PN-SIA49 recognizes a novel broadly neutralizing epitope on HA stem region, which is highly conserved among group 1 subtypes that have been confirmed in humans. In particular, this region is broadly shared among H1N1 isolates spanning from 1918 to 2009, H2N2 subtype responsible for the 1957 pandemic, and highly pathogenic and potentially pandemic H5N1 influenza virus. Finally, PN-SIA49 is protective in mice when given after lethal challenge with either H1N1 or H5N1 virus. This suggests its great potential as broad-spectrum monoclonal antibody for in vivo treatment of influenza virus infections.