protection against challenge with an anti-genically similar H5N1 infl uenza virus A/Hong Kong/483/97. Th e immunogenicity and protective effi cacy of the vaccine were comparable in mice both with and without pre-existing immunity to Ad5, indicating that the BAd3 vector was not suppressed by high levels of pre-existing Ad5 immuni-ty. Unfortunately, mice that received only human Ad5 vaccine vectors were not in-cluded in the challenge studies, although it would be predicted that Ad5 vectors would fail to aff ord protection in the presence of immunity to Ad5. Th ese data, therefore, add to the existing literature showing that novel Ad vectors can eff ectively circum-vent immunity to Ad5.A particularly interesting aspect of this study is the demonstration that a heterolo-gous prime-boost regimen using both bo-vine and human Ad vectors elicited higher HA inhibition titers than did homologous regimens of either vector alone. Moreover, the heterologous regimen also protected against infl uenza virus challenge in the presence of immunity to Ad5, suggesting the potential utility of such combination vaccine regimens. Based on these obser-vations, it is possible that an optimal regi-men may consist of two Ad vectors that are serologically distinct from each other and that both evade immunity to Ad5.Future studies must evaluate the de-gree to which the BAd3-H5HA vaccine will protect against genetically more di-vergent strains of H5N1 infl uenza virus. Moreover, the BAd3 vector system will need to be assessed in greater detail for stability, manufacturability, and scale-up feasibility. Additional biologic aspects of the BAd3 vector will also need to be clarifi ed, such as its cellular receptors, its tropism