In this study, we show that prevaccination serum samples have baseline heterosubtypic HA Ab binding activity to both Group 1 and 2 HA subtypes, including H5 and H7, to which these subjects are most likely unexposed because of their US geographic location. The IgM and IgG Abs to H5 increased significantly after the H5N1 vaccination, whereas this did not happen for IgG Abs to H3. F10-like IgG Abs are also detected in pre-immune serum samples and increased significantly in H5N1 vaccinees. A low level of serum anti-HA Abs that bind and neutralize H5N1 viruses has been reported to be age and influenza exposure dependent [9, 10] . Other investigators have reported enhanced levels of HA-directed anti-H5N1 neutralizing Abs in healthy donors after boosting with unrelated human influenza H1N1/ H3N2 seasonal vaccines [5, 11, 12] . These serum Abs may be directed to the Group 1 stem pocket on HA. Indeed, Corti et al [5] showed that a majority of 2007 and 2008 seasonal vaccinees had preexisting neutralizing Ab titers against pseudotyped H5N1 viruses that markedly increased after seasonal vaccination and that the HA stem-pocket directed Abs were present at relatively low levels, compared with Abs that bind to the globular head of HA.