Clin Exp Vaccine Res.  2015 Jan;4(1):1-10. 10.7774/cevr.2015.4.1.1.

Improvement of DNA vaccination by adjuvants and sophisticated delivery devices: vaccine-platforms for the battle against infectious diseases

• Grunwald T
• Ulbert S

• KMID: 2049102
• DOI: http://doi.org/10.7774/cevr.2015.4.1.1

Abstract

Advantages of DNA vaccination against infectious diseases over more classical immunization methods include the possibilities for rapid manufacture, fast adaptation to newly emerging pathogens and high stability at ambient temperatures. In addition, upon DNA immunization the antigen is produced by the cells of the vaccinated individual, which leads to activation of both cellular and humoral immune responses due to antigen presentation via MHC I and MHC II molecules. However, so far DNA vaccines have shown most efficient immunogenicity mainly in small rodent models, whereas in larger animals including humans there is still the need to improve effectiveness. This is mostly due to inefficient delivery of the DNA plasmid into cells and nuclei. Here, we discuss technologies used to overcome this problem, including physical means such as in vivo electroporation and co-administration of adjuvants. Several of these methods have already entered clinical testing in humans.

Keyword

DNA vaccines; Gene transfer techniques; Immunologic adjuvants; Infection

MeSH Terms

Adjuvants, Immunologic
Animals
Antigen Presentation
Communicable Diseases*
DNA*
Electroporation
Gene Transfer Techniques
Humans
Immunity, Humoral
Immunization
Plasmids
Rodentia
Vaccination*
Vaccines, DNA
Adjuvants, Immunologic
DNA
Vaccines, DNA

Figure

• 

  Fig. 1 Different electroporation delivery devices. Schematic view on DNA immunization by intramuscular and intradermal electroporation. (A) For intramuscular electroporation an array of needle electrodes carry an electrical current to the cells in the muscle layer. After an electronic pulse the cell membrane of muscle cells is temporarily permeable, allowing DNA plasmid to enter the cell. (B) For the intradermal electroporation the needle electrodes are placed on or introduced into the skin. The DNA plasmids are taken up by the dendritic cells (Langerhans cells) of the skin upon the electronic pulses.

Reference

1. Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990; 247:1465–1468.

2. Ulmer JB, Donnelly JJ, Parker SE, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993; 259:1745–1749.

3. Jiao S, Williams P, Berg RK, et al. Direct gene transfer into nonhuman primate myofibers in vivo. Hum Gene Ther. 1992; 3:21–33.

4. Stab V, Nitsche S, Niezold T, et al. Protective efficacy and immunogenicity of a combinatory DNA vaccine against influenza A virus and the respiratory syncytial virus. PLoS One. 2013; 8:e72217.

5. Liu MA. DNA vaccines: an historical perspective and view to the future. Immunol Rev. 2011; 239:62–84.

6. Khan AS, Bodles-Brakhop AM, Fiorotto ML, Draghia-Akli R. Effects of maternal plasmid GHRH treatment on offspring growth. Vaccine. 2010; 28:1905–1910.

7. Davis BS, Chang GJ, Cropp B, et al. West Nile virus recombinant DNA vaccine protects mouse and horse from virus challenge and expresses in vitro a noninfectious recombinant antigen that can be used in enzyme-linked immunosorbent assays. J Virol. 2001; 75:4040–4047.

8. Kilpatrick AM, Dupuis AP, Chang GJ, Kramer LD. DNA vaccination of American robins (Turdus migratorius) against West Nile virus. Vector Borne Zoonotic Dis. 2010; 10:377–380.

9. Turell MJ, Bunning M, Ludwig GV, et al. DNA vaccine for West Nile virus infection in fish crows (Corvus ossifragus). Emerg Infect Dis. 2003; 9:1077–1081.

10. Bunning ML, Fox PE, Bowen RA, et al. DNA vaccination of the American crow (Corvus brachyrhynchos) provides partial protection against lethal challenge with West Nile virus. Avian Dis. 2007; 51:573–577.

11. Anderson ED, Mourich DV, Fahrenkrug SC, LaPatra S, Shepherd J, Leong JA. Genetic immunization of rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis virus. Mol Mar Biol Biotechnol. 1996; 5:114–122.

12. Corbeil S, Lapatra SE, Anderson ED, et al. Evaluation of the protective immunogenicity of the N, P, M, NV and G proteins of infectious hematopoietic necrosis virus in rainbow trout oncorhynchus mykiss using DNA vaccines. Dis Aquat Organ. 1999; 39:29–36.

13. Bergman PJ, McKnight J, Novosad A, et al. Long-term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial. Clin Cancer Res. 2003; 9:1284–1290.

14. Burckstummer T, Baumann C, Bluml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009; 10:266–272.

15. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009; 458:514–518.

16. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009; 458:509–513.

17. Unterholzner L, Keating SE, Baran M, et al. IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010; 11:997–1004.

18. Stetson DB, Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 2006; 24:93–103.

19. Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013; 38:870–880.

20. Bhat N, Fitzgerald KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur J Immunol. 2014; 44:634–640.

21. Lechardeur D, Lukacs GL. Intracellular barriers to non-viral gene transfer. Curr Gene Ther. 2002; 2:183–194.

22. Otten G, Schaefer M, Doe B, et al. Enhancement of DNA vaccine potency in rhesus macaques by electroporation. Vaccine. 2004; 22:2489–2493.

23. Verstrepen BE, Bins AD, Rollier CS, et al. Improved HIV-1 specific T-cell responses by short-interval DNA tattooing as compared to intramuscular immunization in non-human primates. Vaccine. 2008; 26:3346–3351.

24. Widera G, Austin M, Rabussay D, et al. Increased DNA vaccine delivery and immunogenicity by electroporation in vivo. J Immunol. 2000; 164:4635–4640.

25. Kutzler MA, Weiner DB. DNA vaccines: ready for prime time? Nat Rev Genet. 2008; 9:776–788.

26. Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992; 356:152–154.

27. Luckay A, Sidhu MK, Kjeken R, et al. Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques. J Virol. 2007; 81:5257–5269.

28. Fazio VM. "Naked" DNA transfer technology for genetic vaccination against infectious disease. Res Virol. 1997; 148:101–108.

29. Hartikka J, Bozoukova V, Jones D, et al. Sodium phosphate enhances plasmid DNA expression in vivo. Gene Ther. 2000; 7:1171–1182.

30. Satkauskas S, Bureau MF, Mahfoudi A, Mir LM. Slow accumulation of plasmid in muscle cells: supporting evidence for a mechanism of DNA uptake by receptor-mediated endocytosis. Mol Ther. 2001; 4:317–323.

31. March JB. Modern vaccine adjuvants and delivery systems: second international conference. Expert Rev Vaccines. 2006; 5:753–759.

32. Kanitakis J. Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol. 2002; 12:390–399.

33. Mathers AR, Larregina AT. Professional antigen-presenting cells of the skin. Immunol Res. 2006; 36:127–136.

34. Klinman DM, Conover J, Bloom ET, Weiss W. Immunogenicity and efficacy of a DNA vaccine in aged mice. J Gerontol A Biol Sci Med Sci. 1998; 53:B281–B286.

35. Mitragotri S. Immunization without needles. Nat Rev Immunol. 2005; 5:905–916.

36. Bahloul C, Taieb D, Diouani MF, et al. Field trials of a very potent rabies DNA vaccine which induced long lasting virus neutralizing antibodies and protection in dogs in experimental conditions. Vaccine. 2006; 24:1063–1072.

37. Maruyama H, Ataka K, Higuchi N, Sakamoto F, Gejyo F, Miyazaki J. Skin-targeted gene transfer using in vivo electroporation. Gene Ther. 2001; 8:1808–1812.

38. Heller LC, Jaroszeski MJ, Coppola D, McCray AN, Hickey J, Heller R. Optimization of cutaneous electrically mediated plasmid DNA delivery using novel electrode. Gene Ther. 2007; 14:275–280.

39. Hooper JW, Golden JW, Ferro AM, King AD. Smallpox DNA vaccine delivered by novel skin electroporation device protects mice against intranasal poxvirus challenge. Vaccine. 2007; 25:1814–1823.

40. Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine delivery and potency in pigs and rhesus macaques. Vaccine. 2008; 26:440–448.

41. Grunwald T, Tenbusch M, Schulte R, et al. Novel vaccine regimen elicits strong airway immune responses and control of respiratory syncytial virus in nonhuman primates. J Virol. 2014; 88:3997–4007.

42. Bins AD, Jorritsma A, Wolkers MC, et al. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression. Nat Med. 2005; 11:899–904.

43. Pokorna D, Rubio I, Muller M. DNA-vaccination via tattooing induces stronger humoral and cellular immune responses than intramuscular delivery supported by molecular adjuvants. Genet Vaccines Ther. 2008; 6:4.

44. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408:740–745.

45. Zhang A, Jin H, Zhang F, et al. Effects of multiple copies of CpG on DNA vaccination. DNA Cell Biol. 2005; 24:292–298.

46. Jayakumar A, Castilho TM, Park E, Goldsmith-Pestana K, Blackwell JM, McMahon-Pratt D. TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T Cell responses providing protection against Leishmania (Viannia). PLoS Negl Trop Dis. 2011; 5:e1204.

47. Luo Z, Shi H, Zhang H, et al. Plasmid DNA containing multiple CpG motifs triggers a strong immune response to hepatitis B surface antigen when combined with incomplete Freund's adjuvant but not aluminum hydroxide. Mol Med Rep. 2012; 6:1309–1314.

48. Jin H, Li Y, Ma Z, et al. Effect of chemical adjuvants on DNA vaccination. Vaccine. 2004; 22:2925–2935.

49. Chuang CM, Monie A, Hung CF, Wu TC. Treatment with imiquimod enhances antitumor immunity induced by therapeutic HPV DNA vaccination. J Biomed Sci. 2010; 17:32.

50. Saade F, Petrovsky N. Technologies for enhanced efficacy of DNA vaccines. Expert Rev Vaccines. 2012; 11:189–209.

51. Ulmer JB, DeWitt CM, Chastain M, et al. Enhancement of DNA vaccine potency using conventional aluminum adjuvants. Vaccine. 1999; 18:18–28.

52. Wang S, Liu X, Fisher K, et al. Enhanced type I immune response to a hepatitis B DNA vaccine by formulation with calcium- or aluminum phosphate. Vaccine. 2000; 18:1227–1235.

53. Ruiz W, McClements WL, Jansen KU, Esser MT. Kinetics and isotype profile of antibody responses in rhesus macaques induced following vaccination with HPV 6, 11, 16 and 18 L1-virus-like particles formulated with or without Merck aluminum adjuvant. J Immune Based Ther Vaccines. 2005; 3:2.

54. Redig PT, Tully TN, Ritchie BW, Roy AF, Baudena MA, Chang GJ. Effect of West Nile virus DNA-plasmid vaccination on response to live virus challenge in red-tailed hawks (Buteo jamaicensis). Am J Vet Res. 2011; 72:1065–1070.

55. Chang GJ, Davis BS, Stringfield C, Lutz C. Prospective immunization of the endangered California condors (Gymnogyps californianus) protects this species from lethal West Nile virus infection. Vaccine. 2007; 25:2325–2330.

56. Quijano-Hernandez IA, Bolio-Gonzalez ME, Rodriguez-Buenfil JC, Ramirez-Sierra MJ, Dumonteil E. Therapeutic DNA vaccine against Trypanosoma cruzi infection in dogs. Ann N Y Acad Sci. 2008; 1149:343–346.

57. Quirk EK, Brown EL, Leavitt RY, et al. Safety profile of the Merck human immunodeficiency virus-1 clade B gag DNA plasmid vaccine with and without adjuvants. Open Forum Infect Dis. 2014 Apr 18 [Epub] http://dx.doi.org/10.1093/ofid/ofu016/.

58. Verdier F, Burnett R, Michelet-Habchi C, Moretto P, Fievet-Groyne F, Sauzeat E. Aluminium assay and evaluation of the local reaction at several time points after intramuscular administration of aluminium containing vaccines in the cynomolgus monkey. Vaccine. 2005; 23:1359–1367.

59. Flarend RE, Hem SL, White JL, et al. In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine. 1997; 15:1314–1318.

60. Reyes L, Hartikka J, Bozoukova V, et al. Vaxfectin enhances antigen specific antibody titers and maintains Th1 type immune responses to plasmid DNA immunization. Vaccine. 2001; 19:3778–3786.

61. Vilalta A, Shlapobersky M, Wei Q, Planchon R, Rolland A, Sullivan S. Analysis of biomarkers after intramuscular injection of Vaxfectin-formulated hCMV gB plasmid DNA. Vaccine. 2009; 27:7409–7417.

62. Smith LR, Wodal W, Crowe BA, et al. Preclinical evaluation of Vaxfectin-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines. Hum Vaccin Immunother. 2013; 9:1333–1345.

63. Raviprakash K, Luke T, Doukas J, et al. A dengue DNA vaccine formulated with Vaxfectin(R) is well tolerated, and elicits strong neutralizing antibody responses to all four dengue serotypes in New Zealand white rabbits. Hum Vaccin Immunother. 2012; 8:1764–1768.

64. Veselenak RL, Shlapobersky M, Pyles RB, Wei Q, Sullivan SM, Bourne N. A Vaxfectin((R))-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes. Vaccine. 2012; 30:7046–7051.

65. Sullivan SM, Doukas J, Hartikka J, Smith L, Rolland A. Vaxfectin: a versatile adjuvant for plasmid DNA- and protein-based vaccines. Expert Opin Drug Deliv. 2010; 7:1433–1446.

66. Lin WH, Vilalta A, Adams RJ, Rolland A, Sullivan SM, Griffin DE. Vaxfectin adjuvant improves antibody responses of juvenile rhesus macaques to a DNA vaccine encoding the measles virus hemagglutinin and fusion proteins. J Virol. 2013; 87:6560–6568.

67. Smith LR, Wloch MK, Ye M, et al. Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine. 2010; 28:2565–2572.

68. Chiang YW, Jennen CM, Holt TM, et al. Demonstration of efficacy of a West Nile virus DNA vaccine in foals. In : Proceedings of the 51st Annual Convention of the American Association of Equine Practitioners; 2005 Dec 3-7; Seattle, WA. Lexington: American Association of Equine Practitioners;2005. p. 183–190.

69. Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A. 2008; 105:2574–2579.

70. Tenbusch M, Ignatius R, Nchinda G, et al. Immunogenicity of DNA vaccines encoding simian immunodeficiency virus antigen targeted to dendritic cells in rhesus macaques. PLoS One. 2012; 7:e39038.

71. Flingai S, Czerwonko M, Goodman J, Kudchodkar SB, Muthumani K, Weiner DB. Synthetic DNA vaccines: improved vaccine potency by electroporation and co-delivered genetic adjuvants. Front Immunol. 2013; 4:354.

72. Takeshita F, Tanaka T, Matsuda T, et al. Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity. J Virol. 2006; 80:6218–6224.

73. Ullas PT, Desai A, Madhusudana SN. Immunogenicity and efficacy of a plasmid DNA rabies vaccine incorporating Myd88 as a genetic adjuvant. Clin Exp Vaccine Res. 2014; 3:202–211.

74. Liniger M, Summerfield A, Ruggli N. MDA5 can be exploited as efficacious genetic adjuvant for DNA vaccination against lethal H5N1 influenza virus infection in chickens. PLoS One. 2012; 7:e49952.

75. Luo M, Qu X, Pan R, et al. The virus-induced signaling adaptor molecule enhances DNA-raised immune protection against H5N1 influenza virus infection in mice. Vaccine. 2011; 29:2561–2567.

76. Luke JM, Simon GG, Soderholm J, et al. Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine. J Virol. 2011; 85:1370–1383.

77. Dunn MD, Rossi SL, Carter DM, et al. Enhancement of anti-DIII antibodies by the C3d derivative P28 results in lower viral titers and augments protection in mice. Virol J. 2010; 7:95.

78. Capitani M, Saade F, Havas KM, et al. Plasmids encoding protein aggregation domains act as molecular adjuvants for DNA vaccines. Curr Gene Ther. 2014; 14:161–169.

79. Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. Curr Opin Immunol. 2011; 23:421–429.

80. Cristillo AD, Weiss D, Hudacik L, et al. Persistent antibody and T cell responses induced by HIV-1 DNA vaccine delivered by electroporation. Biochem Biophys Res Commun. 2008; 366:29–35.

81. Jalah R, Kulkarni V, Patel V, et al. DNA and protein co-immunization improves the magnitude and longevity of humoral immune responses in macaques. PLoS One. 2014; 9:e91550.

82. Hammer SM, Sobieszczyk ME, Janes H, et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013; 369:2083–2092.

83. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008; 372:1881–1893.

84. Ondondo BO. The influence of delivery vectors on HIV vaccine efficacy. Front Microbiol. 2014; 5:439.

85. Uberla K. Developing an HIV vaccine: the role of efficacy studies in nonhuman primates. PLoS Med. 2005; 2:e119.

86. Johnson TR, Rangel D, Graham BS, Brough DE, Gall JG. Genetic vaccine for respiratory syncytial virus provides protection without disease potentiation. Mol Ther. 2014; 22:196–205.

87. Vasan S, Hurley A, Schlesinger SJ, et al. In vivo electroporation enhances the immunogenicity of an HIV-1 DNA vaccine candidate in healthy volunteers. PLoS One. 2011; 6:e19252.

88. Kopycinski J, Cheeseman H, Ashraf A, et al. A DNA-based candidate HIV vaccine delivered via in vivo electroporation induces CD4 responses toward the alpha4beta7-binding V2 loop of HIV gp120 in healthy volunteers. Clin Vaccine Immunol. 2012; 19:1557–1559.

89. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012; 366:1275–1286.

90. Hartikka J, Geall A, Bozoukova V, et al. Physical characterization and in vivo evaluation of poloxamer-based DNA vaccine formulations. J Gene Med. 2008; 10:770–782.

91. Kharfan-Dabaja MA, Boeckh M, Wilck MB, et al. Reanalysis of TransVax immunogenicity. Lancet Infect Dis. 2013; 13:18.

92. Lu S. Heterologous prime-boost vaccination. Curr Opin Immunol. 2009; 21:346–351.

93. Sandstrom E, Nilsson C, Hejdeman B, et al. Broad immunogenicity of a multigene, multiclade HIV-1 DNA vaccine boosted with heterologous HIV-1 recombinant modified vaccinia virus Ankara. J Infect Dis. 2008; 198:1482–1490.

94. Gudmundsdotter L, Nilsson C, Brave A, et al. Recombinant modified vaccinia Ankara (MVA) effectively boosts DNA-primed HIV-specific immune responses in humans despite pre-existing vaccinia immunity. Vaccine. 2009; 27:4468–4474.

95. Bakari M, Aboud S, Nilsson C, et al. Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania. Vaccine. 2011; 29:8417–8428.

96. Hel Z, Tsai WP, Thornton A, et al. Potentiation of simian immunodeficiency virus (SIV)-specific CD4(+) and CD8(+) T cell responses by a DNA-SIV and NYVAC-SIV prime/boost regimen. J Immunol. 2001; 167:7180–7191.

97. Kent SJ, Zhao A, Best SJ, Chandler JD, Boyle DB, Ramshaw IA. Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus. J Virol. 1998; 72:10180–10188.

98. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009; 361:2209–2220.

99. Shiver JW, Fu TM, Chen L, et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature. 2002; 415:331–335.

100. Borthwick NJ, Ahmed T, Dorrell L, Van Hateren A, Elliot T, Hanke T. Phase I clinical trial HIV-CORE002 of a universal T-cell vaccine: mapping of CD8+ T cell epitopes. AIDS Res Hum Retroviruses. 2014; 30:Suppl 1. A187.