Advertisement

Springer Seminars in Immunopathology

, Volume 19, Issue 2, pp 245–256 | Cite as

DNA vaccines: safety and efficacy issues

  • Dennis M. Klinman
  • Mitsuhiro Takeno
  • Motohide Ichino
  • Mili Gu
  • Galina Yamshchikov
  • Gil Mor
  • Jacqueline Conover
Article

Summary

DNA technology has been harnessed to produce a variety of plasmid-based vaccines designed to prevent viral, bacterial and parasitic infections. The rapid adoption and implementation of this novel vaccine strategy carries with it important safety and efficacy concerns. This review will focus on whether DNA vaccines (1) are likely to induce systemic or organ-specific autoimmune disease, (2) have the potential to induce tolerance rather than immunity, and (3) are as effective in individuals with depressed immune function as they are in healthy adults.

Keywords

Internal Medicine Autoimmune Disease Immune Function Healthy Adult Harness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Points to consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications (1996) Obtain from: Office of Communication, Training and Manufacturers Assistance (HFM-10) Center for Biologics Evaluation and Research, FDA, BethesdaGoogle Scholar
  2. 2.
    Bloom ET, Kubota LF, Kawakami K (1988) Age-related decline in the lethal hit but not the binding stage of cytotoxic T cell activity in mice. Cell Immunol 114:440PubMedGoogle Scholar
  3. 3.
    Broody JA, Brock DB (1985) In: Finch CE, Schneider FL (eds) Handbook of the biology of aging, 2nd edn. Epidemiologic and statistical characteristics of this United States elderly population. Van Nostrand Reinhold, New York, pp 3–20Google Scholar
  4. 4.
    Cardon LR, Burge C, Clayton DA, Karlin S (1994) Pervasive CpG suppression in animal mitochondrial genomes. Proc Natl Acad Sci USA 91:3799PubMedGoogle Scholar
  5. 5.
    Cox GJ, Zamb TJ, Babiuk LA (1993) Bovine herpesvirus 1: immune responses in mice and cattle injected with plasmid DNA. J Virol 67:5664PubMedGoogle Scholar
  6. 6.
    Ebling FM, Hahn BH (1980) Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus. Arthritis Rheum 23:392PubMedGoogle Scholar
  7. 7.
    Effros RB, Watford RL (1983) Diminished T cell response to influenza virus in aged mice. Immunology 49:387PubMedGoogle Scholar
  8. 8.
    Effros RB, Walford RL (1984) The effect of age on the antigen-presenting mechanism in limiting dilution precursor cell frequency analysis. Cell Immunol 88:531PubMedGoogle Scholar
  9. 9.
    Ernst DN, Hobbs MV, Torbert BE, Glasebrook AL, Rehse MA, Bottomly K, Hayakawa K, Hardy RR, Weigle WO (1990) Differences in the expression profiles of CD45 membrane antigens and in the pattems of lymphokine secretion by splenic CD4+ T cells from young and aged mice. J Immunol 145:1295PubMedGoogle Scholar
  10. 10.
    Gilkeson GS, Riuz P, Howell D, Lefkowith JB, Pisetsky DS (1993) Induction of immune-mediated glomerulonephritis in normal mice immunized with bacterial DNA. Clin Immunol Immunopathol 68:283PubMedGoogle Scholar
  11. 11.
    Gilkeson GS, Pippen AM, Pisetsky DS (1995) Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA. J Clin Invest 95:1398PubMedGoogle Scholar
  12. 12.
    Hagiwara E, Gourley M, Lee S, Klinman DM (1996) Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of IL-10: IFN-gamma secreting cells in the peripheral blood. Arthritis Rheum 39:379PubMedGoogle Scholar
  13. 13.
    Halpern MD, Kurlander RJ, Pisetsky DS (1996) Bacterial DNA induces murine interferon-gamma production by stimulation of IL-12 and tumor necrosis factor-alpha. Cell Immunol 167:72PubMedGoogle Scholar
  14. 14.
    Hobbs MV, Weigle WO, Ernst DN (1994) IL-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol 154:264PubMedGoogle Scholar
  15. 15.
    Horvath JA, Mostowski HS, Okumura K, Bloom ET (1992) Pore-forming protein in individual CTL. The effect of senescence provides a probe for understanding the lytic mechanism. Eur J Immunol 22:2649PubMedGoogle Scholar
  16. 16.
    Klinman NR (1972) The mechanism of antigenic stimulation of primary and secondary clonal precursor cells. J Exp Med 136:241PubMedGoogle Scholar
  17. 17.
    Klinman DM (1990) Polyclonal B cell activation in lupus-prone mice precedes and predicts the development of autoimmune disease. J Clin Invest 86:1249PubMedGoogle Scholar
  18. 18.
    Klinman DM (1992) Analysis of B lymphocytes cross-reactivity at the single cell level. J Immunol Methods 152:217PubMedGoogle Scholar
  19. 19.
    Klinman DM, Steinberg AD (1987) Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med 165:1755PubMedGoogle Scholar
  20. 20.
    Klinman NR, Sigal NH, Metcalf ES, Pierce SK, Gearhart PJ (1976) The interplay of evolution and environment in B-Cell diversification. Cold Spr Harbor Symp Quant Biol 41:165Google Scholar
  21. 21.
    Klinman DM, Shirai A, Ishigatsubo Y, Conover J, Steinberg AD (1991) Quantitation of IgG and IgM secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Arthritis Rheum 34:1404PubMedGoogle Scholar
  22. 22.
    Klinman DM, Yi A, Beaucage SL, Conover J, Krieg AM (1996) CpG motifs expressed by bacterial DNA rapidly induce lymphocytes to secrete IL-6, IL-12 and IFN-γ. Proc Natl Acad Sci USA 93:2879PubMedGoogle Scholar
  23. 23.
    Klinman DM, Yamshchikov G, Ishigatsubo Y (1997) Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol 158:3635PubMedGoogle Scholar
  24. 24.
    Krieg AM, Yi A, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546CrossRefPubMedGoogle Scholar
  25. 25.
    Kubo M, Cinader B (1990) Polymorphism of age-related changes in interleukin production: differential changes of T helper subpopulations, synthesizing IL-2, IL-3, and IL-4. Eur J Immunol 20:1289PubMedGoogle Scholar
  26. 26.
    Lambert PH, Dixon FJ (1968) Pathogenesis of the glomerulonephritis of NZB/W mice. J Exp Med 127:507PubMedGoogle Scholar
  27. 27.
    Lehtonen L, Eskola J, Vainio O, Lehtonen A (1990) Changes in lymphocyte subsets and immune competence in very advanced age. J Gerontol 45:M108PubMedGoogle Scholar
  28. 28.
    Linker-Israeli M, Deans R, Wallace D, Prehn J, Ozeri-Chen T, Klinenberg J (1991) Elevated levels of endogenous IL-6 in systemic lupus erythematosus. J Immunol 147:117PubMedGoogle Scholar
  29. 29.
    Manthorpe M, Comefert JF, Hartikka J, Felgner J, Rundell A, Margalith M, Dwarki V (1993) Gene therapy by intramuscular injection of plasmid DNA: studies on firefly luciferase gene expression in mice. Hum Gene Ther 4:419PubMedGoogle Scholar
  30. 30.
    Marodon G, Rocha B (1995) Activation and ‘deletion’ of self-reactive mature and immature T cells during ontogeny of Mls-la: implications for neonatal tolerance induction. Int Immunol 6:1899Google Scholar
  31. 31.
    Miller RA (1989) The cell biology of aging: immunologic models. J Gerontol 44:114Google Scholar
  32. 32.
    Mor G, Klinman DM, Shapiro S, Hagiwara E, Sedegah M, Norman JA, Hoffman SL, Steinberg AD (1995) Complexity of the cytokine and antibody response elicited by immunizing mice withPlasmodium yoelii circumsporozoite protein plasmid DNA. J Immunol 155:2039PubMedGoogle Scholar
  33. 33.
    Mor G, Singla M, Steinberg AD, Hoffman SL, Okuda K, Klinman DM (1997) Do DNA vaccines induce autoimmune disease? Hum Gene Ther 8:293PubMedGoogle Scholar
  34. 34.
    Oshima T, Delespesse G (1997) T cell derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloamigen primed naive human CD4 T cells. J Immunol 158:629PubMedGoogle Scholar
  35. 35.
    Paganelli R, Scala E, Quinti I, Ansotegui IJ (1994) Humoral immunity in aging. Aging Clin Exp Res 6:143Google Scholar
  36. 36.
    Pincus T, Schur PH, Rose JA, Decker JL, Talal N (1970) Measurement of serum anti-DNA binding activity in systemic lupus erythematosus. N Engl J Med 281:701Google Scholar
  37. 37.
    Pisetsky DS, Reich C, Crowley SD, Halpern MD (1995) Immunological properties of bacterial DNA. Ann NY Acad Sci 772:152PubMedGoogle Scholar
  38. 38.
    Razin A, Friedman aJ (1981) DNA methylation and its possible biological roles. Prog Nucleic Acid Res Mol Biol 25:33PubMedGoogle Scholar
  39. 39.
    Robinson HL, Feltquate DM, Morin MJ, Haynes JR, Webster RG (1995) DNA vaccines: a new approach to immunization. Int J Immunopharmacol 17:79PubMedGoogle Scholar
  40. 40.
    Sarzotti M, Robbins DS, Hoffman PM (1996) Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 271:1726PubMedGoogle Scholar
  41. 41.
    Sato Y, Roman M, Tighe H, Lee D, Corm M, Nguyen M, Carson DA, Raz E (1996) Non-coding bacterial DNA sequences necessary for effective intradermal gene immunization. Science 273:352Google Scholar
  42. 42.
    Scollary RGE, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210PubMedGoogle Scholar
  43. 43.
    Sedegah M, Hedstrom R, Hobart P, Hoffman SL (1994) Protection against malaria by immunization with plasmid DNA encoding circumsporozoite protein. Proc Natl Acad Sci USA 91:9866PubMedGoogle Scholar
  44. 44.
    Shirai A, Holmes K, Klinman DM (1993) Detection and quantitation of cells secreting IL-6 under physiological conditions in BALB/c mice. J Immunol 150:793PubMedGoogle Scholar
  45. 45.
    Shirai A, Sierra V, Kelly CI, Klinman DM (1994) Individual cells simultaneously produce both IL-4 and IL-6 under physiologic conditions in vivo. Cytokine 6:329PubMedGoogle Scholar
  46. 46.
    Silverstein AM (1997) Ontogeny of the immune response: a perspective. In: Cooper MD (ed) Development of Host Defenses. Raven Press, New York, pp 1–10Google Scholar
  47. 47.
    Silverstein AM, Segal S (1975) The ontogeny of antigen-specific T cells. J Exp Med 142:802PubMedGoogle Scholar
  48. 48.
    Steinberg AD, Krieg AM, Gourley MF, Klinman DM (1990) Theoretical and experimental approaches to generalized autoimmunity. Immunol Rev 118:129PubMedGoogle Scholar
  49. 49.
    Sterzl J, Silverstein AM. (1967) Developmental aspects of immunity. Adv Immunol 6:337PubMedGoogle Scholar
  50. 50.
    Steward MW, Hay FC (1976) Changes in immunoglobulin class and subclass of anti-DNA antibodies to DNA and RNA. II. Sequential switch from IgM to IgG in NZB/W F1 mice. Clin Exp Immunol 26:363PubMedGoogle Scholar
  51. 51.
    Tang D, DeVit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356:152PubMedGoogle Scholar
  52. 52.
    Tascon RE, Colston MJ, Ragno S, Stavropoulos E, Gregory D, Lowrie DB (1996) Vaccination against tuberculosis by DNA injection. Nature Med 2:888PubMedGoogle Scholar
  53. 53.
    Thoman ML, Weigle WO (1989) The cellular and subcellular bases of immunosenescence. Adv Immunol 46:221PubMedGoogle Scholar
  54. 54.
    Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, Gromkoski SH, Deck RR, DeWitt CM, Friedman A (1993) Heterologous protection against influenza by injection of DNA encoding a viral protein [see comments]. Science 259:1745PubMedGoogle Scholar
  55. 55.
    Wang B, Ugen KE, Srikantan V, Agadjanyan MG, Dang K, Refaeli Y, Sato A, Boyer J, Williams WV, Weiner DB (1993) Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc Natl Acad Sci USA 90:4156PubMedGoogle Scholar
  56. 56.
    Wolff JA, Malone RW, Williams P, Chong W, Ascadi G, Jani A, Felgner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Dennis M. Klinman
    • 1
  • Mitsuhiro Takeno
    • 1
  • Motohide Ichino
    • 1
  • Mili Gu
    • 1
  • Galina Yamshchikov
    • 1
  • Gil Mor
    • 1
  • Jacqueline Conover
    • 1
  1. 1.Section of Retroviral Immunology, Division of Viral ProductsCenter for Biologics Research and Evaluation, Food and Drug AdministrationBethesdaUSA

Personalised recommendations