c-di-GMP as a vaccine adjuvant enhances protection against systemic methicillin-resistant Staphylococcus aureus (MRSA) infection

• Published in: Vaccine 2009-07, Vol.27 (35), p.4867-4873
• Main Authors: Hu, Dong-Liang, Narita, Kouji, Hyodo, Mamoru, Hayakawa, Yoshihiro, Nakane, Akio, Karaolis, David K.R
• Format: Article
• Language: English
• Subjects: Adjuvant; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Allergy and Immunology; Alum Compounds - administration & dosage; Alum Compounds - pharmacology; Animals; Antibodies, Bacterial - blood; Antigens, Bacterial - administration & dosage; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Applied microbiology; Bacteriology; Biological and medical sciences; c-di-GMP; Coagulase - administration & dosage; Coagulase - genetics; Coagulase - immunology; Colony Count, Microbial; Cyclic GMP - administration & dosage; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Enterotoxins - administration & dosage; Enterotoxins - genetics; Enterotoxins - immunology; Female; Fundamental and applied biological sciences. Psychology; Immunoglobulin G - blood; Immunomodulator; Injections, Subcutaneous; Liver - microbiology; Methicillin-Resistant Staphylococcus aureus - immunology; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; MRSA; Spleen - microbiology; Staphylococcal Infections - prevention & control; Staphylococcal Vaccines - administration & dosage; Staphylococcal Vaccines - genetics; Staphylococcal Vaccines - immunology; Staphylococcus aureus; Vaccine; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects)
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2009.04.053

Abstract Cyclic diguanylate (c-di-GMP) is a novel immunomodulator and immune enhancer that triggers a protective host innate immune response. The protective effect of c-di-GMP as a vaccine adjuvant against Staphylococcus aureus infection was investigated by subcutaneous (s.c.) vaccination with two different S. aureus antigens, clumping factor A (ClfA) and a nontoxic mutant staphylococcal enterotoxin C (mSEC), then intravenous (i.v.) challenge with viable methicillin-resistant S. aureus (MRSA) in a systemic infection model. Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA vaccines then challenged with MRSA produced strong antigen-specific antibody responses demonstrating immunogenicity of the vaccines. Bacterial counts in the spleen and liver of c-di-GMP plus mSEC and c-di-GMP plus ClfA-immunized mice were significantly lower than those of control mice ( P < 0.001). Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA showed significantly higher survival rates at day 7 (87.5%) than those of the non-immunized control mice (33.3%) ( P < 0.05). Furthermore, immunization of mice with c-di-GMP plus mSEC or c-di-GMP plus ClfA induced not only very high titers of immunoglobulin G1 (IgG1), but c-di-GMP plus mSEC also induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant ( P < 0.01 and P < 0.001, respectively) and c-di-GMP plus ClfA induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant ( P < 0.001). Our results show that c-di-GMP should be developed as an adjuvant and immunotherapeutic to provide protection against systemic infection caused by S. aureus (MRSA).