In mice, DNA/rAd5 vaccination with NP and M2 from the H1N1 PR/8 strain induced both humoral and cellular immune responses that protected against lethal H5N1 challenges [12] . However, the mouse model is not ideal for the evaluation of H5N1 infection and vaccines due to differences in HA receptor specificity and distribution, influenza pathogenicity, as well as clinical symptomatology [13] [14] [15] [16] [17] . Infection in the ferret shows greater similarity to human infection in terms of anatomical distribution and disease. Outbred ferrets exhibit severe lethargy, fever, weight loss, and transient lymphopenia, as well as viral replication in the upper and lower respiratory tract, brain, and multiple systemic organs after infection with various strains of H5N1 virus. Thus, this model is widely considered to be more reflective of human influenza infection [13, 18, 19] . While we continued to evaluate the protective efficacy of NP and M2 in the mouse model, we extended our investigation into the ferret model in this study.