While HI titers against heterologous virus (cross-clade) were significantly reduced compared to HI titers against homologous virus in the current study, the heterologous virus titers were generally above 1:100, and in humans, a HI titer of 1:40 has been associated with protection [41] , and so all of the constructs might be protective after multiple immunizations. At the same time, the titers observed in mice may not be the same as in humans. While HI titers have been associated with protection, H5 HA DNA vaccines described in the current report were not tested for protection against challenge and so there is the possibility that only some of these constructs may not protect against clinical disease or lethal infection.