Current Allergy and Asthma Reports

, Volume 5, Issue 3, pp 197–203 | Cite as

Genetically engineered vaccines

  • Wayne R. Thomas
  • Belinda J. Hales
  • Wendy-Anne Smith
Article

Abstract

The application of recombinant DNA technology to allergen research has provided the sequence information and genetic material to produce new types of allergy vaccines. One general strategy has been to use the knowledge to produce synthetic peptides that represent selected T-cell or B-cell epitopes. The production of genetically engineered allergens provides an alternative strategy to construct hypoallergenic vaccines, which can provide a better and less selected representation of the epitopes. Many strategies have been used to produce such hypoallergens, and their ability to reduce allergenicity has been amply demonstrated by skin and nasal provocation tests. The retention of T cell-stimulating activity has also been demonstrated, and a consistent feature of the vaccines has been, despite the reduced immunoglobulin E (IgE)-binding reactivity, the ability to induce anti-allergen IgG antibody. The lead hypoallergens have been polypeptide fragments and trimeric constructs of the birch allergen Bet v 1. A clinical trial with these medicaments has shown the ability to modify IgE and IgG antibody production, skin test reactivity, and symptom scores. This is the first trial of a recombinant allergy vaccine, and it has set a benchmark for further studies. A new generation of hypoallergens is now being produced based on the detailed knowledge of the tertiary structures of the allergens and of the T-cell and B-cell epitopes. The modifications have been made to change the topography of the allergens while retaining a stable, folding structure. In the case of Bet v 1, tertiary structures of hypoallergens have been determined. Structurally modeled hypoallergens have been produced for pollen, venom, food, and latex allergens, with promising characteristics from preclinical studies.

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References and Recommended Reading

  1. 1.
    Till SJ, Francis JN, Nouri-Aria K, Durham SR: Mechanisms of immunotherapy. J Allergy Clin Immunol 2004, 113:1025–1034. quiz 1035.PubMedCrossRefGoogle Scholar
  2. 2.
    Smith AM, Chapman MD: Reduction in IgE binding to allergen variants generated by site-directed mutagenesis: contribution of disulfide bonds to the antigenic structure of the major house dust mite allergen Der p 2. Mol Immunol 1996, 33:399–405.PubMedCrossRefGoogle Scholar
  3. 3.
    Kronqvist M, Johansson E, Whitley P, et al.: A hypoallergenic derivative of the major allergen of the dust mite Lepidoglyphus destructor, Lep d 2.6Cys, induces less IgE reactivity and cellular response in the skin than recombinant Lep d 2. Int Arch Allergy Immunol 2001, 126:41–49.PubMedCrossRefGoogle Scholar
  4. 4.
    Takai T, Yokota T, Yasue M, et al.: Engineering of the major house dust mite allergen Der f 2 for allergen-specific immunotherapy. Nat Biotechnol 1997, 15:754–758.PubMedCrossRefGoogle Scholar
  5. 5.
    Yasue M, Yokota T, Fukada M, et al.: Hyposensitization to allergic reaction in rDer f 2-sensitized mice by the intranasal administration of a mutant of rDer f 2, C8/119S. Clin Exp Immunol 1998, 113:1–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Korematsu S, Tanaka Y, Hosoi S, et al.: C8/119S mutation of major mite allergen Derf-2 leads to degenerate secondary structure and molecular polymerization and induces potent and exclusive Th1 cell differentiation. J Immunol 2000, 165:2895–2902.PubMedGoogle Scholar
  7. 7.
    Orlandi A, Grasso F, Corinti S, et al.: The recombinant major allergen of Parietaria judaica and its hypoallergenic variant: in vivo evaluation in a murine model of allergic sensitization. Clin Exp Allergy 2004, 34:470–477.PubMedCrossRefGoogle Scholar
  8. 8.
    Kauppinen J, Zeiler T, Rautiainen J, et al.: Mutant derivatives of the main respiratory allergen of cow are less allergenic than the intact molecule. Clin Exp Allergy 1999, 29:989–996.PubMedCrossRefGoogle Scholar
  9. 9.
    Smith AM, Chapman MD: Localization of antigenic sites on Der p 2 using oligonucleotide-directed mutagenesis targeted to predicted surface residues. Clin Exp Allergy 1997, 27:593–599.PubMedCrossRefGoogle Scholar
  10. 10.
    Takai T, Ichikawa S, Hatanaka H, et al.: Effects of proline mutations in the major house dust mite allergen Der f 2 on IgE-binding and histamine-releasing activity. Eur J Biochem 2000, 267:6650–6656.PubMedCrossRefGoogle Scholar
  11. 11.
    Vrtala S, Hirtenlehner K, Vangelista L, et al.: Conversion of the major birch pollen allergen, Bet v 1, into two nonanaphylactic T cell epitope-containing fragments: candidates for a novel form of specificimmunotherapy. J Clin Invest 1997, 99:1673–1681.PubMedCrossRefGoogle Scholar
  12. 12.
    Pauli G, Purohit A, Oster JP, et al.: Comparison of genetically engineered hypoallergenic rBet v 1 derivatives with rBet v 1 wild-type by skin prick and intradermal testing: results obtained in a French population. Clin Exp Allergy 2000, 30:1076–1084.PubMedCrossRefGoogle Scholar
  13. 13.
    van Hage-Hamsten M, Kronqvist M, Zetterstrom O, et al.: Skin test evaluation of genetically engineered hypoallergenic derivatives of the major birch pollen allergen, Bet v 1: results obtained with a mix of two recombinant Bet v 1 fragments and recombinant Bet v 1 trimer in a Swedish population before the birch pollen season. J Allergy Clin Immunol 1999, 104:969–977.PubMedCrossRefGoogle Scholar
  14. 14.
    Vrtala S, Akdis C, Budak F, et al.: T cell epitope-containing hypoallergenic recombinant fragments of the major birch pollen allergen, Bet v 1, induce blocking antibodies. J Immunol 2000, 165:6653–6659.PubMedGoogle Scholar
  15. 15.
    Mahler V, Vrtala S, Kuss O, et al.: Vaccines for birch pollen allergy based on genetically engineered hypoallergenic derivatives of the major birch pollen allergen, Bet v 1. Clin Exp Allergy 2004, 34:115–122.PubMedCrossRefGoogle Scholar
  16. 16.
    van Hage-Hamsten M, Johansson E, Roquet A, et al.: Nasal challenges with recombinant derivatives of the major birch pollen allergen Bet v 1 induce fewer symptoms and lower mediator release than rBet v 1 wild-type in patients with allergic rhinitis. Clin Exp Allergy 2002, 32:1448–1453.PubMedCrossRefGoogle Scholar
  17. 17.
    Nopp A, Hallden G, Lundahl J, et al.: Comparison of inflammatory responses to genetically engineered hypoallergenic derivatives of the major birch pollen allergen Bet v 1 and to recombinant bet v 1 wild type in skin chamber fluids collected from birch pollen-allergic patients. J Allergy Clin Immunol 2000, 106:101–109.PubMedCrossRefGoogle Scholar
  18. 18.
    Wiedermann U, Herz U, Vrtala S, et al.: Mucosal tolerance induction with hypoallergenic molecules in a murine model of allergic asthma. Int Arch Allergy Immunol 2001, 124:391–394.PubMedCrossRefGoogle Scholar
  19. 19.
    Hochreiter R, Stepanoska T, Ferreira F, et al.: Prevention of allergen-specific IgE production and suppression of an established Th2-type response by immunization with DNA encoding hypoallergenic allergen derivatives of Bet v 1, the major birch-pollen allergen. Eur J Immunol 2003, 33:1667–1676.PubMedCrossRefGoogle Scholar
  20. 20.
    Takai T, Yuuki T, Okumura Y, et al.: Determination of the N- and C-terminal sequences required to bind human IgE of the major house dust mite allergen Der f 2 and epitope mapping for monoclonal antibodies. Mol Immunol 1997, 345:255–259.CrossRefGoogle Scholar
  21. 21.
    Westritschnig K, Focke M, Verdino P, et al.: Generation of an allergy vaccine by disruption of the three-dimensional structure of the cross-reactive calcium-binding allergen, Phl p 7. J Immunol 2004, 172:5684–5692.PubMedGoogle Scholar
  22. 22.
    Vrtala S, Hirtenlehner K, Susani M, et al.: Genetic engineering of a hypoallergenic trimer of the major birch pollen allergen Bet v 1. FASEB J 2001, 15:2045–2047.PubMedGoogle Scholar
  23. 23.
    Shin DS, Compadre CM, Maleki SJ, et al.: Biochemical and structural analysis of the IgE binding sites on Ara h 1, an abundant and highly allergenic peanut protein. J Biol Chem 1998, 273:13753–13759.PubMedCrossRefGoogle Scholar
  24. 24.
    Burks AW, Shin DS, Cockrell G, et al.: Mapping and mutational analysis of the IgE-binding epitopes on Ara h 1, a legume vicilin protein and a major allergen in peanut hypersensitivity. Eur J Biochem 1997, 1997:334–339.CrossRefGoogle Scholar
  25. 25.
    Stanley JS, King N, Burks AW, et al.: Identification and mutational analysis of the immunodominant IgE binding epitopes of the major peanut allergen Ara h 2. Arch Biochem Biophys 1997, 342:244–253.PubMedCrossRefGoogle Scholar
  26. 26.
    Rabjohn P, West CM, Connaughton C, et al.: Modification of peanut allergen Ara h 3: effects on IgE binding and T cell stimulation. Int Arch Allergy Immunol 2002, 128:15–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Bannon GA, Cockrell G, Connaughton C, et al.: Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int Arch Allergy Immunol 2001, 124:70–72.PubMedCrossRefGoogle Scholar
  28. 28.
    Li XM, Srivastava K, Huleatt JW, et al.: Engineered recombinant peanut protein and heat-killed Listeria monocytogenes coadministration protects against peanut-induced anaphylaxis in a murine model. J Immunol 2003, 170:3289–3295.PubMedGoogle Scholar
  29. 29.
    Swoboda I, De Weerd N, Bhalla PL, et al.: Mutants of the major ryegrass pollen allergen, Lol p 5, with reduced IgEbinding capacity: candidates for grass pollen-specific immunotherapy. Eur J Immunol 2002, 32:270–280. Systematic study showing that mutation of conserved residues in sequences of the major grass allergen targeted by IgE peptide mapping. Hypoallergens with a conserved overall folding and T-cell reactivity were produced.PubMedCrossRefGoogle Scholar
  30. 30.
    Karisola P, Mikkola J, Kalkkinen N, et al.: Construction of hevein (Hev b 6.02) with reduced allergenicity for immunotherapy of latex allergy by comutation of six amino acid residues on the conformational IgE epitopes. J Immunol 2004, 172:2621–26288. Scanning site-directed mutagenesis and structural modeling were used to create hypoallergen. This strategy has general applicability to a number of small allergens.PubMedGoogle Scholar
  31. 31.
    Vailes LD, Sun AW, Ichikawa K, et al.: High-level expression of immunoreactive recombinant cat allergen (Fel d 1): targeting to antigen-presenting cells. J Allergy Clin Immunol 2002, 110:757–762.PubMedCrossRefGoogle Scholar
  32. 32.
    Toda M, Kasai M, Hosokawa H, et al.: DNA vaccine using invariant chain gene for delivery of CD4+ T cell epitope peptide derived from Japanese cedar pollen allergen inhibits allergen-specific IgE response. Eur J Immunol 2002, 32:1631–1639.PubMedCrossRefGoogle Scholar
  33. 33.
    Linhart B, Jahn-Schmid B, Verdino P, et al.: Combination vaccines for the treatment of grass pollen allergy consisting of genetically engineered hybrid molecules with increased immunogenicity. FASEB J 2002, 16:1301–1303.PubMedGoogle Scholar
  34. 34.
    King TP, Jim SY, Monsalve RI, et al.: Recombinant allergens with reduced allergenicity but retaining immunogenicity of the natural allergens: hybrids of yellow jacket and paper wasp venom allergen antigen 5s. J Immunol 2001, 166:6057–6065.PubMedGoogle Scholar
  35. 35.
    Punnonen J: Molecular breeding of allergy vaccines and antiallergic cytokines. Int Arch Allergy Immunol 2000, I121:173–182.CrossRefGoogle Scholar
  36. 36.
    Okada T, Swoboda I, Bhalla PL, et al.: Engineering of hypoallergenic mutants of the Brassica pollen allergen, Bra r 1, for immunotherapy. FEBS Lett 1998, 434:255–260.PubMedCrossRefGoogle Scholar
  37. 37.
    Schramm G, Kahlert H, Suck R, et al.: ‘Allergen engineering’: variants of the timothy grass pollen allergen Phl p 5b with reduced IgE-binding capacity but conserved T cell reactivity. J Immunol 1999, 162:2406–2414.PubMedGoogle Scholar
  38. 38.
    Buhot C, Chenal A, Sanson A, et al.: Alteration of the tertiary structure of the major bee venom allergen Api m 1 by multiple mutations is concomitant with low IgE reactivity. Protein Sci 2004, 13:2970–2978. A knowledge-based approach was used to produce a hypoallergen of bee venom phospholipaseA2, taking the structure and promiscuous T-cell epitopes into account. Previous studies with peptides have shown that allergy vaccination targeting phospholipaseA2 can be effective.PubMedCrossRefGoogle Scholar
  39. 39.
    Hirahara K, Tatsuta T, Takatori T, et al.: Preclinical evaluation of an immunotherapeutic peptide comprising 7 T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen allergens. J Allergy Clin Immunol 2001, 108:94–100.PubMedCrossRefGoogle Scholar
  40. 40.
    Kwon SS, Kim N, Yoo TJ: The effect of vaccination with DNA encoding murine T-cell epitopes on the Der p 1 and 2 induced immunoglobulin E synthesis. Allergy 2001, 56:741–748.PubMedCrossRefGoogle Scholar
  41. 41.
    Ferreira F, Ebner C, Kramer B, et al.: Modulation of IgE reactivity of allergens by site-directed mutagenesis: potential use of hypoallergenic variants for immunotherapy. FASEB J 1998, 12:231–242.PubMedGoogle Scholar
  42. 42.
    Spangfort MD, Mirza O, Ipsen H, et al.: Dominating IgEbinding epitope of Bet v 1, the major allergen of birch pollen, characterized by X-ray crystallography and site directed mutagenesis. J Immunol 2003, 171:3084–3090.PubMedGoogle Scholar
  43. 43.
    Mirza O, Henriksen A, Ipsen H, et al.: Dominant epitopes and allergic cross-reactivity: complex formation between a Fab fragment of a monoclonal murine IgG antibody and the major allergen from birch pollen Bet v 1. J Immunol 2000, 165:331–338.PubMedGoogle Scholar
  44. 44.
    Holm J, Gajhede M, Ferreras M, et al.: Allergy vaccine engineering: epitope modulation of recombinant Bet v 1 reduces IgE binding but retains protein folding pattern for induction of protective blocking-antibody responses. J Immunol 2004, 173:5258–5267. Hypoallergenic mutants of Bet v 1 were produced based on x-ray crystallographic and epitope analyses. The paper emphasizes the importance of producing hypoallergens with stable and verifiable structures.PubMedGoogle Scholar
  45. 45.
    Neudecker P, Lehmann K, Nerkamp J, et al.: Mutational epitope analysis of Pru av 1 and Api g 1, the major allergens of cherry (Prunus avium) and celery (Apium graveolens): correlating IgE reactivity with three-dimensional structure. Biochem J 2003, 376:97–107.PubMedCrossRefGoogle Scholar
  46. 46.
    Niederberger V, Horak F, Vrtala S, et al.: Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci 2004, 101(Suppl 2):14677–14682. A clinical trial has been conducted with recombinant allergen fragments and trimers of Bet v 1. It sets the benchmark for the development of genetically engineered hypoallergens and has produced significant modifications of IgE responses, skin tests, and symptom scores. It constitutes the first trial with recombinant allergy vaccines.PubMedCrossRefGoogle Scholar
  47. 47.
    Nair DT, Singh K, Sahu N, et al.: Crystal structure of an antibody bound to an immunodominant peptide epitope: novel features in peptide-antibody recognition. J Immunol 2000, 165:6949–6955.PubMedGoogle Scholar
  48. 48.
    Winkler B, Bolwig C, Seppala U, et al.: Allergen-specific immunosuppression by mucosal treatment with recombinant Ves v 5, a major allergen of Vespula vulgaris venom, in a murine model of wasp venom allergy. Immunology 2003, 110:376–385.PubMedCrossRefGoogle Scholar
  49. 49.
    von der Weid T, Bulliard C, Fritsche R: Suppression of specific and bystander IgE responses in a mouse model of oral sensitization to beta-lactoglobulin. Int Arch Allergy Immunol 2001, 125:307–315.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Wayne R. Thomas
    • 1
  • Belinda J. Hales
    • 1
  • Wendy-Anne Smith
    • 1
  1. 1.Centre for Child Health ResearchUniversity of Western Australia, Telethon Institute for Child Health ResearchSubiacoWestern Australia

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