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Background: Highly-pathogenic avian influenza virus (HPAIV) and Newcastle disease virus (NDV) are the two most important poultry viruses in the world. Natural low-virulence NDV strains have been used as vaccines over the past 70 years with proven track records. We have previously developed a reverse genetics system to produce low-virulent NDV vaccine strain LaSota from cloned cDNA. This system allows us to use NDV as a vaccine vector for other avian pathogens. Methodology/Principal Finding: Here, we constructed two recombinant NDVs (rNDVs) each of which expresses the hemagglutinin (HA) gene of HPAIV H5N1strain A/Vietnam/1203/2004 from an added gene. In one, rNDV (rNDV-HA), the open reading frame (ORF) of HA gene was expressed without modification. In the second, rNDV (rNDV-HAF), the ORF was modified so that the transmembrane and cytoplasmic domains of the encoded HA gene were replaced with those of the NDV F protein. The insertion of either version of the HA ORF did not increase the virulence of the rNDV vector. The HA protein was found to be incorporated into the envelopes of both rNDV-HA and rNDV-HAF. However, there was an enhanced incorporation of the HA protein in rNDV-HAF. Chickens immunized with a single dose of either rNDV-HA or rNDV-HAF induced a high titer of HPAIV H5-specific antibodies and were completely protected against challenge with NDV as well as lethal challenges of both homologous and heterologous HPAIV H5N1. Conclusion and Significance: Our results suggest that these chimeric viruses have potential as safe and effective bivalent vaccines against NDV and. HPAIV. These vaccines will be convenient and affordable, which will be highly beneficial to the poultry industry. Furthermore, immunization with these vaccines will permit serological differentiation of vaccinated and avian influenza field virus infected animals. [ABSTRACT FROM AUTHOR]

H5N1 and H9N2 avian influenza virus subtypes top the World Health Organization's list for the greatest pandemic potential. Inactivated H5N1 vaccines induce limited immune responses and, in the case of live-attenuated influenza virus vaccines (LAIV), there are safety concerns regarding the possibility of reassortment between the H5 gene segment and circulating influenza viruses. In order to overcome these drawbacks, we rearranged the genome of an avian H9N2 influenza virus and expressed the entire H5 hemagglutinin open reading frame (ORF) from the segment 8 viral RNA. These vectors had reduced polymerase activities as well as viral replication in vitro and excellent safety profiles in vivo. Immunization with the dual H9-H5 influenza virus resulted in protection against lethal H5N1 challenge in mice and ferrets, and also against a potentially pandemic H9 virus. Our studies demonstrate that rearranging the influenza virus genome has great potential for the development of improved vaccines against influenza virus as well as other pathogens. [ABSTRACT FROM AUTHOR]