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Adjuvant Properties of CpG Oligonucleotides in Primates

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DNA Vaccines

Part of the book series: Methods in Molecular Medicineā„¢ ((MIMM,volume 127))

Abstract

Unlike mammalian DNA, bacterial, plasmid, and synthetic DNA containing unmethylated CpG dinucleotides in specific sequence contexts are recognized by the Toll-like receptor 9 expressed by B cells and plasmacytoid dendritic cells, and trigger the activation of the innate and adaptive immune system. Upon signaling, CpG DNA induces B cells, natural killer cells, macrophages, and dendritic cells to proliferate, differentiate, take up, and present antigen and secrete a variety of immunoglobulins, chemokines, and predominantly Th1-type cytokines. Preclinical studies in mice and primates show that DNA sequences containing CpG motifs can selectively promote cellular and/or humoral immune responses in vivo. Early results from ongoing clinical studies indicate that CpG oligonucleotides (ODN) are well tolerated and improve the immune response to microbial vaccines. This work examines the progress in utilizing CpG ODN as adjuvants in conventional and DNA vaccines.

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References

  1. Singh, M. and Oā€™Hagan, D. (1999) Advances in vaccine adjuvants. Nat. Biotechnol. 17, 1075ā€“1081.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  2. Krieg, A. M. and Davis, H. L. (2001) Enhancing vaccines with immune stimulatory CpG DNA. Curr. Opin. Mol. Ther. 3, 15ā€“24.

    CASĀ  PubMedĀ  Google ScholarĀ 

  3. Messina, J. P., Gilkeson, G. S., and Pisetsky, D. S. (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J. Immunol. 147, 1759ā€“1764.

    CASĀ  PubMedĀ  Google ScholarĀ 

  4. Yamamoto, S., Yamamoto, T., Shimada, S., et al. (1992) DNA from bacteria, but not vertebrates, induces interferons, activate NK cells and inhibits tumor growth. Microbiol. Immunol. 36, 983ā€“997.

    CASĀ  PubMedĀ  Google ScholarĀ 

  5. Yamamoto, S., Yamamoto, T., and Tokunaga, T. (2002) Historical perspectives. In: Microbial DNA and Host Immunity, (Raz, E., ed.), Humana Press, Totowa, NJ, pp. 9ā€“14.

    ChapterĀ  Google ScholarĀ 

  6. Krieg, A. M., Yi, A., Matson, S., et al. (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546ā€“548.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  7. Krieg, A. M. (2002) CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709ā€“760.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  8. Takeshita, S., Takeshita, F., Haddad, D. E., Ishii, K. J., and Klinman, D. M. (2000) CpG oligodeoxynucleotides induce murine macrophages to up-regulate chemokine mRNA expression. Cell Immunol. 206, 101ā€“106.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  9. Lang, R., Hultner, L., Lipford, G. B., Wagner, H., and Heeg, K. (1999) Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of murine bone marrow cells. Eur. J. Immunol. 29, 3496ā€“3506.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  10. Klinman, D. M., Yi, A., Beaucage, S. L., Conover, J., and Krieg, A. M. (1996) CpG motifs expressed by bacterial DNA rapidly induce lymphocytes to secrete IL-6, IL-12 and IFNg. Proc. Natl. Acad. Sci. USA 93, 2879ā€“2883.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  11. Krug, A., Rothenfusser, S., Hornung, V., et al. (2001) Identification of CpG oligonucleotide sequences with high induction of IFNa/b in plasmacytoid dendritic cells. Eur. J. Immunol. 31, 2154ā€“2163.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. Gursel, M., Verthelyi, D., and Klinman, D. M. (2002) CpG oligodeoxynucleotides induce human monocytes to mature into functional dendritic cells. Eur. J. Immunol. 32, 2617ā€“2622.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  13. Krug, A., Towarowski, A., Britsch, S., et al. (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur. J. Immunol. 31, 3026ā€“3037.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  14. Verthelyi, D., Ishii, K. J., Gursel, M., Takeshita, F., and Klinman, D. M. (2001) Human peripheral blood cells differentially recognize and respond to two distinct CpG motifs. J. Immunol. 166, 2372ā€“2377.

    CASĀ  PubMedĀ  Google ScholarĀ 

  15. Rothenfusser, S., Hornung, V., Krug, A., et al. (2001) Distinct CpG oligonucleotide sequences activate human gamma delta T cells via interferon-alpha/-beta. Eur. J. Immunol. 31, 3525ā€“3534.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Krug, A., Rothenfusser, S., Selinger, S., et al. (2003) CpG-A oligonucleotides induce a monocyte-derived dendritic cell-like phenotype that preferentially activates CD8 T cells. J. Immunol. 170, 3468ā€“3477.

    CASĀ  PubMedĀ  Google ScholarĀ 

  17. Mendez, S., Tabbara, K., Belkaid, S., et al. (2004) Coinjection with CpG-containing immunostimulatory oligodeoxynucleotides reduces the pathogenicity of a live vaccine against cutaneous Leishmaniasis but maintains its potency and durability. Inect. Immun. 71, 5121ā€“5129.

    ArticleĀ  CASĀ  Google ScholarĀ 

  18. Heit, A., Maurer, T., Hochrein, H., et al. (2003) Cutting edge: toll-like receptor 9 expression is not required for CpG DNA-aided cross-presentation of DNA-conjugated antigens but essential for cross-priming of CD8 T cells. J. Immunol. 170, 2802ā€“2805.

    CASĀ  PubMedĀ  Google ScholarĀ 

  19. Schirmbeck, R., Riedl, P., Zurbriggen, R., Akira, S., and Reimann, J. (2003) Antigenic epitopes fused to cationic peptide bound to oligonucleotides facilitate toll-like receptor 9-dependent, but CD4+ T cell help-independent, priming of CD8+ T cells. J. Immunol. 171, 5198ā€“5207.

    CASĀ  PubMedĀ  Google ScholarĀ 

  20. Verthelyi, D., Kenney, R. T., Seder, R. A., Gam, A. A., Friedag, B., and Klinman, D. M. (2002) CpG oligodeoxynucleotides as vaccine adjuvants in primates. J. Immunol. 168, 1659ā€“1663.

    CASĀ  PubMedĀ  Google ScholarĀ 

  21. Hartmann, G., Battiany, J., Poeck, H., et al. (2003) Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur. J. Immunol. 33, 1633ā€“1641.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  22. Marshall, J. D., Fearon, K., Abbate, C, et al. (2003) Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. J. Leukoc. Biol. 73, 781ā€“792.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. Kerkmann, M., Rothenfusser, S., Hornung, V., et al. (2003) Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J. Immunol. 170, 4465ā€“4474.

    CASĀ  PubMedĀ  Google ScholarĀ 

  24. Krug, A., Rothenfusser, S., Hornung, V., et al. (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-Ī±/Ī² in plasmacytoid dendritic cells. Eur. J. Immunol. 31, 2154ā€“2163.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  25. Wu, C. C. N., Lee, J., Raz, E., Corr, M., and Carson, D. (2004) Necessity of oligonucleotide aggregation for toll-like receptor 9 activation. J. Biol. Chem. 279, 33,071ā€“33,078.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  26. Hemmi, H., Kaisho, T., Takeda, K., and Akira, S. (2003) The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059ā€“3064.

    CASĀ  PubMedĀ  Google ScholarĀ 

  27. Hacker, H., Vabulas, R. M., Takeuchi, O., Hoshino, K., Akira, S., and Wagner, H. (2000) Immune cell activation by bacterial CpG-DNA through myeroid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192, 595ā€“600.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  28. Hemmi, H., Takeuchi, O., Kawai, T., et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408, 740ā€“745.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  29. Takeshita, F., Leifer, C. A., Gursel, I., et al. (2001) Cutting edge: role of toll-like receptor 9 in CpG DNA-induced activation of human cells. J. Immunol. 167, 3555ā€“3558.

    CASĀ  PubMedĀ  Google ScholarĀ 

  30. Bauer, S., Kirschning, C. J., Hacker, H., et al. (2001) Human TLR9 confers responsiveness to bacterial DNA via species specific CpG motif recognition. Proc. Natl. Acad. Sci. USA 98, 9237ā€“9242.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  31. Latz, E., Schoenmeyer, A., Visintin, A., et al. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190ā€“198.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  32. Gursel, M., Verthelyi, D., Gursel, I., Ishii, K. J., and Klinman, D. M. (2002) Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide. J. Leukoc. Biol. 71, 813ā€“820.

    CASĀ  PubMedĀ  Google ScholarĀ 

  33. Ahmad-Nejad, P., Hacker, H., Rutz, M., Bauer, S., Vabulas, R. M., and Wagner, H. (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958ā€“1968.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  34. Ishii, K. J., Takeshita, F., Gursel, I., et al. (2002) Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J. Exp. Med. 196, 269ā€“274.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  35. Klinman, D. M. and Currie, D. (2003) Hierarchical recognition of CpG motifs in immunostimulatory oligodeoxynucleotides. Cell Immunol. 133, 227ā€“232.

    CASĀ  Google ScholarĀ 

  36. Verthelyi, D. and Zeuner, R. A. (2003) Differential signaling by CpG DNA in DCs and B cells: not just TLR9. Trends Immunol. 10, 519ā€“522.

    ArticleĀ  CASĀ  Google ScholarĀ 

  37. Chu, R. S., Targoni, O. S., Krieg, A. M., Lehmann, P. V., and Harding, C. V. (1997) CpG oligodeoxynucleotides act as adjuvants that switch on T helper (Th1) immunity. J. Exp. Med. 186, 1623ā€“1631.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  38. Davis, H. L., Weeranta, R., Waldschmidt, T. J., Tygrett, L., Schorr, J., and Krieg, A. M. (1998) CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol. 160, 870ā€“876.

    CASĀ  PubMedĀ  Google ScholarĀ 

  39. Walker, P. S., Scharton-Kersten, T., Krieg, A. M., et al. (1999) Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12-and IFN-Ī³-dependent mechanisms. Proc. Natl. Acad. Sci. USA 96, 6970ā€“6975.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  40. Deml, L., Schirmbeck, R., Reimann, J., Wolf, H., and Wagner, R. (1999) Immunostimulatory CpG motifs trigger a Thelper-1 immune response to human immunodeficiency virus type-1 (HIV-1) gp 160 envelope proteins. Clin. Chem. Lab. Med. 37, 199ā€“204.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  41. Rhee, E. G., Mendez, S., Shah, J. A., et al. (2004) Vaccination with heat killed Leishmania antigen or recombinant leishmanial protein and CpG oligodeoxynucleotides induces long-term memory CD4+ and CD8+ T cell responses and potection agaist Leishmania major infection. J. Exp. Med. 195, 1565ā€“1573.

    ArticleĀ  CASĀ  Google ScholarĀ 

  42. Kumar, S., Jones, T. R., Oakley, M. S., et al. (2004) CpG oligodeoxynucleotide and montanide ISA 51 adjuvant combination enhanced the protective efficacy of a subunit malaria vaccine. Infect. Immun. 72, 949ā€“957.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  43. Mutwiri, G. K., Nichani, A. K., Babiuk, S., and Babiuk, L. A. (2004) Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides. J. Controlled Release 97, 1ā€“17.

    ArticleĀ  CASĀ  Google ScholarĀ 

  44. Yu, D., Kandimalla, E. R., Bhagat, L., Cong, Y., Tang, J., and Agrawal, S. (2002) ā€œImmunomersā€ā€”novel 3ā€²-3ā€²-linked CpG oligodeoxyribonucleotides as potent immunomodulatory agents. Nucleic Acid Res. 30, 4460ā€“4469.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  45. Yu, D., Kandimalla, E. R., Zhao, Q., Cong, Y., and Agrawal, S. (2001) Immunostimulatory activity of CpG oligonucleotides containing non-ionic methylphosphonate linkages. Bio. Med. Chem. 9, 2803ā€“2808.

    ArticleĀ  CASĀ  Google ScholarĀ 

  46. Oā€™Hagan, D. T. and Singh, M. (2003) Microparticles as vaccine adjuvants and delivery systems. Expert Rev. Vaccines 2, 269ā€“283.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  47. Tighe, H., Takabayashi, K., Schwartz, D., et al. (2000) Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur. J. Immunol. 30, 1939ā€“1947.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  48. Gursel, I., Gursel, M., Ishii, K. J., and Klinman, D. M. (2001) Sterically stabilized cationic liposomes improve the uptake and immunostimulatory activity of CpG oligonucleotides. J. Immunol. 167, 3324ā€“3328.

    CASĀ  PubMedĀ  Google ScholarĀ 

  49. Moldoveanu, Z., Love-Homan, L., Huang, W. Q., and Krieg, A. M. (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16, 1216ā€“1224.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  50. McCluskie, M. J. and Davis, H. L. (1998) CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J. Immunol. 161, 4463ā€“4466.

    CASĀ  PubMedĀ  Google ScholarĀ 

  51. McCluskie, M. J., Weetman, A. P., Payette, P. J., and Davis, H. L. (2001) The potential of CpG oligodeoxy nucleotides as mucosal adjuvants. Crit. Rev. Immunol. 21, 103ā€“120.

    CASĀ  PubMedĀ  Google ScholarĀ 

  52. Prince, G. A., Mond, J. J., Porter, D. D., Yim, K. C., Lan, S. J., and Klinman, D. M. (2003) Immunoprotective activity and safety of a respiratory syncytial virus vaccine: mucosal delivery of fusion glycoprotein with a CpG oligodeoxynucleotide adjuvant. J. Virol. 77, 13,156ā€“13,160.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  53. Sommer, F., Wilken, H., Faller, G., and Lohoff, M. (2004) Systemic Th1 immunization of mice against Helicobacter pylori infection with CpG oligodeoxynucleotides as adjuvants does not protect from infection but enhances gastritis. Infect. Immun. 72, 1029ā€“1035.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  54. Sato, Y., Roman, M., Tighe, H., et al. (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352ā€“354.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  55. Klinman, D. M., Yamshchikov, G., and Ishigatsubo, Y. (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J. Immunol. 158, 3635ā€“3642.

    CASĀ  PubMedĀ  Google ScholarĀ 

  56. Krieg, A. M., Wu, T., Weeratna, R., et al. (1998) Sequence motifs in adenoviral DNA block immune activation by stimuatory CpG motifs. Proc. Natl. Acad. Sci. USA 95, 12,631ā€“12,636.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  57. Roman, M., Martin-Orozco, E., Goodman, J. S., et al. (1997) Immunostimulatory DNA sequences function as T helper-1 promoting adjuvants. Nat. Med. 3, 849ā€“854.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  58. Klinman, D. M., Barnhart, K. M., and Conover, J. (1999) CpG motifs as immune adjuvants. Vaccine 17, 19ā€“25.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  59. Brazolot Millan, C. L., Weeratna, R., Krieg, A. M., Siegrist, C. A., and Davis, H. L. (1998) CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc. Natl. Acad. Sci. USA 95, 15,553ā€“15,558.

    Google ScholarĀ 

  60. Kojima, Y., Xin, K. Q., Ooki, T., et al. (2002) Adjuvant effect of multi-CpG motifs on an HIV-1 DNA vaccine. Vaccine 20, 2857ā€“2865.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  61. Weeratna, R., Brazolot, C. L., Millan, B., Krieg, A. M., and Davis, H. L. (1998) Reduction of antigen expression from DNA vaccines by coadministered oligodeoxynucleotides. Antisense Nuc. Acid Drug Dev. 8, 351ā€“356.

    CASĀ  Google ScholarĀ 

  62. Hartmann, G., Weeratna, R. D., Ballas, Z. K., et al. (2000) Delineation of a CpG phosphorothioate oligodeoxinucleotide for activating primate immune responses in vitro and in vivo. J. Immunol. 164, 1617ā€“1624.

    CASĀ  PubMedĀ  Google ScholarĀ 

  63. Verthelyi, D. and Klinman, D. M. (2003) Immunoregulatory activity of CpG oligonucleotides in humans and nonhuman primates. Clin. Immunol. 109, 64ā€“71.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  64. Jones, T. R., Obaldia, N., Gramzinski, R. A., et al. (1999) Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine 17, 3065ā€“3071.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  65. Verthelyi, D., Wang, V. W., Lifson, J. D., and Klinman, D. M. (2004) CpG oligodeoxynucleotides improve the response to hepatitis B immunization in healthy and SIV-infected rhesus macaques. AIDS 18, 1003ā€“1008.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  66. Flynn, B., Wang, V., Sacks, D. L., Seder, R. A. and Verthelyi, D. (2005) Prevention and treatment of cutaneous leishmaniasis in primates using type D CpG ODN. Infect. Immun. 73, 4948ā€“4954.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  67. Chelvarajan, R. L., Raithatha, R., Venkataraman, C., et al. (1999) CpG oligodeoxynucleotides overcome the unresponsiveness of neonatal B cells to stimulation with the thymus-independent stimuli anti-IgM and TNP-Ficoll. Eur. J. Immunol. 29, 2808ā€“2818.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  68. Kovarik, J., Bozzotti, P., Love-Homan, L., et al. (1999) CpG oligonucleotides can cirmcuvent the TH2 polorization of neonatal responses to vaccines but fail to fully redirect TH2 responses established by neonatal priming. J. Immunol. 162, 1611ā€“1617.

    CASĀ  PubMedĀ  Google ScholarĀ 

  69. Pihlgren, M., Tougne, C., Schallert, N., Bozzotti, P., Lambert, P. H., and Siegrist, C. A. (2003) CpG-motifs enhance initial and sustained primary tetanus-specific antibody secreting cell responses in spleen and bone marrow, but are more effective in adult than in neonatal mice. Vaccine 21, 2492ā€“2499.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  70. Weeratna, R. D., Brazolot Millan, C. L., McCluskie, M. J., Siegrist, C. A., and Davis, H. L. (2001) Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies. Immunol. Med. Microbiol. 30, 241ā€“247.

    Google ScholarĀ 

  71. Davis, H. L., Suparto, I. I., Weeratna, R. R., et al. (2000) CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine 19, 413ā€“422.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  72. Verthelyi, D., Gursel, M., Kenney, R. T., et al. (2003) CpG Oligodeoxynucleotides protect normal and SIV infected macaques from Leishmania infection. J. Immunol. 170, 4717ā€“4723.

    CASĀ  PubMedĀ  Google ScholarĀ 

  73. Verthelyi, D. and Klinman, D. M. (2002) CpG ODN: safety considerations. In: Microbial DNA and Immune Modulation (Raz, E., ed.), Humana Press, Totowa, NJ, pp. 385ā€“396.

    ChapterĀ  Google ScholarĀ 

  74. Klinman, D. M., Conover, J., and Coban, C. (1999) Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection. Infect. Immun. 67, 5658ā€“5663.

    CASĀ  PubMedĀ  Google ScholarĀ 

  75. Levin, A. A. (1999) A review of issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochimica et Biophysica Acta. 1489, 69ā€“84.

    CASĀ  PubMedĀ  Google ScholarĀ 

  76. Heikenwalder, M., Polymenidou, M., Junt, T., et al. (2004) Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat. Med. 10, 187ā€“192.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  77. Cowdery, J. S., Chace, J. H., Yi, A.-K., and Krieg, A. M. (1996) Bacterial DNA induces NK cells to produce IFNgamma in vivo and increases the toxicity of lipopolysaccharides. J. Immunol. 156, 4570ā€“4575.

    CASĀ  PubMedĀ  Google ScholarĀ 

  78. Sparwasser, T., Meithke, T., Lipford, G., et al. (1997) Bacterial DNA causes septic shock. Nature 386, 336ā€“338.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  79. Deng, G. M. and Tarkowski, A. (2000) The features of arthritis induced by CpG motifs in bacterial DNA. Arthritis Rheum. 43, 356ā€“364.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  80. Zeuner, R. A., Ishii, K. J., Lizak, M. J., et al. (2002) Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum. 46, 2219ā€“2224.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  81. Krieg, A. M. (2003) Mechanisms and therapeutic applications of immune stimulatory CpG ODN. Sixth NIH Symposium on Therapeutic Oligonucleotides, Bethesda, MD, December 16ā€“17, 2002, Abstract.

    Google ScholarĀ 

  82. Halperin, S. A., Van Nest, G., Smith, B., Abtahi, S., Whiley, H., and Eiden, J. J. (2003) A phase I study of the safety and immunogenicity of recombinant hepatitis b surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21, 2461ā€“2467.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  83. Davis, L. S., Krieg, A. M., Cooper, C. L., Cameron, D. W., and Heathcote, J. (2001) CpG ODN is generally well tolerated and highly effective in humans as adjuvant to HBV vaccine: preliminary results of phase I trial with CpG ODN 7909. 2nd International Symposium ā€œActivating Immunity with CpG Oligos. Amelia Island, FL, October 7ā€“10.

    Google ScholarĀ 

  84. Krieg, A. M. (2001) From bugs to drugs: therapeutic immunomodulation with oligodeoxynucleotides contaiining CpG sequences from bacterial DNA. Antisense Nuc. Acid Drug Dev. 11, 181ā€“188.

    ArticleĀ  CASĀ  Google ScholarĀ 

  85. Zwaveling, S., Mota, S. C. F., Nouta, J., et al. (2002) Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J. Immunol. 169, 350ā€“358.

    CASĀ  PubMedĀ  Google ScholarĀ 

  86. Al-Marari, A., Tibor, A., Mertens, P., et al. (2001) Protection of BALB/c mice against Brucella abortus 544 challenge by vaccination with bacterioferritin or P39 recombinant proteins with CpG oligodeoxynucleotides as adjuvant. Infect. Immunol. 69, 4816ā€“4822.

    ArticleĀ  Google ScholarĀ 

  87. Coban, C., Ishii, K. J., Stowers, A. W., Keister, D. B., Klinman, D. M., and Kumar, N. (2004) Effect of CpG oligodeoxynucleotides on the immunogenicity of Pfs25, a Plasmodium falciparum transmission-blocking vaccine antigen. Infect. Immun. 72, 584ā€“588.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  88. Stacey, K. J. and Blackwell, J. M. (1999) Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major. Infect. Immun. 67, 3719ā€“3726.

    CASĀ  PubMedĀ  Google ScholarĀ 

  89. Gallichan, W. S., Woolstencroft, R. N., Guarasci, T., McCluskie, M. J., Davis, H. L., and Rosenthal, K. L. (2001) Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus-2 in the genital tract. J. Immunol. 166, 3451ā€“3457.

    CASĀ  PubMedĀ  Google ScholarĀ 

  90. Pal, S., Davis, H. L., Peterson, E. M., and de la Maza, L. M. (2002) Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein by use of CpG oligodeoxynucleotides as an adjuvant induces a protective immune response against an intranasal chlamydial challenge. Infect. Immun. 70, 4812ā€“4817.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  91. Dumaris, N., Patrick, A., Moss, R. B., Davis, H. L., and Rosenthal, K. L. (2002) Mucosal immunization with inactivated human immunodeficiency virus plus CpG oligodeoxynucleotides induces genital immune responses and protection against intravaginal challenge. J. Infect. Dis. 186, 1098ā€“1105.

    ArticleĀ  Google ScholarĀ 

  92. Bozza, S., Gaziano, R., Lipford, G. B., et al. (2002) Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes Infect. 4, 1281ā€“1290.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  93. Hammarskjold, M., Li, H., Recosh, D., and Prasad, S. (1993) Human Immunodeficiency Virus env expression becomes Rev-independent if the env region is not defined as an intron. J. Virol. 68, 951ā€“958.

    Google ScholarĀ 

  94. Corral, R. S. and Petray, P. B. (2000) CpG DNA as a Th1-promoting adjuvant in immunization against Trypanosoma cruzi. Vaccine 19, 234ā€“242.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  95. Frank, F. M., Petray, P. B., Cazorla, S. I., et al. (2003) Use of a purified Trypanosoma cruzi antigen and CpG oligodeoxynucleotides for immunoprotection against a lethal challenge with trypomastigotes. Vaccine 22, 77ā€“86.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  96. Zhang, Q., Zhu, M. W., Yang, Y. Q., et al. (2003) A recombinant fusion protein and DNA vaccines against foot-and-mouth disease virus type Asia 1 infection in guinea pigs. Acta. Virol. 47, 237ā€“243.

    CASĀ  PubMedĀ  Google ScholarĀ 

  97. Alcon, V. L., Foldvari, M., Snider, M., et al. (2003) Induction of protective immunity in pigs after immunisation with CpG oligodeoxynucleotides formulated in a lipid-based delivery system (Biphasix). Vaccine 21, 1811ā€“1814.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  98. Gramzinski, R. A., Millan, C. L., Obaldia, N., Hoffman, S. L., and Davis, H. L. (1998) Immune response to a hepatitis B DNA vaccine in Aotus monkeys: a comparison of vaccine formulation, route, and method of administration. Mol. Med. 4, 109ā€“118.

    CASĀ  PubMedĀ  Google ScholarĀ 

  99. Wang, X., Jiang, P., Deen, S., Wu, J., Liu, X., and Xu, J. (2003) Efficacy of DNA vaccines against infectious bursal disease virus in chickens enhanced by coadministration with CpG oligodeoxynucleotide. Avian Dis. 47, 1305ā€“1312.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  100. Zhou, X., Zheng, L., Liu, L., Xiang, L., and Yuan, Z. (2003) T helper 2 immunity to hepatitis B surface antigen primed by gene-gun-mediated DNA vaccination can be shifted towards T helper 1 immunity by codelivery of CpG motif-containing oligodeoxynucleotides. Scand. J. Immunol. 58, 350ā€“357.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  101. Encke, J., Putlitz, J., Stremmel, W., and Wands, J. R. (2003) CpG immunostimulatory motifs enhance humoral immune responses against hepatitis C virus core protein after DNA-based immunization. Arch. Virol. 148, 435ā€“448.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  102. Moss, R. B., Dively, J., Jensen, F., Gouveia, E., and Carlo, D. J. (2001) Human immunodeficiency virus (HIV)-specific immune responses are generated with the simultaneous vaccination of a gp120-depleted, whole-killed HIV-1 immunogen with cytosine-phosphorothioate-guanine dinucleotide immunostimulatory sequences of DNA. J. Hum. Virol. 4, 39ā€“43.

    CASĀ  PubMedĀ  Google ScholarĀ 

  103. Temperton, N. J., Quenelle, D. C., Lawson, K. M., et al. (2003) Enhancement of humoral immune responses to a human cytomegalovirus DNA vaccine: adjuvant effects of aluminum phosphate and CpG oligodeoxynucleotides. J. Med. Virol. 70, 86ā€“90.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  104. Porter, K. R., Kochel, T. J., Wu, S.-J., Raviprakash, K., Phillips, I., and Hayes, C.G. (2004) Protective efficacy of a dengue 2 DNA vaccine in mice and the effect of CpG immuno-stimulatory motifs on antibody responses. Arch. Virol. 145, 997ā€“1003.

    Google ScholarĀ 

  105. Fensterle, J., Grode, L., Hess, J., and Kaufmann, S. H. E. (1999) Effective DNA vaccination against listeriosis by prime/boost inoculation with the gene gun. J. Immunol. 163, 4510ā€“4518.

    CASĀ  PubMedĀ  Google ScholarĀ 

  106. McCluskie, M. J., Weeratna, R. D., Payette, P. J., and Davis, H. L. (2002) Parenteral and mucosal prime-boost immunization strategies in mice with hepatitis B surface antigen and CpG DNA. FEMS Immuno. Med. Microbiol. 32, 179ā€“185.

    ArticleĀ  CASĀ  Google ScholarĀ 

  107. Hirunpetcharat, C., Wipasa, J., Sakkhachornphop, S., et al. (2003) CpG oligodeoxynucleotide enhances immunity against blood-stage malaria infection in mice parenterally immunized with a yeast-expressed 19 kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP1(19)) formulated in oil-based Montanides. Vaccine 21, 2923ā€“2932.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  108. Mui, B., Raney, S. G., Semple, S. C., and Hope, M. J. (2001) Immune stimulation by a CpG-containing oligodeoxynucleotide is enhanced when encapsulated and delivered in lipid particles. J. Pharmacol. Exp. Ther. 298, 1185ā€“1892.

    CASĀ  PubMedĀ  Google ScholarĀ 

  109. Diwan, M., Tafaghodi, M., and Samuel, J. (2002) Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J. Control Release 85, 247ā€“262.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  110. Agrawal, S. and Kandimalla, E. R. (2003) Modulation of toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA. Ann. NY Acad. Sci. 1002, 30ā€“42.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  111. Storni, T., Ruedl, C., Schwarz, K., Schwendener, R. A., Renner, W. A., and Bachmann, M. F. (2004) Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J. Immunol. 172, 1777ā€“1785.

    CASĀ  PubMedĀ  Google ScholarĀ 

  112. Ahlers, J. D., Belyakov, I. M., and Berzovsky, J. A. (2003) Cytokine, chemokine, and costimulatory molecule modulation to enhance efficacy of HIV vaccines. Curr. Mol. Med. 3, 285ā€“301.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  113. Fearon, K., Marshall, C., Abbate, S., et al. (2003) A minimal human immunostimulatory CpG motif that potently induces IFN-gamma and IFN-alpha production. Eur. J. Immunol. 33, 2114ā€“2122.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

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Verthelyi, D. (2006). Adjuvant Properties of CpG Oligonucleotides in Primates. In: Saltzman, W.M., Shen, H., Brandsma, J.L. (eds) DNA Vaccines. Methods in Molecular Medicineā„¢, vol 127. Humana Press. https://doi.org/10.1385/1-59745-168-1:139

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  • DOI: https://doi.org/10.1385/1-59745-168-1:139

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-484-5

  • Online ISBN: 978-1-59745-168-0

  • eBook Packages: Springer Protocols

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