Although subunit vaccines based on the full-length S protein may elicit potent immune responses and/or protection, studies have found that antibodies induced by some of these vaccines mediate enhancement of viral infection in vitro, as in the case of SARS-CoV (Kam et al., 2007; Jaume et al., 2012), raising safety concerns for the development of full-length S protein-based subunit vaccines against SARS-CoV and MERS-CoV. In contrast, RBD-based subunit vaccines comprise the major critical neutralizing domain (Du and Jiang, 2015; Zhou et al., 2019). Therefore, these vaccines may generate potent neutralizing antibodies with strong protective immunity against viral infection. S1 subunit, for example, is much shorter than the full-length S protein, but it is no less able to induce strong immune responses and/or protection against viral infection (Li et al., 2013; Adney et al., 2019). Thus, this fragment can be used as an alternative target for subunit vaccine development. Despite their ability to induce immune responses and/or neutralizing antibodies, NTD and S2 as the targets of subunit vaccines are less immunogenic, eliciting significantly lower antibody titers, cellular immune responses, and/or protection than the other regions, such as full-length, S1, and RBD (Guo et al., 2005; Jiaming et al., 2017). Therefore, in terms of safety and efficacy, the RBD and/or S1 of S protein could be applied as critical targets for the development of subunit vaccine candidates against SARS-CoV, MERS-CoV, SARSr-CoV, and MERSr-CoV. Because of its conserved amino acid sequences and high homology among different virus strains (Elshabrawy et al., 2012; Zhou et al., 2018), the S2 subunit has potential to be used as a target for the development of universal vaccines against divergent virus strains.