We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Recombinant allergens for pollen immunotherapy

    Michael Wallner

    * Author for correspondence

    Christian Doppler Laboratory for Allergy Diagnosis & Therapy, Department of Molecular Biology, University of Salzburg, Hellbrunnerstr. 34, A-5020 Salzburg, Austria.

    ,
    Ulrike Pichler

    Christian Doppler Laboratory for Allergy Diagnosis & Therapy, Department of Molecular Biology, University of Salzburg, Hellbrunnerstr. 34, A-5020 Salzburg, Austria

    &
    Fatima Ferreira

    Christian Doppler Laboratory for Allergy Diagnosis & Therapy, Department of Molecular Biology, University of Salzburg, Hellbrunnerstr. 34, A-5020 Salzburg, Austria

    Published Online:https://doi.org/10.2217/imt.13.114

    Specific immunotherapy (IT) represents the only potentially curative therapeutic intervention of allergic diseases capable of suppressing allergy-associated symptoms not only during treatment, but also after its cessation. Presently, IT is performed with allergen extracts, which represent a heterogeneous mixture of allergenic, as well as nonallergenic, compounds of a given allergen source. To overcome many of the problems associated with extract-based IT, strategies based on the use of recombinant allergens or derivatives thereof have been developed. This review focuses on recombinant technologies to produce allergy therapeuticals, especially for allergies caused by tree, grass and weed pollen, as they are among the most prevalent allergic disorders affecting the population of industrialized societies. The reduction of IgE-binding of recombinant allergen derivatives appears to be mandatory to increase the safety profile of vaccine candidates. Moreover, increased immunogenicity is expected to reduce the dosage regimes of the presently cumbersome treatment. In this regard, it has been convincingly demonstrated in animal models that hypoallergenic molecules can be engineered to harbor inherent antiallergenic immunologic properties. Thus, strategies to modulate the allergenic and immunogenic properties of recombinant allergens will be discussed in detail. In recent years, several successful clinical studies using recombinant wild-type or hypoallergens as active ingredients have been published and, currently, novel treatment forms with higher safety and efficacy profiles are under investigation in clinical trials. These recent developments are summarized and discussed.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Breiteneder H, Hassfeld W, Pettenburger K et al. Isolation and characterization of messenger RNA from male inflorescences and pollen of the white birch (Betula verrucosa). Int. Arch. Allergy Appl. Immunol.87(1),19–24 (1988).
    • Thomas WR, Stewart GA, Simpson RJ et al. Cloning and expression of DNA coding for the major house dust mite allergen Der p 1 in Escherichia coli. Int. Arch. Allergy Appl. Immunol.85(1),127–129 (1988).
    • Fang KS, Vitale M, Fehlner P, King TP. cDNA cloning and primary structure of a white-face hornet venom allergen, antigen 5. Proc. Natl Acad. Sci. USA85(3),895–899 (1988).
    • Cromwell O, Hafner D, Nandy A. Recombinant allergens for specific immunotherapy. J. Allergy Clin. Immunol.127(4),865–872 (2011).▪▪ Detailed review on recombinant allergens for immunotherapy.
    • Moverare R, Elfman L, Vesterinen E, Metso T, Haahtela T. Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System. Allergy57(5),423–430 (2002).
    • Pauli G, Larsen TH, Rak S et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J. Allergy Clin. Immunol.122(5),951–960 (2008).▪▪ Clinical trial comparing the efficacy of a recombinant wild-type allergen (Bet v 1) with its natural counterpart and birch pollen extract.
    • Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J. Allergy Clin. Immunol.116(3),608–613 (2005).▪▪ Clinical trial using a cocktail of recombinant wild-type grass pollen allergens for immunotherapy.
    • D’Amato G, Cecchi L, Bonini S et al. Allergenic pollen and pollen allergy in Europe. Allergy62(9),976–990 (2007).
    • Hauser M, Asam C, Himly M et al. Bet v 1-like pollen allergens of multiple Fagales species can sensitize atopic individuals. Clin. Exp. Allergy41(12),1804–1814 (2011).
    • 10  Moverare R, Westritschnig K, Svensson M et al. Different IgE reactivity profiles in birch pollen-sensitive patients from six European populations revealed by recombinant allergens: an imprint of local sensitization. Int. Arch. Allergy Immunol.128(4),325–335 (2002).
    • 11  Wallner M, Erler A, Hauser M et al. Immunologic characterization of isoforms of Car b 1 and Que a 1, the major hornbeam and oak pollen allergens. Allergy64(3),452–460 (2009).
    • 12  Breiteneder H, Ferreira F, Hoffmann-Sommergruber K et al. Four recombinant isoforms of Cor a I, the major allergen of hazel pollen, show different IgE-binding properties. Eur. J. Biochem.212(2),355–362 (1993).
    • 13  Breiteneder H, Ferreira F, Reikerstorfer A et al. Complementary DNA cloning and expression in Escherichia coli of Aln g I, the major allergen in pollen of alder (Alnus glutinosa). J. Allergy Clin. Immunol.90(6 Pt 1),909–917 (1992).
    • 14  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 specific immunotherapy. J. Clin. Invest.99(7),1673–1681 (1997).
    • 15  Vrtala S, Hirtenlehner K, Vangelista L et al. Division of the major birch pollen allergen, Bet v 1, into two non-anaphylactic fragments. Int. Arch. Allergy Immunol.113(1–3),246–248 (1997).
    • 16  Vrtala S, Akdis CA, 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.165(11),6653–6659 (2000).
    • 17  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.15(11),2045–2047 (2001).
    • 18  Campana R, Vrtala S, Maderegger B et al. Altered IgE epitope presentation: a model for hypoallergenic activity revealed for Bet v 1 trimer. Mol. Immunol.48(4),431–441 (2011).
    • 19  Vrtala S, Fohr M, Campana R, Baumgartner C, Valent P, Valenta R. Genetic engineering of trimers of hypoallergenic fragments of the major birch pollen allergen, Bet v 1, for allergy vaccination. Vaccine29(11),2140–2148 (2011).
    • 20  Campana R, Vrtala S, Maderegger B et al. Hypoallergenic derivatives of the major birch pollen allergen Bet v 1 obtained by rational sequence reassembly. J. Allergy Clin. Immunol.126(5),1024–1031, 1031.e1021–1028 (2010).
    • 21  Wallner M, Stocklinger A, Thalhamer T et al. Allergy multivaccines created by DNA shuffling of tree pollen allergens. J. Allergy Clin. Immunol.120(2),374–380 (2007).
    • 22  Kahlert H, Suck R, Weber B et al. Characterization of a hypoallergenic recombinant Bet v 1 variant as a candidate for allergen-specific immunotherapy. Int. Arch. Allergy Immunol.145(3),193–206 (2008).
    • 23  Meyer W, Narkus A, Salapatek AM, Hafner D. Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy68(6),724–731 (2013).
    • 24  Thalhamer T, Dobias H, Stepanoska T et al. Designing hypoallergenic derivatives for allergy treatment by means of in silico mutation and screening. J. Allergy Clin. Immunol.125(4),926–934.e910 (2010).
    • 25  Wallner M, Hauser M, Himly M et al. Reshaping the Bet v 1 fold modulates Th polarization. J. Allergy Clin. Immunol.127(6),1571–1578.e1579 (2011).
    • 26  Kitzmuller C, Wallner M, Deifl S et al. A hypoallergenic variant of the major birch pollen allergen shows distinct characteristics in antigen processing and T-cell activation. Allergy67(11),1375–1382 (2012).
    • 27  Ferreira F, Hirtenlehner K, Jilek A et al. Dissection of immunoglobulin E and T lymphocyte reactivity of isoforms of the major birch pollen allergen Bet v 1: potential use of hypoallergenic isoforms for immunotherapy. J. Exp. Med.183(2),599–609 (1996).
    • 28  Wallner M, Himly M, Neubauer A et al. The influence of recombinant production on the immunologic behavior of birch pollen isoallergens. PLoS ONE4(12),e8457(2009).
    • 29  Focke M, Linhart B, Hartl A et al. Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin. Exp. Allergy34(10),1525–1533 (2004).
    • 30  Marth K, Breyer I, Focke-Tejkl M et al. A nonallergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG toward IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype. J. Immunol.190(7),3068–3078 (2013).
    • 31  Twaroch TE, Focke M, Civaj V et al. Carrier-bound, nonallergenic Ole e 1 peptides for vaccination against olive pollen allergy. J. Allergy Clin. Immunol.128(1),178–184.e177 (2011).
    • 32  Bohle B, Breitwieser A, Zwolfer B et al. A novel approach to specific allergy treatment: the recombinant fusion protein of a bacterial cell surface (S-layer) protein and the major birch pollen allergen Bet v 1 (rSbsC-Bet v 1) combines reduced allergenicity with immunomodulating capacity. J. Immunol.172(11),6642–6648 (2004).
    • 33  Bublin M, Hoflehner E, Wagner B et al. Use of a genetic cholera toxin B subunit/allergen fusion molecule as mucosal delivery system with immunosuppressive activity against Th2 immune responses. Vaccine25(50),8395–8404 (2007).
    • 34  Wild C, Wallner M, Hufnagl K et al. A recombinant allergen chimer as novel mucosal vaccine candidate for prevention of multi-sensitivities. Allergy62(1),33–41 (2007).
    • 35  Hoflehner E, Hufnagl K, Schabussova I et al. Prevention of birch pollen-related food allergy by mucosal treatment with multi-allergen-chimers in mice. PLoS ONE7(6),e39409(2012).
    • 36  Lombardero M, Obispo T, Calabozo B, Lezaun A, Polo F, Barber D. Cross-reactivity between olive and other species. Role of Ole e 1-related proteins. Allergy57(Suppl. 71),29–34 (2002).
    • 37  Batanero E, Crespo JF, Monsalve RI, Martin-Esteban M, Villalba M, Rodriguez R. IgE-binding and histamine-release capabilities of the main carbohydrate component isolated from the major allergen of olive tree pollen, Ole e 1. J. Allergy Clin. Immunol.103(1 Pt 1),147–153 (1999).
    • 38  Marazuela EG, Rodriguez R, Barber D, Villalba M, Batanero E. Hypoallergenic mutants of Ole e 1, the major olive pollen allergen, as candidates for allergy vaccines. Clin. Exp. Allergy37(2),251–260 (2007).
    • 39  Charpin D, Calleja M, Lahoz C, Pichot C, Waisel Y. Allergy to cypress pollen. Allergy60(3),293–301 (2005).
    • 40  Hashimoto M, Nigi H, Sakaguchi M et al. Sensitivity to two major allergens (Cry j I and Cry j II) in patients with Japanese cedar (Cryptomeria japonica) pollinosis. Clin. Exp. Allergy25(9),848–852 (1995).
    • 41  Iacovacci P, Pini C, Afferni C et al. A monoclonal antibody specific for a carbohydrate epitope recognizes an IgE-binding determinant shared by taxonomically unrelated allergenic pollens. Clin. Exp. Allergy31(3),458–465 (2001).
    • 42  Rea G, Iacovacci P, Ferrante P et al. Refolding of the Cupressus arizonica major pollen allergen Cup a1.02 overexpressed in Escherichia coli. Protein Expr. Purif.37(2),419–425 (2004).
    • 43  Liu Z, Bhattacharyya S, Ning B et al. Plant-expressed recombinant mountain cedar allergen Jun a 1 is allergenic and has limited pectate lyase activity. Int. Arch. Allergy Immunol.153(4),347–358 (2010).
    • 44  Esch RE. Grass pollen allergens. Clin. Allergy Immunol.18,185–205 (2004).
    • 45  Weber RW. Patterns of pollen cross-allergenicity. J. Allergy Clin. Immunol.112(2),229–239; quiz 240 (2003).
    • 46  Andersson K, Lidholm J. Characteristics and immunobiology of grass pollen allergens. Int. Arch. Allergy Immunol.130(2),87–107 (2003).
    • 47  Sekerkova A, Polackova M, Striz I. Detection of Phl p 1, Phl p 5, Phl p 7 and Phl p 12 specific IgE antibodies in the sera of children and adult patients allergic to Phleum pollen. Allergol. Int.61(2),339–346 (2012).
    • 48  Laffer S, Spitzauer S, Susani M et al. Comparison of recombinant timothy grass pollen allergens with natural extract for diagnosis of grass pollen allergy in different populations. J. Allergy Clin. Immunol.98(3),652–658 (1996).
    • 49  Vrtala S, Sperr WR, Reimitzer I et al. cDNA cloning of a major allergen from timothy grass (Phleum pratense) pollen; characterization of the recombinant Phl pV allergen. J. Immunol.151(9),4773–4781 (1993).
    • 50  Vrtala S, Susani M, Sperr WR et al. Immunologic characterization of purified recombinant timothy grass pollen (Phleum pratense) allergens (Phl p 1, Phl p2, Phl p 5). J. Allergy Clin. Immunol.97(3),781–787 (1996).
    • 51  Suck R, Kamionka T, Schaffer B et al. Bacterially expressed and optimized recombinant Phl p 1 is immunobiochemically equivalent to natural Phl p 1. Biochim. Biophys. Acta1764(11),1701–1709 (2006).
    • 52  Ball T, Fuchs T, Sperr WR et al. B cell epitopes of the major timothy grass pollen allergen, phl p 1, revealed by gene fragmentation as candidates for immunotherapy. FASEB J.13(11),1277–1290 (1999).
    • 53  Focke M, Mahler V, Ball T et al. Nonanaphylactic synthetic peptides derived from B cell epitopes of the major grass pollen allergen, Phl p 1, for allergy vaccination. FASEB J.15(11),2042–2044 (2001).
    • 54  Ball T, Linhart B, Sonneck K et al. Reducing allergenicity by altering allergen fold: a mosaic protein of Phl p 1 for allergy vaccination. Allergy64(4),569–580 (2009).
    • 55  Levin M, Rydnert F, Kallstrom E et al. Phl p 1-specific human monoclonal IgE and design of a hypoallergenic group 1 grass pollen allergen fragment. J. Immunol.191(2),551–560 (2013).
    • 56  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.162(4),2406–2414 (1999).
    • 57  Wald M, Kahlert H, Reese G et al. Hypoallergenic mutants of the Timothy grass pollen allergen Phl p 5 generated by proline mutations. Int. Arch. Allergy Immunol.159(2),130–142 (2012).
    • 58  Vrtala S, Focke M, Kopec J et al. Genetic engineering of the major timothy grass pollen allergen, Phl p 6, to reduce allergenic activity and preserve immunogenicity. J. Immunol.179(3),1730–1739 (2007).
    • 59  Westritschnig K, Linhart B, Focke-Tejkl M et al. A hypoallergenic vaccine obtained by tail-to-head restructuring of timothy grass pollen profilin, Phl p 12, for the treatment of cross-sensitization to profilin. J. Immunol.179(11),7624–7634 (2007).
    • 60  Tripodi S, Frediani T, Lucarelli S et al. Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implications for specific immunotherapy. J. Allergy Clin. Immunol.129(3),834–839.e838 (2012).
    • 61  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.16(10),1301–1303 (2002).
    • 62  Linhart B, Hartl A, Jahn-Schmid B et al. A hybrid molecule resembling the epitope spectrum of grass pollen for allergy vaccination. J. Allergy Clin. Immunol.115(5),1010–1016 (2005).
    • 63  Linhart B, Mothes-Luksch N, Vrtala S, Kneidinger M, Valent P, Valenta R. A hypoallergenic hybrid molecule with increased immunogenicity consisting of derivatives of the major grass pollen allergens, Phl p 2 and Phl p 6. Biol. Chem.389(7),925–933 (2008).
    • 64  Hauser M, Ferreira F, Gadermaier G. Allergens of weed pollen: an overview on recombinant and natural molecules. Methods doi:10.1016/j.ymeth.2013.06.014 (2013) (Epub ahead of print).
    • 65  Hauser M, Roulias A, Ferreira F, Egger M. Panallergens and their impact on the allergic patient. Allergy Asthma Clin. Immunol.6(1),1 (2010).
    • 66  Siegert M, Pertl-Obermeyer H, Gadermaier G, Ferreira F, Obermeyer G. Expression of the major mugwort pollen allergen Art v 1 in tobacco plants and cell cultures: problems and perspectives for allergen production in plants. Plant Cell Rep.31(3),561–571 (2012).
    • 67  Wopfner N, Jahn-Schmid B, Schmidt G et al. The alpha and beta subchain of Amb a 1, the major ragweed-pollen allergen show divergent reactivity at the IgE and T-cell level. Mol. Immunol.46(10),2090–2097 (2009).
    • 68  Jahn-Schmid B, Wopfner N, Hubinger G et al. The T-cell response to Amb a 1 is characterized by 3 dominant epitopes and multiple MHC restriction elements. J. Allergy Clin. Immunol.126(5),1068–1071, 1071 e1061–1062 (2010).
    • 69  Jahn -Schmid B, Hauser M, Wopfner N et al. Humoral and cellular cross-reactivity between Amb a 1, the major ragweed pollen allergen, and its mugwort homolog Art v 6. J. Immunol.188(3),1559–1567 (2012).
    • 70  Czerwinski EW, Midoro-Horiuti T, White MA, Brooks EG, Goldblum RM. Crystal structure of Jun a 1, the major cedar pollen allergen from Juniperus ashei, reveals a parallel beta-helical core. J. Biol. Chem.280(5),3740–3746 (2005).
    • 71  Gadermaier G, Wopfner N, Wallner M et al. Array-based profiling of ragweed and mugwort pollen allergens. Allergy63(11),1543–1549 (2008).
    • 72  Himly M, Jahn-Schmid B, Dedic A et al. Art v 1, the major allergen of mugwort pollen, is a modular glycoprotein with a defensin-like and a hydroxyproline-rich domain. FASEB J.17(1),106–108 (2003).
    • 73  Razzera G, Gadermaier G, De Paula V et al. Mapping the interactions between a major pollen allergen and human IgE antibodies. Structure18(8),1011–1021 (2010).
    • 74  Gadermaier G, Jahn-Schmid B, Vogel L et al. Targeting the cysteine-stabilized fold of Art v 1 for immunotherapy of Artemisia pollen allergy. Mol. Immunol.47(6),1292–1298 (2010).
    • 75  Gadermaier G, Dedic A, Obermeyer G, Frank S, Himly M, Ferreira F. Biology of weed pollen allergens. Curr. Allergy Asthma Rep.4(5),391–400 (2004).
    • 76  Duro G, Colombo P, Costa MA et al. cDNA cloning, sequence analysis and allergological characterization of Par j 2.0101, a new major allergen of the Parietaria judaica pollen. FEBS Lett.399(3),295–298 (1996).
    • 77  Tordesillas L, Sirvent S, Diaz-Perales A et al. Plant lipid transfer protein allergens: no cross-reactivity between those from foods and olive and Parietaria pollen. Int. Arch. Allergy Immunol.156(3),291–296 (2011).
    • 78  Bonura A, Amoroso S, Locorotondo G et al. Hypoallergenic variants of the Parietaria judaica major allergen Par j 1: a member of the non-specific lipid transfer protein plant family. Int. Arch. Allergy Immunol.126(1),32–40 (2001).
    • 79  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. Allergy34(3),470–477 (2004).
    • 80  Costa MA, Duro G, Izzo V et al. The IgE-binding epitopes of rPar j 2, a major allergen of Parietaria judaica pollen, are heterogeneously recognized among allergic subjects. Allergy55(3),246–250 (2000).
    • 81  Pace E, Duro G, La Grutta S et al. Hypoallergenic fragment of Par j 2 increases functional expression of Toll-like receptors in atopic children. Allergy61(12),1459–1466 (2006).
    • 82  Bonura A, Corinti S, Artale A et al. A hybrid expressing genetically engineered major allergens of the Parietaria pollen as a tool for specific allergy vaccination. Int. Arch. Allergy Immunol.142(4),274–284 (2007).
    • 83  Bonura A, Passantino R, Costa MA et al. Characterization of a Par j 1/Par j 2 mutant hybrid with reduced allergenicity for immunotherapy of Parietaria allergy. Clin. Exp. Allergy42(3),471–480 (2012).
    • 84  Gonzalez-Rioja R, Ibarrola I, Arilla MC et al. Genetically engineered hybrid proteins from Parietaria judaica pollen for allergen-specific immunotherapy. J. Allergy Clin. Immunol.120(3),602–609 (2007).
    • 85  Nouri HR, Varasteh A, Vahedi F, Chamani J, Afsharzadeh D, Sankian M. Constructing a hybrid molecule with low capacity of IgE binding from Chenopodium album pollen allergens. Immunol. Lett.144(1–2),67–77 (2012).
    • 86  Nouri HR, Sankian M, Afsharzadeh D, Varasteh A. Immunotherapy with a recombinant hybrid molecule alleviates allergic responses more efficiently than an allergenic cocktail or pollen extract in a model of Chenopodium album allergy. Int. Arch. Allergy Immunol.161(4),325–332 (2013).
    • 87  Assarehzadegan MA, Sankian M, Jabbari F, Tehrani M, Varasteh A. Expression of the recombinant major allergen of Salsola kali pollen (Sal k 1) and comparison with its low-immunoglobulin E-binding mutant. Allergol. Int.59(2),213–222 (2010).
    • 88  Klimek L, Schendzielorz P, Pinol R, Pfaar O. Specific subcutaneous immunotherapy with recombinant grass pollen allergens: first randomized dose-ranging safety study. Clin. Exp. Allergy42(6),936–945 (2012).
    • 89  Larenas-Linnemann D. Oralair birch, a recombinant major birch pollen allergen tablet for sublingual immunotherapy of allergic rhinitis caused by birch pollen. Curr. Opin. Investig. Drugs11(5),586–596 (2010).
    • 90  Niederberger V, Horak F, Vrtala S et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc. Natl Acad. Sci. USA101(Suppl. 2),14677–14682 (2004).▪ First clinical study using hypoallergenic allergen derivatives.
    • 91  Purohit A, Niederberger V, Kronqvist M et al. Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin. Exp. Allergy38(9),1514–1525 (2008).
    • 92  Pellaton C, Perrin Y, Boudousquie C et al. Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides. Clin. Transl. Allergy3(1),17 (2013).
    • 93  Fellrath JM, Kettner A, Dufour N et al. Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a Phase I trial. J. Allergy Clin. Immunol.111(4),854–861 (2003).
    • 94  Etto T, de Boer C, Prickett S et al. Unique and cross-reactive T cell epitope peptides of the major Bahia grass pollen allergen, Pas n 1. Int. Arch. Allergy Immunol.159(4),355–366 (2012).
    • 95  Hafner RP, Salapatek A, Patel D, Larché M, Laidler P. Validation of peptide immunotherapy as a new approach in the treatment of allergic rhinoconjunctivitis: the clinical benefits of treatment with Amb a 1 derived T cell epitopes. J. Allergy Clin. Immunol.129(Suppl. 2),AB368 (2012).
    • 96  Midoro-Horiuti T, Goldblum RM, Kurosky A, Goetz DW, Brooks EG. Isolation and characterization of the mountain cedar (Juniperus ashei) pollen major allergen, Jun a 1. J. Allergy Clin. Immunol.104(3 Pt 1),608–612 (1999).
    • 97  Gadermaier G, Hauser M, Ferreira F. Allergens of weed pollen: an overview on recombinant and natural molecules. Methods doi: 10.1016/j.ymeth.2013.06.014 (2013) (Epub ahead of print).▪ Detailed review of recombinant and natural weed pollen allergens.
    • 98  Winther L, Poulsen LK, Robin B, Melac M, Malling HJ. Safety and tolerability of recombinant Bet v 1 (rBet v 1) tablets in sublingual immunotherapy (SLIT). J. Allergy Clin. Immunol.123(Suppl.),S215 (2009).
    • 101  Allergen nomenclature. IUIS Allergen Nomenclature Sub-Committee. www.allergen.org
    • 102  Immunological and histological evaluation of specific immunotherapy with recombinant hypoallergenic derivative. http://clinicaltrials.gov/show/NCT00841516
    • 103  Skin prick tests with AllerT in subjects allergic to birch pollen. http://clinicaltrials.gov/show/NCT01719133
    • 104  Safety and tolerability of toleromune grass in grass allergic subjects with rhinoconjunctivitis. http://clinicaltrials.gov/show/NCT01166061
    • 105  Safety of ToleroMune ragweed to treat ragweed allergy in ragweed allergic subjects with rhinoconjunctivitis. http://clinicaltrials.gov/show/NCT00878774
    • 106  Drug information online. www.drugs.com