Skip to main content

Advertisement

Log in

The role of CpG in DNA vaccines

  • Published:
Springer Seminars in Immunopathology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. 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

    Article  PubMed  CAS  Google Scholar 

  2. 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

    Article  PubMed  CAS  Google Scholar 

  3. 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

    PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. 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

    Article  PubMed  CAS  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Davis HL, McCluskie MJ (1999) DNA vaccines for viral diseases. Microbes Infect 1: 7

    Article  PubMed  CAS  Google Scholar 

  10. 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

    PubMed  CAS  Google Scholar 

  11. 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

    PubMed  CAS  Google Scholar 

  12. Gursel M, Tunca S, Ozkan M, Ozcengiz G, Alaeddinoglu G (1999) Immunoadjuvant action of plasmid DNA in liposomes. Vaccine 17: 1376

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  CAS  Google Scholar 

  14. 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

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. Hogg J. C. (1997) The pathology of asthma. APMIS 105: 735

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Kay AB (1996) TH2-type cytokines in asthma. Ann N Y Acad Sci 796: 1

    Article  PubMed  CAS  Google Scholar 

  22. 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

    PubMed  CAS  Google Scholar 

  23. 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

    PubMed  CAS  Google Scholar 

  24. Klinman DM, Yamshchikov G, Ishigatsubo Y (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 158: 3635

    PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. Knoell, DL, Yiu IM (1998) Human gene therapy for hereditary diseases: a review of trials. Am J Health Syst Pharm 55: 899

    PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. Krieg AM, Yi AK, Schorr J, Davis HL (1998) The role of CpG dinucleotides in DNA vaccines. Trends Microbiol 6: 23

    Article  PubMed  CAS  Google Scholar 

  30. 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

    PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  CAS  Google Scholar 

  34. 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

    PubMed  CAS  Google Scholar 

  35. 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

    PubMed  CAS  Google Scholar 

  36. 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

    PubMed  CAS  Google Scholar 

  37. 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

    PubMed  CAS  Google Scholar 

  38. McCluskie MJ, Davis HL (1999) Novel strategies using DNA for the induction of mucosal immunity. Crit Rev Immunol 19:303

    PubMed  CAS  Google Scholar 

  39. 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

    Article  PubMed  CAS  Google Scholar 

  40. 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

    Article  PubMed  CAS  Google Scholar 

  41. 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

    PubMed  CAS  Google Scholar 

  42. 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

    Article  PubMed  CAS  Google Scholar 

  43. 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

    PubMed  CAS  Google Scholar 

  44. 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

    Article  PubMed  CAS  Google Scholar 

  45. 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

    Article  PubMed  CAS  Google Scholar 

  46. Romero R, Lavine JE (1996) Cytokine inhibition of the hepatitis B virus core promoter. Hepatology 23: 17

    Article  PubMed  CAS  Google Scholar 

  47. 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

    PubMed  CAS  Google Scholar 

  48. 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

    PubMed  CAS  Google Scholar 

  49. 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

    Article  PubMed  CAS  Google Scholar 

  50. 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

    Article  PubMed  CAS  Google Scholar 

  51. 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

    Article  PubMed  CAS  Google Scholar 

  52. 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

    Article  Google Scholar 

  53. Tang DC, De Vit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356: 152–154

    Article  PubMed  CAS  Google Scholar 

  54. 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

    Article  PubMed  CAS  Google Scholar 

  55. 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

    Article  PubMed  CAS  Google Scholar 

  56. 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

    PubMed  CAS  Google Scholar 

  57. 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

    Article  PubMed  CAS  Google Scholar 

  58. Xiang ZQ, He Z, Wang Y, Ertl HCJ (1997) The effect of interferon-γ on genetic immunization. Vaccine 15: 896

    Article  PubMed  CAS  Google Scholar 

  59. 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

    Article  PubMed  CAS  Google Scholar 

  60. 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

    Article  PubMed  CAS  Google Scholar 

  61. 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

    PubMed  CAS  Google Scholar 

  62. 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

    Article  PubMed  CAS  Google Scholar 

  63. 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

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints 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

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002810000014

Keywords

Navigation