DNA vaccines targeting hemagglutinin from 18 subtypes of influenza A virus to antigen-presenting cells confer broad protection

Novel vaccines that confer broad protection against influenza A viruses (IAVs) are urgently needed. Hemagglutinin (HA) is the major influenza antigen targeted by protective immune responses. We have here developed a DNA vaccine that simultaneously presents HA from 18 subtypes of IAV to the immune system. The vaccine consists of a DNA plasmid mixture that encodes a variety of dimeric vaccine proteins. Each dimer expresses two different HAs, as well as a targeting moiety directing the vaccine protein to antigen-presenting cells (APCs). When the vaccine proteins were targeted toward chemokine receptors 1, 3, and 5 (CCR1/3/5) on APC by means of macrophage inflammatory protein 1-alpha (MIP1α) (CCL3), vaccinated mice were broadly protected against infection with H1N1, H3N2, H5N1, and H7N1 influenza viruses. Furthermore, antibody-mediated protection against H1N1 was maintained when the H1 antigen was removed from the plasmid mixture, indicating that the diversity of HAs in the mixture promoted formation of antibodies specific for shared, conservative epitopes. The results may guide the development of a broadly protective influenza A vaccine for humans.