title: Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets.
abstract: Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus-like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine ("Split") alone, influenza split vaccine supplemented with M2e5x VLP ("Split+M2e5x"), M2e5x VLP alone ("M2e5x"), or mock immunized. Vaccine efficacy was measured serologically and by protection against a serologically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addition, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These studies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone.
authors.affiliation: Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA; Battelle Memorial Institute, Atlanta, GA, USA.
authors.forename: Nedzad
authors.initials: N
authors.lastname: Music
authors.affiliation: Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Reber
authors.affiliation: Center for Inflammation, Immunity & Infection, and Department of Biology, Georgia State University, Atlanta, GA, USA; Animal and Plant Quarantine Agency, 175 Anyangro, Anyangsi 14089, Gyeonggido, Republic of Korea.
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Kim
authors.affiliation: Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: ite1@cdc.gov.
authors.forename: Ian A
authors.initials: IA
authors.lastname: York
authors.affiliation: Center for Inflammation, Immunity & Infection, and Department of Biology, Georgia State University, Atlanta, GA, USA. Electronic address: skang24@gsu.edu.
authors.forename: Sang-Moo
authors.initials: SM
authors.lastname: Kang
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D056738:Cross Protection; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D008297:Male; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines; D058425:Vaccines, Virus-Like Particle; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Cross-protection; Ferret; M2e protein