ABSTRACTWe have utilized a de novo designed two‐stranded α‐helical coiled‐coil template to display conserved α‐helical epitopes from the stem region of hemagglutinin (HA) glycoproteins of influenza A. The immunogens have all the surface‐exposed residues of the native α‐helix in the native HA protein of interest displayed on the surface of the two‐stranded α‐helical coiled‐coil template. This template when used as an immunogen elicits polyclonal antibodies which bind to the α‐helix in the native protein. We investigated the highly conserved sequence region 421–476 of HA by inserting 21 or 28 residue sequences from this region into our template. The cross‐reactivity of the resulting rabbit polyclonal antibodies prepared to these immunogens was determined using a series of HA proteins from H1N1, H2N2, H3N2, H5N1, H7N7, and H7N9 virus strains which are representative of Group 1 and Group 2 virus subtypes of influenza A. Antibodies from region 449–476 were Group 1 specific. Antibodies to region 421–448 showed the greatest degree of cross‐reactivity to Group 1 and Group 2 and suggested that this region has a great potential as a “universal” synthetic peptide vaccine for influenza A. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 144–159, 2016.