Potential Targets for Development of SARS-CoV and MERS-CoV Subunit Vaccines
The S protein of SARS-CoV and MERS-CoV plays a vital role in receptor binding and membrane fusion. Thus, the S protein, but not other structural proteins, is the major antigen to induce protective neutralizing antibodies to block viruses from binding their respective receptor and thus inhibit viral infection (Bisht et al., 2004; Buchholz et al., 2004; Bukreyev et al., 2004; Yang et al., 2004). As a result, the S protein is also a major target for the development of subunit vaccines against SARS-CoV and MERS-CoV. Both full-length S protein and its antigenic fragments, including S1 subunit, NTD, RBD, and S2 subunit, can serve as important targets for the development of subunit vaccines (Guo et al., 2005; Mou et al., 2013; Wang et al., 2015; Jiaming et al., 2017; Zhou et al., 2018).
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.
In addition to the S protein, the N protein of SARS-CoV and MERS-CoV may serve as an additional target for the development of subunit vaccines. Unlike S protein, the N protein has no ability to elicit neutralizing antibodies to block virus-receptor interaction and neutralize viral infection, but it may induce specific antibody and cellular immune responses (Liu et al., 2006; Zheng et al., 2009). Several immunodominant B-cell and T-cell epitopes have been identified in the N protein of SARS-CoV and MERS-CoV, some of which are conserved in mice, non-human primates, and humans (Liu et al., 2006; Chan et al., 2011; Veit et al., 2018). Other proteins, such as M protein, can be used as potential targets of SARS-CoV and MERS-CoV subunit vaccines. Notably, SARS-CoV M protein-derived peptides have immunogenicity to induce high-titer antibody responses in the immunized animals (He et al., 2005b), suggesting the potential for utilizing this protein to develop subunit vaccines.