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Analysis of Epitope-Specific Immune Responses Induced by Vaccination with Structurally Folded and Unfolded Recombinant Bet v 1 Allergen Derivatives in Man¹

Ines Pree^*, Jürgen Reisinger^*, Margit Focke, Susanne Vrtala, Gabrielle Pauli, Marianne van Hage, Oliver Cromwell^¶, Elisabeth Gadermaier, Cornelia Egger^||, Norbert Reider^||, Friedrich Horak^*, Rudolf Valenta^2, and Verena Niederberger^*

^* Department of Otolaryngology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; Service de Pneumologie, Hôpitaux Universitaires de Strasbourg, France; Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet and University Hospital, Stockholm, Sweden; ^¶ Allergopharma Joachim Ganzer KG, Reinbek, Germany; and ^|| Clinical Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria

Previously, we have constructed recombinant derivatives of the major birch pollen allergen, Bet v 1, with a more than 100-fold reduced ability to induce IgE-mediated allergic reactions. These derivatives differed from each other because the two recombinant Bet v 1 fragments represented unfolded molecules whereas the recombinant trimer resembled most of the structural fold of the Bet v 1 allergen. In this study, we analyzed the Ab (IgE, IgG subclass, IgA, IgM) response to Bet v 1, recombinant and synthetic Bet v 1-derived peptides in birch pollen allergic patients who had been vaccinated with the derivatives or adjuvant alone. Furthermore, we studied the induction of IgE-mediated skin responses in these patients using Bet v 1 and Bet v 1 fragments. Both types of vaccines induced a comparable IgG1 and IgG4 response against new sequential epitopes which overlap with the conformational IgE epitopes of Bet v 1. This response was 4- to 5-fold higher than that induced by immunotherapy with birch pollen extract. Trimer more than fragments induced also IgE responses against new epitopes and a transient increase in skin sensitivity to the fragments at the beginning of therapy. However, skin reactions to Bet v 1 tended to decrease one year after treatment in both actively treated groups. We demonstrate that vaccination with folded and unfolded recombinant allergen derivatives induces IgG Abs against new epitopes. These data may be important for the development of therapeutic as well as prophylactic vaccines based on recombinant allergens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants F 1803, F 1815, F 1818, and L214 - B13 of the Austrian Science Fund (FWF), by the Christian Doppler Research Association, by the Swedish Research Council and the Swedish Asthma and Allergy Research Foundation.

² Address correspondence and reprint requests to Dr. Rudolf Valenta, Christian Doppler Laboratory for Allergy Research, Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Vienna General Hospital, Allegemeines Krankenhaus, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria. E-mail address: rudolf.valenta{at}meduniwien.ac.at