Skip to main content

Development of a Poly (lactic-co-glycolic acid) Particle Vaccine to Protect Against House Dust Mite Induced Allergy

Abstract

Poly(lactic-co-glycolic acid) (PLGA) particles carrying antigen and adjuvant is a promising vaccine system which has been shown to stimulate systemic antigen-specific immune responses. In this study, we investigated the relationship of (i) the sizes of PLGA particle and (ii) the presence of cytosine-phosphate-guanine motifs (CpG), with the extent and type of immune response stimulated against Dermatophagoides pteronyssinus-2 (Der p2) antigen. Different sizes of PLGA particles encapsulating CpG were prepared using a double emulsion solvent evaporation method. Mice were vaccinated with Der p2 and different sizes of empty or CpG-loaded PLGA particles. Vaccinated mice were exposed to daily intranasal instillation of Der p2 for 10 days followed by euthanization to estimate leukocyte accumulation in bronchoalveolar lavage (BAL) fluids, antibody profiles, and airway hyperresponsiveness. PLGA particles showed a size-dependent decrease in the proportion of eosinophils found in BAL fluids. Mice vaccinated with the Der p2 coated on 9-μm-sized empty PLGA particles showed increased levels of IgE and IgG1 antibodies as well as increased airway hyperresponsiveness. All sizes of PLGA particles encapsulating CpG prevented airway hyperresponsiveness after Der p2 exposures. Inflammatory responses to Der p2 exposure were significantly reduced when smaller PLGA particles were used for vaccination. In addition, encapsulating CpG in PLGA particles increased IgG2a secretion. This study shows that the size of PLGA particles used for vaccination plays a major role in the prevention of house dust mite-induced allergy and that incorporation of CpG into the PLGA particles preferentially develops a Th1-type immune response.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Arbes Jr SJ, Cohn RD, Yin M, Muilenberg ML, Burge HA, Friedman W, et al. House dust mite allergen in US beds: results from the First National Survey of lead and allergens in housing. J Allergy Clin Immunol. 2003;111(2):408–14.

    PubMed  Article  Google Scholar 

  2. 2.

    Busse WW, Lemanske Jr RF. Asthma. N Engl J Med. 2001;344(5):350–62.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012;18(5):684–92.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, Coyle AJ, et al. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care. 2004;169(3):378–85.

    Article  Google Scholar 

  5. 5.

    Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108(2):E36.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012;129(1):48–59.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Incorvaia C, Di Rienzo A, Celani C, Makri E, Frati F. Treating allergic rhinitis by sublingual immunotherapy: a review. Ann Ist Super Sanita. 2012;48(2):172–6.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Eifan AO, Akkoc T, Yildiz A, Keles S, Ozdemir C, Bahceciler NN, et al. Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial. Clin Exp Allergy. 2010;40(6):922–32.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Eifan AO, Calderon MA, Durham SR. Allergen immunotherapy for house dust mite: clinical efficacy and immunological mechanisms in allergic rhinitis and asthma. Expert Opin Biol Ther. 2013;13(11):1543–56.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Mazzarella G, Bianco A, Catena E, De Palma R, Abbate GF. Th1/Th2 lymphocyte polarization in asthma. Allergy. 2000;55:6–9.

    PubMed  Article  Google Scholar 

  11. 11.

    Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol. 1999;17:255–81.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Wohlleben G, Erb KJ. Atopic disorders: a vaccine around the corner? Trends Immunol. 2001;22(11):618–26.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol. 2013;131(5):1288–96 e3.

    PubMed  Article  Google Scholar 

  14. 14.

    Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1–55.

    PubMed  Article  Google Scholar 

  15. 15.

    Arlian LG, Morgan MS, Neal JS. Dust mite allergens: ecology and distribution. Curr Allergy Asthma Rep. 2002;2(5):401–11.

    PubMed  Article  Google Scholar 

  16. 16.

    Kidon MI, Chiang WC, Liew WK, Ong TC, Tiong YS, Wong KN, et al. Mite component-specific IgE repertoire and phenotypes of allergic disease in childhood: the tropical perspective. Pediatr Allergy Immunol. 2011;22(2):202–10.

    PubMed  Article  Google Scholar 

  17. 17.

    Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457(7229):585–8.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Trombone APF, Tobias KRC, Ferriani VPL, Schuurman J, Aalberse RC, Smith AM, et al. Use of a chimeric ELISA to investigate immunoglobulin E antibody responses to Der p 1 and Der p 2 in mite-allergic patients with asthma, wheezing and/or rhinitis. Clin Exp Allergy. 2002;32(9):1323–8.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Tan LK, Huang CH, Kuo IC, Liew LM, Chua KY. Intramuscular immunization with DNA construct containing Der p 2 and signal peptide sequences primed strong IgE production. Vaccine. 2006;24(29–30):5762–71.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Huang TJ, MacAry PA, Eynott P, Moussavi A, Daniel KC, Askenase PW, et al. Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-gamma. J Immunol. 2001;166(1):207–17.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kline JN, Krieg AM. Toll-Like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy. Drug News Perspect. 2008;21(8):434–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Fonseca DE, Kline JN. Use of CpG oligonucleotides in treatment of asthma and allergic disease. Adv Drug Deliv Rev. 2009;61(3):256–62.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Pulsawat P, Pitakpolrat P, Prompetchara E, Kaewamatawong T, Techakriengkrai N, Sirivichayakul S, et al. Optimization of a Der p 2-based prophylactic DNA vaccine against house dust mite allergy. Immunol Lett. 2013;151(1–2):23–30.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Heeg K, Zimmermann S. CpG DNA as a Th1 trigger. Int Arch Allergy Immunol. 2000;121(2):87–97.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Mo JH, Park SW, Rhee CS, Takabayashi K, Lee SS, Quan SH, et al. Suppression of allergic response by CpG motif oligodeoxynucleotide-house-dust mite conjugate in animal model of allergic rhinitis. Am J Rhinol. 2006;20(2):212–8.

    PubMed  Google Scholar 

  26. 26.

    Simons FE, Shikishima Y, Van Nest G, Eiden JJ, HayGlass KT. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol. 2004;113(6):1144–51.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Kaburaki Y, Fujimura T, Kurata K, Masuda K, Toda M, Yasueda H, et al. Induction of Th1 immune responses to Japanese cedar pollen allergen (Cry j 1) in mice immunized with Cry j 1 conjugated with CpG oligodeoxynucleotide. Comp Immunol Microbiol Infect Dis. 2011;34(2):157–61.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Shirota H, Sano K, Kikuchi T, Tamura G, Shirato K. Regulation of T-helper type 2 cell and airway eosinophilia by transmucosal coadministration of antigen and oligodeoxynucleotides containing CpG motifs. Am J Respir Cell Mol. 2000;22(2):176–82.

    CAS  Article  Google Scholar 

  29. 29.

    Gomez JMM, Fischer S, Csaba N, Kundig TM, Merkle HP, Gander B, et al. A protective allergy vaccine based on CpG- and protamine-containing PLGA microparticles. Pharm Res. 2007;24(10):1927–35.

    CAS  Article  Google Scholar 

  30. 30.

    Scholl I, Kopp T, Bohle B, Jensen-Jarolim E. Biodegradable PLGA particles for improved systemic and mucosal treatment of Type I allergy. Immunol Allergy Clin N Am. 2006;26(2):349–64. ix.

    Article  Google Scholar 

  31. 31.

    Martinez Gomez JM, Fischer S, Csaba N, Kundig TM, Merkle HP, Gander B, et al. A protective allergy vaccine based on CpG- and protamine-containing PLGA microparticles. Pharm Res. 2007;24(10):1927–35.

    PubMed  Article  Google Scholar 

  32. 32.

    Zhang XQ, Dahle CE, Baman NK, Rich N, Weiner GJ, Salem AK. Potent antigen-specific immune responses stimulated by codelivery of CpG ODN and antigens in degradable microparticles. J Immunother. 2007;30(5):469–78.

    PubMed  Article  Google Scholar 

  33. 33.

    Joshi VB, Geary SM, Salem AK. Biodegradable particles as vaccine delivery systems: size matters. AAPS J. 2013;15(1):85–94.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  34. 34.

    Thorne PS, McCray PB, Howe TS, O'Neill MA. Early-onset inflammatory responses in vivo to adenoviral vectors in the presence or absence of lipopolysaccharide-induced inflammation. Am J Respir Cell Mol. 1999;20(6):1155–64.

    CAS  Article  Google Scholar 

  35. 35.

    George CL, White ML, Kulhankova K, Mahajan A, Thorne PS, Snyder JM, et al. Early exposure to a nonhygienic environment alters pulmonary immunity and allergic responses. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L512–22.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    De S, Robinson DH. Particle size and temperature effect on the physical stability of PLGA nanospheres and microspheres containing Bodipy. AAPS PharmSciTech. 2004;5(4):e53.

    PubMed  Article  Google Scholar 

  37. 37.

    Gregory LG, Lloyd CM. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 2011;32(9):402–11.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  38. 38.

    Wang X, Yang Q, Wang P, Luo L, Chen Z, Liao B, et al. Derp2-mutant gene vaccine inhibits airway inflammation and up-regulates Toll-like receptor 9 in an allergic asthmatic mouse model. Asian Pac J Allergy Immunol. 2010;28(4):287–93.

    PubMed  Google Scholar 

  39. 39.

    Daan de Boer J, Roelofs JJ, de Vos AF, de Beer R, Schouten M, Hommes TJ, et al. Lipopolysaccharide inhibits Th2 lung inflammation induced by house dust mite allergens in mice. Am J Respir Cell Mol. 2013;48(3):382–9.

    CAS  Article  Google Scholar 

  40. 40.

    Sumino K, Sugar EA, Irvin CG, Kaminsky DA, Shade D, Wei CY, et al. Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications. J Allergy Clin Immunol. 2012;130(1):69–75 e6.

    PubMed  Article  Google Scholar 

  41. 41.

    Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. NCHS Data Brief. 2012;94:1–8.

    PubMed  Google Scholar 

  42. 42.

    Bharadwaj AS, Bewtra AK, Agrawal DK. Dendritic cells in allergic airway inflammation. Can J Physiol Pharmacol. 2007;85(7):686–99.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Suzuki K, Kaminuma O, Yang L, Takai T, Mori A, Umezu-Goto M, et al. Prevention of allergic asthma by vaccination with transgenic rice seed expressing mite allergen: induction of allergen-specific oral tolerance without bystander suppression. Plant Biotechnol J. 2011;9(9):982–90.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Kündig TM, Senti G, Schnetzler G, Wolf C, Prinz Vavricka BM, Fulurija A, et al. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J Allergy Clin Immunol. 2006;117(6):1470–6.

    PubMed  Article  Google Scholar 

  45. 45.

    Standley SM, Mende I, Goh SL, Kwon YJ, Beaudette TT, Engleman EG, et al. Incorporation of CpG oligonucleotide ligand into protein-loaded particle vaccines promotes antigen-specific CD8 T-cell immunity. Bioconjug Chem. 2007;18(1):77–83.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    O'Hagan DT, Rappuoli R. Novel approaches to pediatric vaccine delivery. Adv Drug Deliv Rev. 2006;58(1):29–51.

    PubMed  Article  Google Scholar 

  47. 47.

    Shen J, Burgess DJ. Drugs for long acting injections and implants. In: Wright JC, Burgess DJ, editors. Long acting injections and implants. New York: Springer; 2012. p. 73–92.

  48. 48.

    Hamdy S, Haddadi A, Hung RW, Lavasanifar A. Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations. Adv Drug Deliv Rev. 2011;63(10–11):943–55.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Scholl I, Weissenbock A, Forster-Waldl E, Untersmayr E, Walter F, Willheim M, et al. Allergen-loaded biodegradable poly (D, L-lactic-co-glycolic) acid nanoparticles down-regulate an ongoing Th2 response in the BALB/c mouse model. Clin Exp Allergy. 2004;34(2):315–21.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Senti G, Johansen P, Haug S, Bull C, Gottschaller C, Müller P, et al. Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial. Clin Exp Allergy. 2009;39(4):562–70.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    van Ree R, Antonicelli L, Akkerdaas JH, Garritani MS, Aalberse RC, Bonifazi F. Possible induction of food allergy during mite immunotherapy. Allergy. 1996;51(2):108–13.

    PubMed  Article  Google Scholar 

  52. 52.

    Bosnjak B, Stelzmueller B, Erb KJ, Epstein MM. Treatment of allergic asthma: modulation of Th2 cells and their responses. Respir Res. 2011;12:114.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  53. 53.

    Tang MLK, Powell CVE. Childhood asthma as an allergic disease: rationale for the development of future treatment. Eur J Pediatr. 2001;160(12):696–704.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Pulsawat P, Pitakpolrat P, Prompetchara E, Kaewamatawong T, Techakriengkrai N, Sirivichayakul S, et al. Optimization of a Der p 2-based prophylactic DNA vaccine against house dust mite allergy. Immunol Lett. 2013;151(1–2):23–30.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Zhang F, Huang G, Hu B, Song Y, Shi Y. Induction of immune tolerance in asthmatic mice by vaccination with DNA encoding an allergen-cytotoxic T lymphocyte-associated antigen 4 combination. Clin Vaccine Immunol: CVI. 2011;18(5):807–14.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge support from the National Institute of Environmental Health Sciences-funded Environmental Health Sciences Research Center (NIH P30 ES005605). Other sources of support include the American Cancer Society (RSG-09-015-01-CDD), the National Cancer Institute (NIH 1R21CA13345-01/1R21CA128414-01A2/UI Mayo Clinic Lymphoma SPORE), and the Lyle and Sharon Bighley Professorship. We thank Sean Geary for expert reading of the manuscript.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Peter S. Thorne or Aliasger K. Salem.

Additional information

Vijaya B. Joshi, Andrea Adamcakova-Dodd, and Xuefang Jing contributed equally to this work.

Guest Editor: Aliasger K. Salem

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Joshi, V.B., Adamcakova-Dodd, A., Jing, X. et al. Development of a Poly (lactic-co-glycolic acid) Particle Vaccine to Protect Against House Dust Mite Induced Allergy. AAPS J 16, 975–985 (2014). https://doi.org/10.1208/s12248-014-9624-5

Download citation

Keywords

  • allergy
  • CpG
  • Der p2
  • house dust mite
  • PLGA
  • vaccine