that scientific understanding, research, and technology evolved at the pace of the pandemic.