Vaccination of poultry against avian influenza is of high priority, in particular after the dramatic spread of subtype H5N1 in Asia, Africa and Europe. Newcastle disease virus (NDV) has been developed as a vector for the expression of the main immunogen of avian influenza virus, hemagglutinin (HA). An NDV vector based vaccine has several advantages. It allows easy serological differentiation between infected and vaccinated animals by the detection of antibodies against non-HA influenza proteins. Moreover, it can be administered easily to large numbers of animals by spray or drinking water. We recently showed that chickens could be protected against infection with highly pathogenic avian influenza virus (HPAIV) A/chicken/Italy/8/98 (H5N2) after immunization with a recombinant Newcastle disease virus, NDVH5m, which expresses the homologous hemagglutinin. Here, we describe that immunization with NDVH5m conferred only partial protection against lethal infection with heterologous HPAIV A/duck/Vietnam/TG24-01/05 (H5N1). Comparison of amino acid sequences of both H5 proteins showed only 93.6% amino acid identity. Therefore, a new NDV recombinant (NDVH5Vm) was generated which expresses the H5 protein of HPAIV A/chicken/Vietnam/P41/05 (H5N1). This recombinant virus protected chickens against lethal infection with HPAIV H5N1 (Vietnam) already after one immunization. Our data thus show that application of a vector-based vaccine in the control of influenza may require adaptation of the vaccine to currently circulating viruses.