Initially, sequence comparisons of neutralizing epitopes on the S protein suggested that the antigenic variations between classical and emerging non-S INDEL (highly virulent) PEDV strains are the major reason for vaccine failure (Table 3) . Several regions on PEDV S protein were recognized as containing the neutralizing epitopes, including a CO-26 K equivalent epitope COE (aa 499-638), SS2 (aa 748-755), SS6 (aa 764-771) and 2C10 (aa 1368-1374) (Chang et al., 2002; Ge et al., 2012; Kang et al., 2005; Oszvald et al., 2007) . Compared with classical PEDV vaccine strains, several SNPs leading to 8-11 individual amino acid changes located on COE epitope and 1-2 amino acid changes located on SS6 epitope were observed in highly virulent PEDV strains . Among them, three (A522S, A554 S and G599S) and one (Y766S) were serine substitutions (Table 3 ) (Chiou et al., 2015; Hao et al., 2014; Huang et al., 2013; . In addition, bioinformatics predicted that the S protein of highly virulent PEDV strains changed in primary/secondary structures, high-specificity N-glycosylation sites, potential phosphorylation sites, and palmitoylation sites (Chiou et al., 2015; Hao et al., 2014) . These changes may affect viral antigenicity and change viral neutralizing activity.