Perspectives in Allergen-Specific Immunotherapy: Molecular Evolution of Peptide- and Protein-Based Strategies

Alain      Jacquet
Abstract

Allergen-specific Immunotherapy (AIT), through repetitive subcutaneous or sublingual administrations of allergen extracts, represents up to now the unique treatment against allergic sensitizations. However, the clinical efficacy of AIT can be largely dependent on the quality of natural allergen extracts. Moreover, the long duration and adverse side effects associated with AIT negatively impact patient adherence. Tremendous progress in the field of molecular allergology has made possible the design of safer, shorter and more effective new immunotherapeutic approaches based on purified and characterized natural or recombinant allergen derivatives and peptides. This review will summarize the characteristics of these different innovative vaccines including their effects in preclinical studies and clinical trials.
Keywords: Immunotherapy, hypoallergen, IgE binding epitope, T cell epitope, blocking antibodies, allergic disease, recombinant, synthetic peptide.
Graphical Abstract

[1] 
Jacobsen, L.; Niggemann, B.; Dreborg, S.; Ferdousi, H.A.; Halken, S.; Høst, A.; Koivikko, A.; Norberg, L.A.; Valovirta, E.; Wahn, U.; Möller, C. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy,  2007, 62(8), 943-948.
[http://dx.doi.org/10.1111/j.1398-9995.2007.01451.x] [PMID:  17620073] 
[2] 
Des Roches, A.; Paradis, L.; Menardo, J.L.; Bouges, S.; Daurés, J.P.; Bousquet, J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J. Allergy Clin. Immunol.,  1997, 99(4), 450-453.
[http://dx.doi.org/10.1016/S0091-6749(97)70069-1] [PMID:  9111487] 
[3] 
Pajno, G.B.; Barberio, G.; De Luca, F.; Morabito, L.; Parmiani, S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin. Exp. Allergy,  2001, 31(9), 1392-1397.
[http://dx.doi.org/10.1046/j.1365-2222.2001.01161.x] [PMID:  11591189] 
[4] 
Cox, L.S.; Hankin, C.; Lockey, R. Allergy immunotherapy adherence and delivery route: location does not matter. J. Allergy Clin. Immunol. Pract.,  2014, 2(2), 156-160.
[http://dx.doi.org/10.1016/j.jaip.2014.01.010] [PMID:  24607042] 
[5] 
Focke, M.; Swoboda, I.; Marth, K.; Valenta, R. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity. Clin. Exp. Allergy,  2010, 40(3), 385-397.
[http://dx.doi.org/10.1111/j.1365-2222.2009.03443.x] [PMID:  20210812] 
[6] 
Di Bona, D.; Plaia, A.; Leto-Barone, M.S.; La Piana, S.; Di Lorenzo, G. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A meta-analysis-based comparison. J. Allergy Clin. Immunol.,  2012, 130(5), 1097-1107.e2.
[http://dx.doi.org/10.1016/j.jaci.2012.08.012] [PMID:  23021885] 
[7] 
Durham, S.R.; Penagos, M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J. Allergy Clin. Immunol.,  2016, 137(2), 339-349.e10.
[http://dx.doi.org/10.1016/j.jaci.2015.12.1298] [PMID:  26853126] 
[8] 
Calderón, M.A.; Bousquet, J.; Canonica, G.W.; Cardell, L.O.; Fernandez de Rojas, D.H.; Kleine-Tebbe, J.; Demoly, P. Guideline recommendations on the use of allergen immunotherapy in house dust mite allergy: Time for a change? J. Allergy Clin. Immunol.,  2017, 140(1), 41-52.
[http://dx.doi.org/10.1016/j.jaci.2017.01.049] [PMID:  28526624] 
[9] 
Jutel, M.; Agache, I.; Bonini, S.; Burks, A.W.; Calderon, M.; Canonica, W.; Cox, L.; Demoly, P.; Frew, A.J.; O’Hehir, R.; Kleine-Tebbe, J.; Muraro, A.; Lack, G.; Larenas, D.; Levin, M.; Nelson, H.; Pawankar, R.; Pfaar, O.; van Ree, R.; Sampson, H.; Santos, A.F.; Du Toit, G.; Werfel, T.; Gerth van Wijk, R.; Zhang, L.; Akdis, C.A. International consensus on allergy immunotherapy. J. Allergy Clin. Immunol.,  2015, 136(3), 556-568.
[http://dx.doi.org/10.1016/j.jaci.2015.04.047] [PMID:  26162571] 
[10] 
Batard, T.; Baron-Bodo, V.; Martelet, A.; Le Mignon, M.; Lemoine, P.; Jain, K.; Mariano, S.; Horiot, S.; Chabre, H.; Harwanegg, C.; Marquette, C.A.; Corgier, B.P.; Soh, W.T.; Satitsuksanoa, P.; Jacquet, A.; Chew, F.T.; Nony, E.; Moingeon, P. Patterns of IgE sensitization in house dust mite-allergic patients: implications for allergen immunotherapy. Allergy,  2016, 71(2), 220-229.
[http://dx.doi.org/10.1111/all.12796] [PMID:  26485347] 
[11] 
Valenta, R.; Karaulov, A.; Niederberger, V.; Zhernov, Y.; Elisyutina, O.; Campana, R.; Focke-Tejkl, M.; Curin, M.; Namazova-Baranova, L.; Wang, J.Y.; Pawankar, R.; Khaitov, M. Allergen Extracts for In Vivo Diagnosis and Treatment of Allergy: Is There a Future? J. Allergy Clin. Immunol. Pract.,  2018, 6(6), 1845-1855.e2.
[http://dx.doi.org/10.1016/j.jaip.2018.08.032] [PMID:  30297269] 
[12] 
Jacquet, A. Innate immune responses in house dust mite allergy. ISRN Allergy,  2013, 2013735031
[http://dx.doi.org/10.1155/2013/735031] [PMID:  23724247] 
[13] 
Chevigné, A.; Jacquet, A. Emerging roles of the protease allergen Der p 1 in house dust mite-induced airway inflammation. J. Allergy Clin. Immunol.,  2018, 142(2), 398-400.
[http://dx.doi.org/10.1016/j.jaci.2018.05.027] [PMID:  29906529] 
[14] 
Riccio, A.M.; De Ferrari, L.; Chiappori, A.; Ledda, S.; Passalacqua, G.; Melioli, G.; Canonica, G.W. Molecular diagnosis and precision medicine in allergy management. Clin. Chem. Lab. Med.,  2016, 54(11), 1705-1714.
[http://dx.doi.org/10.1515/cclm-2016-0007] [PMID:  26985687] 
[15] 
Shamji, M.H.; Durham, S.R. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J. Allergy Clin. Immunol.,  2017, 140(6), 1485-1498.
[http://dx.doi.org/10.1016/j.jaci.2017.10.010] [PMID:  29221580] 
[16] 
van de Veen, W.; Stanic, B.; Yaman, G.; Wawrzyniak, M.; Söllner, S.; Akdis, D.G.; Rückert, B.; Akdis, C.A.; Akdis, M. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J. Allergy Clin. Immunol.,  2013, 131(4), 1204-1212.
[http://dx.doi.org/10.1016/j.jaci.2013.01.014] [PMID:  23453135] 
[17] 
Strait, R.T.; Morris, S.C.; Finkelman, F.D. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J. Clin. Invest.,  2006, 116(3), 833-841.
[http://dx.doi.org/10.1172/JCI25575] [PMID:  16498503] 
[18] 
Holm, J.; Willumsen, N.; Würtzen, P.A.; Christensen, L.H.; Lund, K. Facilitated antigen presentation and its inhibition by blocking IgG antibodies depends on IgE repertoire complexity. J. Allergy Clin. Immunol.,  2011, 127(4), 1029-1037.
[http://dx.doi.org/10.1016/j.jaci.2011.01.062] [PMID:  21377718] 
[19] 
Shamji, M.H.; Ljørring, C.; Francis, J.N.; Calderon, M.A.; Larché, M.; Kimber, I.; Frew, A.J.; Ipsen, H.; Lund, K.; Würtzen, P.A.; Durham, S.R. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy,  2012, 67(2), 217-226.
[http://dx.doi.org/10.1111/j.1398-9995.2011.02745.x] [PMID:  22077562] 
[20] 
Flicker, S.; Gadermaier, E.; Madritsch, C.; Valenta, R. Passive immunization with allergen-specific antibodies. Curr. Top. Microbiol. Immunol.,  2011, 352, 141-159.
[http://dx.doi.org/10.1007/82_2011_143] [PMID:  21681684] 
[21] 
Orengo, J.M.; Radin, A.R.; Kamat, V.; Badithe, A.; Ben, L.H.; Bennett, B.L.; Zhong, S.; Birchard, D.; Limnander, A.; Rafique, A.; Bautista, J.; Kostic, A.; Newell, D.; Duan, X.; Franklin, M.C.; Olson, W.; Huang, T.; Gandhi, N.A.; Lipsich, L.; Stahl, N.; Papadopoulos, N.J.; Murphy, A.J.; Yancopoulos, G.D. Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat. Commun.,  2018, 9(1), 1421-1435.
[http://dx.doi.org/10.1038/s41467-018-03636-8] [PMID:  29650949] 
[22] 
O’Hehir, R.E.; Prickett, S.R.; Rolland, J.M. T Cell Epitope Peptide Therapy for Allergic Diseases. Curr. Allergy Asthma Rep.,  2016, 16(2), 14-22.
[http://dx.doi.org/10.1007/s11882-015-0587-0] [PMID:  26768622] 
[23] 
Hoyne, G.F.; O’Hehir, R.E.; Wraith, D.C.; Thomas, W.R.; Lamb, J.R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J. Exp. Med.,  1993, 178(5), 1783-1788.
[http://dx.doi.org/10.1084/jem.178.5.1783] [PMID:  8228823] 
[24] 
Briner, T.J.; Kuo, M.C.; Keating, K.M.; Rogers, B.L.; Greenstein, J.L. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I. Proc. Natl. Acad. Sci. USA,  1993, 90(16), 7608-7612.
[http://dx.doi.org/10.1073/pnas.90.16.7608] [PMID:  8356062] 
[25] 
Müller, U.; Akdis, C.A.; Fricker, M.; Akdis, M.; Blesken, T.; Bettens, F.; Blasér, K. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J. Allergy Clin. Immunol.,  1998, 101(6 Pt 1), 747-754.
[http://dx.doi.org/10.1016/S0091-6749(98)70402-6] [PMID:  9648701] 
[26] 
Norman, P.S.; Ohman, J.L., Jr; Long, A.A.; Creticos, P.S.; Gefter, M.A.; Shaked, Z.; Wood, R.A.; Eggleston, P.A.; Hafner, K.B.; Rao, P.; Lichtenstein, L.M.; Jones, N.H.; Nicodemus, C.F. Treatment of cat allergy with T-cell reactive peptides. Am. J. Respir. Crit. Care Med.,  1996, 154(6 Pt 1), 1623-1628.
[http://dx.doi.org/10.1164/ajrccm.154.6.8970345] [PMID:  8970345] 
[27] 
Larche, M.; Hickey, P.; Hebert, J.; Hafner, R. Safety and Tolerability of Escalating Doses of House Dust Mite- Peptide Antigen Desensitization (HDM-PAD). J. Allergy Clin. Immunol.,  2013, 131, AB37.
[http://dx.doi.org/10.1016/j.jaci.2012.12.814] 
[28] 
Hafner, R.P.; Couroux, P.; Armstrong, K.; Salapatek, A.M.; Patel, D.; Larche, M. Four doses of Der p derived synthetic peptide immuno-regulatory epitopes over 3 months results in a persistent treatment effect at 1 year on symptoms of House Dust Mite allergy. Allergy,  2014, 69, 31-32.
[29] 
Ellis, A.K.; Frankish, C.W.; Armstrong, K.; Larche, M. A short course of synthetic peptide immuno-regulatory epitopes derived from grass allergens leads to a reduction in grass allergy symptoms. Allergy,  2014, 69, 32.
[30] 
Hafner, R.; Salapatek, A.; Patel, D.; Larche, 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.,  2012, 129, AB368.
[http://dx.doi.org/10.1016/j.jaci.2012.01.017] 
[31] 
Worm, M.; Patel, D.; Creticos, P.S. Cat peptide antigen desensitisation for treating cat allergic rhinoconjunctivitis. Expert Opin. Investig. Drugs,  2013, 22(10), 1347-1357.
[http://dx.doi.org/10.1517/13543784.2013.827661] [PMID:  23964728] 
[32] 
Worm, M.; Lee, H.H.; Kleine-Tebbe, J.; Hafner, R.P.; Laidler, P.; Healey, D.; Buhot, C.; Verhoef, A.; Maillère, B.; Kay, A.B.; Larché, M. Development and preliminary clinical evaluation of a
peptide immunotherapy vaccine for cat allergy. J. Allergy Clin.
Immunol,  2011, 127(1), 89-97, 97.e1-97.e14.
[http://dx.doi.org/10.1016/j.jaci.2010.11.029] [PMID:  21211644] 
[33] 
Patel, D.; Couroux, P.; Hickey, P.; Salapatek, A.M.; Laidler, P.; Larché, M.; Hafner, R.P. Fel d 1-derived peptide antigen desensitization
shows a persistent treatment effect 1 year after the start of
dosing: a randomized, placebo-controlled study. J. Allergy Clin.
Immunol,  2013, 131(1), 103-9.e1, 7.
[http://dx.doi.org/10.1016/j.jaci.2012.07.028] [PMID:  22981787] 
[34] 
Available from. http://www.circassia.com/media/pressreleases/
[35] 
Pellaton, C.; Perrin, Y.; Boudousquié, C.; Barbier, N.; Wassenberg, J.; Corradin, G.; Thierry, A.C.; Audran, R.; Reymond, C.; Spertini, F. Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides. Clin. Transl. Allergy,  2013, 3(1), 17-27.
[http://dx.doi.org/10.1186/2045-7022-3-17] [PMID:  23725004] 
[36] 
Spertini, F.; Perrin, Y.; Audran, R.; Pellaton, C.; Boudousquié, C.; Barbier, N.; Thierry, A.C.; Charlon, V.; Reymond, C. Safety and immunogenicity of immunotherapy with Bet v 1-derived contiguous overlapping peptides. J. Allergy Clin. Immunol.,  2014, 134(1), 239-240.e13.
[http://dx.doi.org/10.1016/j.jaci.2014.04.001] [PMID:  24797422] 
[37] 
Spertini, F.; DellaCorte, G.; Kettner, A.; de Blay, F.; Jacobsen, L.; Jutel, M.; Worm, M.; Charlon, V.; Reymond, C. Efficacy of 2 months of allergen-specific immunotherapy with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: Results of a phase IIb study. J. Allergy Clin. Immunol.,  2016, 138(1), 162-168.
[http://dx.doi.org/10.1016/j.jaci.2016.02.044] [PMID:  27373329] 
[38] 
Shamji, M.H.; Ceuppens, J.; Bachert, C.; Hellings, P.; Placier, G.; Thirion, G.; Bovy, N.; Durham, S.R.; Duchateau, J.; Legon, T.; Pirotton, S. Lolium perenne peptides for treatment of grass pollen allergy: A randomized, double-blind, placebo-controlled clinical trial. J. Allergy Clin. Immunol.,  2018, 141(1), 448-451.
[http://dx.doi.org/10.1016/j.jaci.2017.09.013] [PMID:  29030102] 
[39] 
Mösges, R.; Koch, A.F.; Raskopf, E.; Singh, J.; Shah-Hosseini, K.; Astvatsatourov, A.; Hauswald, B.; Yarin, Y.; Corazza, F.; Haazen, L.; Pirotton, S.; Allekotte, S.; Zadoyan, G.; Legon, T.; Durham, S.R.; Shamji, M.H. Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B-cell response in seasonal allergic rhinitis patients. Allergy,  2018, 73(6), 1254-1262.
[http://dx.doi.org/10.1111/all.13392] [PMID:  29322510] 
[40] 
Mösges, R.; Bachert, C.; Panzner, P.; Calderon, M.A.; Haazen, L.; Pirotton, S.; Wathelet, N.; Durham, S.R.; Bonny, M.A.; Legon, T.; von Frenckell, R.; Pfaar, O.; Shamji, M.H. Short course of grass allergen peptides immunotherapy over 3 weeks reduces seasonal symptoms in allergic rhinoconjunctivitis with/without asthma: A randomized, multicenter, double-blind, placebo-controlled trial. Allergy,  2018, 73(9), 1842-1850.
[http://dx.doi.org/10.1111/all.13433] [PMID:  29512827] 
[41] 
Available from. www.asitbiotech.comhttps://www.asitbiotech.com/images/gb/pdf/PR_ASIT_hdm_results_follow-up_final_EN.pdf2017.
[42] 
Jutel, M.; Jaeger, L.; Suck, R.; Meyer, H.; Fiebig, H.; Cromwell, O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J. Allergy Clin. Immunol.,  2005, 116(3), 608-613.
[http://dx.doi.org/10.1016/j.jaci.2005.06.004] [PMID:  16159631] 
[43] 
Pauli, G.; Larsen, T.H.; Rak, S.; Horak, F.; Pastorello, E.; Valenta, R.; Purohit, A.; Arvidsson, M.; Kavina, A.; Schroeder, J.W.; Mothes, N.; Spitzauer, S.; Montagut, A.; Galvain, S.; Melac, M.; André, C.; Poulsen, L.K.; Malling, H.J. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J. Allergy Clin. Immunol.,  2008, 122(5), 951-960.
[http://dx.doi.org/10.1016/j.jaci.2008.09.017] [PMID:  19000581] 
[44] 
Nony, E.; Bouley, J.; Le Mignon, M.; Lemoine, P.; Jain, K.; Horiot, S.; Mascarell, L.; Pallardy, M.; Vincentelli, R.; Leone, P.; Roussel, A.; Batard, T.; Abiteboul, K.; Robin, B.; de Beaumont, O.; Arvidsson, M.; Rak, S.; Moingeon, P. Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients. Allergy,  2015, 70(7), 795-804.
[http://dx.doi.org/10.1111/all.12622] [PMID:  25846209] 
[45] 
Khinchi, M.S.; Poulsen, L.K.; Carat, F.; André, C.; Hansen, A.B.; Malling, H.J. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy,  2004, 59(1), 45-53.
[http://dx.doi.org/10.1046/j.1398-9995.2003.00387.x] [PMID:  14674933] 
[46] 
Fritsch, R.; Bohle, B.; Vollmann, U.; Wiedermann, U.; Jahn-Schmid, B.; Krebitz, M.; Breiteneder, H.; Kraft, D.; Ebner, C. Bet v 1, the major birch pollen allergen, and Mal d 1, the major apple allergen, cross-react at the level of allergen-specific T helper cells. J. Allergy Clin. Immunol.,  1998, 102(4 Pt 1), 679-686.
[http://dx.doi.org/10.1016/S0091-6749(98)70287-8] [PMID:  9802379] 
[47] 
Kinaciyan, T.; Nagl, B.; Faustmann, S.; Frommlet, F.; Kopp, S.; Wolkersdorfer, M.; Wöhrl, S.; Bastl, K.; Huber, H.; Berger, U.; Bohle, B. Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy. J. Allergy Clin. Immunol.,  2018, 141(3), 1002-1008.
[http://dx.doi.org/10.1016/j.jaci.2017.07.036] [PMID:  28870463] 
[48] 
Leung, N.Y.H.; Wai, C.Y.Y.; Shu, S.A.; Chang, C.C.; Chu, K.H.; Leung, P.S.C. Low-Dose Allergen-Specific Immunotherapy Induces Tolerance in a Murine Model of Shrimp Allergy. Int. Arch. Allergy Immunol.,  2017, 174(2), 86-96.
[http://dx.doi.org/10.1159/000479694] [PMID:  29065408] 
[49] 
Meechan, P.; Tungtrongchitr, A.; Chaisri, U.; Maklon, K.; Indrawattana, N.; Chaicumpa, W.; Sookrung, N. Intranasal, liposome-adjuvanted cockroach allergy vaccines made of refined major allergen and whole-body extract of Periplaneta americana. Int. Arch. Allergy Immunol.,  2013, 161(4), 351-362.
[http://dx.doi.org/10.1159/000348314] [PMID:  23689057] 
[50] 
Gregory, J.A.; Shepley-McTaggart, A.; Umpierrez, M.; Hurlburt, B.K.; Maleki, S.J.; Sampson, H.A.; Mayfield, S.P.; Berin, M.C. Immunotherapy using algal-produced Ara h 1 core domain suppresses peanut allergy in mice. Plant Biotechnol. J.,  2016, 14(7), 1541-1550.
[http://dx.doi.org/10.1111/pbi.12515] [PMID:  26801740] 
[51] 
Tasaniyananda, N.; Chaisri, U.; Tungtrongchitr, A.; Chaicumpa, W.; Sookrung, N. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine. PLoS One,  2016, 11(3)e0150463
[http://dx.doi.org/10.1371/journal.pone.0150463] [PMID:  26954254] 
[52] 
Chaisri, U.; Tungtrongchitr, A.; Indrawattana, N.; Meechan, P.; Phurttikul, W.; Tasaniyananda, N.; Saelim, N.; Chaicumpa, W.; Sookrung, N. Immunotherapeutic efficacy of liposome-encapsulated refined allergen vaccines against Dermatophagoides pteronyssinus allergy. PLoS One,  2017, 12(11)e0188627
[http://dx.doi.org/10.1371/journal.pone.0188627] [PMID:  29182623] 
[53] 
Hesse, L.; van Ieperen, N.; Habraken, C.; Petersen, A.H.; Korn, S.; Smilda, T.; Goedewaagen, B.; Ruiters, M.H.; van der Graaf, A.C.; Nawijn, M.C. Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model. Allergy,  2018, 73(4), 862-874.
[http://dx.doi.org/10.1111/all.13382] [PMID:  29318623] 
[54] 
Mueller, G.A. Contributions and Future Directions for Structural Biology in the Study of Allergens. Int. Arch. Allergy Immunol.,  2017, 174(2), 57-66.
[http://dx.doi.org/10.1159/000481078] [PMID:  28992615] 
[55] 
Martínez, D.; Cantillo, J.F.; Herazo, H.; Wortmann, J.; Keller, W.; Caraballo, L.; Puerta, L. Characterization of a hybrid protein designed with segments of allergens from Blomia tropicalis and Dermatophagoides pteronyssinus. Immunol. Lett.,  2018, 196, 103-112.
[http://dx.doi.org/10.1016/j.imlet.2018.01.012] [PMID:  29408409] 
[56] 
Chen, K.W.; Blatt, K.; Thomas, W.R.; Swoboda, I.; Valent, P.; Valenta, R.; Vrtala, S. Hypoallergenic Der p 1/Der p 2 combination vaccines for immunotherapy of house dust mite allergy. J. Allergy Clin. Immunol.,  2012, 130(2), 435-43.e4.
[http://dx.doi.org/10.1016/j.jaci.2012.05.035] [PMID:  22789398] 
[57] 
Asturias, J.A.; Ibarrola, I.; Arilla, M.C.; Vidal, C.; Ferrer, A.; Gamboa, P.M.; Viñuela, J.E.; Sanz, M.L.; Andreu, C.; Martínez, A. Engineering of major house dust mite allergens Der p 1 and Der p 2 for allergen-specific immunotherapy. Clin. Exp. Allergy,  2009, 39(7), 1088-1098.
[http://dx.doi.org/10.1111/j.1365-2222.2009.03264.x] [PMID:  19400901] 
[58] 
Sancho, A.I.; Wallner, M.; Hauser, M.; Nagl, B.; Himly, M.; Asam, C.; Ebner, C.; Jahn-Schmid, B.; Bohle, B.; Ferreira, F. T Cell Epitope-Containing Domains of Ragweed Amb a 1 and Mugwort Art v 6 Modulate Immunologic Responses in Humans and Mice. PLoS One,  2017, 12(1)e0169784
[http://dx.doi.org/10.1371/journal.pone.0169784] [PMID:  28081194] 
[59] 
Zhao, B.B.; Diao, J.D.; Liu, Z.M.; Li, C.P.; Jiang, Y.X. Generation of a chimeric dust mite hypoallergen using DNA shuffling for application in allergen-specific immunotherapy. Int. J. Clin. Exp. Pathol.,  2014, 7(7), 3608-3619.
[PMID:  25120738] 
[60] 
Chen, K.W.; Fuchs, G.; Sonneck, K.; Gieras, A.; Swoboda, I.; Douladiris, N.; Linhart, B.; Jankovic, M.; Pavkov, T.; Keller, W.; Papadopoulos, N.G.; Valent, P.; Valenta, R.; Vrtala, S. Reduction of the in vivo allergenicity of Der p 2, the major house-dust mite allergen, by genetic engineering. Mol. Immunol.,  2008, 45(9), 2486-2498.
[http://dx.doi.org/10.1016/j.molimm.2008.01.006] [PMID:  18295887] 
[61] 
Walgraffe, D.; Mattéotti, C.; El Bakkoury, M.; Garcia, L.; Marchand, C.; Bullens, D.; Vandenbranden, M.; Jacquet, A. A hypoallergenic variant of Der p 1 as a candidate for mite allergy vaccines. J. Allergy Clin. Immunol.,  2009, 123(5), 1150-1156.
[http://dx.doi.org/10.1016/j.jaci.2008.11.038] [PMID:  19152967] 
[62] 
Magi, M.; Garcia, L.; Vandenbranden, M.; Palmantier, R.; Jacquet, A. Heat denaturation affects the ProDer p 1 IgE reactivity and downregulates the development of the specific allergic response. J. Allergy Clin. Immunol.,  2004, 114(3), 545-552.
[http://dx.doi.org/10.1016/j.jaci.2004.04.014] [PMID:  15356555] 
[63] 
Toda, M.; Reese, G.; Gadermaier, G.; Schulten, V.; Lauer, I.; Egger, M.; Briza, P.; Randow, S.; Wolfheimer, S.; Kigongo, V.; Del Mar San Miguel Moncin, M.; Fötisch, K.; Bohle, B.; Vieths, S.; Scheurer, S. Protein unfolding strongly modulates the allergenicity
and immunogenicity of Pru p 3, the major peach allergen. J. Allergy
Clin. Immunol,  2011, 128(5), 1022-30.e1, 7.
[http://dx.doi.org/10.1016/j.jaci.2011.04.020] [PMID:  21571358] 
[64] 
Pacheco-Soares, T.; de Oliveira Carvalho, A.; da Silva Araújo, J.; de Souza, G.D.S.; Machado, O.L.T. A modified, hypoallergenic variant of the Ricinus communis Ric c1 protein retains biological activity. Biosci. Rep.,  2018, 38BSR20171245
[http://dx.doi.org/10.1042/BSR20171245] [PMID:  29444820] 
[65] 
Dhanapala, P.; Withanage-Dona, D.; Tang, M.L.; Doran, T.; Suphioglu, C. Hypoallergenic Variant of the Major Egg White Allergen Gal d 1 Produced by Disruption of Cysteine Bridges. Nutrients,  2017, 9(2)E171
[http://dx.doi.org/10.3390/nu9020171] [PMID:  28230769] 
[66] 
Ferrari, E.; Casali, E.; Burastero, S.E.; Spisni, A.; Pertinhez, T.A. The allergen Mus m 1.0102: Dissecting the relationship between molecular conformation and allergenic potency. Biochim. Biophys. Acta,  2016, 1864(11), 1548-1557.
[http://dx.doi.org/10.1016/j.bbapap.2016.08.003] [PMID:  27519162] 
[67] 
Sircar, G.; Jana, K.; Dasgupta, A.; Saha, S.; Gupta Bhattacharya, S. Epitope Mapping of Rhi o 1 and Generation of a Hypoallergenic Variant: A CANDIDATE MOLECULE FOR FUNGAL ALLERGY VACCINES. J. Biol. Chem.,  2016, 291(34), 18016-18029.
[http://dx.doi.org/10.1074/jbc.M116.732032] [PMID:  27358405] 
[68] 
Wai, C.Y.; Leung, N.Y.; Ho, M.H.; Gershwin, L.J.; Shu, S.A.; Leung, P.S.; Chu, K.H. Immunization with Hypoallergens of shrimp allergen tropomyosin inhibits shrimp tropomyosin specific IgE reactivity. PLoS One,  2014, 9(11)e111649
[http://dx.doi.org/10.1371/journal.pone.0111649] [PMID:  25365343] 
[69] 
Levin, M.; Rydnert, F.; Källström, E.; Tan, L.W.; Wormald, P.J.; Lindstedt, M.; Greiff, L.; Ohlin, M. Phl p 1-specific human monoclonal IgE and design of a hypoallergenic group 1 grass pollen allergen fragment. J. Immunol.,  2013, 191(2), 551-560.
[http://dx.doi.org/10.4049/jimmunol.1202051] [PMID:  23761636] 
[70] 
Paulus, K.E.; Schmid, B.; Zajic, D.; Schäfer, A.; Mahler, V.; Sonnewald, U. Hypoallergenic profilin--a new way to identify allergenic determinants. FEBS J.,  2012, 279(15), 2727-2736.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08656.x] [PMID:  22682106] 
[71] 
Wald, M.; Kahlert, H.; Reese, G.; Krontal, N.; Zafred, D.; Keller, W.; Cromwell, O.; Fiebig, H.; Nandy, A. Hypoallergenic mutants of the Timothy grass pollen allergen Phl p 5 generated by proline mutations. Int. Arch. Allergy Immunol.,  2012, 159(2), 130-142.
[http://dx.doi.org/10.1159/000336651] [PMID:  22653364] 
[72] 
Chen, J.C.; Chiu, L.L.; Lee, K.L.; Huang, W.N.; Chuang, J.G.; Liao, H.K.; Chow, L.P. Identification of critical amino acids in an immunodominant IgE epitope of Pen c 13, a major allergen from Penicillium citrinum. PLoS One,  2012, 7(4)e34627
[http://dx.doi.org/10.1371/journal.pone.0034627] [PMID:  22506037] 
[73] 
Yang, Z.; Li, Y.; Li, C.; Wang, Z. Synthesis of hypoallergenic derivatives of the major allergen Fag t 1 from tartary buckwheat via sequence restructuring. Food Chem. Toxicol.,  2012, 50(8), 2675-2680.
[http://dx.doi.org/10.1016/j.fct.2012.03.039] [PMID:  22449541] 
[74] 
Marazuela, E.G.; Hajek, R.; Villalba, M.; Barber, D.; Breiteneder, H.; Rodríguez, R.; Batanero, E. A non-allergenic Ole e 1-like protein from birch pollen as a tool to design hypoallergenic vaccine candidates. Mol. Immunol.,  2012, 50(1-2), 83-90.
[http://dx.doi.org/10.1016/j.molimm.2011.12.006] [PMID:  22266079] 
[75] 
Tordesillas, L.; Gamboa, P.; Sanz, M.L.; Palacín, A.; Gómez-Casado, C.; Cuesta-Herranz, J.; Pacios, L.F.; Salcedo, G.; Díaz-Perales, A. A mutant of the major melon allergen, Cuc m 2, with reduced IgE binding capacity is a good candidate for specific immunotherapy. Mol. Immunol.,  2011, 49(3), 504-511.
[http://dx.doi.org/10.1016/j.molimm.2011.09.020] [PMID:  22014685] 
[76] 
Woodfolk, J.A.; Glesner, J.; Wright, P.W.; Kepley, C.L.; Li, M.; Himly, M.; Muehling, L.M.; Gustchina, A.; Wlodawer, A.; Chapman, M.D.; Pomés, A. Antigenic Determinants of the Bilobal Cockroach Allergen Bla g 2. J. Biol. Chem.,  2016, 291(5), 2288-2301.
[http://dx.doi.org/10.1074/jbc.M115.702324] [PMID:  26644466] 
[77] 
Reese, G.; Viebranz, J.; Leong-Kee, S.M.; Plante, M.; Lauer, I.; Randow, S.; Moncin, M.S.; Ayuso, R.; Lehrer, S.B.; Vieths, S. Reduced allergenic potency of VR9-1, a mutant of the major shrimp allergen Pen a 1 (tropomyosin). J. Immunol.,  2005, 175(12), 8354-8364.
[http://dx.doi.org/10.4049/jimmunol.175.12.8354] [PMID:  16339577] 
[78] 
Devanaboyina, S.C.; Cornelius, C.; Lupinek, C.; Fauland, K.; Dall’Antonia, F.; Nandy, A.; Hagen, S.; Flicker, S.; Valenta, R.; Keller, W. High-resolution crystal structure and IgE recognition of the major grass pollen allergen Phl p 3. Allergy,  2014, 69(12), 1617-1628.
[http://dx.doi.org/10.1111/all.12511] [PMID:  25123586] 
[79] 
Linhart, B.; Focke-Tejkl, M.; Weber, M.; Narayanan, M.; Neubauer, A.; Mayrhofer, H.; Blatt, K.; Lupinek, C.; Valent, P.; Valenta, R. Molecular evolution of hypoallergenic hybrid proteins for vaccination against grass pollen allergy. J. Immunol.,  2015, 194(8), 4008-4018.
[http://dx.doi.org/10.4049/jimmunol.1400402] [PMID:  25786690] 
[80] 
Curin, M.; Weber, M.; Thalhamer, T.; Swoboda, I.; Focke-Tejkl, M.; Blatt, K.; Valent, P.; Marth, K.; Garmatiuk, T.; Grönlund, H.; Thalhamer, J.; Spitzauer, S.; Valenta, R. Hypoallergenic derivatives of Fel d 1 obtained by rational reassembly for allergy vaccination and tolerance induction. Clin. Exp. Allergy,  2014, 44(6), 882-894.
[http://dx.doi.org/10.1111/cea.12294] [PMID:  24552249] 
[81] 
Niederberger, V.; Horak, F.; Vrtala, S.; Spitzauer, S.; Krauth, M.T.; Valent, P.; Reisinger, J.; Pelzmann, M.; Hayek, B.; Kronqvist, M.; Gafvelin, G.; Grönlund, H.; Purohit, A.; Suck, R.; Fiebig, H.; Cromwell, O.; Pauli, G.; van Hage-Hamsten, M.; Valenta, R. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc. Natl. Acad. Sci. USA,  2004, 101(Suppl. 2), 14677-14682.
[http://dx.doi.org/10.1073/pnas.0404735101] [PMID:  15310844] 
[82] 
Purohit, A.; Niederberger, V.; Kronqvist, M.; Horak, F.; Grönneberg, R.; Suck, R.; Weber, B.; Fiebig, H.; van Hage, M.; Pauli, G.; Valenta, R.; Cromwell, O. Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin. Exp. Allergy,  2008, 38(9), 1514-1525.
[http://dx.doi.org/10.1111/j.1365- 2222.2008.03042.x] 
[83] 
Kahlert, H.; Suck, R.; Weber, B.; Nandy, A.; Wald, M.; Keller, W.; Cromwell, O.; Fiebig, H. Characterization of a hypoallergenic recombinant Bet v 1 variant as a candidate for allergen-specific immunotherapy. Int. Arch. Allergy Immunol.,  2008, 145(3), 193-206.
[http://dx.doi.org/10.1159/000109288] [PMID:  17912007] 
[84] 
Meyer, W.; Narkus, A.; Salapatek, A.M.; Häfner, D. Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy,  2013, 68(6), 724-731.
[http://dx.doi.org/10.1111/all.12148] [PMID:  23621350] 
[85] 
Klimek, L.; Bachert, C.; Lukat, K.F.; Pfaar, O.; Meyer, H.; Narkus, A. Allergy immunotherapy with a hypoallergenic recombinant birch pollen allergen rBet v 1-FV in a randomized controlled trial. Clin. Transl. Allergy,  2015, 5, 28.
[http://dx.doi.org/10.1186/s13601-015-0071-x] [PMID:  26328056] 
[86] 
Treudler, R.; Franke, A.; Schmiedeknecht, A.; Ballmer-Weber, B.; Worm, M.; Werfel, T.; Jappe, U.; Biedermann, T.; Schmitt, J.; Brehler, R.; Kleinheinz, A.; Kleine-Tebbe, J.; Brüning, H.; Ruëff, F.; Ring, J.; Saloga, J.; Schäkel, K.; Holzhauser, T.; Vieths, S.; Simon, J.C. BASALIT trial: double-blind placebo-controlled allergen immunotherapy with rBet v 1-FV in birch-related soya allergy. Allergy,  2017, 72(8), 1243-1253.
[http://dx.doi.org/10.1111/all.13112] [PMID:  27998002] 
[87] 
Zuidmeer-Jongejan, L.; Huber, H.; Swoboda, I.; Rigby, N.; Versteeg, S.A.; Jensen, B.M.; Quaak, S.; Akkerdaas, J.H.; Blom, L.; Asturias, J.; Bindslev-Jensen, C.; Bernardi, M.L.; Clausen, M.; Ferrara, R.; Hauer, M.; Heyse, J.; Kopp, S.; Kowalski, M.L.; Lewandowska-Polak, A.; Linhart, B.; Maderegger, B.; Maillere, B.; Mari, A.; Martinez, A.; Mills, E.N.; Neubauer, A.; Nicoletti, C.; Papadopoulos, N.G.; Portoles, A.; Ranta-Panula, V.; Santos-Magadan, S.; Schnoor, H.J.; Sigurdardottir, S.T.; Stahl-Skov, P.; Stavroulakis, G.; Stegfellner, G.; Vázquez-Cortés, S.; Witten, M.; Stolz, F.; Poulsen, L.K.; Fernandez-Rivas, M.; Valenta, R.; van Ree, R. Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy. Int. Arch. Allergy Immunol.,  2015, 166(1), 41-51.
[http://dx.doi.org/10.1159/000371657] [PMID:  25765512] 
[88] 
Freidl, R.; Gstoettner, A.; Baranyi, U.; Swoboda, I.; Stolz, F.; Focke-Tejkl, M.; Wekerle, T.; van Ree, R.; Valenta, R.; Linhart, B. Blocking antibodies induced by immunization with a hypoallergenic parvalbumin mutant reduce allergic symptoms in a mouse model of fish allergy. J. Allergy Clin. Immunol.,  2017, 139(6), 1897-1905.e1.
[http://dx.doi.org/10.1016/j.jaci.2016.10.018] [PMID:  27876628] 
[89] 
Wood, R.A.; Sicherer, S.H.; Burks, A.W.; Grishin, A.; Henning, A.K.; Lindblad, R.; Stablein, D.; Sampson, H.A. A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy. Allergy,  2013, 68(6), 803-808.
[http://dx.doi.org/10.1111/all.12158] [PMID:  23621498] 
[90] 
Valenta, R.; Campana, R.; Niederberger, V. Recombinant allergy vaccines based on allergen-derived B cell epitopes. Immunol. Lett.,  2017, 189, 19-26.
[http://dx.doi.org/10.1016/j.imlet.2017.04.015] [PMID:  28472641] 
[91] 
Focke, M.; Linhart, B.; Hartl, A.; Wiedermann, U.; Sperr, W.R.; Valent, P.; Thalhamer, J.; Kraft, D.; Valenta, R. Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin. Exp. Allergy,  2004, 34(10), 1525-1533.
[http://dx.doi.org/10.1111/j.1365-2222.2004.02081.x] [PMID:  15479266] 
[92] 
Marth, K.; Breyer, I.; Focke-Tejkl, M.; Blatt, K.; Shamji, M.H.; Layhadi, J.; Gieras, A.; Swoboda, I.; Zafred, D.; Keller, W.; Valent, P.; Durham, S.R.; Valenta, R. 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.,  2013, 190(7), 3068-3078.
[http://dx.doi.org/10.4049/jimmunol.1202441] [PMID:  23440415] 
[93] 
Linhart, B.; Narayanan, M.; Focke-Tejkl, M.; Wrba, F.; Vrtala, S.; Valenta, R. Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides lacking allergen-specific T cell epitopes reduces Bet v 1-specific T cell responses via blocking antibodies in a murine model for birch pollen allergy. Clin. Exp. Allergy,  2014, 44(2), 278-287.
[http://dx.doi.org/10.1111/cea.12216] [PMID:  24447086] 
[94] 
Edlmayr, J.; Niespodziana, K.; Linhart, B.; Focke-Tejkl, M.; Westritschnig, K.; Scheiblhofer, S.; Stoecklinger, A.; Kneidinger, M.; Valent, P.; Campana, R.; Thalhamer, J.; Popow-Kraupp, T.; Valenta, R. A combination vaccine for allergy and rhinovirus infections based on rhinovirus-derived surface protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen Phl p 1. J. Immunol.,  2009, 182(10), 6298-6306.
[http://dx.doi.org/10.4049/jimmunol.0713622] [PMID:  19414783] 
[95] 
Focke-Tejkl, M.; Campana, R.; Reininger, R.; Lupinek, C.; Blatt, K.; Valent, P.; Pavkov-Keller, T.; Keller, W.; Valenta, R. Dissection of the IgE and T-cell recognition of the major group 5 grass pollen allergen Phl p 5. J. Allergy Clin. Immunol.,  2014, 133(3), 836-45.e11.
[http://dx.doi.org/10.1016/j.jaci.2013.08.038] [PMID:  24182774] 
[96] 
Focke-Tejkl, M.; Weber, M.; Niespodziana, K.; Neubauer, A.; Huber, H.; Henning, R.; Stegfellner, G.; Maderegger, B.; Hauer, M.; Stolz, F.; Niederberger, V.; Marth, K.; Eckl-Dorna, J.; Weiss, R.; Thalhamer, J.; Blatt, K.; Valent, P.; Valenta, R. Development
and characterization of a recombinant, hypoallergenic, peptidebased
vaccine for grass pollen allergy. J. Allergy Clin. Immunol,  2015, 135(5), 1207-7.e1, 11.
[http://dx.doi.org/10.1016/j.jaci.2014.09.012] [PMID:  25441634] 
[97] 
Narayanan, M.; Freidl, R.; Focke-Tejkl, M.; Baranyi, U.; Wekerle, T.; Valenta, R.; Linhart, B.A. B Cell Epitope Peptide Derived from the Major Grass Pollen Allergen Phl p 1 Boosts Allergen-Specific Secondary Antibody Responses without Allergen-Specific T Cell Help. J. Immunol.,  2017, 198(4), 1685-1695.
[http://dx.doi.org/10.4049/jimmunol.1501741] [PMID:  28093528] 
[98] 
Twaroch, T.E.; Focke, M.; Civaj, V.; Weber, M.; Balic, N.; Mari, A.; Ferrara, R.; Quirce, S.; Spitzauer, S.; Swoboda, I.; Valenta, R. Carrier-bound, nonallergenic Ole e 1 peptides for vaccination against olive pollen allergy. J. Allergy Clin. Immunol.,  2011, 128(1), 178-184.e7.
[http://dx.doi.org/10.1016/j.jaci.2011.03.011] [PMID:  21513971] 
[99] 
Twaroch, T.E.; Focke, M.; Fleischmann, K.; Balic, N.; Lupinek, C.; Blatt, K.; Ferrara, R.; Mari, A.; Ebner, C.; Valent, P.; Spitzauer, S.; Swoboda, I.; Valenta, R. Carrier-bound Alt a 1 peptides without allergenic activity for vaccination against Alternaria alternata allergy. Clin. Exp. Allergy,  2012, 42(6), 966-975.
[http://dx.doi.org/10.1111/j.1365-2222.2012.03996.x] [PMID:  22909168] 
[100] 
Niespodziana, K.; Focke-Tejkl, M.; Linhart, B.; Civaj, V.; Blatt, K.; Valent, P.; van Hage, M.; Grönlund, H.; Valenta, R. A hypoallergenic cat vaccine based on Fel d 1-derived peptides fused to hepatitis B PreS. J. Allergy Clin. Immunol.,  2011, 127(6), 1562-70.e6.
[http://dx.doi.org/10.1016/j.jaci.2011.02.004] [PMID:  21411130] 
[101] 
Chen, K.W.; Focke-Tejkl, M.; Blatt, K.; Kneidinger, M.; Gieras, A.; Dall’Antonia, F.; Faé, I.; Fischer, G.; Keller, W.; Valent, P.; Valenta, R.; Vrtala, S. Carrier-bound nonallergenic Der p 2 peptides induce IgG antibodies blocking allergen-induced basophil activation in allergic patients. Allergy,  2012, 67(5), 609-621.
[http://dx.doi.org/10.1111/j.1398-9995.2012.02794.x] [PMID:  22339348] 
[102] 
Banerjee, S.; Weber, M.; Blatt, K.; Swoboda, I.; Focke-Tejkl, M.; Valent, P.; Valenta, R.; Vrtala, S. Conversion of Der p 23, a new major house dust mite allergen, into a hypoallergenic vaccine. J. Immunol.,  2014, 192(10), 4867-4875.
[http://dx.doi.org/10.4049/jimmunol.1400064] [PMID:  24733847] 
[103] 
Niederberger, V.; Marth, K.; Eckl-Dorna, J.; Focke-Tejkl, M.; Weber, M.; Hemmer, W.; Berger, U.; Neubauer, A.; Stolz, F.; Henning, R.; Valenta, R. Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. J. Allergy Clin. Immunol.,  2015, 136(4), 1101-3.e8.
[http://dx.doi.org/10.1016/j.jaci.2015.03.034] [PMID:  26048664] 
[104] 
Weber, M.; Niespodziana, K.; Linhart, B.; Neubauer, A.; Huber, H.; Henning, R.; Valenta, R.; Focke-Tejkl, M. Comparison of the immunogenicity of BM32, a recombinant hypoallergenic B cell epitope-based grass pollen allergy vaccine with allergen extract-based vaccines. J. Allergy Clin. Immunol.,  2017, 140(5), 1433-1436.e6.
[http://dx.doi.org/10.1016/j.jaci.2017.03.048] [PMID:  28576673] 
[105] 
Zieglmayer, P.; Focke-Tejkl, M.; Schmutz, R.; Lemell, P.; Zieglmayer, R.; Weber, M.; Kiss, R.; Blatt, K.; Valent, P.; Stolz, F.; Huber, H.; Neubauer, A.; Knoll, A.; Horak, F.; Henning, R.; Valenta, R. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine,  2016, 11, 43-57.
[http://dx.doi.org/10.1016/j.ebiom.2016.08.022] [PMID:  27650868] 
[106] 
Niederberger, V.; Neubauer, A.; Gevaert, P.; Zidarn, M.; Worm, M.; Aberer, W.; Malling, H.J.; Pfaar, O.; Klimek, L.; Pfützner, W.; Ring, J.; Darsow, U.; Novak, N.; Gerth van Wijk, R.; Eckl-Dorna, J.; Focke-Tejkl, M.; Weber, M.; Müller, H.H.; Klinger, J.; Stolz, F.; Breit, N.; Henning, R.; Valenta, R. Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32. J. Allergy Clin. Immunol.,  2018, 142(2), 497-509.e9.
[http://dx.doi.org/10.1016/j.jaci.2017.09.052] [PMID:  29361332] 
[107] 
Crameri, R.; Flückiger, S.; Daigle, I.; Kündig, T.; Rhyner, C. Design, engineering and in vitro evaluation of MHC class-II targeting allergy vaccines. Allergy,  2007, 62(2), 197-206.
[http://dx.doi.org/10.1111/j.1398-9995.2006.01292.x] [PMID:  17298430] 
[108] 
Martínez-Gómez, J.M.; Johansen, P.; Rose, H.; Steiner, M.; Senti, G.; Rhyner, C.; Crameri, R.; Kündig, T.M. Targeting the MHC class II pathway of antigen presentation enhances immunogenicity and safety of allergen immunotherapy. Allergy,  2009, 64(1), 172-178.
[http://dx.doi.org/10.1111/j.1398-9995.2008.01812.x] [PMID:  19076537] 
[109] 
Senti, G.; Crameri, R.; Kuster, D.; Johansen, P.; Martinez-Gomez, J.M.; Graf, N.; Steiner, M.; Hothorn, L.A.; Grönlund, H.; Tivig, C.; Zaleska, A.; Soyer, O.; van Hage, M.; Akdis, C.A.; Akdis, M.; Rose, H.; Kündig, T.M. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J. Allergy Clin. Immunol.,  2012, 129(5), 1290-1296.
[http://dx.doi.org/10.1016/j.jaci.2012.02.026] [PMID:  22464647] 
[110] 
Zhu, D.; Kepley, C.L.; Zhang, K.; Terada, T.; Yamada, T.; Saxon, A. A chimeric human-cat fusion protein blocks cat-induced allergy. Nat. Med.,  2005, 11(4), 446-449.
[http://dx.doi.org/10.1038/nm1219] [PMID:  15793580] 
[111] 
Terada, T.; Zhang, K.; Belperio, J.; Londhe, V.; Saxon, A. A chimeric human-cat Fcgamma-Fel d1 fusion protein inhibits systemic, pulmonary, and cutaneous allergic reactivity to intratracheal challenge in mice sensitized to Fel d1, the major cat allergen. Clin. Immunol.,  2006, 120(1), 45-56.
[http://dx.doi.org/10.1016/j.clim.2005.12.010] [PMID:  16473552] 
[112] 
Zhang, K.; Zhu, D.; Kepley, C.; Terada, T.; Saxon, A. Chimeric human fcgamma-allergen fusion proteins in the prevention of allergy. Immunol. Allergy Clin. North Am.,  2007, 27(1), 93-103.
[http://dx.doi.org/10.1016/j.iac.2006.11.002] [PMID:  17276881] 
[113] 
Lin, L.H.; Zheng, P.; Yuen, J.W.; Wang, J.; Zhou, J.; Kong, C.Q.; Peng, X.; Li, J.; Li, L. Prevention and treatment of allergic inflammation by an Fcγ-Der f2 fusion protein in a murine model of dust mite-induced asthma. Immunol. Res.,  2012, 52(3), 276-283.
[http://dx.doi.org/10.1007/s12026-012-8339-x] [PMID:  22539132] 
[114] 
Liu, Y.; Sun, Y.; Chang, L.J.; Li, N.; Li, H.; Yu, Y.; Bryce, P.J.; Grammer, L.C.; Schleimer, R.P.; Zhu, D. Blockade of peanut allergy
with a novel Ara h 2-Fcγ fusion protein in mice. J. Allergy
Clin. Immunol,  2013, 131(1), 213-21.e1, 5.
[http://dx.doi.org/10.1016/j.jaci.2012.10.018] [PMID:  23199607] 
[115] 
Gunawardana, N.C.; Durham, S.R. New approaches to allergen immunotherapy. Ann. Allergy Asthma Immunol.,  2018, 121(3), 293-305.
[http://dx.doi.org/10.1016/j.anai.2018.07.014] [PMID:  30025907] 
[116] 
Toussi, D.N.; Massari, P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel),  2014, 2(2), 323-353.
[http://dx.doi.org/10.3390/vaccines2020323] [PMID:  26344622] 
[117] 
Rosewich, M.; Lee, D.; Zielen, S. Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis. Hum. Vaccin. Immunother.,  2013, 9(7), 1523-1531.
[http://dx.doi.org/10.4161/hv.24631] [PMID:  23584250] 
[118] 
Schülke, S.; Waibler, Z.; Mende, M.S.; Zoccatelli, G.; Vieths, S.; Toda, M.; Scheurer, S. Fusion protein of TLR5-ligand and allergen potentiates activation and IL-10 secretion in murine myeloid DC. Mol. Immunol.,  2010, 48(1-3), 341-350.
[http://dx.doi.org/10.1016/j.molimm.2010.07.006] [PMID:  20965571] 
[119] 
Schülke, S.; Burggraf, M.; Waibler, Z.; Wangorsch, A.; Wolfheimer, S.; Kalinke, U.; Vieths, S.; Toda, M.; Scheurer, S. A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy. J. Allergy Clin. Immunol.,  2011, 128(6), 1340-1348.e12.
[http://dx.doi.org/10.1016/j.jaci.2011.07.036] [PMID:  21872305] 
[120] 
Schülke, S.; Kuttich, K.; Wolfheimer, S.; Duschek, N.; Wangorsch, A.; Reuter, A.; Briza, P.; Pablos, I.; Gadermaier, G.; Ferreira, F.; Vieths, S.; Toda, M.; Scheurer, S. Conjugation of wildtype and hypoallergenic mugwort allergen Art v 1 to flagellin induces IL-10-DC and suppresses allergen-specific TH2-responses in vivo. Sci. Rep.,  2017, 7(1), 11782.
[http://dx.doi.org/10.1038/s41598-017-11972-w] [PMID:  28924222] 
[121] 
Kitzmüller, C.; Kalser, J.; Mutschlechner, S.; Hauser, M.; Zlabinger, G.J.; Ferreira, F.; Bohle, B. Fusion proteins of flagellin and the major birch pollen allergen Bet v 1 show enhanced immunogenicity, reduced allergenicity, and intrinsic adjuvanticity. J. Allergy Clin. Immunol.,  2018, 141(1), 293-299.e6.
[http://dx.doi.org/10.1016/j.jaci.2017.02.044] [PMID:  28456624] 
[122] 
Marshall, J.D.; Abtahi, S.; Eiden, J.J.; Tuck, S.; Milley, R.; Haycock, F.; Reid, M.J.; Kagey-Sobotka, A.; Creticos, P.S.; Lichtenstein, L.M.; Van Nest, G. Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes T(H)1 cytokine expression while downregulating T(H)2 cytokine expression in PBMCs from human patients with ragweed allergy. J. Allergy Clin. Immunol.,  2001, 108(2), 191-197.
[http://dx.doi.org/10.1067/mai.2001.116984] [PMID:  11496233] 
[123] 
Creticos, P.S.; Schroeder, J.T.; Hamilton, R.G.; Balcer-Whaley, S.L.; Khattignavong, A.P.; Lindblad, R.; Li, H.; Coffman, R.; Seyfert, V.; Eiden, J.J.; Broide, D. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med.,  2006, 355(14), 1445-1455.
[http://dx.doi.org/10.1056/NEJMoa052916] [PMID:  17021320] 
[124] 
Krishnaswamy, J.K.; Jirmo, A.C.; Baru, A.M.; Ebensen, T.; Guzmán, C.A.; Sparwasser, T.; Behrens, G.M. Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia. Am. J. Respir. Cell Mol. Biol.,  2012, 47(6), 852-863.
[http://dx.doi.org/10.1165/rcmb.2011-0414OC] [PMID:  22962064] 
[125] 
Schülke, S.; Vogel, L.; Junker, A.C.; Hanschmann, K.M.; Flaczyk, A.; Vieths, S.; Scheurer, S. A Fusion Protein Consisting of the Vaccine Adjuvant Monophosphoryl Lipid A and the Allergen Ovalbumin Boosts Allergen-Specific Th1, Th2, and Th17 Responses In Vitro. J. Immunol. Res., 2016. 20164156456
[http://dx.doi.org/10.1155/2016/4156456] [PMID:  27340679] 
[126] 
Filì, L.; Vultaggio, A.; Cardilicchia, E.; Manuelli, C.; Casini, A.; Nencini, F.; Maggi, L.; Pratesi, S.; Petroni, G.; Boscaro, F.; Guarna, A.; Occhiato, E.G.; Romagnani, S.; Maggi, E.; Parronchi, P. A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy. J. Allergy Clin. Immunol.,  2013, 132(1), 84-92.
[http://dx.doi.org/10.1016/j.jaci.2013.01.030] [PMID:  23498597] 
[127] 
Nencini, F.; Pratesi, S.; Petroni, G.; Filì, L.; Cardilicchia, E.; Casini, A.; Occhiato, E.G.; Calosi, L.; Bani, D.; Romagnani, S.; Maggi, E.; Parronchi, P.; Vultaggio, A. Treatment with 8-OH-modified adenine (TLR7 ligand)-allergen conjugates decreases T helper type 2-oriented murine airway inflammation. Immunology,  2015, 145(4), 570-582.
[http://dx.doi.org/10.1111/imm.12475] [PMID:  25930741] 
[128] 
Jutel, M.; Rudert, M.; Kreimendahl, F.; Kuna, P. Efficacy and tolerability of a house dust mite allergoid in allergic bronchial asthma: a randomized dose-ranging trial. Immunotherapy,  2018, 10(13), 1149-1161.
[http://dx.doi.org/10.2217/imt-2018-0087] [PMID:  30089430] 
[129] 
Pfaar, O.; Hohlfeld, J.M.; Al-Kadah, B.; Hauswald, B.; Homey, B.; Hunzelmann, N.; Schliemann, S.; Velling, P.; Worm, M.; Klimek, L. Dose-response relationship of a new Timothy grass pollen allergoid in comparison with a 6-grass pollen allergoid. Clin. Exp. Allergy,  2017, 47(11), 1445-1455.
[http://dx.doi.org/10.1111/cea.12977] [PMID:  28696503] 
[130] 
Morales, M.; Gallego, M.T.; Iraola, V.; Moya, R.; Santana, S.; Carnés, J. Preclinical safety and immunological efficacy of Alternaria alternata polymerized extracts. Immun. Inflamm. Dis.,  2018, 6(2), 234-244.
[http://dx.doi.org/10.1002/iid3.212] [PMID:  29265735] 
[131] 
Dhami, S.; Nurmatov, U.; Arasi, S.; Khan, T.; Asaria, M.; Zaman, H.; Agarwal, A.; Netuveli, G.; Roberts, G.; Pfaar, O.; Muraro, A.; Ansotegui, I.J.; Calderon, M.; Cingi, C.; Durham, S.; van Wijk, R.G.; Halken, S.; Hamelmann, E.; Hellings, P.; Jacobsen, L.; Knol, E.; Larenas-Linnemann, D.; Lin, S.; Maggina, P.; Mösges, R.; Oude Elberink, H.; Pajno, G.; Panwankar, R.; Pastorello, E.; Penagos, M.; Pitsios, C.; Rotiroti, G.; Timmermans, F.; Tsilochristou, O.; Varga, E.M.; Schmidt-Weber, C.; Wilkinson, J.; Williams, A.; Worm, M.; Zhang, L.; Sheikh, A. Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis. Allergy,  2017, 72(11), 1597-1631.
[http://dx.doi.org/10.1111/all.13201] [PMID:  28493631] 
[132] 
Roberts, G.; Pfaar, O.; Akdis, C.A.; Ansotegui, I.J.; Durham, S.R.; Gerth van Wijk, R.; Halken, S.; Larenas-Linnemann, D.; Pawankar, R.; Pitsios, C.; Sheikh, A.; Worm, M.; Arasi, S.; Calderon, M.A.; Cingi, C.; Dhami, S.; Fauquert, J.L.; Hamelmann, E.; Hellings, P.; Jacobsen, L.; Knol, E.F.; Lin, S.Y.; Maggina, P.; Mösges, R.; Oude Elberink, J.N.G.; Pajno, G.B.; Pastorello, E.A.; Penagos, M.; Rotiroti, G.; Schmidt-Weber, C.B.; Timmermans, F.; Tsilochristou, O.; Varga, E.M.; Wilkinson, J.N.; Williams, A.; Zhang, L.; Agache, I.; Angier, E.; Fernandez-Rivas, M.; Jutel, M.; Lau, S.; van Ree, R.; Ryan, D.; Sturm, G.J.; Muraro, A. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy,  2018, 73(4), 765-798.
[http://dx.doi.org/10.1111/all.13317] [PMID:  28940458] 
[133] 
Sirvent, S.; Soria, I.; Cirauqui, C.; Cases, B.; Manzano, A.I.; Diez-Rivero, C.M.; Reche, P.A.; López-Relaño, J.; Martínez-Naves, E.; Cañada, F.J.; Jiménez-Barbero, J.; Subiza, J.; Casanovas, M.; Fernández-Caldas, E.; Subiza, J.L.; Palomares, O. Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. J. Allergy Clin. Immunol.,  2016, 138(2), 558-567.e11.
[http://dx.doi.org/10.1016/j.jaci.2016.02.029] [PMID:  27177779] 
[134] 
Riiser, A. The human microbiome, asthma, and allergy. Allergy Asthma Clin. Immunol.,  2015, 11, 35.
[http://dx.doi.org/10.1186/s13223-015-0102-0] [PMID:  26664362] 
[135] 
McCoy, K.D.; Ignacio, A.; Geuking, M.B. Microbiota and Type 2 immune responses. Curr. Opin. Immunol.,  2018, 54, 20-27.
[http://dx.doi.org/10.1016/j.coi.2018.05.009] [PMID:  29864675] 
[136] 
Gollwitzer, E.S.; Saglani, S.; Trompette, A.; Yadava, K.; Sherburn, R.; McCoy, K.D.; Nicod, L.P.; Lloyd, C.M.; Marsland, B.J. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med.,  2014, 20(6), 642-647.
[http://dx.doi.org/10.1038/nm.3568] [PMID:  24813249] 
[137] 
Fujimura, K.E.; Sitarik, A.R.; Havstad, S.; Lin, D.L.; Levan, S.; Fadrosh, D.; Panzer, A.R.; LaMere, B.; Rackaityte, E.; Lukacs, N.W.; Wegienka, G.; Boushey, H.A.; Ownby, D.R.; Zoratti, E.M.; Levin, A.M.; Johnson, C.C.; Lynch, S.V. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med.,  2016, 22(10), 1187-1191.
[http://dx.doi.org/10.1038/nm.4176] [PMID:  27618652] 
[138] 
de Roock, S.; van Elk, M.; van Dijk, M.E.A.; Timmerman, H.M.; Rijkers, G.T.; Prakken, B.J.; Hoekstra, M.O.; de Kleer, I.M. Lactic acid bacteria differ in their ability to induce functional regulatory T cells in humans. Clin. Exp. Allergy,  2010, 40(1), 103-110.
[PMID:  19817754] 
[139] 
de Azevedo, M.S.; Innocentin, S.; Dorella, F.A.; Rocha, C.S.; Mariat, D.; Pontes, D.S.; Miyoshi, A.; Azevedo, V.; Langella, P.; Chatel, J.M. Immunotherapy of allergic diseases using probiotics or recombinant probiotics. J. Appl. Microbiol.,  2013, 115(2), 319-333.
[http://dx.doi.org/10.1111/jam.12174] [PMID:  23437848] 
[140] 
Rigaux, P.; Daniel, C.; Hisbergues, M.; Muraille, E.; Hols, P.; Pot, B.; Pestel, J.; Jacquet, A. Immunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergy. Allergy,  2009, 64(3), 406-414.
[http://dx.doi.org/10.1111/j.1398-9995.2008.01825.x] [PMID:  19120072] 
[141] 
Kruisselbrink, A.; Heijne Den Bak-Glashouwer, M.J.; Havenith, C.E.; Thole, J.E.; Janssen, R. Recombinant Lactobacillus plantarum inhibits house dust mite-specific T-cell responses. Clin. Exp. Immunol.,  2001, 126(1), 2-8.
[http://dx.doi.org/10.1046/j.1365-2249.2001.01642.x] [PMID:  11678893] 
[142] 
Ai, C.; Zhang, Q.; Ding, J.; Wang, G.; Liu, X.; Tian, F.; Zhao, J.; Zhang, H.; Chen, W. Mucosal delivery of allergen peptides expressed by Lactococcus lactis inhibit allergic responses in a BALB/c mouse model. Appl. Microbiol. Biotechnol.,  2016, 100(4), 1915-1924.
[http://dx.doi.org/10.1007/s00253-015-7187-8] [PMID:  26621801] 
[143] 
Ai, C.; Zhang, Q.; Ding, J.; Ren, C.; Wang, G.; Liu, X.; Tian, F.; Zhao, J.; Zhang, H.; Chen, Y.Q.; Chen, W. Suppression of dust mite allergy by mucosal delivery of a hypoallergenic derivative in a mouse model. Appl. Microbiol. Biotechnol.,  2015, 99(10), 4309-4319.
[http://dx.doi.org/10.1007/s00253-015-6407-6] [PMID:  25661808] 
[144] 
Ai, C.; Zhang, Q.; Ren, C.; Wang, G.; Liu, X.; Tian, F.; Zhao, J.; Zhang, H.; Chen, Y.Q.; Chen, W. Genetically engineered Lactococcus lactis protect against house dust mite allergy in a BALB/c mouse model. PLoS One,  2014, 9(10)e109461
[http://dx.doi.org/10.1371/journal.pone.0109461] [PMID:  25290938] 
[145] 
Charng, Y.C.; Lin, C.C.; Hsu, C.H. Inhibition of allergen-induced airway inflammation and hyperreactivity by recombinant lactic-acid bacteria. Vaccine,  2006, 24(33-34), 5931-5936.
[http://dx.doi.org/10.1016/j.vaccine.2005.07.107] [PMID:  16814902] 
[146] 
Hazebrouck, S.; Oozeer, R.; Adel-Patient, K.; Langella, P.; Rabot, S.; Wal, J.M.; Corthier, G. Constitutive delivery of bovine beta-lactoglobulin to the digestive tracts of gnotobiotic mice by engineered Lactobacillus casei. Appl. Environ. Microbiol.,  2006, 72(12), 7460-7467.
[http://dx.doi.org/10.1128/AEM.01032-06] [PMID:  16997983] 
[147] 
Cortes-Perez, N.G.; Ah-Leung, S.; Bermúdez-Humarán, L.G.; Corthier, G.; Langella, P.; Wal, J.M.; Adel-Patient, K. Allergy therapy by intranasal administration with recombinant Lactococcus lactis Producing bovine beta-lactoglobulin. Int. Arch. Allergy Immunol.,  2009, 150(1), 25-31.
[http://dx.doi.org/10.1159/000210377] [PMID:  19339799] 
[148] 
Adel-Patient, K.; Ah-Leung, S.; Creminon, C.; Nouaille, S.; Chatel, J.M.; Langella, P.; Wal, J.M. Oral administration of recombinant Lactococcus lactis expressing bovine beta-lactoglobulin partially prevents mice from sensitization. Clin. Exp. Allergy,  2005, 35(4), 539-546.
[http://dx.doi.org/10.1111/j.1365-2222.2005.02225.x] [PMID:  15836765] 
[149] 
Huibregtse, I.L.; Snoeck, V.; de Creus, A.; Braat, H.; De Jong, E.C.; Van Deventer, S.J.; Rottiers, P. Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology,  2007, 133(2), 517-528.
[http://dx.doi.org/10.1053/j.gastro.2007.04.073] [PMID:  17681173] 
[150] 
Ren, C.; Zhang, Q.; Wang, G.; Ai, C.; Hu, M.; Liu, X.; Tian, F.; Zhao, J.; Chen, Y.; Wang, M.; Zhang, H.; Chen, W. Modulation of peanut-induced allergic immune responses by oral lactic acid bacteria-based vaccines in mice. Appl. Microbiol. Biotechnol.,  2014, 98(14), 6353-6364.
[http://dx.doi.org/10.1007/s00253-014-5678-7] [PMID:  24770368] 
[151] 
Ghasemi, Z.; Varasteh, A.R.; Moghadam, M.; Jalali, S.A.; Anissian, A.; Sankian, M. Sublingual Immunotherapy with Sal k1 Expressing Lactococcus lactis Down-regulates Th2 Immune Responses in Balb/c Mice. Iran. J. Allergy Asthma Immunol.,  2018, 17(3), 281-290.
[PMID:  29908546] 
[152] 
Minic, R.; Gavrovic-Jankulovic, M.; Petrusic, V.; Zivkovic, I.; Eijsink, V.G.; Dimitrijevic, L.; Mathiesen, G. Effects of orally applied Fes p1-displaying L. plantarum WCFS1 on Fes p1 induced allergy in mice. J. Biotechnol.,  2015, 199, 23-28.
[http://dx.doi.org/10.1016/j.jbiotec.2015.01.028] [PMID:  25687100] 
[153] 
Ohkouchi, K.; Kawamoto, S.; Tatsugawa, K.; Yoshikawa, N.; Takaoka, Y.; Miyauchi, S.; Aki, T.; Yamashita, M.; Murooka, Y.; Ono, K. Prophylactic effect of Lactobacillus oral vaccine expressing a Japanese cedar pollen allergen. J. Biosci. Bioeng.,  2012, 113(4), 536-541.
[http://dx.doi.org/10.1016/j.jbiosc.2011.11.025] [PMID:  22196937] 
[154] 
Schwarzer, M.; Repa, A.; Daniel, C.; Schabussova, I.; Hrncir, T.; Pot, B.; Stepankova, R.; Hudcovic, T.; Pollak, A.; Tlaskalova-Hogenova, H.; Wiedermann, U.; Kozakova, H. Neonatal colonization of mice with Lactobacillus plantarum producing the aeroallergen Bet v 1 biases towards Th1 and T-regulatory responses upon systemic sensitization. Allergy,  2011, 66(3), 368-375.
[http://dx.doi.org/10.1111/j.1398-9995.2010.02488.x] [PMID:  20880132] 
[155] 
Daniel, C.; Repa, A.; Wild, C.; Pollak, A.; Pot, B.; Breiteneder, H.; Wiedermann, U.; Mercenier, A. Modulation of allergic immune responses by mucosal application of recombinant lactic acid bacteria producing the major birch pollen allergen Bet v 1. Allergy,  2006, 61(7), 812-819.
[http://dx.doi.org/10.1111/j.1398-9995.2006.01071.x] [PMID:  16792578] 
[156] 
Boulos, S.; Yan, A.C. Current concepts in the prevention of atopic dermatitis. Clin. Dermatol.,  2018, 36(5), 668-671.
[http://dx.doi.org/10.1016/j.clindermatol.2017.03.004] [PMID:  30217281] 
[157] 
Tang, M.L.; Ponsonby, A.L.; Orsini, F.; Tey, D.; Robinson, M.; Su, E.L.; Licciardi, P.; Burks, W.; Donath, S. Administration of a probiotic with peanut oral immunotherapy: A randomized trial. J. Allergy Clin. Immunol.,  2015, 135(3), 737-44.e8.
[http://dx.doi.org/10.1016/j.jaci.2014.11.034] [PMID:  25592987] 
[158] 
Schirmbeck, R.; Melber, K.; Mertens, T.; Reimann, J. Selective stimulation of murine cytotoxic T cell and antibody responses by particulate or monomeric hepatitis B virus surface (S) antigen. Eur. J. Immunol.,  1994, 24(5), 1088-1096.
[http://dx.doi.org/10.1002/eji.1830240512] [PMID:  8181520] 
[159] 
Bachmann, M.F.; Jennings, G.T.; Zahirović, A.; Lunder, M. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol.,  2010, 10(11), 787-796.
[http://dx.doi.org/10.1038/nri2868] [PMID:  20948547] 
[160] 
Kündig, T.M.; Senti, G.; Schnetzler, G.; Wolf, C.; Prinz Vavricka, B.M.; Fulurija, A.; Hennecke, F.; Sladko, K.; Jennings, G.T.; Bachmann, M.F. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J. Allergy Clin. Immunol.,  2006, 117(6), 1470-1476.
[http://dx.doi.org/10.1016/j.jaci.2006.01.040] [PMID:  16751015] 
[161] 
Schmitz, N.; Dietmeier, K.; Bauer, M.; Maudrich, M.; Utzinger, S.; Muntwiler, S.; Saudan, P.; Bachmann, M.F. Displaying Fel d1 on virus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: a novel therapy for cat allergy. J. Exp. Med.,  2009, 206(9), 1941-1955.
[http://dx.doi.org/10.1084/jem.20090199] [PMID:  19667059] 
[162] 
Engeroff, P.; Caviezel, F.; Storni, F.; Thoms, F.; Vogel, M.; Bachmann, M.F. Allergens displayed on virus-like particles are highly immunogenic but fail to activate human mast cells. Allergy,  2018, 73(2), 341-349.
[http://dx.doi.org/10.1111/all.13268] [PMID:  28787769] 
[163] 
Manzano-Szalai, K.; Thell, K.; Willensdorfer, A.; Weghofer, M.; Pfanzagl, B.; Singer, J.; Ritter, M.; Stremnitzer, C.; Flaschberger, I.; Michaelis, U.; Jensen-Jarolim, E. Adeno-associated virus-like particles as new carriers for B-cell vaccines: testing immunogenicity and safety in BALB/c mice. Viral Immunol.,  2014, 27(9), 438-448.
[http://dx.doi.org/10.1089/vim.2014.0059] [PMID:  25247267] 
[164] 
Kratzer, B.; Köhler, C.; Hofer, S.; Smole, U.; Trapin, D.; Iturri, J.; Pum, D.; Kienzl, P.; Elbe-Bürger, A.; Gattinger, P.; Mittermann, I.; Linhart, B.; Gadermaier, G.; Jahn-Schmid, B.; Neunkirchner, A.; Valenta, R.; Pickl, W.F. Prevention of allergy by virus-like nanoparticles (VNP) delivering shielded versions of major allergens in a humanized murine allergy model. Allergy,  2019, 74(2), 246-260.
[http://dx.doi.org/10.1111/all.13573] [PMID:  30035810] 
[165] 
Moldaver, D.M.; Bharhani, M.S.; Rudulier, C.D.; Wattie, J.; Inman, M.D.; Larché, M. Induction of bystander tolerance and immune
deviation after Fel d 1 peptide immunotherapy. J. Allergy
Clin. Immunol,  2018, 143(3), 1087-1099e4.
[166] 
Senti, G.; Kündig, T.M. Novel Delivery Routes for Allergy Immunotherapy: Intralymphatic, Epicutaneous, and Intradermal. Immunol. Allergy Clin. North Am.,  2016, 36(1), 25-37.
[http://dx.doi.org/10.1016/j.iac.2015.08.006] [PMID:  26617225] 
[167] 
Westman, M.; Asarnoj, A.; Hamsten, C.; Wickman, M.; van Hage, M. Windows of opportunity for tolerance induction for allergy by studying the evolution of allergic sensitization in birth cohorts. Semin. Immunol.,  2017, 30, 61-66.
[http://dx.doi.org/10.1016/j.smim.2017.07.005] [PMID:  28789818] 
[168] 
Posa, D.; Perna, S.; Resch, Y.; Lupinek, C.; Panetta, V.; Hofmaier, S.; Rohrbach, A.; Hatzler, L.; Grabenhenrich, L.; Tsilochristou, O.; Chen, K.W.; Bauer, C.P.; Hoffman, U.; Forster, J.; Zepp, F.; Schuster, A.; Wahn, U.; Keil, T.; Lau, S.; Vrtala, S.; Valenta, R.; Matricardi, P.M. Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life. J. Allergy Clin. Immunol.,  2017, 139(2), 541-549.e8.
[http://dx.doi.org/10.1016/j.jaci.2016.08.014] [PMID:  27793411] 
[169] 
Tham, E.H.; Lee, A.J.; Bever, H.V. Aeroallergen sensitization and allergic disease phenotypes in Asia. Asian Pac. J. Allergy Immunol.,  2016, 34(3), 181-189.
[PMID:  27543739] 
[170] 
Shafique, R.H.; Klimov, P.B.; Inam, M.; Chaudhary, F.R. OConnor, B.M. Group 1 Allergen Genes in Two Species of House Dust Mites, Dermatophagoides farinae and D. pteronyssinus (Acari: Pyroglyphidae): Direct Sequencing, Characterization and Polymorphism. PLoS One,  2014, 9(12)e114636
[http://dx.doi.org/10.1371/journal.pone.0114636] [PMID:  25494056] 
[171] 
Piboonpocanun, S.; Malainual, N.; Jirapongsananuruk, O.; Vichyanond, P.; Thomas, W.R. Genetic polymorphisms of major house dust mite allergens. Clin. Exp. Allergy,  2006, 36(4), 510-516.
[http://dx.doi.org/10.1111/j.1365-2222.2006.02464.x] [PMID:  16630157] 
Cite As
Current Protein & Peptide Science

Perspectives in Allergen-Specific Immunotherapy: Molecular Evolution of Peptide- and Protein-Based Strategies

Abstract

Graphical Abstract
