Due to their genetic diversity and the availability of several significantly different isolates, avian influenza H5N1 viruses provide a valuable and challenging disease model for evaluating broad immune responses generated by potential adenovirus vectors. The external hemagglutinin (HA) glycoprotein mediates receptor binding, fusion, and can generate both strong antibody and cell-mediated immune responses [16] which can be directly assayed and provide useful comparison of adenovirus platforms. Highly pathogenic avian influenza H5N1 viruses have spread throughout domestic and aquatic bird populations in South East Asia and the World Health Organization (WHO) has confirmed 500 clinical cases of H5N1 cross-transmission into humans. Despite the limited incidence of human-to-human-transmission, high mortality rates (.60%) and continuous evolution of the virus represent a concern for future influenza pandemics [17, 18] . The emergence of pandemic swine-like H1N1 influenza A virus isolates in early 2009 highlights the need to generate cross-protective and lasting immune responses against diverging human and zoonotic influenza viruses. In addition to evaluation of different adenovirus platforms, the development of improved influenza vaccines would also help in better preparation against emerging pandemic viruses and could reduce the impact of infection on public health.