title: Evidence for cyclic diguanylate as a vaccine adjuvant with novel immunostimulatory activities.
abstract: Cyclic diguanylate (c-di-GMP), a bacterial signaling molecule, possesses protective immunostimulatory activity in bacterial challenge models. This study explored the potential of c-di-GMP as a vaccine adjuvant comparing it with LPS, CpG oligonucleotides, and a conventional aluminum salt based adjuvant. In this evaluation, c-di-GMP was a more potent activator of both humoral and Th1-like immune responses as evidenced by the robust IgG2a antibody response it induced in mice and the strong IFN-γ, TNF-α and IP-10 responses, it elicited in mice and in vitro in non-human primate peripheral blood mononuclear cells. Further, compared to LPS or CpG, c-di-GMP demonstrated a more pronounced ability to induce germinal center formation, a hallmark of long-term memory, in immunized mice. Together, these data add to the growing body of evidence supporting the utility of c-di-GMP as an adjuvant in vaccination for sustained and robust immune responses and provide a rationale for further evaluation in appropriate models of immunization.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, United States. peter_gray@merck.com
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gray
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Gene
authors.initials: G
authors.lastname: Porter
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Freed
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Joseph
authors.initials: J
authors.lastname: Leone
authors.forename: Tong-Ming
authors.initials: TM
authors.lastname: Fu
authors.forename: Kalpit A
authors.initials: KA
authors.lastname: Vora
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000276:immunology; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000008:administration & dosage; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008253:Macaca mulatta; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; C408982:CPG-oligonucleotide; D006514:Hepatitis B Surface Antigens; C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C041524:aluminum sulfate; C062025:bis(3',5')-cyclic diguanylic acid; D007371:Interferon-gamma; D006152:Cyclic GMP