The potential for a global influenza pandemic remains significant with epidemiologic and ecologic indicators revealing the entrenchment of highly pathogenic avian influenza A H5N1 in both wild bird populations and domestic poultry flocks in Asia and in many African and European countries. Indisputably, the single most effective public health intervention in mitigating the devastation such a pandemic could unleash is the availability of a safe and effective vaccine that can be rapidly deployed for pre-exposure vaccination of millions of people. We have developed two vaccinia-based influenza vaccines that are molecularly adjuvanted with the immune-stimulatory cytokine IL-15. The pentavalent Wyeth/IL-15/5Flu vaccine expresses the hemagglutinin, neuraminidase, and nucleoprotein, derived from the H5N1 influenza virus A/Vietnam/1203/2004 and the matrix proteins M1 and M2 from H5N1 A/CK/Indonesia/PA/2003 virus on the backbone of a currently licensed smallpox vaccine. The bivalent MVA/IL-15/HA/NA vaccine expresses only the H5 hemagglutinin and N1 neuraminidase on the modified vaccinia virus Ankara (MVA) backbone. Both vaccines induced cross-neutralizing antibodies and robust cellular immune responses in vaccinated mice and conferred sterile cross-clade protection when challenged with H5N1 virus of a different clade. In addition to having the potential as a universal influenza vaccine, in the event of an impending pandemic, the Wyeth/IL-15/5Flu is also readily amenable for bulk production to cover the global population. For those individuals for whom the use of Wyeth vaccine is contraindicated, our MVA/IL-15/HA/NA offers a substitute or a prevaccine to be used in a mass vaccination campaign similar to the smallpox eradication campaigns of few decades ago.