title: Adjuvanted inactivated influenza A(H3N2) vaccines induce stronger immunogenicity in mice and confer higher protection in ferrets than unadjuvanted inactivated vaccines.
abstract: Influenza viruses are major respiratory pathogens and the development of improved vaccines to prevent these infections is of high priority. Here, we evaluated split inactivated A(H3N2) vaccines (A/Uruguay/716/2007) combined or not with adjuvants (AS03, AS25 and Protollin) and administered by three different routes, intramuscular (i.m.), intranasal (i.n.) or intradermal (i.d.), both in BALB/c mice and in ferrets. Ferrets were challenged with the homologous strain A/Uruguay/716/2007 (H3N2) or the heterologous strain A/Perth/16/2009 (H3N2) 4 weeks after the second immunization with A/Uruguay/716/2007 vaccines. Temperature, weight loss and clinical signs were monitored on a daily basis and nasal washes were performed to evaluate viral titers in the upper respiratory tract. All adjuvanted vaccines induced stronger humoral immune responses than unadjuvanted ones in both mice and ferrets. In mice, the AS03- and AS25-adjuvanted i.m. vaccines generated a mixed Th1-Th2 response at 6 and 19 weeks after the last immunization as shown by the production of IgG1 and IgG2a antibodies as well as the production of IL-2, IL-4 and IFN-γ by CD4+ and CD8+ T cells. HAI and MN titers were also higher in those groups when compared to the i.n. Protollin-adjuvanted and unadjuvanted groups. The Protollin-adjuvanted i.n. vaccine induced a more Th1 oriented response with a significant production of IgA in bronchoalveolar lavages. In ferrets, the AS03- and AS25-adjuvanted i.m. vaccines also induced higher HAI and MN titers compared to the other groups. These vaccines also significantly decreased viral titers after challenge with both the homologous A/Uruguay/716/2007 (H3N2) and the heterologous A/Perth/16/2009 (H3N2) strains. In conclusion, adjuvanted influenza vaccines elicited stronger humoral response in mice and conferred greater protection in naive ferrets than unadjuvanted ones. Interestingly, the AS25 adjuvant system containing monophosphoryl-lipid-A appears particularly promising for developing more potent inactivated influenza vaccines.
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Ann
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Samant
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Rheaume
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada.
authors.forename: Carole
authors.initials: C
authors.lastname: Dumas
authors.affiliation: GlaxoSmithKline Vaccines, Laval, Quebec, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Beaulieu
authors.affiliation: GlaxoSmithKline Vaccines, Laval, Quebec, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Morasse
authors.affiliation: GlaxoSmithKline Vaccines, Laval, Quebec, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Mallett
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Hamelin
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada. Electronic address: Barbara.Papadopoulou@crchul.ulaval.ca.
authors.forename: Barbara
authors.initials: B
authors.lastname: Papadopoulou
authors.affiliation: CHU de Quebec Research Center (CHUL) and Laval University, 2705 Laurier Blvd, Québec City, Quebec, Canada. Electronic address: Guy.Boivin@crchul.ulaval.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D056738:Cross Protection; D003546:Cysteine Endopeptidases / Q000008:administration & dosage; D016207:Cytokines / Q000276:immunology; D004338:Drug Combinations; D005260:Female; D005289:Ferrets; D056724:Immunity, Humoral; D018928:Immunity, Mucosal; D007074:Immunoglobulin G / Q000097:blood; D053122:Influenza A Virus, H3N2 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016207:Cytokines; D004338:Drug Combinations; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D008070:Lipopolysaccharides; C493785:Protollin; D015164:Vaccines, Inactivated; D003546:Cysteine Endopeptidases
keywords: Adjuvants; Ferrets; H3N2 vaccine; Influenza; Mice