Influenza (flu) virus is the cause of major respiratory illness in humans resulting in 20,000–40,000 deaths annually in the United States alone  and killing millions in pandemic years. Viral subtypes are classified on the basis of the sequences of HA and neuraminidase (NA) surface proteins. Currently only strains of the H1N1, H3N2 subtypes and the B-type viruses circulate in human population. In recent years, however, certain strains of highly pathogenic avian influenza (H5N1) have been identified as the causative agents of a severe form of flu in humans, and it has been suggested that these have the potential to cause a pandemic .
Influenza viruses infect cells of the respiratory tract by first binding to the plasma membrane and then entering the cell through the endocytotic pathway. Hemagglutinin (HA) is an important and the most abundant influenza virus surface antigen (membrane glycoprotein) that is highly topical in influenza research and it is responsible for both binding and fusion. It contains two disulfide-linked polypeptide chains, HA1 and HA2-subunit, a relatively hydrophobic sequence of amino acids referred to as the fusion peptide. HA is the primary target of neutralizing antibodies during infection, and its sequence undergoes genetic drift and shift in response to immune pressure. Thus, it is constantly mutating, and consequently new vaccines must be developed each year against the new variants. Although HA2 is considerably more conserved than HA1 (Table 1, approximately 90% vs. 67% for Influenza A H1 and H3 subtypes in the surface-exposed regions) and might serve as a “universal” influenza vaccine candidate if it were to provide sufficient immunogenicity and protection), early mapping studies of antigenic regions on HA revealed that neutralizing antibodies are directed only against the receptor binding HA1 subunit . HA2- interacting residues consisted largely of residues (7–46) and (290–321) of HA1 (Fig. 1).