title: Comparison of AS03 and Alum on immune responses elicited by A/H3N2 split influenza vaccine in young, mature and aged BALB/c mice.
abstract: BACKGROUND
  There is great interest in developing more effective influenza vaccines for the elderly. Oil-in-water adjuvants can boost humoral responses to seasonal vaccines in elderly subjects but relatively little is known about their mechanism of action.
  
  
  METHODS
  We compared humoral and cellular immune profiles in young adult (2 months), mature (11-12 months) or aged (16-17 month) female BALB/c mice following two doses of Alum or AS03-adjuvanted A/H3N2 split-virus antigen (A/Uruguay/716/2007) at 0.75 or 3 μg hemagglutinin (HA) per dose intramuscularly versus 3 μg HA without adjuvant.
  
  
  RESULTS
  Overall, hemagglutination inhibition (HAI), microneutralization (MN) and end-point ELISA titres were higher in the young mice and when an adjuvant was used. Both adjuvants increased humoral responses in older animals but the highest titres across all groups were observed in the AS03-adjuvanted groups. Neither IgG avidity nor A/H3N2-specific splenocyte proliferation was influenced by age, antigen dose or adjuvant. In contrast, cytokine production by ex vivo-stimulated splenocytes differed widely between groups. Most cytokine levels in older mice vaccinated with antigen alone (3 μg HA/dose) were ≤ 50% of those in young animals. In young mice, cytokine levels increased modestly with Alum and significantly with AS03. Increases tended to be greatest at the lower antigen dose (0.75 μg versus 3 μg HA). In the older animals, Alum had little impact on cytokine production but responses in the AS03 groups paralleled those of the young mice (broad activation of Th1, Th2, and Th17-type cytokines) and the greatest increases were seen with the higher antigen dose (3 μg HA).
  
  
  CONCLUSIONS
  In both young and aged mice, Alum and AS03 increased the magnitude of humoral and cellular responses to split influenza virus vaccination. Overall, these effects were most pronounced in the younger animals and the groups receiving AS03. These data support the use of oil-in-water adjuvants in influenza vaccines targeting the elderly.
authors.affiliation: Department of Experimental Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Yam
authors.affiliation: Department of Experimental Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Department of Experimental Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Allen
authors.affiliation: Department of Experimental Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Kayla R
authors.initials: KR
authors.lastname: Burt
authors.affiliation: GSK Vaccines, Laval, QC, Canada.
authors.forename: Édith
authors.initials: É
authors.lastname: Beaulieu
authors.affiliation: GSK Vaccines, Laval, QC, Canada.
authors.forename: Corey P
authors.initials: CP
authors.lastname: Mallett
authors.affiliation: GSK Vaccines, Laval, QC, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Burt
authors.affiliation: Department of Experimental Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; Vaccine Study Centre, Research Institute of the McGill University Health Centre, Montreal, QC, Canada. Electronic address: brian.ward@mcgill.ca.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ward
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000367:Age Factors; D000534:Alum Compounds / Q000008:administration & dosage*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D005260:Female; D006385:Hemagglutination Inhibition Tests; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D053122:Influenza A Virus, H3N2 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage*; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011136:Polysorbates / Q000008:administration & dosage*; D013154:Spleen / Q000276:immunology; D013185:Squalene / Q000008:administration & dosage*; D024502:alpha-Tocopherol / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000914:Antibodies, Viral; D016207:Cytokines; D004338:Drug Combinations; D007252:Influenza Vaccines; D011136:Polysorbates; C041524:aluminum sulfate; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: AS03; Adjuvant; Aged mice; Alhydrogel; Alum; Avidity; Chemokine; Cytokine; H3N2 virus; Hemagglutination inhibition; Immunosenescence; Influenza virus; Microneutralization; Vaccine