Previous studies have investigated the protective efficacy of these conserved epitopes against lethal influenza challenge in mice and ferrets [7, 20, 21] . DNA vaccination with NP in combination with M2 formulated with Vaxfectin has been shown to protect mice against heterosubtypic challenge with H3N2 and H1N1 viruses [7] . Vaxfectin-formulated DNA vaccine encoding NP+M2 protected mice, but against high challenge doses of H5N1 virus in ferrets it only delayed time to illness and death [20] . However, triple prime with rAd boost regimens of NP in combination with M2 have been shown to protect ferrets against the H5N1 virus, albeit at a relatively low challenge dose [21] . In this study, we evaluated protective immunity induced by NP and M2 alone or in combination with HA in a triple prime, rAd boost regimen against high dose lethal H5N1 challenge. Initially, we tested the ability of DNA immunization with HA alone, NP alone, HA+NP, and HA+NP+M2 to protect against high doses of lethal H5N1 challenge in mice. We then assessed the ability of NP and M2, alone or in combination, to protect ferrets against a high challenge dose of lethal H5N1 virus, when delivered in a triple DNA prime, rAd5 boost regimen. We compared these groups to ferrets immunized with HA alone or in combination with NP+M2.