The bacterial second messenger cdiGMP exhibits promising activity as a mucosal adjuvant.
The development of mucosal adjuvants is still a critical need in vaccinology. In the present work, we show that bis(3',5')-cyclic dimeric GMP (cdiGMP), a second messenger that modulates cell surface properties of several microorganisms, exerts potent activity as a mucosal adjuvant. BALB/c mice were immunized intranasally with the model antigen beta-galactosidase (beta-Gal) coadministered with cdiGMP. Animals receiving cdiGMP as an adjuvant showed significantly higher anti-beta-Gal immunoglobulin G (IgG) titers in sera than controls (i.e., 512-fold [P < 0.05]). Coadministration of cdiGMP also stimulated efficient beta-Gal-specific secretory IgA production in the lung (P < 0.016) and vagina (P < 0.036). Cellular immune responses were observed in response to both the beta-Gal protein and a peptide encompassing its major histocompatibility complex class I-restricted epitope. The IgG1-to-IgG2a ratio of anti-beta-Gal antibodies and the observed profiles of secreted cytokines suggest that a dominant Th1 response pattern is promoted by mucosal coadministration of cdiGMP. Finally, the use of cdiGMP as a mucosal adjuvant also led to the stimulation of in vivo cytotoxic T-lymphocyte responses in C57BL/6 mice intranasally immunized with ovalbumin and cdiGMP (up to 30% of specific lysis). The results obtained indicate that cdiGMP is a promising tool for the development of mucosal vaccines.
Ebensen
Thomas
T
Department of Vaccinology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
Schulze
Kai
K
Riese
Peggy
P
Morr
Michael
M
Guzmán
Carlos A
CA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000276:immunology* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D005260:Female; D018928:Immunity, Mucosal; D007114:Immunization; D007071:Immunoglobulin A, Secretory / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D015290:Second Messenger Systems / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic; D014621:Vagina / Q000276:immunology; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D010047:Ovalbumin; D001616:beta-Galactosidase; D006152:Cyclic GMP