title: Flagellin-HA vaccines protect ferrets and mice against H5N1 highly pathogenic avian influenza virus (HPAIV) infections.
abstract: In order to meet the global demand for rapid production of pandemic influenza vaccines, we have developed a recombinant fusion vaccine platform in which the globular head of hemagglutinin (HA) antigen is genetically fused to bacterial flagellin (a TLR5 ligand). These flagellin-HA fusion vaccine candidates elicit highly protective immunity against a lethal challenge with 2009 pandemic H1N1 (Liu, et al. PLoS ONE 2011; 6:e20928) or H5N1 influenza A/Vietnam/1203/04 (A/VN) infections in mice (Song, et al. Vaccine 2009;27:5875-88). Here we provide the first evidence showing that two A/VN vaccine candidates elicited HA-specific IgG, reduced nasal virus shedding, and conferred full protection against a lethal A/VN infection in ferrets. Furthermore, we show that similar flagellin-HA vaccine candidates of two other H5N1 HPAIV are immunogenic and/or efficacious in mice. Vaccines of A/Indonesia/5/05 (A/IN) induced significant HAI titers to homologous and heterologous A/Anhui/1/05 (A/AN) H5N1 viruses. Two subcutaneous immunizations with doses of either 0.3 μg or 3 μg of A/IN candidates resulted in ≥ 2.5 log(10) unit reduction in day 5 lung virus titer and 90-100% protection against a lethal A/IN challenge in mice. Both R3.HA5 IN and R3.2xHA5 IN vaccines elicited robust neutralizing antibody responses that last for at least 9 months and demonstrated a significant anamnestic antibody response upon further booster immunization. Finally, we found that two vaccine candidates of A/AN induced significant HAI titers in mice. Taken together, our recombinant flagellin-HA platform has been successfully used to generate potent H5N1 HPAIV vaccine candidates. These promising preclinical results justify the advancement of these candidates into the clinic.
authors.affiliation: VaxInnate Corporation, 3 Cedar Brook Drive, Cranbury, NJ 08512, USA. ge.liu@vaxinnate.com
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.forename: Langzhou
authors.initials: L
authors.lastname: Song
authors.forename: Lucia
authors.initials: L
authors.lastname: Reiserova
authors.forename: Umang
authors.initials: U
authors.lastname: Trivedi
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.forename: Diana
authors.initials: D
authors.lastname: Noah
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Hou
authors.forename: Bruce
authors.initials: B
authors.lastname: Weaver
authors.forename: Lynda
authors.initials: L
authors.lastname: Tussey
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D005289:Ferrets; D005408:Flagellin / Q000008:administration & dosage* / Q000235:genetics; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D017201:Virus Shedding
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C109963:hemagglutinin, avian influenza A virus; D005408:Flagellin