Development of Vaccine Delivery System and Challenges

백신 전달기술 개발 동향과 과제

  • Received : 2010.10.08
  • Accepted : 2010.12.20
  • Published : 2010.12.31


Vaccine is a protective clinical measure capable of persuading immune system against infectious agents. Vaccine can be categorized as live attenuated and inactivated. Live attenuated vaccines activate immunity similar to natural infection by replicating living organisms whereas inactivated vaccines are either whole cell vaccines, eliciting immune response by killed organisms,or subunit vaccines, stimulating immunity by non-replicating sub cellular parts. The components of vaccine play a critical role in deciding the immune response mediated by the vaccine. The innate immune responds against the antigen component. Adjuvants represent an importantcomponent of vaccine for enhancing the immunogenicity of the antigens. Subunit vaccines with isolated fractions of killed and recombinant antigens are mostly co-administered with adjuvants. The delivery system of the vaccine is another essential component to ensurethat vaccine is delivered to the right target with right dosage form. Furthermore, vaccine delivery system ensures that the desired immune response is achieved by manipulating the optimal interaction of vaccine and adjuvantwith the immune cell. The aforementioned components along with routes of administration of vaccine are the key elements of a successful vaccination procedure. Vaccines can be administered either orally or by parenteral routes. Many groups had made remarkable efforts for the development of new vaccine and delivery system. The emergence of new vaccine delivery system may lead to pursue the immunization goals with better clinical practices.



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  1. Pier, G. B., J. B. Lyczak, and L. M. Wetzler (2004) Immunology, Infection, and Immunity. ASM Press.
  2. Janeway, C. A. Jr., P. Travers, M. Walport, and M. J. Shlomchik (2001) Immunobiology. (5th ed.). Garland Publishing.
  3. Kantoff, P. W., C. S. Higano, N. D. Shore, E. R. Berger, E. J. Small, D. F. Penson, C. H. Redfern, A. C. Ferrari, R. Dreicer, R. B. Sims, Y. Xu, M. W. Frohlich, and P. F. Schellhammer (2010) Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N. Eng. J. of Med. 363: 411-422.
  4. Jennings, G. T. and M. F. Bachmann (2007) Designing recombinant vaccines with viral properties: a rational approach to more effective vaccines. Curr. Mol. Med. 7: 143-155.
  5. Martin F. B. and T. J. Gary (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns Nat. Rev. Immunol. 10: 787-796.
  6. Petrovsky N., S. Heinzel, Y. Honda, and A. B. Lyons (2007) New-age vaccine adjuvants: Friend or foe? BioPharm International 20: A24-A33.
  7. Hackett, C. J., D. A. Harn, and Jr. (2006) Vaccine Adjuvants: Immunological and Clinical Principles. Humana Press.
  8. Allison A. C. and N. E. Byars (1991) Immunological adjuvants: Desirable properties and side-effects. Mol. Immunol. 28: 279-284.
  9. Ahsan, F., I. P. Rivas, M. A. Khan, and A. I. Torres Suarez (2002) Targeting to macrophages: role of physicochemical properties of particulate carriers - liposomes and microspheres - on the phagocytosis by macrophages. J. Control. Release 79: 29-40.
  10. Reddy, S. T., A. J. van der Vlies, E. Simeoni, V. Angeli, G. J. Randolph, C. P. O'Neil, L. K. Lee, M. A. Swartz, and J. A. Hubbell (2007) Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nature Biotech. 25: 1159-1164.
  11. Leak, L. V. (1971) Studies on the permeability of lymphatic capillaries. J. Cell Biol. 50: 300-323.
  12. Swartz, M. A., D. A. Berk, and R. K. Jain (1996) Transport in lymphatic capillaries. I. Macroscopic measurements using residence time distribution theory. Am. J. Physiol. 270: H324-329.
  13. Edelman, R. (1994) Vaccine adjuvants. Rev. infect Dis. 24: 2421-2428.
  14. Singh, M. and D. T. O'Hagan (2003) Recent advances in veterinary vaccine adjuvants. Int. J. for Parasitol. 33: 469-478.
  15. Gupta, R. K. (1998) Aluminum compounds as vaccine adjuvants. Adv. Drug Deliv. Rev. 32: 155-172.
  16. Lewis, P. A. and D. Loomis (1924) Allergic irritability. The formation of anti-sheep hemolytic amboceptor in the normal and tuberculous guinea pig. J. Exp. Med. 40: 503.
  17. Akasaki. M, T. Takashi, Y. Kita, and W. Tsukada (1987) Augmentation of immune responses by a muramyl dipeptide analog, MDP-Lys (L18). Agents Actions 22: 144-150.
  18. Licciardi, P. V. and J. R. Underwood (2010) Identification of a novel vaccine adjuvant that stimulates and maintains diphtheria toxoid immunity. Vaccine 28: 3865-3873.
  19. Dalsgaard, K. (1978) A study of the isolation and characterization of the saponin quil A. Evaluation of its adjuvant activity, with a special reference to the application in the vaccination of cattle against foot-and mouth disease. Acta. Vet. Stand 69: 1-40.
  20. Newman, M. J., Y. J. Wu, B. H. Gardner, K. K. J. Munroe, D. Leombruno, J. Recchai, C. R. Kensiil, and R. T. Coughlin, Saponin adjuvant induction of ovalbuminspecific CD8+ cytotoxic T lymphocyte responses. J. Immunol. 148: 2357-2362.
  21. Pardoll, D. M. (1995) Paracrine cytokine adjuvants in cancer immunotherapy. Annu. Rev. Immunol.13: 399-415.
  22. Bliss, J., V. Van Cleave, K. Murray, A. Wiencis, M. Ketchum, R. Maylor, T. Haire, C. Resmini, A. K. Abbas, and S. F. Wolf (1996) IL-12, as an adjuvant, promotes a T helper 1 cell, but does not suppress a T helper 2 cell recall response. J. Immunol. 156: 887-894.
  23. Odean, M. J., C. M. Frane, M. Van der Vieren, M. A. Tomai, and A. G. Johnson (1990) Involvement of gamma interferon in antibody enhancement by adjuvants. Infect Immun. 58: 427-432.
  24. Luis, C., C. Afonso, T. M. Scharton, L. Q. Vieira, M. Wysocka, G. Trinchieri, and P. Scott (1994)The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263: 235-237.
  25. Nohria, A. and R. H. Rubin (1994) Cytokines as potential vaccine adjuvants. Biotherapy 7: 261-269.
  26. Le, Moignic and Pinoy (1916) Application to man of vaccines consisting of emulsions in fatty substances (lipo-vaccines). Commp. Rend. Sot. Bio. 29: 352-358.
  27. Gkick, R. R. Mischler, B. Finkel, J. U. Que, B. Scarpa, and S. J. Cryz Jr. (1994) Immunogenicity of new virosome influenza vaccine in elderly people. Lancet 344: 160-163.
  28. Pedersen, I. R., T. C. Bog-Hansen, K. Dalsgaard, P. M. H. Heegaard (1992) Iscom immunization with synthetic peptides representing measles virus hemagglutinin. Virus Res. 24: 145-169.
  29. Barr, I. G., A. Sjolander, and J. C. Cox (1998) ISCOMs and other saponin based adjuvants. Adv. Drug. Deliv. Rev. 32: 247-271.
  30. Morein, B. K. F. Hu, and Abusugra (2004) Current status and potential application of ISCOMs in veterinary medicine. Adv. Drug Del. Rev. 56: 1367-1382.
  31. Men, Y., H. P. Merkle, B. Gander, and G. Corradin (1996) Induction of sustained and elevated immune responses to weakly immunogenic synthetic malaria peptides by encapsulation in biodegradable polymer microspheres. Vaccine 14: 1442-1450.
  32. Zhao, K., G. X. Li, Y. Y. Jin, H. X. Wei, Q. S. Sun, T. T. Huang, Y. F. Wang, and G. Z. Tong (2010) Preparation and immunological effectiveness of a Swine influenza DNA vaccine encapsulated in PLGA microspheres. J. Microencapsul. 27: 178-186.
  33. Kang, M. L., C. S. Cho, and H. S. Yoo (2009) Application of chitosan microspheres for nasal delivery of vaccines Biotechnol. Adv. 27: 857-865.
  34. Lambert, P. H. and P. E. Laurent (2008) Intradermal vaccine delivery: Will new delivery systems transform vaccine administration. Vaccine 26: 3197-3208.
  35. Kimpen, J. L. and P. L. Ogra (1990) Poliovirus vaccines. A continuing challenge. Pediatr. Clin. North Am. 37: 627-649.
  36. Dennehy, P. H. (2008) Rotavirus vaccines: an overview. Clin. Microbiol. Rev. 21: 198-208.
  37. Dalsgaard, K. A. Uttenthal, and T. D. Jones (1997) Plant derived vaccines protects target animals against a viral disease. Nat. Biotechnol. 15: 248-252.
  38. Sandhu, J. S., S. F. Krasnyanski, L. L. Domier, S. S. Korban, M. D. Osadjan, and D. E. Buetow (2000) Oral immunization of mice with transgenic tomato fruit expressingrespiratory syncytial virus-F protein induces a systemic immune response. Transgenic Res. 9: 127-135.
  39. Chikwamba, R., J. Cunnick, D. Hathaway, J. McMurray, H. Mason, and K. Wang (2002) A functional antigen in a practical crop: LT-B producing maize protects mice against Escherichia coli heat labile enterotoxin (LT) and cholera toxin (CT). Transgenic Res. 11: 479-493.
  40. Marquet-Blouin, E., F. B. Bouche, A. Steinmetz, and C. P. Muller (2003) Neutralizing immunogenicity of transgenic carrot (Daucus carota L.) derived measles virus hemagglutinin. Plant Mol. Biol. 51: 459-469.
  41. Rols, M. P. (2008) Mechanism by which electroporation mediates DNA migration and entry into cells and targeted tissues. Methods Mol. Biol. 423: 19-33.
  42. Escoffre, J. M., T. Portet, L. Wasungu, J. Teissie, D. Dean, and M. P. Rols (2009). What is (still not) known of the mechanism by which electroporation mediates gene transfer and expression in cells and tissues. Mol.Biotechnol. 41: 286-295.
  43. Bodles-Brakhop, A. M., R. Heller, and R. Draghia-Akli (2009) Electroporation for the Delivery of DNA-based Vaccines and Immunotherapeutics: Current Clinical Developments. The Am. Soc. of Gene Ther. 17: 589-592.
  44. Weber, L. W., W. B. Bowne, J. D. Wolchok, R. Srinivasan, J. Qin, Y. Moroi, R. Clynes, P. Song, J. J. Lewis, and A. N. Houghton (1998) Tumor immunity and autoimmunity induced by immunization with homologous DNA. J. Clin. Invest. 102: 1258-1264.
  45. Bowne, W. B., R. Srinivasan, J. D. Wolchok, W. G. Hawkins, N. E. Blachere, R. Dyall, J. J. Lewis, and A. N. Houghton (1999) Coupling and uncoupling of tumor immunity and autoimmunity. J. Exp. Med. 190: 1717-1722.
  46. Kalat, M., Z. Kupcu, S. Schuller, D. Zalusky, M. Zehetner, W. Paster, and T. Schweighoffer (2002) In vivo plasmid electroporation induces tumor antigen-specific CD8+ T-cell responses and delays tumor growth in a syngeneic mouse melanoma model. Cancer Res. 62: 5489-5494.
  47. Liao, J. C., P. Gregor, J. D. Wolchok, F. Orlandi, D. Craft, C. Leung, A. N. Houghton, and P. J. Bergman (2006) Vaccination with human tyrosinase DNA induces antibody responses in dogs with advanced melanoma. Cancer Immun. 6: 8-24.
  48. Clinical Trials. gov ID NCT00471133.
  49. Chen, M. W., T. J. Cheng, Y. Huang, J. T. Jan, S. H. Ma, A. L. Yu, C. H. Wong, and D. D. Ho (2008) A consensushemagglutinin- based DNA vaccine that protects mice against divergent H5N1 influenza viruses. Proc. Natl. Acad. Sci. USA 105: 13538-13543.
  50. Inovio Pharmaceuticals, Inc. homepage.
  51. Tezel, A., S. Paliwal, Z. Shen, and S. Mitragotri (2005) Low-frequency ultrasound as a transcutaneous immunization adjuvant. Vaccine 23: 3800-3807.
  52. Glenn, G. M., M. Rao, G. R. Matyas, and C. R. Alving (1998) Skin immunization made possible by cholera toxin. Nature 391: 851-852.
  53. Fechheimer, M., J. F. Boylan, S. Parker, J. E. Sisken, G. L. Patel, and S. G. Zimmer (1987) Transfection ofmammaliancells with plasmid DNA by scrape loading and sonication loading. Proc. Natl. Acad. Sci. USA 84: 8463-8467.
  54. Ohta, S., K. Suzuhi, K. Tachibana, and G. Yamada (2003) Microbubble-enhanced sonoporation: efficient gene transduction technique for chick embryos. Genesis 37: 91-101.
  55. Un, K., S. Kawakami, R. Suzuki, K. Maruyama, and F. Yamashita (2010) Development of an ultrasound-responsive and mannose-modified gene carrier for DNA vaccine therapy. Biomaterials 31: 7813-7826.
  56. Jackson, L. A., G. Austin, R. T. Chen, R. Stout, F. DeStefano, G. J. Gorse, F. K. Newman, O. Yu, and B. G. Weniger (2001) Safety and immunogenicity of varying dosages of trivalent inactivated influenza vaccine administered by needle free jet injectors. Vaccine19: 4703-4709.
  57. Giudice, E. L. and J. D. Campbell (2006) Needle-free vaccine delivery. Adv. Drug Deliv. 58: 68-89.
  58. Weniger, B. G. (2004) New high speed jet injectors for mass vaccination: pros and cons of DCJIs versus MUNJIs. WHO initiative for vaccine research: Global Vaccine Research Forum, Montreux, Switzerland.
  59. Mumper, R. J. and Z. Cui (2003) Genetic immunization by jet injection of targeted pDMA coated nanoparticles. Methods 31: 255-266.
  60. Williams, C. G. (2000) Poliomyelitis: extinct by year 2000: But not over. AAOHIN J. 48: 25-31.
  61. Laurent, P. E., S. Bonnet, P. Regolini, P. Alchas, J. A. Mikszta, R. Pettis, and N. G. Harvey (2007) Evaluation of the clinical performance of new intradermal vaccine administration technique and associated delivery system. Vaccine 25: 8833-8842.
  62. Henry, S., D. V. McAllister, M. G. Allen, and M. R. Prausnitz (1998) Microfabricated microneedles: a novel approach to transdermal drug delivery. J. Pharm Sci. 87: 922-925.
  63. Lee, J. W., J. H. Park, and M. R. Prausnitz (2008) Dissolving microneedles for transdermal drug delivery. Biomaterials 29: 2113-2124.
  64. Kenney, R. T., S. A. Frech, L. R. Muenz, C. P. Villar, and G. M. Glenn. (2004) Dose sparing with intradermal injection of influenza vaccine. N. Engl. J. Med. 351: 2295-2301.
  65. Dimitrios, G. K., M. del P. Martin, V. G. Zarnitsyn, S. P. Sullivan, R. W. Compans, M. R. Prausnitz, and L. Skountzou (2009) Transdermal influenza immunization with vaccine-coated microneedle arrays. PLos ONE 4: e4773.
  66. Sullivan, S. P., D. G. Koutsonanos, M. del P. Martin, J. W. Lee, V. Zarnitsyn, S. O. Choi, N. Murthy, R. W. Compans, L. Skountzou, and M. R. Prausnitz (2010) Dissolving polymer microneedle patches for influenza vaccination. Nature Med. 16: 915-920.
  67. Laurent, P. E., S. Bonnet, P. Alchas, P. Regolini, J. A. Mikszta, R. Pettis, and N. G. Harvey (2007) Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. Vaccine 25: 8833-8842.
  68. Seo, K. Y., S. J. Han, H. R. Cha, S. U. Seo, J. H. Song, S. H. Chung, and M. N. Kweon (2010) Eye Mucosa: An Efficient Vaccine Delivery Route for Inducing Protective Immunity. J. Immunol. 185: 3610-3619.