title: Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88.
abstract: Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a three-component vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the high-level antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Toll-like receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway.
authors.affiliation: Novartis Vaccines and Diagnostics, 53100 Siena, Italy. anja.seubert@novartis.com
authors.forename: Anja
authors.initials: A
authors.lastname: Seubert
authors.forename: Samuele
authors.initials: S
authors.lastname: Calabro
authors.forename: Laura
authors.initials: L
authors.lastname: Santini
authors.forename: Barbara
authors.initials: B
authors.lastname: Galli
authors.forename: Alessia
authors.initials: A
authors.lastname: Genovese
authors.forename: Sara
authors.initials: S
authors.lastname: Valentini
authors.forename: Susanna
authors.initials: S
authors.lastname: Aprea
authors.forename: Annalisa
authors.initials: A
authors.lastname: Colaprico
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.forename: Marzia M
authors.initials: MM
authors.lastname: Giuliani
authors.forename: Michele
authors.initials: M
authors.lastname: Pallaoro
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D001428:Bacterial Vaccines / Q000008:administration & dosage; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004655:Emulsions; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D038541:Neisseria meningitidis, Serogroup B / Q000276:immunology; D011136:Polysorbates / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D013185:Squalene / Q000008:administration & dosage / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D002352:Carrier Proteins; D004655:Emulsions; C089950:MF59 oil emulsion; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011136:Polysorbates; D051193:Toll-Like Receptors; D014614:Vaccines, Synthetic; C041524:aluminum sulfate; D013185:Squalene; D005620:Freund's Adjuvant