Abstract
One of the most exciting developments in the field of vaccine research in recent years has been DNA vaccines, with which immune responses are induced sub-sequent to the in vivo expression of antigen from directly introduced plasmid DNA. Strong immune responses have been demonstrated in a number of animal models against many viral, bacterial and parasitic pathogens, and several human clinical trials have been undertaken. The strong and long-lasting antigen-specific humoral (antibodies) and cell-mediated (T help, other cytokine functions and cytotoxic T cells) immune responses induced by DNA vaccines appear to be due to the sustained in vivo expression of antigen, efficient antigen presentation and the presence of stimulatory CpG motifs. These features are desirable for the development of prophylactic vaccines against numerous infectious agents. Furthermore, the strong cellular responses are also very desirable for the development of therapeutic DNA vaccines to treat chronic viral infections or cancer. Efforts are now focusing on understanding the mechanisms for the induction of these immune responses, which in turn should aid in the optimization of DNA vaccines. This review will focus on the role of CpG motifs in DNA vaccines.
Similar content being viewed by others
References
Alton EWFW, Middleton PG, Caplen NJ, Smith SN, Steel DM, Munkonge FM, Jeffery PK, Geddes DM, Hart SL, Williamson R, Fasold KI, Miller AD, Dickinson P, Stevenson BJ, McLachlan G, Dorin JR, Porteous DJ (1993) Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice. Nat Genet 5: 135
Asakura Y, Hinkula J, Leandersson AC, Fukushima J, Okuda K, Wahren B (1997) Induction of HIV-1 specific mucosal immune responses by DNA vaccination. Scand J Immunol 46: 326
Broide D, Schwarze J, Tighe H, Gifford T, Nguyen MD, Malek S, Van Uden J, Martin-Orozco E, Gelfand EW, Raz E (1998) Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol 161: 7054
Calarota S, Bratt G, Nordlund S, Hinkula J, Leandersson AC, Sandstrom E, Wahren B (1998) Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients. Lancet 351: 1320
Caplen NJ, Alton EWFW, Middleton PG, Dorin JR, Stevenson BJ, Gao X, Durham SR, Jeffrey PK, Hodson ME, Coutelle C, Huang L, Porteous DJ, Williamson R, Geddes DM (1995) Liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1: 39
Casares S, Inaba K, Brumeanu TD, Steinman RM, Bona CA (1997) Antigen presentation by dendritic cells after immunization with DNA encoding a major histocompatibility complex class II-restricted viral epitope. J Exp Med 186: 1481
Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo LD Jr (1996) DNA-based immunization by in vivo transfection of dendritic cells. Nat Med 2: 1122
Davis HL, Brazolot Millan CL, Watkins SC (1997) Immune-mediated destruction of transfected muscle fibers after direct gene transfer with antigen-expressing plasmid DNA. Gene Ther 4: 181
Davis HL, McCluskie MJ (1999) DNA vaccines for viral diseases. Microbes Infect 1: 7
Davis HL, Weeranta R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM (1998) CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol 160:870
Freimark BD, Blezinger HP, Florack VJ, Nordstrom JL, Long SD, Deshpande DS, Nochumson S, Petrak KL (1998) Cationic lipids enhance cytokine and cell influx levels in the lung following administration of plasmid: cationic lipid complexes. J Immunol 160: 4580
Gursel M, Tunca S, Ozkan M, Ozcengiz G, Alaeddinoglu G (1999) Immunoadjuvant action of plasmid DNA in liposomes. Vaccine 17: 1376
Halpern MD, Kurlander RJ, Pisetsky DS (1996) Bacterial DNA induces murine interferon-γ production by stimulation of interleukin-12 and tumor necrosis factor-α. Cell Immunol 167: 72
Harms JS, Splitter GA (1995) Interferon-gamma inhibits transgene expression driven by SV40 or CMV promoters but augments expression driven by the mammalian MHC I promoter. Hum Gene Ther 6:1291
Hogan SP, Foster PS, Tan X, Ramsay AJ (1998) Mucosal IL-12 gene delivery inhibits allergic airways disease and restores local antiviral immunity. Eur J Immunol 28: 413
Hogg J. C. (1997) The pathology of asthma. APMIS 105: 735
Horner AA, Ronaghy A, Cheng PM, Nguyen MD, Cho HJ, Broide D, Raz E (1998) Immunostimulatory DNA is a potent mucosal adjuvant. Cell Immunol 190: 77
Hug M, Silke J, Georgiev O, Rusconi S, Schaffner W, Matsuo K (1996) Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG-rich regions. FEBS Lett 379: 251
Ishii N, Fukushima J, Kaneko T, Okada E, Tani K, Tanaka SI, Hamajima K, Xin KQ, Kawamoto S, Koff W, Nishioka K, Yasuda T, Okuda K (1997) Cationic liposomes are a strong adjuvant for a DNA vaccine of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 13: 1421
Karpati G, Ajdukovic D, Arnold D, Glendhill RB, Guttmann R, Holland P, Koch PA, Shoubridge E, Spence D, Vanasse M, Watters GV, Abrahamowicz M, Duff C, Worton RG (1993) Myoblast transfer in Duchenne muscular dystrophy. Ann Neurol 34: 8
Kay AB (1996) TH2-type cytokines in asthma. Ann N Y Acad Sci 796: 1
Klavinskis LS, Barnfield C, Gao L, Parker S (1999) Intranasal immunization with plasmid DNA-lipid complexes elicits mucosal immunity in the female genital and rectal tracts. J Immunol 162: 254
Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock JV, Thome PS, Krieg AM (1998) Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 160: 2555
Klinman DM, Yamshchikov G, Ishigatsubo Y (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 158: 3635
Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM (1996) CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci USA 93:2879
Knoell, DL, Yiu IM (1998) Human gene therapy for hereditary diseases: a review of trials. Am J Health Syst Pharm 55: 899
Krieg AM, Wu T, Weeratna R, Efler SM, Love-Homan L, Yang L, Yi AK, Short D, Davis HL (1998) Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 95: 12631
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374: 546
Krieg AM, Yi AK, Schorr J, Davis HL (1998) The role of CpG dinucleotides in DNA vaccines. Trends Microbiol 6: 23
Kuklin N, Daheshia M, Karem K, Manickan E, Rouse BT (1997) Induction of mucosal immunity against herpes simplex virus by plasmid DNA immunization. J Virol 71: 3138
Leclerc C, Deriaud E, Rojas M, Whalen RG (1997) The preferential induction of a Th1 immune response by DNA-based immunization is mediated by the immunostimulatory effect of plasmid DNA. Cell Immunol 179: 97
Lee ER, Marshall J, Siegel CS, Jiang CW, Yew NS, Nichols MR, Nietupski JB, Ziegler RJ, Lane MB, Wang KX, Wan NC, Scheule RK, Harris DJ, Smith AE, Cheng SH (1996) Detailed analysis of structures and formulations of cationic lipids for efficient gene transfer to the lung. Hum Gene Ther 7: 1701
Lee SW, Sung YC (1998) Immuno-stimulatory effects of bacterial-derived plasmids depend on the nature of the antigen in intramuscular DNA inoculations. Immunology 94: 285
Li XM, Chopra RK, Chou TY, Schofield BH, Wills-Karp M, Huang SK (1996) Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice. J Immunol 157: 3216
MacGregor RR, Boyer JD, Ugen KE, Lacy KE, Gluckman SJ, Bagarazzi ML, Chattergoon MA, Baine Y, Higgins TJ, Ciccarelli RB, Coney LR, Ginsberg RS, Weiner DB (1998) First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. J Infect Dis 178: 92
McCluskie MJ, Chu Y, Xia JL, Jessee J, Gebyehu G, Davis HL (1998) Direct gene transfer to the respiratory tract of mice with pure plasmid and lipid-formulated DNA. Antisense Nucleic Acid Drug Dev 8: 401
McCluskie MJ, Davis HL (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: 4463
McCluskie MJ, Davis HL (1999) Novel strategies using DNA for the induction of mucosal immunity. Crit Rev Immunol 19:303
McCluskie MJ, Wen Y-M, Di Q, Davis HL (1998) Immunization against hepatitis B virus by mucosal administration of antigen-antibody complexes. Viral Immunol 11: 245
Mendell JR, Kissel JT, Amato AA, King W, Signore L, Prior TW, Sahenk Z, Benson S, McAndrew PE, Rice R, Nagaraja H, Stephens R, Lantry L, Morris GE, Burghes AHM (1995). Myoblast transfer in the treatment of Duchenne’s muscular dystrophy. N Engl J Med 333: 832
Meyer KB, Thompson M, Levy M, Barron L, Szoka FJ (1995) Intratracheal gene delivery to the mouse airway: characterization of plasmid DNA expression and pharmacokinetics. Gene Ther 2: 450
Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16: 1216
Okada E, Sasaki S, Ishii N, Aoki I, Yasuda T, Nishioka K, Fukushima J, Miyazaki J, Wahren B, Okuda K (1997) Intranasal immunization of a DNA vaccine with IL-12- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing plasmids in liposomes induces strong mucosal and cell-mediated immune responses against HIV-1 antigens. J Immunol 159: 3638
Parker SE, Vahlsing HL, Serfilippi LM, Franklin CL, Doh SG, Gromkowski SH, Lew D, Manthorpe M, Norman J (1995) Cancer gene therapy using plasmid DNA: safety evaluation in rodents and non-human primates. Hum Gene Ther 6: 575
Porter KR, Kochel TJ, Wu SJ, Raviprakash K, Phillips I, Hayes CG (1998) Protective efficacy of a dengue 2 DNA vaccine in mice and the effect of CpG immuno-stimulatory motifs on antibody responses. Arch Virol 143: 997
Romero R, Lavine JE (1996) Cytokine inhibition of the hepatitis B virus core promoter. Hepatology 23: 17
Sasaki S, Hamajima K, Fukushima J, Ihata A, Ishii N, Gorai I, Hirahara F, Mohri H, Okuda K (1998) Comparison of intranasal and intramuscular immunization against human immunodeficiency virus type 1 with a DNA-monophosphoryl lipid A adjuvant vaccine. Infect Immun 66: 823
Sasaki S, Sumino K, Hamajima K, Fukushima J, Ishii N, Kawamoto S, Mohri H, Kensil CR, Okuda K (1998) Induction of systemic and mucosal immune responses to human immunodeficiency virus type 1 by a DNA vaccine formulated with QS-21 saponin adjuvant via intramuscular and intranasal routes. J Virol 72: 4931
Sato Y, Roman M, Tighe H, Lee D, Corr M, Nguyen MD, Silverman GJ, Lotz M, Carson DA, Raz E (1996). Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273: 352
Scheule RK, St George JA, Bagley RG, Marshall J, Kaplan JM, Akita GY, Wang KX, Lee ER, Harris DJ, Jiang C, Yew NS, Smith AE, Cheng SH (1997) Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung. Hum Gene Ther 8: 689
Sparwasser T, Koch ES, Vabulas RM, Heeg K, Lipford GB, Ellwart JW, Wagner H (1998) Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28: 2045
Tacket CO, Roy MJ, Widera G, Swain WF, Broome S, Edelman R (1999) Phase 1 safety and immune response studies of a DNA vaccine encoding hepatitis B surface antigen delivered by a gene delivery device. Vaccine 22: 2826
Tang DC, De Vit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356: 152–154
Ugen KE, Nyland SB, Boyer JD, Vidal C, Lera L, Rasheid S, Chattergoon M, Bagarazzi ML, Ciccarelli R, Higgins T, Baine Y, Ginsberg R, Macgregor RR, Weiner DB (1998) DNA vaccination with HIV-1 expressing constructs elicits immune responses in humans. Vaccine. 16: 1818
Wang R, Doolan DL, Le TP, Hedstrom RC, Coonan KM, Charoenvit Y, Jones TR, Hobart P, Margalith M, Ng J, Weiss WR, Sedegah M, de Taisne C, Norman JA, Hoffman SL (1998) Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 282: 476
Weeratna R, Brazolot-Millan CL, Krieg AM, Davis HL (1998) Reduction of antigen expression from DNA vaccines by co-administered oligonucleotides. Antisense Nucleic Acid Drug Dev 8: 351
Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Feigner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 247: 1465
Xiang ZQ, He Z, Wang Y, Ertl HCJ (1997) The effect of interferon-γ on genetic immunization. Vaccine 15: 896
Yew NS, Wang KX, Przybylska M, Bagley RG, Stedman M, Marshall J, Scheule RK, Cheng SH (1999) Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes. Hum Gene Ther 10: 223
Yew NS, Wysokenski DM, Wang KX, Ziegler RJ, Marshall J, Mcneilly D, Cherry M, Osburn W, Cheng SH (1997) Optimization of plasmid vectors for high-level expression in lung epithelial cells. Hum Gene Ther 8: 575
Yi AK, Klinman DM, Martin TL, Matson S, Krieg AM (1996) Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 157: 5394
Zabner J, Cheng SH, Meeker D, Launspach J, Balfour R, Perricone MA, Morris JE, Marshall J, Fasbender A, Smith AE, Welsh MJ (1997) Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J Clin Invest 100: 1529
Zhao Q, Matson S, Herrera CJ, Fisher E, Yu H, Krieg AM (1993) Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate and mixed phosphorothioate and methylphos-phonate oligonucleotides. Antisense Res Develop 3: 53
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McCluskie, M.J., Weeratna, R.D. & Davis, H.L. The role of CpG in DNA vaccines. Springer Semin Immunopathol 22, 125–132 (2000). https://doi.org/10.1007/s002810000014
Issue Date:
DOI: https://doi.org/10.1007/s002810000014