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
Singh, M. and OāHagan, D. (1999) Advances in vaccine adjuvants. Nat. Biotechnol. 17, 1075ā1081.
Krieg, A. M. and Davis, H. L. (2001) Enhancing vaccines with immune stimulatory CpG DNA. Curr. Opin. Mol. Ther. 3, 15ā24.
Messina, J. P., Gilkeson, G. S., and Pisetsky, D. S. (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J. Immunol. 147, 1759ā1764.
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, 983ā997.
Yamamoto, S., Yamamoto, T., and Tokunaga, T. (2002) Historical perspectives. In: Microbial DNA and Host Immunity, (Raz, E., ed.), Humana Press, Totowa, NJ, pp. 9ā14.
Krieg, A. M., Yi, A., Matson, S., et al. (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546ā548.
Krieg, A. M. (2002) CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709ā760.
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, 101ā106.
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, 3496ā3506.
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, 2879ā2883.
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, 2154ā2163.
Gursel, M., Verthelyi, D., and Klinman, D. M. (2002) CpG oligodeoxynucleotides induce human monocytes to mature into functional dendritic cells. Eur. J. Immunol. 32, 2617ā2622.
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, 3026ā3037.
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, 2372ā2377.
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, 3525ā3534.
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, 3468ā3477.
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, 5121ā5129.
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, 2802ā2805.
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, 5198ā5207.
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, 1659ā1663.
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, 1633ā1641.
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, 781ā792.
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, 4465ā4474.
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, 2154ā2163.
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, 33,071ā33,078.
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, 3059ā3064.
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, 595ā600.
Hemmi, H., Takeuchi, O., Kawai, T., et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408, 740ā745.
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, 3555ā3558.
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, 9237ā9242.
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, 190ā198.
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, 813ā820.
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, 1958ā1968.
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, 269ā274.
Klinman, D. M. and Currie, D. (2003) Hierarchical recognition of CpG motifs in immunostimulatory oligodeoxynucleotides. Cell Immunol. 133, 227ā232.
Verthelyi, D. and Zeuner, R. A. (2003) Differential signaling by CpG DNA in DCs and B cells: not just TLR9. Trends Immunol. 10, 519ā522.
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, 1623ā1631.
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, 870ā876.
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, 6970ā6975.
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, 199ā204.
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, 1565ā1573.
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, 949ā957.
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, 1ā17.
Yu, D., Kandimalla, E. R., Bhagat, L., Cong, Y., Tang, J., and Agrawal, S. (2002) āImmunomersāānovel 3ā²-3ā²-linked CpG oligodeoxyribonucleotides as potent immunomodulatory agents. Nucleic Acid Res. 30, 4460ā4469.
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, 2803ā2808.
OāHagan, D. T. and Singh, M. (2003) Microparticles as vaccine adjuvants and delivery systems. Expert Rev. Vaccines 2, 269ā283.
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, 1939ā1947.
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, 3324ā3328.
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, 1216ā1224.
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, 4463ā4466.
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, 103ā120.
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, 13,156ā13,160.
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, 1029ā1035.
Sato, Y., Roman, M., Tighe, H., et al. (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352ā354.
Klinman, D. M., Yamshchikov, G., and Ishigatsubo, Y. (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J. Immunol. 158, 3635ā3642.
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, 12,631ā12,636.
Roman, M., Martin-Orozco, E., Goodman, J. S., et al. (1997) Immunostimulatory DNA sequences function as T helper-1 promoting adjuvants. Nat. Med. 3, 849ā854.
Klinman, D. M., Barnhart, K. M., and Conover, J. (1999) CpG motifs as immune adjuvants. Vaccine 17, 19ā25.
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, 15,553ā15,558.
Kojima, Y., Xin, K. Q., Ooki, T., et al. (2002) Adjuvant effect of multi-CpG motifs on an HIV-1 DNA vaccine. Vaccine 20, 2857ā2865.
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, 351ā356.
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, 1617ā1624.
Verthelyi, D. and Klinman, D. M. (2003) Immunoregulatory activity of CpG oligonucleotides in humans and nonhuman primates. Clin. Immunol. 109, 64ā71.
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, 3065ā3071.
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, 1003ā1008.
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, 4948ā4954.
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, 2808ā2818.
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, 1611ā1617.
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, 2492ā2499.
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, 241ā247.
Davis, H. L., Suparto, I. I., Weeratna, R. R., et al. (2000) CpG DNA overcomes hyporesponsiveness to hepatitis B vaccine in orangutans. Vaccine 19, 413ā422.
Verthelyi, D., Gursel, M., Kenney, R. T., et al. (2003) CpG Oligodeoxynucleotides protect normal and SIV infected macaques from Leishmania infection. J. Immunol. 170, 4717ā4723.
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. 385ā396.
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, 5658ā5663.
Levin, A. A. (1999) A review of issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochimica et Biophysica Acta. 1489, 69ā84.
Heikenwalder, M., Polymenidou, M., Junt, T., et al. (2004) Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat. Med. 10, 187ā192.
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, 4570ā4575.
Sparwasser, T., Meithke, T., Lipford, G., et al. (1997) Bacterial DNA causes septic shock. Nature 386, 336ā338.
Deng, G. M. and Tarkowski, A. (2000) The features of arthritis induced by CpG motifs in bacterial DNA. Arthritis Rheum. 43, 356ā364.
Zeuner, R. A., Ishii, K. J., Lizak, M. J., et al. (2002) Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum. 46, 2219ā2224.
Krieg, A. M. (2003) Mechanisms and therapeutic applications of immune stimulatory CpG ODN. Sixth NIH Symposium on Therapeutic Oligonucleotides, Bethesda, MD, December 16ā17, 2002, Abstract.
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, 2461ā2467.
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 āActivating Immunity with CpG Oligos. Amelia Island, FL, October 7ā10.
Krieg, A. M. (2001) From bugs to drugs: therapeutic immunomodulation with oligodeoxynucleotides contaiining CpG sequences from bacterial DNA. Antisense Nuc. Acid Drug Dev. 11, 181ā188.
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, 350ā358.
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, 4816ā4822.
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, 584ā588.
Stacey, K. J. and Blackwell, J. M. (1999) Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major. Infect. Immun. 67, 3719ā3726.
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, 3451ā3457.
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, 4812ā4817.
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, 1098ā1105.
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, 1281ā1290.
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, 951ā958.
Corral, R. S. and Petray, P. B. (2000) CpG DNA as a Th1-promoting adjuvant in immunization against Trypanosoma cruzi. Vaccine 19, 234ā242.
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, 77ā86.
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, 237ā243.
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, 1811ā1814.
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, 109ā118.
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, 1305ā1312.
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, 350ā357.
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, 435ā448.
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, 39ā43.
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, 86ā90.
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, 997ā1003.
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, 4510ā4518.
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, 179ā185.
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, 2923ā2932.
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, 1185ā1892.
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, 247ā262.
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, 30ā42.
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, 1777ā1785.
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, 285ā301.
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, 2114ā2122.
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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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