title: Bis-(3',5')-cyclic dimeric adenosine monophosphate: strong Th1/Th2/Th17 promoting mucosal adjuvant.
abstract: New effective adjuvants are required to improve the performance of subunit vaccines. Here, we showed that bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP), a second messenger molecule in bacteria and archaea, exerts strong adjuvant activities when delivered by mucosal route. In vitro studies showed that c-di-AMP was able to both stimulate pre-activated murine macrophages and promote the activation and maturation of dendritic cells of murine and human origin. Co-administration of c-di-AMP with β-galactosidase (β-Gal) by intranasal route to BALB/c mice resulted in the elicitation of significantly higher serum antigen-specific IgG titres than in controls. The induction of local immune responses was shown by the production of antigen-specific secretory IgA in different mucosal territories. In addition, strong cellular immune responses were observed against both the β-Gal protein and a peptide encompassing its MHC class I-restricted epitope. The ratio of β-Gal-specific antibodies and the secreted cytokine profiles by in vitro re-stimulated splenocytes suggested that a balanced Th1/Th2/Th17 response pattern is promoted by c-di-AMP. When C57BL/6 mice were immunized with OVA and c-di-AMP, vigorous in vivo CTL responses were also observed. These results indicated that c-di-AMP exhibits a high potential as adjuvant for the development of mucosal vaccines, in particular when cellular immunity is needed.
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany. thomas.ebensen@helmholtz-hzi.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.forename: Rimma
authors.initials: R
authors.lastname: Libanova
authors.forename: Kai
authors.initials: K
authors.lastname: Schulze
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.forename: Michael
authors.initials: M
authors.lastname: Morr
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D022223:Vaccines, Subunit; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D015226:Dinucleoside Phosphates; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022223:Vaccines, Subunit; C528998:cyclic diadenosine phosphate; D001616:beta-Galactosidase