title: MF59 and Pam3CSK4 boost adaptive responses to influenza subunit vaccine through an IFN type I-independent mechanism of action.
abstract: The innate immune pathways induced by adjuvants required to increase adaptive responses to influenza subunit vaccines are not well characterized. We profiled different TLR-independent (MF59 and alum) and TLR-dependent (CpG, resiquimod, and Pam3CSK4) adjuvants for the ability to increase the immunogenicity to a trivalent influenza seasonal subunit vaccine and to tetanus toxoid (TT) in mouse. Although all adjuvants boosted the Ab responses to TT, only MF59 and Pam3CSK4 were able to enhance hemagglutinin Ab responses. To identify innate immune correlates of adjuvanticity to influenza subunit vaccine, we investigated the gene signatures induced by each adjuvant in vitro in splenocytes and in vivo in muscle and lymph nodes using DNA microarrays. We found that flu adjuvanticity correlates with the upregulation of proinflammatory genes and other genes involved in leukocyte transendothelial migration at the vaccine injection site. Confocal and FACS analysis confirmed that MF59 and Pam3CSK4 were the strongest inducers of blood cell recruitment in the muscle compared with the other adjuvants tested. Even though it has been proposed that IFN type I is required for adjuvanticity to influenza vaccines, we found that MF59 and Pam3CSK4 were not good inducers of IFN-related innate immunity pathways. By contrast, resiquimod failed to enhance the adaptive response to flu despite a strong activation of the IFN pathway in muscle and lymph nodes. By blocking IFN type I receptor through a mAb, we confirmed that the adjuvanticity of MF59 and Pam3CSK4 to a trivalent influenza vaccine and to TT is IFN independent.
authors.affiliation: Research Center, Novartis Vaccine and Diagnostics, 53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Caproni
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.forename: Mario
authors.initials: M
authors.lastname: Cortese
authors.forename: Alessandro
authors.initials: A
authors.lastname: Muzzi
authors.forename: Flaviana
authors.initials: F
authors.lastname: Mosca
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Monaci
authors.forename: Barbara
authors.initials: B
authors.lastname: Baudner
authors.forename: Anja
authors.initials: A
authors.lastname: Seubert
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D009981:Influenza B virus / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology*; D055666:Lipopeptides / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000276:immunology / Q000378:metabolism; D011136:Polysorbates / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013185:Squalene / Q000494:pharmacology*; D013745:Tetanus Toxoid / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D007252:Influenza Vaccines; D016898:Interferon-alpha; D055666:Lipopeptides; C089950:MF59 oil emulsion; C508075:Pam(3)CSK(4) peptide; D011136:Polysorbates; D013745:Tetanus Toxoid; D022223:Vaccines, Subunit; D013185:Squalene