Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy Petra Zieglmayer, Margarete Focke-Tejkl, Ren´e Schmutz, Patrick Lemell, Ren´e Zieglmayer, Milena Weber, Renata Kiss, Katharina Blatt, Peter Valent, Frank Stolz, Hans Huber, Angela Neubauer, Anette Knoll, Friedrich Horak, Rainer Henning, Rudolf Valenta PII: DOI: Reference:
S2352-3964(16)30371-1 doi: 10.1016/j.ebiom.2016.08.022 EBIOM 744
To appear in:
EBioMedicine
Received date: Revised date: Accepted date:
31 July 2016 13 August 2016 15 August 2016
Please cite this article as: Zieglmayer, Petra, Focke-Tejkl, Margarete, Schmutz, Ren´e, Lemell, Patrick, Zieglmayer, Ren´e, Weber, Milena, Kiss, Renata, Blatt, Katharina, Valent, Peter, Stolz, Frank, Huber, Hans, Neubauer, Angela, Knoll, Anette, Horak, Friedrich, Henning, Rainer, Valenta, Rudolf, Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy, EBioMedicine (2016), doi: 10.1016/j.ebiom.2016.08.022
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ACCEPTED MANUSCRIPT Zieglmayer et al.,
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Mechanisms, safety and efficacy of a B cell epitope-based
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vaccine for immunotherapy of grass pollen allergy
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Petra Zieglmayera, Margarete Focke-Tejklb, René Schmutza, Patrick Lemella, René Zieglmayera, Milena Weberb, Renata Kissb, Katharina Blattc, Peter Valentc, Frank Stolzd, Hans Huberd, Angela Neubauerd, Anette Knolle, Friedrich Horaka, Rainer
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Henningd, Rudolf Valentab,*.
Vienna Challenge Chamber, Vienna, Austria
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Division of Immunopathology, Department of Pathophysiology and Allergy
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Research, Center for Pathophysiology, Infectiology and Immunology, Medical
c
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University of Vienna, Vienna, Austria Department of Internal Medicine I, Division of Hematology & Hemostaseology,
Medical University of Vienna, Vienna, Austria d
BIOMAY AG, Vienna, Austria
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SynteractHCR, Munich, Germany.
*Corresponding author at: Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. Email:
[email protected] (R. Valenta)
ACCEPTED MANUSCRIPT Zieglmayer et al.,
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Key words: vaccine, grass pollen, B cell- epitope, challenge chamber,
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immunotherapy
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Highlights:
BM32 is a recombinant allergy vaccine consisting of the preS domain of the
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large envelope protein of hepatitis B virus (HBV) and grass pollen allergen-derived peptides
Vaccination of allergic patients with BM32 is well tolerated and protects
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against allergic symptoms induced by grass pollen exposure in a challenge chamber
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by induction of allergen-specific IgG antibodies without boosting of allergic immune
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allergy
BM32 may be useful as therapeutic and prophylactic vaccine for grass pollen
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responses
Research in context Allergen-specific immunotherapy (AIT) is the only treatment for allergy which prevents the progression of disease to severe manifestations and has long-lasting effects even after discontinuation. However, current forms of AIT based on natural allergen extracts, induce side effects, require multiple administrations, inconvenient up-dosing protocols and thus patients compliance is poor. Our study is the first to investigate the effects of vaccination with a B cell epitope-based recombinant allergy vaccine in patients who were exposed to grass pollen in a pollen chamber. The vaccine contains recombinant fusion proteins consisting of allergen-derived peptides
ACCEPTED MANUSCRIPT Zieglmayer et al.,
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bound to a hepatitis B virus surface antigen as immunological carrier. It is demonstrated that three injections of the recombinant B cell epitope-based allergy
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vaccine are well tolerated and protect allergic patients against allergic symptoms by
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induction of allergen-specific IgG antibody responses without inducing allergic
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sensitization. Thus recombinant hypoallergenic B cell epitope-based vaccines have potential to improve safety and convenience of AIT when used as therapeutic vaccine and, due to low allergenicity, may be used even for prophylactic allergy
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vaccination.
ACCEPTED MANUSCRIPT Zieglmayer et al.,
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ABSTRACT Background: We have developed a recombinant B cell epitope-based vaccine
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(BM32) for allergen-specific immunotherapy (AIT) of grass pollen allergy. The
IP
vaccine contains recombinant fusion proteins consisting of allergen-derived peptides
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and the hepatitis B surface protein domain preS as immunological carrier. Methods: We conducted a randomized, double-blind, placebo-controlled AIT study to
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determine safety, clinical efficacy and immunological mechanism of three subcutaneous injections of three BM32 doses adsorbed to aluminum hydroxide
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versus aluminum hydroxide (placebo) applied monthly to grass pollen allergic patients (n=70). Primary efficacy endpoint was the difference in total nasal symptom
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score (TNSS) through grass pollen chamber exposure before treatment and 4 weeks
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after the last injection. Secondary clinical endpoints were total ocular symptom score
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(TOSS) and allergen-specific skin response evaluated by titrated skin prick testing (SPT) at the same time points. Treatment-related side effects were evaluated as safety endpoints. Changes in allergen-specific antibody, cellular and cytokine
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responses were measured in patients before and after treatment. Results: Sixty-eight patients completed the trial. TNSS significantly decreased with mean changes of -1.41 (BM32/20µg) (P=0.03) and -1.34 (BM32/40µg) (P=0.003) whereas mean changes in the BM32/10µg and placebo group were not significant. TOSS and SPT reactions showed a dose-dependent decrease. No systemic immediate type side effects were observed. Only few grade 1 systemic late phase reactions occurred in BM32 treated patients. The number of local injection site reactions was similar in actively and placebo-treated patients. BM32 induced highly significant allergen-specific IgG responses (P
