title: Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets.
abstract: BACKGROUND
  Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic.
  
  
  RESULTS
  Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 10(6) 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses.
  
  
  CONCLUSIONS
  The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Amorsolo L
authors.initials: AL
authors.lastname: Suguitan
authors.forename: Josephine
authors.initials: J
authors.lastname: McAuliffe
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Mills
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Greg
authors.initials: G
authors.lastname: Duke
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Luke
authors.forename: Brian
authors.initials: B
authors.lastname: Murphy
authors.forename: David E
authors.initials: DE
authors.lastname: Swayne
authors.forename: George
authors.initials: G
authors.lastname: Kemble
authors.forename: Kanta
authors.initials: K
authors.lastname: Subbarao
mesh_terms: D000818:Animals; D002645:Chickens; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005289:Ferrets; D007115:Immunization Schedule; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005585:Influenza in Birds / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
chemical_list: D007252:Influenza Vaccines; D014613:Vaccines, Attenuated