Bis-(3',5')-cyclic dimeric adenosine monophosphate: strong Th1/Th2/Th17 promoting mucosal adjuvant

Vaccine. 2011 Jul 18;29(32):5210-20. doi: 10.1016/j.vaccine.2011.05.026. Epub 2011 May 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Administration, Intranasal
  • Animals
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dinucleoside Phosphates / administration & dosage
  • Dinucleoside Phosphates / immunology*
  • Female
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin G / blood
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Nasal Mucosa / immunology*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Th2 Cells / immunology*
  • Vaccines, Subunit
  • beta-Galactosidase / administration & dosage
  • beta-Galactosidase / immunology


  • Adjuvants, Immunologic
  • Cytokines
  • Dinucleoside Phosphates
  • Immunoglobulin A
  • Immunoglobulin G
  • Vaccines, Subunit
  • cyclic diadenosine phosphate
  • beta-Galactosidase