Furthermore, it acts as a critical factor for tissue tropism and the determination of host range (45). Notably, S protein is one of the vital immunodominant proteins of CoVs capable of inducing host immune responses (45). The ectodomains in all CoVs S proteins have similar domain organizations, divided into two subunits, S1 and S2 (43). The first one, S1, helps in host receptor binding, while the second one, S2, accounts for fusion. The former (S1) is further divided into two subdomains, namely, the N-terminal domain (NTD) and C-terminal domain (CTD). Both of these subdomains act as receptor-binding domains, interacting efficiently with various host receptors (45). The S1 CTD contains the receptor-binding motif (RBM). In each coronavirus spike protein, the trimeric S1 locates itself on top of the trimeric S2 stalk (45). Recently, structural analyses of the S proteins of COVID-19 have revealed 27 amino acid substitutions within a 1,273-amino-acid stretch (16). Six substitutions are located in the RBD (amino acids 357 to 528), while four substitutions are in the RBM at the CTD of the S1 domain (16). Of note, no amino acid change is seen in the RBM, which binds directly to the angiotensin-converting enzyme-2 (ACE2) receptor in SARS-CoV (16, 46). At present, the main emphasis is knowing how many differences would be required to change the host tropism. Sequence comparison revealed 17 nonsynonymous changes between the early sequence of SARS-CoV-2 and the later isolates of SARS-CoV. The changes were found scattered over the genome of the virus, with nine substitutions in ORF1ab, ORF8 (4 substitutions), the spike gene (3 substitutions), and ORF7a (single substitution) (4). Notably, the same nonsynonymous changes were found in a familial cluster, indicating that the viral evolution happened during person-to-person transmission (4, 47). Such adaptive evolution events are frequent and constitute a constantly ongoing process once the virus spreads among new hosts (47). Even though no functional changes occur in the virus associated with this adaptive evolution, close monitoring of the viral mutations that occur during subsequent human-to-human transmission is warranted.