title: Immunogenicity and efficacy of flagellin-fused vaccine candidates targeting 2009 pandemic H1N1 influenza in mice.
abstract: We have previously demonstrated that the globular head of the hemagglutinin (HA) antigen fused to flagellin of Salmonella typhimurium fljB (STF2, a TLR5 ligand) elicits protective immunity to H1N1 and H5N1 lethal influenza infections in mice (Song et al., 2008, PLoS ONE 3, e2257; Song et al., 2009, Vaccine 27, 5875-5888). These fusion proteins can be efficiently and economically manufactured in E. coli fermentation systems as next generation pandemic and seasonal influenza vaccines. Here we report immunogenicity and efficacy results of three vaccine candidates in which the HA globular head of A/California/07/2009 (H1N1) was fused to STF2 at the C-terminus (STF2.HA1), in replace of domain 3 (STF2R3.HA1), or in both positions (STF2R3.2xHA1). For all three vaccines, two subcutaneous immunizations of BALB/c mice with doses of either 0.3 or 3 µg elicit robust neutralizing (HAI) antibodies, that lead to > = 2 Log(10) unit reduction in day 4 lung virus titer and full protection against a lethal A/California/04/2009 challenge. Vaccination with doses as low as 0.03 µg results in partial to full protection. Each candidate, particularly the STF2R3.HA1 and STF2R3.2xHA1 candidates, elicits robust neutralizing antibody responses that last for at least 8 months. The STF2R3.HA1 candidate, which was intermediately protective in the challenge models, is more immunogenic than the H1N1 components of two commercially available trivalent inactivated influenza vaccines (TIVs) in mice. Taken together, the results demonstrate that all three vaccine candidates are highly immunogenic and efficacious in mice, and that the STF2R3.2xHA1 format is the most effective candidate vaccine format.
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, United States of America. ge.liu@vaxinnate.com
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.forename: Bart
authors.initials: B
authors.lastname: Tarbet
authors.forename: Langzhou
authors.initials: L
authors.lastname: Song
authors.forename: Lucia
authors.initials: L
authors.lastname: Reiserova
authors.forename: Bruce
authors.initials: B
authors.lastname: Weaver
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Fu
authors.initials: F
authors.lastname: Hou
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.forename: Jason
authors.initials: J
authors.lastname: Parent
authors.forename: Scott
authors.initials: S
authors.lastname: Umlauf
authors.forename: Alan
authors.initials: A
authors.lastname: Shaw
authors.forename: Lynda
authors.initials: L
authors.lastname: Tussey
mesh_terms: D000818:Animals; D005260:Female; D005408:Flagellin / Q000737:chemistry / Q000235:genetics*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009976:Orthomyxoviridae Infections / Q000453:epidemiology* / Q000517:prevention & control; D058873:Pandemics / Q000517:prevention & control*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; D005408:Flagellin