Skip to main content
Log in

Enhancing Immunogenicity and Reducing Dose of Microparticulated Synthetic Vaccines: Single Intradermal Administration

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Our purpose was to evaluate the ability of a polymeric vehicle to release a model synthetic vaccine to the skin in order to reach a potent activation of the specific immune response.

Methods. The peptide-loaded poly-d,l-lactide-co-glycolide acid (PLGA) microparticles were prepared by a double emulsion technique and administered to Balb/c mice. The immune response (antibody and T cell activation) obtained by the intradermal (i.d.) and the subcutaneous (s.c.) routes was tested.

Results. When similar doses of peptide-loaded microparticles were injected s.c. or i.d. in mice, the antipeptide IgG antibody immune response was found to be significantly higher after i.d. injection into the skin. We could also reduce the dose of antigen 10 times by the i.d. route and find a similar antibody response to that obtained by the s.c. immunization. At the lowest i.d. dose level, the IgG2a/IgG1 ratio was also incremented and the IgE production decreased. The i.d. microparticles induced, at both dose levels, a marked IFN-γ secretion by peptide-stimulated splenocytes and lymph node cells and a significant T cell proliferation in spleen cell cultures.

Conclusions. The results demonstrate that peptide-loaded microparticles were efficiently administered by the i.d. route because lower doses were required and powerful antibody and T cell responses were obtained compared to the conventional s.c. administration.

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. E. H. Beachey, J. M. Seyer, J. B. Dale, W. A. Simpson, and A. W. Kang. Type-specific protective immunity evoked by synthetic peptide of Streptococcus pyogenes M protein. Nature 292:457-459 (1981).

    Google Scholar 

  2. J. L. Bittle, R. A. Houghten, H. Alexander, T. M. Shinnick, J. G. Sutcliffe, R. A. Lerner, D. J. Rowlands, and F. Brown. Protection against foot-and-mouth disease by immunization with a chemically synthesized peptide predicted from the viral nucleotide sequence. Nature 298:30-33 (1982).

    Google Scholar 

  3. W. Zauner, K. Lingnau, F. Mattner, A. von Gabain, and M. Buschle. Defined synthetic vaccines. Biol. Chem. 382:581-595 (2001).

    Google Scholar 

  4. Y. Men, B. Gander, H. P. Merkle, and G. Corradin. Induction of sustained and elevated immune responses to weakly immunogenic synthetic malarial peptides by encapsulation in biodegradable polymer microspheres. Vaccine 14:1442-1450 (1996).

    Google Scholar 

  5. J. S. Moyniham, D. H. Jones, G. H. Farrar, and C. R. Howard. A novel microencapsulated peptide vaccine against hepatitis B. Vaccine 19:3292-3300 (2001).

    Google Scholar 

  6. D. F. Nixon, D. F. C. Hioe, P. Chen, Z. Bian, P. Kuebler, M. L. Li, H. Qiu, X. M. Li, M. Singh, J. Richardson, P. McGee, T. Zamb, W. Koff, C. Y. Wang, and D. O'Hagan. Synthetic peptides entrapped in microparticles can elicit cytotoxic T cell activity. Vaccine 14:1523-1530 (1996).

    Google Scholar 

  7. J. E. Rosas, J. L. Pedraz, R. M. Hernández, A. R. Gascón, M. Igartua, F. Guzmán, R. Rodríguez, J. Cortés, and M. E. Patarroyo. Remarkably high antibody levels and protection against P. falciparum malaria in Aotus monkeys after one single immunization of SPf66 encapsulated in PLGA microspheres. Vaccine 20:1707-1710 (2002).

    Google Scholar 

  8. C. Scheicher, M. Mehlig, H. P. Dienes, and K. Reske. Uptake of microparticle-adsorbed protein antigen by bone marrow-derived dendritic cells results in up-regulation of interleukin-1α and interleukin-12 p40/p35 and triggers prolonged, efficient antigen presentation. Eur. J. Immunol. 25:1566-1572 (1995).

    Google Scholar 

  9. J. Banchereau and R. M. Steinman. Dendritic cells and the control of immunity. Nature 392:245-252 (1998).

    Google Scholar 

  10. F. Rahman, A. Dahmen, S. Herzog-Hauff, W. O. Böcher, P. R. Galle, and H. F. Löhr. Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen. Hepatology 31:521-527 (2000).

    Google Scholar 

  11. E. A. Henderson, T. J. Louie, K. Ramotar, D. Ledgerwood, K. M. Hope, and A. Kennedy. Comparison of higher-dose intradermal hepatitis B vaccination to standard intramuscular vaccination of healthcare workers. Infect. Control Hosp. Epidemiol. 21:264-269 (2000).

    Google Scholar 

  12. E. Jäeger, H. Bernhard, P. Romero, M. Ringhoffer, M. Arand, J. Karbach, C. Ilsemann, M. Hagedorn, and A. Knuth. Generation of cytotoxic T-cell reponses with synthetic melanoma-associated peptides in vivo: implications for tumor vaccines with melanoma-associated antigens. Int. J. Cancer 66:162-169 (1996).

    Google Scholar 

  13. B. Asjo, H. Stavang, B. Sorensen, I. Baksaas, J. Nyhus, and N. Langeland. Phase I trial of a therapeutic HIV type 1 vaccine, vacc-4x, in HIV type 1-infected individuals with or without antiretroviral therapy. AIDS Res. Hum. Retrov. 18:1357-1365 (2002).

    Google Scholar 

  14. B. Ludewig, F. Barchiesi, M. Pericin, R. M. Zinkernagel, H. Hengartner, and R. A. Schwendener. In vivo antigen loading and activation of dendritic cells via a liposomal peptide vaccine mediates protective antiviral and antitumor immunity. Vaccine 19:23-32 (2001).

    Google Scholar 

  15. M. E. Patarroyo, R. Amador, P. Clavijo, A. Moreno, F. Guzmán, P. Romero, R. Tascón, A. Franco, L. A. Murillo, G. Pontón, and G. Trujillo. A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum malaria. Nature 332:158-161 (1988).

    Google Scholar 

  16. R. A. Houghten. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction of the level of individual amino acids. Proc. Natl. Acad. Sci. U. S. A. 82:5131-5135 (1985).

    Google Scholar 

  17. Anonymous. Removal of blood from laboratory mammals and birds. First report on the BVA/FRAME/RSPCA/UFAW Joint Working Group on refinement. Lab. Anim. 27:1-22 (1993).

    Google Scholar 

  18. T. Mosmann. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth. 65:55-63 (1983).

    Google Scholar 

  19. G. Lombardi, C. Dianzani, G. Miglio, P. L. Canonico, and R. Fantozzi. Characterization of ionotropic glutamate receptors in human lymphocytes. Br. J. Pharmacol. 133:936-944 (2001).

    Google Scholar 

  20. A. M. Carcaboso, R. M. Hernández, M. Igartua, J. E. Rosas, M. E. Patarroyo, and J. L. Pedraz. Immune response after oral administration of the encapsulated malaria synthetic peptide SPf66. Int. J. Pharm. 260:273-282 (2003).

    Google Scholar 

  21. S. Babiuk, M. Baca-Estrada, L. A. Babiuk, C. Ewen, and M. Foldvari. Cutaneous vaccination: the skin as an immunologically active tissue and the challenge of antigen delivery. J. Control. Rel. 66:199-214 (2000).

    Google Scholar 

  22. N. Puri, E. H. Weyand, S. M. Abdel-Rahman, and P. J. Sinko. An investigation of the intradermal route as an effective means of immunization for microparticulate vaccine delivery systems. Vaccine 18:2600-2612 (2000).

    Google Scholar 

  23. K. D. Newman, P. Elamanchili, G. S. Kwon, and J. Samuel. Uptake of poly(D,L-lactic-co-glycolic acid) microspheres by antigen-presenting cells in vivo. J. Biomed. Mater. Res. 60:480-486 (2002).

    Google Scholar 

  24. S. L. Constant and K. Bottomly. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15:297-322 (1997).

    Google Scholar 

  25. L. F. Wang, J. Y. Lin, K. H. Hsieh, and R. H. Lin. Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J. Immunol. 156:4079-4082 (1996).

    Google Scholar 

  26. S. Vrtala, T. Ball, S. Spitzauer, B. Pandjaitan, C. Suphioglu, B. Knox, W. R. Sperr, P. Valent, D. Kraft, and R. Valenta. Immunization with purified natural and recombinant allergens induces mouse IgG1 antibodies that recognize similar epitopes as human IgE and inhibit the human IgE-allergen interaction and allergen-induced basophil degranulation. J. Immunol. 160:6137-6144 (1998).

    Google Scholar 

  27. D. Chen, R. L. Endres, C. A. Erickson, K. F. Weis, M. W. McGregor, Y. Kawaoka, and L. G. Payne. Epidermal immunization by a needle-free powder delivery technology: immunogenicity of influenza vaccine and protection in mice. Nat. Med. 6:1187-1190 (2000).

    Google Scholar 

  28. J. A. Mikszta, J. B. Alarcon, J. M. Brittingham, D. E. Sutter, R. J. Pettis, and N. G. Harvey. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat. Med. 8:415-419 (2002).

    Google Scholar 

  29. G. M. Glenn, D. N. Taylor, X. Li, S. Frankel, A. Montemarano, and C. R. Alving. Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat. Med. 6:1403-1406 (2000).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to José L. Pedraz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carcaboso, Á.M., Hernández, R.M., Igartua, M. et al. Enhancing Immunogenicity and Reducing Dose of Microparticulated Synthetic Vaccines: Single Intradermal Administration. Pharm Res 21, 121–126 (2004). https://doi.org/10.1023/B:PHAM.0000012159.20895.5b

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000012159.20895.5b

Navigation