Petra Zieglmayer

Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber

BACKGROUND The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. OBJECTIVE We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. METHODS Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. RESULTS In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month (P = .0042) and second month (P = .0203) and was maintained through to the fourth month (P = .0007). In the active group the ARTSS (means +/- SDs) decreased at each challenge: week 1, 7.40 +/- 2.682; month 1, 5.89 +/- 2.431; month 2, 5.09 +/- 2.088; and month 4, 4.85 +/- 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen-specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. CONCLUSIONS In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.

Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy

Background We have developed a recombinant B cell epitope-based vaccine (BM32) for allergen-specific immunotherapy (AIT) of grass pollen allergy. The vaccine contains recombinant fusion proteins consisting of allergen-derived peptides and the hepatitis B surface protein domain preS as immunological carrier. Methods We conducted a randomized, double-blind, placebo-controlled AIT study to determine safety, clinical efficacy and immunological mechanism of three subcutaneous injections of three BM32 doses adsorbed to aluminum hydroxide versus aluminum hydroxide (placebo) applied monthly to grass pollen allergic patients (n = 70). Primary efficacy endpoint was the difference in total nasal symptom score (TNSS) through grass pollen chamber exposure before treatment and 4 weeks after the last injection. Secondary clinical endpoints were total ocular symptom score (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 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 (BM32/20 μg) (P = 0.03) and − 1.34 (BM32/40 μg) (P = 0.003) whereas mean changes in the BM32/10 μg 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 < 0.0001) but no allergen-specific IgE. Allergen-induced basophil activation was reduced in BM32 treated patients and addition of therapy-induced IgG significantly suppressed T cell activation (P = 0.0063). Conclusion The B cell epitope-based recombinant grass pollen allergy vaccine BM32 is well tolerated and few doses are sufficient to suppress immediate allergic reactions as well as allergen-specific T cell responses via a selective induction of allergen-specific IgG antibodies. (ClinicalTrials.gov number, NCT01445002.)

Changes in basophil activation during grass‐pollen sublingual immunotherapy do not correlate with clinical efficacy

To cite this article: Van Overtvelt L, Baron‐Bodo V, Horiot S, Moussu H, Ricarte C, Horak F, Zieglmayer P, Zieglmayer R, Montagut A, Galvain S, de Beaumont O, Le Gall M, Moingeon P. Changes in basophil activation during grass‐pollen sublingual immunotherapy do not correlate with clinical efficacy. Allergy 2011; 66: 1530–1537.

Fluticasone furoate versus placebo in symptoms of grass-pollen allergic rhinitis induced by exposure in the Vienna Challenge Chamber

ABSTRACT Objective: The Vienna Challenge Chamber (VCC) offers a controlled and controllable paradigm in which to reproducibly evaluate the efficacy of anti-allergic treatment. The aim of this study was to assess the efficacy of the novel intranasal corticosteroid fluticasone furoate (FF) in the VCC. Methods: The single-centre, randomised, double-blind, placebo-controlled, two-period crossover study was conducted in 59 adult males with grass pollen allergic rhinitis (AR). Patients received either Fluticasone furoate 200 mcg once-daily, or placebo intranasally for 8 days. AR symptoms were induced during 4-hour allergen challenges with grass pollen in the VCC at the end of each 8-day treatment period. A first challenge was conducted at 1–5 hours post-dose, followed by a second challenge at 22–26 hours post-dose. The primary endpoint was total nasal symptom score (TNSS; sum of itch, sneeze, rhinorrhoea, obstruction symptoms assessed on a categorical scale of 0–3) weighted mean over 2–5 hours post-dose. Secondary endpoints included: TNSS weighted mean over 23–26 hours post-dose and global symptom score, eye symptom score, nasal secretions and nasal airflow weighted means over 2–5 and 23–26 hours post-dose. Results: Fluticasone furoate showed consistent attenuation of AR symptoms in both the early and late challenges. Compared with placebo, weighted mean of TNSS was reduced on average by 4.14 point-scores at 2–5 hours post-dose and 3.63 point scores at 23–26 hours post-dose. These positive effects were also seen across all secondary endpoints. Conclusion: An 8-day treatment course of intranasal FF 200 mcg given once-daily statistically significantly reduced symptoms of AR including associated eye symptoms. Statistical significance was declared where the relevant two-sided 95 % confidence interval did not contain zero. This positive effect was sustained over 24 hours suggesting that fluticasone furoate could be efficacious as a once daily steroid.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 μg (FP), FP 200 μg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Molecular, Structural and Immunological Characterization of Der p 18, a Chitinase-Like House Dust Mite Allergen.

Background The house dust mite (HDM) allergen Der p 18 belongs to the glycoside hydrolase family 18 chitinases. The relevance of Der p 18 for house dust mite allergic patients has only been partly investigated. Objective To perform a detailed characterization of Der p 18 on a molecular, structural and immunological level. Methods Der p 18 was expressed in E. coli, purified to homogeneity, tested for chitin-binding activity and its secondary structure was analyzed by circular dichroism. Der p 18-specific IgG antibodies were produced in rabbits to localize the allergen in mites using immunogold electron microscopy and to search for cross-reactive allergens in other allergen sources (i.e. mites, crustacea, mollusca and insects). IgE reactivity of rDer p 18 was tested with sera from clinically well characterized HDM-allergic patients (n = 98) and its allergenic activity was analyzed in basophil activation experiments. Results Recombinant Der p 18 was expressed and purified as a folded, biologically active protein. It shows weak chitin-binding activity and partial cross-reactivity with Der f 18 from D. farinae but not with proteins from the other tested allergen sources. The allergen was mainly localized in the peritrophic matrix of the HDM gut and to a lower extent in fecal pellets. Der p 18 reacted with IgE from 10% of mite allergic patients from Austria and showed allergenic activity when tested for basophil activation in Der p 18-sensitized patients. Conclusion Der p 18 is a rather genus-specific minor allergen with weak chitin-binding activity but exhibits allergenic activity and therefore should be included in diagnostic test panels for HDM allergy.

Possible effect of landscape design on IgE recognition profiles of two generations revealed with micro‐arrayed allergens

The aim of this study was to investigate possible effects of landscape design on the IgE sensitization profile toward inhalant allergens in patients with respiratory allergy from Uzbekistan where green areas have been changed during the last two decades by a State program. Sera from two different generations of Uzbek (n=58) and, for control purposes, from two generations of Austrian (n=58) patients were analyzed for IgE reactivity to 112 different micro‐arrayed allergen molecules by ImmunoCAP ISAC technology. Changes in molecular IgE sensitization profiles to pollen allergens in the young vs the middle‐aged Uzbek population were associated with replanting, whereas those in the Vienna populations reflected natural changes in plant growth. Our data indicate that anthropologic as well as natural changes in the biome may have effects on IgE sensitization profiles already from one to another generation.

Effects of Nasal Corticosteroids on Boosts of Systemic Allergen-Specific IgE Production Induced by Nasal Allergen Exposure

Background Allergen exposure via the respiratory tract and in particular via the nasal mucosa boosts systemic allergen-specific IgE production. Intranasal corticosteroids (INCS) represent a first line treatment of allergic rhinitis but their effects on this boost of allergen-specific IgE production are unclear. Aim Here we aimed to determine in a double-blind, placebo-controlled study whether therapeutic doses of an INCS preparation, i.e., nasal fluticasone propionate, have effects on boosts of allergen-specific IgE following nasal allergen exposure. Methods Subjects (n = 48) suffering from grass and birch pollen allergy were treated with daily fluticasone propionate or placebo nasal spray for four weeks. After two weeks of treatment, subjects underwent nasal provocation with either birch pollen allergen Bet v 1 or grass pollen allergen Phl p 5. Bet v 1 and Phl p 5-specific IgE, IgG1–4, IgM and IgA levels were measured in serum samples obtained at the time of provocation and one, two, four, six and eight weeks thereafter. Results Nasal allergen provocation induced a median increase to 141.1% of serum IgE levels to allergens used for provocation but not to control allergens 4 weeks after provocation. There were no significant differences regarding the boosts of allergen-specific IgE between INCS- and placebo-treated subjects. Conclusion In conclusion, the application of fluticasone propionate had no significant effects on the boosts of systemic allergen-specific IgE production following nasal allergen exposure. Trial Registration http://clinicaltrials.gov/ NCT00755066

Intranasal administration of allergen increases specific IgE whereas intranasal Omalizumab does not increase serum IgE levels – a pilot study

Administration of the therapeutic anti‐IgE antibody omalizumab to patients induces strong increases in IgE antibody levels.

Underestimation of house dust mite–specific IgE with extract-based ImmunoCAPs compared with molecular ImmunoCAPs

We identified 6 house dust mite (HDM) allergen molecules to comprising the majority of HDM IgE-binding components and show that molecular ImmunoCAPs based on these six allergens are superior to allergen extract-based ImmunoCAPs for quantifying HDM-specific IgE.