Several zoonotic influenza virus subtypes (Table 1) including avian subtypes H5N1, H7N9 and H9N2 and swine subtypes H1N1, H1N2 and H3N2 have been occasionally reported to cross the species barrier to infect humans [57]. However, human-to-human transmission of nonhuman viruses has been limited and non-sustained [154]. Viruses in four historical pandemics acquired strong binding to human-type α2,6Neu5Ac receptors for efficient human-to-human transmission [19,155,156,157]. (i) The H1N1 Spanish pandemic in 1918–1919 was found to include at least two strains with distinct receptor-binding properties during the pandemic period [155]. First, viral HAs have a single aa substitution, E190D, in the receptor-binding site (RBS) and bind to both avian-type and human-type receptors. Second, there are two aa substitutions in the HA RBS, E190D and G225D, that enable HA adaptation to bind only to α2,6Neu5Ac receptors. (ii) The H2N2 Asian pandemic in 1957–1958 had virus isolates from two stages of the pandemic. In the early pandemic stage, virus isolates can be divided into three subpopulations based on receptor binding specificities: avian-like viruses with 226Q and 228G in the HA RBS, atypical viruses with Q226L and 228G, and classic human viruses with Q226L and G228S that have preferential binding to avian-type receptors, both avian-type and human-type receptors, and human-type receptors, respectively. In the subsequent stage, all virus isolates have Q226L and G228S substitutions with preferential binding to human-type receptors [156]. (iii) The virus in the H3N2 Hong Kong pandemic in 1968–1969 had the same acquisition of Q226L and G228S substitutions in the HA RBS as that in the H2 pandemic for switching from avian-type to human-type receptor binding preference [157]. (iv) The virus in the H1N1 swine pandemic in 2009–2010 had 190D and 225D in the HA RBS as in the swine H1 HA RBS recognizing human-type α2,6Neu5Ac receptors that are abundant in the porcine lung, which is the main site of swine IAV replication [19,39]. Protein engineering by chimeragenesis and site-directed mutagenesis of H1 proteins suggested that A200T and A227E substitutions in the H1 swine pandemic were responsible for efficient and sustained human-to-human transmission. Molecular modeling revealed hydrogen bond formation between T200 and Q191 in the 190-helix that is important for receptor binding preference of H1 HAs and between E227 and Gal next to Sia [158].