title: Newcastle disease virus-vectored vaccines expressing the hemagglutinin or neuraminidase protein of H5N1 highly pathogenic avian influenza virus protect against virus challenge in monkeys.
abstract: H5N1 highly pathogenic avian influenza virus (HPAIV) causes periodic outbreaks in humans, resulting in severe infections with a high (60%) incidence of mortality. The circulating strains have low human-to-human transmissibility; however, widespread concerns exist that enhanced transmission due to mutations could lead to a global pandemic. We previously engineered Newcastle disease virus (NDV), an avian paramyxovirus, as a vector to express the HPAIV hemagglutinin (HA) protein, and we showed that this vaccine (NDV/HA) induced a high level of HPAIV-specific mucosal and serum antibodies in primates when administered through the respiratory tract. Here we developed additional NDV-vectored vaccines expressing either HPAIV HA in which the polybasic cleavage site was replaced with that from a low-pathogenicity strain of influenza virus [HA(RV)], in order to address concerns of enhanced vector replication or genetic exchange, or HPAIV neuraminidase (NA). The three vaccine viruses [NDV/HA, NDV/HA(RV), and NDV/NA] were administered separately to groups of African green monkeys by the intranasal/intratracheal route. An additional group of animals received NDV/HA by aerosol administration. Each of the vaccine constructs was highly restricted for replication, with only low levels of virus shedding detected in respiratory secretions. All groups developed high levels of neutralizing antibodies against homologous and heterologous strains of HPAIV and were protected against challenge with 2 x 10(7) PFU of homologous HPAIV. Thus, needle-free, highly attenuated NDV-vectored vaccines expressing either HPAIV HA, HA(RV), or NA have been developed and demonstrated to be individually immunogenic and protective in a primate model of HPAIV infection. The finding that HA(RV) was protective indicates that it would be preferred for inclusion in a vaccine. The study also identified NA as an independent protective HPAIV antigen in primates. Furthermore, we demonstrated the feasibility of aerosol delivery of NDV-vectored vaccines.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-8007, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: DiNapoli
authors.forename: Baibaswata
authors.initials: B
authors.lastname: Nayak
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yang
authors.forename: Brad W
authors.initials: BW
authors.lastname: Finneyfrock
authors.forename: Anthony
authors.initials: A
authors.lastname: Cook
authors.forename: Hanne
authors.initials: H
authors.lastname: Andersen
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres-Velez
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Siba K
authors.initials: SK
authors.lastname: Samal
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Alexander
authors.initials: A
authors.lastname: Bukreyev
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics*; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D009439:Neuraminidase / Q000235:genetics*; D009522:Newcastle disease virus / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D057134:Antibodies, Neutralizing; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009439:Neuraminidase