title: Vectors based on modified vaccinia Ankara expressing influenza H5N1 hemagglutinin induce substantial cross-clade protective immunity.
abstract: BACKGROUND
  New highly pathogenic H5N1 influenza viruses are continuing to evolve with a potential threat for an influenza pandemic. So far, the H5N1 influenza viruses have not widely circulated in humans and therefore constitute a high risk for the non immune population. The aim of this study was to evaluate the cross-protective potential of the hemagglutinins of five H5N1 strains of divergent clades using a live attenuated modified vaccinia Ankara (MVA) vector vaccine.
  
  
  RESULTS
  The replication-deficient MVA virus was used to express influenza hemagglutinin (HA) proteins. Specifically, recombinant MVA viruses expressing the HA genes of the clade 1 virus A/Vietnam/1203/2004 (VN/1203), the clade 2.1.3 virus A/Indonesia/5/2005 (IN5/05), the clade 2.2 viruses A/turkey/Turkey/1/2005 (TT01/05) and A/chicken/Egypt/3/2006 (CE/06), and the clade 2.3.4 virus A/Anhui/1/2005 (AH1/05) were constructed. These experimental live vaccines were assessed in a lethal mouse model. Mice vaccinated with the VN/1203 hemagglutinin-expressing MVA induced excellent protection against all the above mentioned clades. Also mice vaccinated with the IN5/05 HA expressing MVA induced substantial protection against homologous and heterologous AH1/05 challenge. After vaccination with the CE/06 HA expressing MVA, mice were fully protected against clade 2.2 challenge and partially protected against challenge of other clades. Mice vaccinated with AH1/05 HA expressing MVA vectors were only partially protected against homologous and heterologous challenge. The live vaccines induced substantial amounts of neutralizing antibodies, mainly directed against the homologous challenge virus, and high levels of HA-specific IFN-γ secreting CD4 and CD8 T-cells against epitopes conserved among the H5 clades and subclades.
  
  
  CONCLUSIONS
  The highest level of cross-protection was induced by the HA derived from the VN/1203 strain, suggesting that pandemic H5 vaccines utilizing MVA vector technology, should be based on the VN/1203 hemagglutinin. Furthermore, the recombinant MVA-HA-VN, as characterized in the present study, would be a promising candidate for such a vaccine.
authors.affiliation: Department of Virology, Baxter Bioscience, Biomedical Research Center, Orth/Donau, Austria.
authors.forename: Annett
authors.initials: A
authors.lastname: Hessel
authors.forename: Michael
authors.initials: M
authors.lastname: Schwendinger
authors.forename: Georg W
authors.initials: GW
authors.lastname: Holzer
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Orlinger
authors.forename: Sogue
authors.initials: S
authors.lastname: Coulibaly
authors.forename: Helga
authors.initials: H
authors.lastname: Savidis-Dacho
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Zips
authors.forename: Brian A
authors.initials: BA
authors.lastname: Crowe
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kreil
authors.forename: Hartmut J
authors.initials: HJ
authors.lastname: Ehrlich
authors.forename: P Noel
authors.initials: PN
authors.lastname: Barrett
authors.forename: Falko G
authors.initials: FG
authors.lastname: Falkner
mesh_terms: D000818:Animals; D056738:Cross Protection / Q000235:genetics*; D005822:Genetic Vectors; D006388:Hemagglutinins / Q000096:biosynthesis*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry*; D051379:Mice; D013045:Species Specificity; D014611:Vaccination; D014612:Vaccines / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D006388:Hemagglutinins; D014612:Vaccines