Skip to main content
SpringerLink
Log in

Standardization and Regulation of Allergen Products in the European Union

  • Immunologic/Diagnostic Tests in Allergy (M Chapman and A Pomés, Section Editors)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Product-specific standardization is of prime importance to ensure persistent quality, safety, and efficacy of allergen products. The regulatory framework in the EU has induced great advancements in the field in the last years although national implementation still remains heterogeneous. Scores of methods for quantification of individual allergen molecules are developed each year and also the challenging characterization of chemically modified allergen products is progressing. However, despite the unquestionable increase in knowledge and the subsequent improvements in control of quality parameters of allergen products, an important aim has not been reached yet, namely cross-product comparability. Still, comparison of allergen product potency, either based on total allergenic activity or individual allergen molecule content, is not possible due to a lack of standard reference preparations in conjunction with validated standard methods. This review aims at presenting the most recent developments in product-specific standardization as well as activities to facilitate cross-product comparability in the EU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Carnés J, Iraola V, Gallego M, Leonor JR. Control process for manufacturing and standardization of allergenic molecules. Curr Allergy Asthma Rep. 2015;15:541. doi:10.1007/s11882-015-0541-1. Coherent presentation of allergen product manufacturing processes and changes introduced due to regulatory framework in the EU.

    Article  Google Scholar 

  2. Larsen JN, Houghton CG, Vega ML, Løwenstein H. Manufacturing and standardizing allergen extracts in Europe: chapter 18. In: Lockey RF, Ledford DK, editors. Allergens and allergen immunotherapy. 4th ed. New York: Informa Healthcare; 2008. p. 283–301.

    Google Scholar 

  3. van Ree R. Allergen extracts and standardization: chapter 44. In: Kay AB, Kaplan AP, Bousquet J, Holt PG, editors. Allergy and allergic diseases. 2nd ed. Oxford: Wiley-Blackwell; 2008. p. 928–41. doi:10.1002/9781444300918.ch44.

    Google Scholar 

  4. Lowenstein H. Characterization and standardization of allergen extracts. Chem Immunol Allergy. 2014;100:323–32. doi:10.1159/000359989. Comprehensive overview on the international activities in the field of allergen extract standardization in the last 40 years.

    Article  PubMed  Google Scholar 

  5. Becker WM, Vogel L, Vieths S. Standardization of allergen extracts for immunotherapy: where do we stand? Curr Opin Allergy Clin Immunol. 2006;6:470–5.

    Article  PubMed  Google Scholar 

  6. Fernandez-Caldas E, Carnes J, Gallego M, Mari A, Pagan Aleman, JA. Standardization of animal epithelia. Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M 2006:107–16; discussion 116, 155.

  7. Hjelmroos M, Schumacher M, van Hage-Hamsten M. Variation in birch pollen (Betula verrucosa) allergens between different trees in view of both their provenance and traffic exhausts. In: Johansson G, editor. ICACI XV and EAACI ‘94: Allergy and Clinical Immunology News: Abstracts of the 15th International Congress of Allergology and Clinical Immunology. 2nd ed. Seattle, Toronto, Bern, Göttingen: Hogrefe & Huber Publishers, Incorporated, 1994; 1994. p. 138.

  8. Hjelmroos M, Schumacher MJ, van Hage-Hamsten M. Heterogeneity of pollen proteins within individual Betula pendula trees. Int Arch Allergy Immunol. 1995;108:368–76.

    Article  CAS  PubMed  Google Scholar 

  9. Castro AJ, de Dios AJ, Cuevas J, Romero PJ, Alche V, Rodriguez-García MI. Pollen from different olive tree cultivars contains varying amounts of the major allergen Ole e 1. Int Arch Allergy Immunol. 2003;131:164–73.

    Article  CAS  PubMed  Google Scholar 

  10. Esch RE. Allergen source materials and quality control of allergenic extracts. Methods. 1997;13:2–13.

    Article  CAS  PubMed  Google Scholar 

  11. Erler A, Hawranek T, Kruckemeier L, Asam C, Egger M, Ferreira F, et al. Proteomic profiling of birch (Betula verrucosa) pollen extracts from different origins. Proteomics. 2011;11:1486–98.

    Article  CAS  PubMed  Google Scholar 

  12. Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136:556–68. doi:10.1016/j.jaci.2015.04.047. Recent summary of current clinical practice and unmet needs in AIT.

    Article  PubMed  Google Scholar 

  13. Rabin RL, Slater JE. Standardized allergen vaccines in the United States. Allergens and allergen immunotherapy, CRC Press 2014:281–7. Comprehensive description of the current practice of allergen extract standardization in the USA.

  14. Casset A, Mari A, Purohit A, Resch Y, Weghofer M, Ferrara R, et al. Varying allergen composition and content affects the in vivo allergenic activity of commercial Dermatophagoides pteronyssinus extracts. Int Arch Allergy Immunol. 2012;159:253–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaul S, Lüttkopf D, Kastner B, Vogel L, Holtz G, Vieths S, et al. Mediator release assays based on human or murine immunoglobulin E in allergen standardization. Clin Exp Allergy. 2007;37:141–50.

    Article  CAS  PubMed  Google Scholar 

  16. Larenas-Linnemann D, Esch R, Plunkett G, Brown S, Maddox D, Barnes C, et al. Maintenance dosing for sublingual immunotherapy by prominent European allergen manufacturers expressed in bioequivalent allergy units. Ann Allergy Asthma Immunol. 2011;107:448–58. doi:10.1016/j.anai.2011.07.001. e3.

    Article  PubMed  Google Scholar 

  17. Dehus O, Zimmer J, Döring S, Führer F, Hanschmann K, Holzhauser T, et al. Development and in-house validation of an allergen-specific ELISA for quantification of Bet v 4 in diagnostic and therapeutic birch allergen products. Anal Bioanal Chem. 2015. doi:10.1007/s00216-014-8418-z.

    PubMed  Google Scholar 

  18. van Ree R. Indoor allergens: relevance of major allergen measurements and standardization. J Allergy Clin Immunol. 2007;119:270–7. doi:10.1016/j.jaci.2006.10.033. quiz 278–9.

    Article  PubMed  Google Scholar 

  19. Park KH, Son M, Choi SY, Park HJ, Lee JH, Jeong KY, et al. In vitro evaluation of allergen potencies of commercial house dust mite sublingual immunotherapy reagents. Allergy Asthma Immunol Res. 2015;7:124–9. doi:10.4168/aair.2015.7.2.124. Comparison of single allergen content and total allergenic activity in house dust mite AIT products, underlining the differences between marketed products and thus the importance of activities towards cross-product comparability.

    Article  PubMed  PubMed Central  Google Scholar 

  20. European Medicines Agency (EMA) Committee for Proprietary Medicinal Products (CPMP) and Biotechnology Working Party (BWP). Note for Guidance on Allergen Products (CPMP/BWP/243/96)eplaced by EMEA/CHMP/304831/2007 1996.

  21. European Pharmacopoeia 6.6. Monograph on allergen products 01/2010:1063.

  22. Kaul S, May S, Lüttkopf D, Vieths S. Regulatory environment for allergen-specific immunotherapy. Allergy 2011.

  23. Pini C. Regulation of allergen products in Europe (including NPPs). Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013;97:15–22. Overview of the European regulatory framework and the heterogeneous situation in EU member states regarding named patient products.

    PubMed  Google Scholar 

  24. Englert L, May S, Kaul S, Vieths S. Die Therapieallerge-Verordnung Hintergrund und Auswirkungen. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz. 2012;55:351–7.

    Article  CAS  Google Scholar 

  25. Lorenz AR, Lüttkopf D, May S, Scheurer S, Vieths S. The principle of homologous groups in regulatory affairs of allergen products—a proposal. Int Arch Allergy Immunol. 2009;148:1–17.

    Article  CAS  PubMed  Google Scholar 

  26. Ministère de la santé et des solidarités. Décret n8 2004–188 du 23 février 2004 relatif aux allergènes préparés spécialement pour un seul individu et modifiant le code de la santé publique. OJEU 2004:4101.

  27. Agenzia Italiana del Farmaco. UVA/18187 19.02.2010.

  28. Minister van Volksgezondheid, Welzijn en Sport. houdende uitvoering van bepalingen van de Geneesmiddelenwet (Regeling Geneesmiddelenwet, Hoofdstuk 3) 2007-06-25:GMT/MVG 2780607.

  29. Visser J. Allergeenpreparaten blijven vergoed. 2014.

  30. Rabin RL, Vieths S. Regulation and standardization of AIT extracts. Global Atlas of Allergic Rhinitis and Chronic Rhinosinusitis 2015:219–21.

  31. European Pharmacopoeia. Monograph on allergen products. Main legally binding document regulating allergen product manufacturing in the EU.

  32. Chapman MD. Allergen nomenclature. Clin Allergy Immunol. 2008;21:47–58.

    CAS  PubMed  Google Scholar 

  33. Alves RC, Pimentel FB, Nouws H, Marques RCB, Gonzalez-Garcia MB, Oliveira MBPP, et al. Detection of Ara h 1 (a major peanut allergen) in food using an electrochemical gold nanoparticle-coated screen-printed immunosensor. Biosens Bioelectron. 2015;64:19–24. doi:10.1016/j.bios.2014.08.026.

    Article  CAS  PubMed  Google Scholar 

  34. Ruiz-Valdepeñas Montiel V, Campuzano S, Pellicanò A, Torrente-Rodríguez RM, Reviejo AJ, Cosio MS, et al. Sensitive and selective magnetoimmunosensing platform for determination of the food allergen Ara h 1. Anal Chim Acta. 2015;880:52–9. doi:10.1016/j.aca.2015.04.041.

    Article  PubMed  Google Scholar 

  35. Alves RC, Pimentel FB, Nouws HPA, Correr W, González-García MB, Oliveira MBPP, et al. Detection of the peanut allergen Ara h 6 in foodstuffs using a voltammetric biosensing approach. Anal Bioanal Chem. 2015;407:7157–63. doi:10.1007/s00216-015-8879-8.

    Article  CAS  PubMed  Google Scholar 

  36. Belisle D. Quantification of the Aspergillus versicolor allergen in house dust. J Immunol Methods. 2011;372:89–94. doi:10.1016/j.jim.2011.06.034.

    Article  PubMed  Google Scholar 

  37. Khurana T, Dobrovolskaia E, Shartouny JR, Slater JE. Multiplex assay for protein profiling and potency measurement of German cockroach allergen extracts. PLoS One. 2015;10:e0140225. doi:10.1371/journal.pone.0140225.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yang A, Zheng Y, Long C, Chen H, Liu B, Li X, et al. Fluorescent immunosorbent assay for the detection of alpha lactalbumin in dairy products with monoclonal antibody bioconjugated with CdSe/ZnS quantum dots. Food Chem. 2014;150:73–9. doi:10.1016/j.foodchem.2013.10.137.

    Article  CAS  PubMed  Google Scholar 

  39. Lutter P, Parisod V, Weymuth H. Development and validation of a method for the quantification of milk proteins in food products based on liquid chromatography with mass spectrometric detection. J AOAC Int. 2011;94:1043–59.

    CAS  PubMed  Google Scholar 

  40. Chen Q, Zhang J, Ke X, Lai S, Tao B, Yang J, et al. Quantification of bovine β-casein allergen in baked foodstuffs based on ultra-performance liquid chromatography with tandem mass spectrometry. Food Addit Contam. 2015;32:25–34. doi:10.1080/19440049.2014.990994.

    Article  Google Scholar 

  41. Rytkonen-Nissinen M, Saarelainen S, Randell J, Hayrinen J, Kalkkinen N, Virtanen T. IgE reactivity of the dog lipocalin allergen can f 4 and the development of a sandwich ELISA for its quantification. Allergy Asthma Immunol Res. 2015;7:384–92. doi:10.4168/aair.2015.7.4.384.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bublin M, Kostadinova M, Fuchs JE, Ackerbauer D, Moraes AH, Almeida FL, et al. A cross-reactive human single-chain antibody for detection of major fish allergens, parvalbumins, and identification of a major IgE-binding epitope. PLoS One. 2015;10:e0142625. doi:10.1371/journal.pone.0142625.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Foetisch K, Dahl L, Jansen B, Becker WM, Lidholm J, van Ree R, et al. Development and in-house validation of allergen-specific ELISA tests for the quantification of Dau c 1.01, Dau c 1.02 and Dau c 4 in carrot extracts (Daucus carota). Anal Bioanal Chem. 2011;399:935–43.

    Article  CAS  PubMed  Google Scholar 

  44. Julka S, Kuppannan K, Karnoup A, Dielman D, Schafer B, Young SA. Quantification of Gly m 4 protein, a major soybean allergen, by two-dimensional liquid chromatography with ultraviolet and mass spectrometry detection. Anal Chem. 2012;84:10019–30. doi:10.1021/ac3024685.

    Article  CAS  PubMed  Google Scholar 

  45. Geng T, Liu K, Frazier R, Shi L, Bell E, Glenn K, et al. Development of a sandwich ELISA for quantification of Gly m 4, a soybean allergen. J Agric Food Chem. 2015;63:4947–53. doi:10.1021/acs.jafc.5b00792 .

    Article  CAS  PubMed  Google Scholar 

  46. Wang H, Li G, Wu Y, Yuan F, Chen Y. Development of an indirect competitive immunoassay for walnut protein component in food. Food Chem. 2014;147:106–10. doi:10.1016/j.foodchem.2013.09.013.

    Article  CAS  PubMed  Google Scholar 

  47. Alcazar P, Galan C, Torres C, Dominguez-Vilches E. Detection of airborne allergen (Pla a 1) in relation to Platanus pollen in Cordoba, South Spain. Ann Agric Environ Med. 2015;22:96–101.

    Article  PubMed  Google Scholar 

  48. Jiang D, Ji J, An L, Sun X, Zhang Y, Zhang G, et al. Mast cell-based electrochemical biosensor for quantification of the major shrimp allergen Pen a 1 (tropomyosin). Biosens Bioelectron. 2013;50:150–6.

    Article  CAS  PubMed  Google Scholar 

  49. Tungtrongchitr A, Sookrung N, Chaicumpa W, Indrawattana N, Poolphol R, Sae-Lim N, et al. Convenient, rapid and economic detection and semi-quantification of American cockroach allergen in the environment. Asian Pac J Allergy Immunol. 2012;30:99–106.

    CAS  PubMed  Google Scholar 

  50. Seppälä U, Dauly C, Robinson S, Hornshaw M, Larsen JN, Ipsen H. Absolute quantification of allergens from complex mixtures: a new sensitive tool for standardization of allergen extracts for specific immunotherapy. J Proteome Res. 2011;10:2113–22.

    Article  PubMed  Google Scholar 

  51. Posada-Ayala M, Alvarez-Llamas G, Maroto AS, Maes X, Muñoz-Garcia E, Villalba M, et al. Novel liquid chromatography-mass spectrometry method for sensitive determination of the mustard allergen Sin a 1 in food. Food Chem. 2015;183:58–63. doi:10.1016/j.foodchem.2015.02.139.

    Article  CAS  PubMed  Google Scholar 

  52. Lopez-Matas MA, Larramendi CH, Ferrer A, Huertas AJ, Pagán JA, García-Abujeta JL, et al. Identification and quantification of tomato allergens: in vitro characterization of six different varieties. Ann Allergy Asthma Immunol. 2011;106:230–8. doi:10.1016/j.anai.2010.11.022.

    Article  CAS  PubMed  Google Scholar 

  53. Albers DR, Schafer BW, Dielman D. Quantification and characterization of maize lipid transfer protein, a food allergen, by liquid chromatography with ultraviolet and mass spectrometric detection. Anal Chem. 2011;83:516–24. doi:10.1021/ac102201m.

    Article  PubMed  Google Scholar 

  54. Shi C, Provost NB, Desroches T, Miller JD. Quantification of C. globosum spores in house dust samples. Ann Agric Environ Med. 2014;21:525–30.

    Article  PubMed  Google Scholar 

  55. Chu PT, Wen HW. Sensitive detection and quantification of gliadin contamination in gluten-free food with immunomagnetic beads based liposomal fluorescence immunoassay. Anal Chim Acta. 2013;787:246–53.

    Article  CAS  PubMed  Google Scholar 

  56. Ippoushi K, Sasanuma M, Oike H, Kobori M, Maeda-Yamamoto M. Absolute quantification of protein NP24 in tomato fruit by liquid chromatography/tandem mass spectrometry using stable isotope-labelled tryptic peptide standard. Food Chem. 2015;173:238–42. doi:10.1016/j.foodchem.2014.10.008.

    Article  CAS  PubMed  Google Scholar 

  57. Shi C, Belisle D, Levac S, Miller JD. The development and validation of an assay for the quantification of the P. chrysogenum allergen Pch52. J Occup Environ Hyg. 2012;9:211–6. doi:10.1080/15459624.2012.666138.

    Article  CAS  PubMed  Google Scholar 

  58. Zhang H, Lu Y, Ushio H, Shiomi K. Development of sandwich ELISA for detection and quantification of invertebrate major allergen tropomyosin by a monoclonal antibody. Food Chem. 2014;150:151–7. doi:10.1016/j.foodchem.2013.10.154.

    Article  CAS  PubMed  Google Scholar 

  59. Kamath SD, Thomassen MR, Saptarshi SR, Nguyen HMX, Aasmoe L, Bang BE, et al. Molecular and immunological approaches in quantifying the air-borne food allergen tropomyosin in crab processing facilities. Int J Hyg Environ Health. 2014;217:740–50. doi:10.1016/j.ijheh.2014.03.006.

    Article  CAS  PubMed  Google Scholar 

  60. Nagai H, Minatani T, Goto K. Development of a method for crustacean allergens using liquid chromatography/tandem mass spectrometry. J AOAC Int. 2015;98:1355–65. doi:10.5740/jaoacint.14-248.

    Article  PubMed  Google Scholar 

  61. Sega M, Zanetti C, Rizzi C, Olivieri M, Chignola R, Zoccatelli G. Production and characterisation of monoclonal antibodies for the quantification of potentially allergenic xylanase from Aspergillus niger. Food Addit Contam. 2012;29:1356–63. doi:10.1080/19440049.2012.698657.

    Article  CAS  Google Scholar 

  62. Reuter A, Lüttkopf D, Vieths S. New frontiers in allergen standardization. Clin Exp Allergy. 2009;39:307–9.

    Article  CAS  PubMed  Google Scholar 

  63. European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guideline on Allergen Products: Production and Quality Issues; EMEA/CHMP/BWP/304831/2007 2008.

  64. Russell, WMS, Burch RL. The principles of humane experimental technique. Methuen, London: reprinted in 1992 by UFAW (Universities Federation for Animal Welfare); 1959.

  65. Himly M, Carnes J, Fernandez-Caldas E, Briza P, Ferreira F. Characterization of allergoids. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009;96:61–9. discussion 69–70.

    CAS  PubMed  Google Scholar 

  66. Carnes J, Himly M, Gallego M, Iraola V, Robinson DS, Fernández-Caldas E, et al. Detection of allergen composition and in vivo immunogenicity of depigmented allergoids of Betula alba. Clin Exp Allergy. 2009;39:426–34.

    Article  CAS  PubMed  Google Scholar 

  67. Fiebig H, Kahlert H, Weber B, Suck R, Nandy A, Cromwell O. Antibody-based methods for standardization of allergoids and recombinant hypoallergens. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009;96:71–82. discussion 82–3.

    PubMed  Google Scholar 

  68. Wu Z, Lian J, Han Y, Zhou N, Li X, Yang A, et al. Cross-linking of peanut allergen Ara h 2 by polyphenol oxidase: digestibility and potential allergenicity assessment. J Sci Food Agric. 2015. doi:10.1002/jsfa.7542.

    Google Scholar 

  69. Koppelman SJ, Luykx DM, de Jongh HH, de Veldhuizen WJ. Physicochemical characterization of allergens: quantity, identity, purity, aggregation and conformation. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009;96:39–53. discussion 53–4.

    CAS  PubMed  Google Scholar 

  70. Gallego MT, Iraola V, Himly M, Robinson DS, Badiola C, Garcia-Robaina JC, et al. Depigmented and polymerised house dust mite allergoid: allergen content, induction of IgG4 and clinical response. Int Arch Allergy Immunol. 2010;153:61–9.

    Article  CAS  PubMed  Google Scholar 

  71. Luykx D, Cordewener J, de Bruijn J, de Westphal A, Sleijster H, America T, et al. Physicochemical characterisation of mite allergoids and alum-adsorbed mite allergoids. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013;97:97–100.

    PubMed  Google Scholar 

  72. Kerkvliet E, Sinnige N, Franso C, van den Hout R. Antibody-based assays for potency determination of mite allergoids and for stability studies of alum-adsorbed mite vaccines. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013;97:106–11.

    CAS  PubMed  Google Scholar 

  73. Marco FM, Brotons B, Kutsyr O, Ferrer A, Hernández FT, Carrión MA, Diaz P. Development of a capture-ELISA assay for the analysis and quantification of Dermatophagoides pteronyssinus allergoids. Allergy 2015:467

  74. Werther RL, Choo S, Lee KJ, Poole D, Allen KJ, Tang MLK. Variability in skin prick test results performed by multiple operators depends on the device used. World Allergy Organ J. 2012;5:200–4. doi:10.1097/WOX.0b013e31827e6513.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Fatteh S, Rekkerth DJ, Hadley JA. Skin prick/puncture testing in North America: a call for standards and consistency. Allergy Asthma Clin Immunol. 2014;10:44. doi:10.1186/1710-1492-10-44.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Larenas-Linnemann D, Cox LS. European allergen extract units and potency: review of available information. Ann Allergy Asthma Immunol. 2008;100:137–45. doi:10.1016/S1081-1206(10)60422-X.

    Article  PubMed  Google Scholar 

  77. Becker WM, van Ree R, Fiebig H, Cromwell O, Weber B, Monsalve R, et al. Validation of quantitative, allergen-specific ELISAs. Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M 2006:91–7.

  78. Batard T, Nony E, Hrabina M, Chabre H, Frati F, Moingeon P. Advances in the quantification of relevant allergens in allergenic extracts. Eur Ann Allergy Clin Immunol. 2013;45 Suppl 2:33–7. Comparison of advantages and limitations of immunoassays versus mass spectrometry-based techniques for allergen quantification.

    PubMed  Google Scholar 

  79. Koeberl M, Clarke D, Lopata AL. Next generation of food allergen quantification using mass spectrometric systems. J Proteome Res. 2014;13:3499–509. doi:10.1021/pr500247r.

    Article  CAS  PubMed  Google Scholar 

  80. Spiric J, Engin AM, Karas M, Reuter A, Koomen JM. Quality control of biomedicinal allergen products—highly complex isoallergen composition challenges standard MS database search and requires manual data analyses. PLoS One. 2015;10:e0142404. doi:10.1371/journal.pone.0142404.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Briza P. The potential of mass spectrometry as a novel tool in standardization of natural allergen extracts. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013;97:57–62.

    CAS  PubMed  Google Scholar 

  82. Lorenz AR, Lüttkopf D, Seitz R, Vieths S. The regulatory system in Europe with special emphasis on allergen products. Int Arch Allergy Immunol. 2008;147:263–75.

    Article  CAS  PubMed  Google Scholar 

  83. Barber D, de la Torre F, Feo F, Florido F, Guardia P, Moreno C, et al. Understanding patient sensitization profiles in complex pollen areas: a molecular epidemiological study. Allergy. 2008;63:1550–8.

    Article  CAS  PubMed  Google Scholar 

  84. Cases B, Ibáñez MD, Tudela JI, Sanchez-Garcia S, Rodriguez del Rio P, Fernandez EA, et al. Immunological cross-reactivity between olive and grass pollen: implication of major and minor allergens. World Allergy Organ J. 2014;7:11. doi:10.1186/1939-4551-7-11.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Quiralte J, Llanes E, Barral P, Arias de Saavedra JM, Sáenz de San Pedro B, Villalba M, et al. Ole e 2 and Ole e 10: new clinical aspects and genetic restrictions in olive pollen allergy. Allergy. 2005;60:360–5.

    Article  CAS  PubMed  Google Scholar 

  86. Barber D, Polo F, Lombardero M, Villalba M, Rodríguez R. The importance of minor allergens in allergen standardization. Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M 2006:128–34; discussion 134, 155.

  87. Duffort O, Palomares O, Lombardero M, Villalba M, Barber D, Rodríguez R, et al. Variability of Ole e 9 allergen in olive pollen extracts: relevance of minor allergens in immunotherapy treatments. Int Arch Allergy Immunol. 2006;140:131–8.

    Article  CAS  PubMed  Google Scholar 

  88. van Ree R, Chapman MD, Ferreira F, Vieths S, Bryan D, Cromwell O, et al. The CREATE project: development of certified reference materials for allergenic products and validation of methods for their quantification. Allergy. 2008;63:310–26.

    Article  PubMed  Google Scholar 

  89. Chapman MD, Ferreira F, Villalba M, Cromwell O, Bryan D, Becker WM, et al. The European Union CREATE project: a model for international standardization of allergy diagnostics and vaccines. J Allergy Clin Immunol. 2008;122:882–9.

    Article  PubMed  Google Scholar 

  90. Filep S, Tsay A, Vailes L, Gadermaier G, Ferreira F, Matsui E, et al. A multi-allergen standard for the calibration of immunoassays: CREATE principles applied to eight purified allergens. Allergy. 2012;67:235–41. doi:10.1111/j.1398-9995.2011.02750.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Neske F, Schorner C, Buchheit KH, Costanzo A, Hanschmann K, Himly M, et al. BSP090--the follow-up to CREATE. Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M 2009;96:12–9.

  92. Kaul S, Dehus O, Zimmer J, Vieths S. Validation of major allergen references and ELISAs—current state of the BSP090 project. Arbeiten aus dem Paul-Ehrlich-Institut (Bundesamt für Sera und Impfstoffe) zu Frankfurt a.M 2013;97:45–53.

  93. Himly M, Nony E, Chabre H, van Overtvelt L, Neubauer A, van Ree R, et al. Standardization of allergen products: 1. Detailed characterization of GMP-produced recombinant Bet v 1.0101 as biological reference preparation. Allergy. 2009;64:1038–45.

    Article  CAS  PubMed  Google Scholar 

  94. Himly M, Nandy A, Kahlert H, Thilker M, Steiner M, Briza P, et al. Standardization of allergen products: 2. Detailed characterization of GMP-produced recombinant Phl p 5.0109 as European Pharmacopoeia reference standard. Allergy 2015:n/a-n/a. doi:10.1111/all.12824. Detailed description of characterization of the allergen reference preparation for the major Timothy grass allergen, enabling the inclusion in the Monograph on Allergen Products.

  95. Slater JE. Standardized allergen extracts in the United States. Clin Allergy Immunol. 2004;18:421–32.

    CAS  PubMed  Google Scholar 

  96. Esch RE, Plunkett GA. Immunotherapy preparation guidelines, rules, and regulation. Curr Allergy Asthma Rep. 2013;13:406–13. doi:10.1007/s11882-013-0358-8.

    Article  CAS  PubMed  Google Scholar 

  97. Khurana T, Slater JE. Update on the FDA/CBER allergen standardization program. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013;97:37–44.

    CAS  PubMed  Google Scholar 

  98. Jeong KY, Lee JH, Kim EJ, Lee JS, Cho SH, Hong SJ, et al. Current status of standardization of inhalant allergen extracts in Korea. Allergy Asthma Immunol Res. 2014;6:196–200. doi:10.4168/aair.2014.6.3.196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jeong KY, Hong CS, Lee JS, Park JW. Optimization of allergen standardization. Yonsei Med J. 2011;52:393–400. doi:10.3349/ymj.2011.52.3.393.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Health Canada. Regulatory framework for unauthorized new allergenic products of biological origin used for diagnosis or treatment of allergic diseases 2012/11/13.

  101. Bachert C, Larche M, Bonini S, Canonica GW, Kündig T, Larenas-Linnemann D, et al. Allergen immunotherapy on the way to product-based evaluation-a WAO statement. World Allergy Organ J. 2015;8:29. doi:10.1186/s40413-015-0078-8. Joint statement that efficacy cannot be estimated for all SLIT or SCIT products in general, but rather has to be assessed specifically for each product.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, Canonica GW, et al. Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI position paper. Allergy. 2014. doi:10.1111/all.12383.

    PubMed Central  Google Scholar 

  103. Pfaar O, Kleine-Tebbe J, Hörmann K, Klimek L. Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? Immunol Allergy Clin N Am. 2011;31:289–309. doi:10.1016/j.iac.2011.02.004.

    Article  CAS  Google Scholar 

  104. Klimek L, Sperl A, van Twuijver E, van Ree R, Kleinjans H, Boot JD, et al. A prospective study comparing the efficacy and safety of two sublingual birch allergen preparations. Clin Transl Allergy. 2014;4:23. doi:10.1186/2045-7022-4-23. Head-to-head comparison of two AIT products with preceding parallel quantification of major allergen content.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kerkvliet E, Peekel I, Van Tuyn J, Sleijster H, van den Hout R. Amount of major allergen Bet v 1 and allergen activity in different European products for sublingual immunotherapy. Allergy. 2011;66:622–3.

    Google Scholar 

  106. Jutel M, Akdis CA. Novel immunotherapy vaccine development. Curr Opin Allergy Clin Immunol. 2014;14:557–63. doi:10.1097/ACI.0000000000000121.

    Article  CAS  PubMed  Google Scholar 

  107. Jongejan L, van Ree R. Modified allergens and their potential to treat allergic disease. Curr Allergy Asthma Rep. 2014;14:478. doi:10.1007/s11882-014-0478-9.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225, Langen, Germany

    Julia Zimmer, Stefan Vieths & Susanne Kaul

Authors
  1. Julia Zimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Vieths
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanne Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Vieths.

Ethics declarations

Conflict of Interest

Dr. Kaul reports non-financial support from European Academy of Allergy and Clinical Immunology and European Directorate for the Quality of Medicines and Health Care and grants from European Directorate for the Quality of Medicines and Health Care.

Dr. Vieths reports personal fees from the Food Allergy Resource and Research Program, Lincoln, NE, USA, personal fees from the Medical University of Vienna, Austria, grants from the Monsanto Company, personal fees from the American Academy of Asthma, Allergy and Immunology, personal fees from the Deutsche Dermatologische Gesellschaft, personal fees from the Westdeutsche Arbeitsgemeinschaft für pädiatrische Pneumologie und Allergologie e.V., Köln, Germany, personal fees from the Gesellschaft für pädiatrische Allergologie und Umweltmedizin, personal fees from the Ärzteverband Deutscher Allergologen, personal fees from the Swiss Society for Allergy and Immunology, personal fees from the Schattauer Allergologie Handbuch, personal fees from the Elsevier Nahrungsmittelaller-gien und Intoleranzen, personal fees from the Karger Food Allergy: Molecular Basis and Clinical Practice, and non-financial support from the German Research Foundation, from the Federal Institute for Risk Assessment, from the European Directorate for the Quality of Medicines and Health Care, from the European Academy of Allergy and Clinical Immunology , from the Deutscher Allergie- und Asthmabund, from the Association Monégasque pour le Perfectionnement des Connaissances des Médicins, from the Federal Office of Consumer Protection and Food Safety , from the German Chemical Society (GDCh), from the AKM Allergiekongress, and from the International Union of Immunological Societies. Dr. Vieths also reports grants from the European Directorate for the Quality of Medicines and Health Care.

Dr. Zimmer reports grants from the European Directorate for the Quality of Medicines and Health Care.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Immunologic/Diagnostic Tests in Allergy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zimmer, J., Vieths, S. & Kaul, S. Standardization and Regulation of Allergen Products in the European Union. Curr Allergy Asthma Rep 16, 21 (2016). https://doi.org/10.1007/s11882-016-0599-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-016-0599-4

Keywords

Search

Navigation