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      Safety and efficacy of immunotherapy with the recombinant B-cell epitope–based grass pollen vaccine BM32

      , MD a , , PhD b , , MD c , , MD d , , MD e , , MD f , , MD g , , MD h , i , , MD h , , MD j , , MD k , , MD k , , MD l , , MD m , , MD, PhD a , , PhD n , , MSc n , , PhD o , , PhD p , , PhD b , , MSc b , , PhD b , , MD n , q

      The Journal of allergy and clinical immunology

      Allergy, grass pollen allergy, allergen, allergen immunotherapy, recombinant allergen, B-cell epitope–based immunotherapy, efficacy, hypoallergenic, clinical trial, safety

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          Abstract

          Background

          BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein.

          Objective

          We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen–induced rhinitis and controlled asthma.

          Methods

          A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 μg, n = 60) or high dose (160 μg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC.

          Results

          Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year.

          Conclusions

          Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

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          Most cited references 39

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          Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches.

          T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+ T cells secretes cytokines usually associated with inflammation, such as IFN-gamma and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.
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            Long-term clinical efficacy of grass-pollen immunotherapy.

            Pollen immunotherapy is effective in selected patients with IgE-mediated seasonal allergic rhinitis, although it is questionable whether there is long-term benefit after the discontinuation of treatment. We conducted a randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. Cutaneous-biopsy specimens obtained 24 hours after intradermal allergen challenge were examined for T-cell infiltration and the presence of cytokine-producing T helper cells (TH2 cells) (as evidenced by the presence of interleukin-4 messenger RNA). A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease. Scores for seasonal symptoms and the use of rescue antiallergic medication, which included short courses of prednisolone, remained low after the discontinuation of immunotherapy, and there was no significant difference between patients who continued immunotherapy and those who discontinued it. Symptom scores in both treatment groups (median areas under the curve in 1995, 921 for continuation of immunotherapy and 504 for discontinuation of immunotherapy; P=0.60) were markedly lower than those in the group that had not received immunotherapy (median value in 1995, 2863). Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression. Immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity.
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              Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.

              3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.
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                Author and article information

                Journal
                1275002
                4431
                J Allergy Clin Immunol
                J. Allergy Clin. Immunol.
                The Journal of allergy and clinical immunology
                0091-6749
                1097-6825
                22 February 2019
                17 January 2018
                August 2018
                27 February 2019
                : 142
                : 2
                : 497-509.e9
                Affiliations
                [a ]Department of Otorhinolaryngology, Medical University of Vienna, Austria
                [b ]Biomay AG, Vienna, Austria
                [c ]Department Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium
                [d ]University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia
                [e ]Allergy Center, Charité, Berlin, Germany
                [f ]Department of Dermatology and Venerology, Medical University Graz, Austria
                [g ]Allergy Clinic Copenhagen University Hospital, Gentofte, Denmark
                [h ]Center for Rhinology/Allergology, Wiesbaden, Germany
                [i ]Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
                [j ]Department of Dermatology and Allergology, Medical Center Giessen and Marburg GmbH, Marburg, Germany
                [k ]Department of Dermatology and Allergy Biederstein, Technical University Munich (TUM) and ZAUM-Center of Allergy and Environment, Munich, Germany
                [l ]Clinic for Dermatology and Allergology, University of Bonn, Germany
                [m ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
                [n ]Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University Vienna, Austria
                [o ]Institute for Medical Information Technology, Biometrics and Epidemiology, Ludwig-Maximilians-Universität, Munich, and the Institute for Medical Biometry and Epidemiology, Philipps-University, Marburg, Germany
                [p ]SynteractHCR Deutschland GmbH, Munich, Germany
                [q ]NRC Institute of Immunology FMBA of Russia, Moscow, Russia
                Author notes
                Corresponding author: Rudolf Valenta, MD, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Waehringer Guertel 18-20, 3Q, 1090 Vienna, Austria. rudolf.valenta@ 123456meduniwien.ac.at .
                Article
                EMS81971
                10.1016/j.jaci.2017.09.052
                6392176
                29361332

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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