Background The magnitude of effect of sublingual immunotherapy for house dust mite (HDM)–induced allergic rhinitis with or without conjunctivitis is uncertain, partly because there are few ...well-controlled trials with well-defined doses. Objective We sought to determine the dose-related efficacy and onset of action of the HDM sublingual immunotherapy tablet MK-8237 (Merck/ALK-Abelló) using the Vienna Challenge Chamber. Methods In this randomized, double-blind, single-site trial, adults with HDM-induced allergic rhinitis with or without conjunctivitis and with or without asthma (n = 124) received 12 developmental units (DU) of MK-8237, 6 DU of MK-8237, or placebo daily for 24 weeks. Subjects underwent 6-hour exposure challenges at screening and weeks 8, 16, and 24. The total nasal symptom score (TNSS) during chamber challenge at week 24 was the primary end point. The TNSS was the sum of 4 nasal symptom scores (maximum = 12). Total ocular symptom scores (TOSSs; 2 symptoms; maximum = 6) and total symptom scores (TSSs; TSS = TNSS plus TOSS; maximum = 18) were secondary end points. Results Dose- and time-dependent improvements with MK-8237 versus placebo were observed. At week 24, TNSS improvement relative to placebo was 48.6% (95% CI, 35.3% to 60.2%) with 12 DU of MK-8237 and 26.6% (95% CI, 11.2% to 39.6%) with 6 DU of MK-8237. Statistically significant improvements for TNSSs were also observed at weeks 8 (12 DU of MK-8237) and 16 (6 and 12 DU of MK-8237) and for TOSSs and TSSs by both doses at week 24. MK-8237 was well tolerated. No investigator-assessed anaphylactic allergic reactions or reactions requiring epinephrine were observed. Conclusions MK-8237, 12 DU, reduced nasal and ocular symptoms and exceeded World Allergy Organization–established clinical efficacy criteria (≥20% improvement vs placebo). The onset of action for 12 DU of MK-8237 was week 8. MK-8237, 12 DU, is appropriate for further evaluation to determine the magnitude of effect in an uncontrolled allergen exposure environment.
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.
Background Recombinant DNA technology has the potential to produce allergen-specific immunotherapy vaccines with defined composition. Objective To evaluate the effectiveness of a new recombinant ...birch pollen allergen vaccine in patients with birch pollen allergy. Methods A multicenter, randomized, double-blind, placebo-controlled trial was undertaken to compare the following 3 vaccines in 134 adults with birch pollen allergy: recombinant birch pollen allergen vaccine (rBet v 1a), licensed birch pollen extract, natural purified birch pollen allergen (nBet v 1), and placebo. Patients received 12 weekly injections followed by monthly injections of the maintenance dose containing 15 μg Bet v 1 for 2 years. Results Significant reductions (about 50%) in rhinoconjunctivitis symptoms (rBet v 1, P = .0002; nBet v 1, P = .0006; birch extract, P = .0024), rescue medication (rBet v 1, P = .0011; nBet v 1, P = .0025; birch extract, P = .0063), and skin sensitivities ( P < .0001) were observed in the 3 actively treated groups compared with placebo during 2 consecutive pollen seasons. Clinical improvement was accompanied by marked increases in Bet v 1–specific IgG levels, which were higher in the rBet v 1–treated group than in the birch and nBet v 1–treated groups. New IgE specificities were induced in 3 of 29 patients treated with birch pollen extract, but in none of the 32 rBet v 1–treated or 29 nBet v 1–treated patients. No severe systemic adverse events were observed in the rBet v 1–treated group. Conclusion The rBet v 1–based vaccine was safe and effective in treating birch pollen allergy, and induced a highly specific immune response.
Background Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies. Objectives We ...sought to evaluate the sustained efficacy of 2 dosing regimens of a pre- and coseasonal treatment with 300 IR (index of reactivity) 5-grass-pollen SLIT tablets (Oralair) compared with placebo assessed by using the average adjusted symptom score (AAdSS) at season 3 in adults with grass pollen–induced rhinoconjunctivitis. Methods Six hundred thirty-three patients were treated for either 2 or 4 months before and then during the grass pollen season with active or placebo treatment for 3 consecutive seasons. The primary outcome was the AAdSS, a symptom score adjusted for rescue medication use, after 3 consecutive treatment seasons. Secondary outcomes were symptoms and rescue medication score, quality-of-life, and safety assessments. Results The mean AAdSS was reduced by 36.0% and 34.5% at season 3 in the 2- and 4-month pre- and coseasonal active treatment groups, respectively, compared with that in the placebo group ( P < .0001 for both). Reductions were observed in total symptom scores and ISSs and the medication score, with a marked improvement in quality of life for both active groups compared with the placebo group at season 3. Most treatment-emergent adverse events were local reactions expected with SLIT, decreasing in number and intensity in each treatment season. Conclusions Sustained efficacy of 2- and 4-month pre- and coseasonal treatment with the 300 IR tablet over 3 pollen seasons was demonstrated, with reduction in symptoms and rescue medication use. The treatment was well tolerated. Adverse events decreased in number and intensity over the 3 seasons.
Background Sublingual immunotherapy is well tolerated and data suggest its effectiveness for the treatment of allergic rhinitis in adults, but it lacks optimum dose definition. Objective To assess ...the efficacy, safety, and optimal dose of grass pollen tablets for immunotherapy of patients with allergic rhinoconjunctivitis. Methods In this multinational, randomized, double-blind, placebo-controlled study, 628 adults with grass pollen rhinoconjunctivitis (confirmed by positive skin prick test and serum-specific IgE) received 1 of 3 doses of a standardized 5–grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation. The treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was Rhinoconjunctivitis Total Symptom Score; secondary outcomes included 6 individual symptom scores, rescue medication use, quality of life, and safety assessments. Results Both the 300–index of reactivity (IR) and 500-IR doses significantly reduced mean Rhinoconjunctivitis Total Symptom Score (3.58 ± 3.0, P = .0001; and 3.74 ± 3.1, P = .0006, respectively) compared with placebo (4.93 ± 3.2) in the intent-to-treat and per-protocol analyses. The 100-IR group (4.70 ± 3.1) score was not significantly different from placebo. Analysis of all secondary efficacy variables (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes, rescue medication usage, and quality of life) confirmed the efficacy of the 300-IR and 500-IR doses. No serious side effects were reported. Conclusion In the first pollen season, the efficacy and safety of sublingual immunotherapy with grass tablets was confirmed. The 300-IR and 500-IR doses both demonstrated significant efficacy compared with placebo. Clinical implications The risk-benefit ratio favors the use of 300-IR tablets for clinical practice.
Background Given their pivotal role in the polarization of T-cell responses, molecular changes at the level of dendritic cells (DCs) could represent an early signature indicative of the subsequent ...orientation of adaptive immune responses during immunotherapy. Objective We sought to investigate whether markers of effector and regulatory DCs are affected during allergen immunotherapy in relationship with clinical benefit. Methods Differential gel electrophoresis and label-free mass spectrometry approaches were used to compare whole proteomes from human monocyte-derived DCs differentiated toward either regulatory or effector functions. The expression of those markers was assessed by using quantitative PCR in PBMCs from 79 patients with grass pollen allergy enrolled in a double-blind, placebo-controlled clinical study evaluating the efficacy of sublingual tablets in an allergen exposure chamber over a 4-month period. Results We identified several markers associated with DC1 and/or DC17 effector DCs, including CD71, FSCN1, IRF4, NMES1, MX1, TRAF1. A substantial phenotypic heterogeneity was observed among various types of tolerogenic DCs, with ANXA1, Complement component 1 (C1Q), CATC, GILZ, F13A, FKBP5, Stabilin-1 (STAB1), and TPP1 molecules established as shared or restricted regulatory DC markers. The expression of 2 of those DCs markers, C1Q and STAB1, was increased in PBMCs from clinical responders in contrast to that seen in nonresponders or placebo-treated patients. Conclusion C1Q and STAB1 represent candidate biomarkers of early efficacy of allergen immunotherapy as the hallmark of a regulatory innate immune response predictive of clinical tolerance.
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.
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 4weeks 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.
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<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).
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.)
•BM32 is a recombinant allergy vaccine consisting of the preS domain of the 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 against allergic symptoms induced by grass pollen exposure in a challenge chamber by induction of allergen-specific IgG antibodies without boosting of allergic immune responses•BM32 may be useful as therapeutic and prophylactic vaccine for grass pollen allergy
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 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 vaccine are well tolerated and protect allergic patients against allergic symptoms by induction of allergen-specific IgG antibody responses without inducing allergic 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 vaccination.
Background
The 300IR (index of reactivity) 5‐grass pollen tablet has favorable short‐term and sustained clinical efficacy in patients with grass pollen‐induced allergic rhinoconjunctivitis (ARC). ...Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation.
Methods
Randomized, double‐blind, placebo‐controlled, parallel‐group, multicenter Phase 3 trial in patients aged 18–50 years with ARC. During study years 1–3, patients received a daily sublingual tablet containing either 300IR 5‐grass pollen extract or placebo, according to a discontinuous pre‐ and coseasonal protocol. Study years 4 and 5 were treatment‐free. In response to health authorities’ recommendations, the daily combined score (DCS) was assessed in a post‐hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS).
Results
633 patients with ARC were randomized to placebo (n = 219) or 300IR 5‐grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season's end. During the first post‐treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: −0.16, 95% confidence interval (CI95%): −0.26, −0.06, p = 0.0019; −31.1%; 300IR (4 M) point estimate: −0.13, CI95%: −0.23, −0.03, p = 0.0103, −25.3%). During the second post‐treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: −0.11, CI95%: −0.21; 0.00, p = 0.0478, −28.1%). This significant efficacy seen during the post‐treatment years in patients previously treated with 5‐grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post‐treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post‐treatment year.
Conclusions
In adults with grass pollen‐associated ARC, 5‐grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season's end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post‐treatment.
Trial registration
ClinicalTrials.gov identifier: NCT00418379.
Background
Several studies indicate that Der p 7 is an important and clinically relevant allergen of
Dermatophagoides pteronyssinus
which should be included in vaccines for treatment of house dust ...mite (HDM) allergy. Aim of this study was to characterize the IgE epitopes of Der p 7.
Methods
Recombinant Der p 7 was expressed and purified, analyzed for fold by circular dichroism and tested for its allergenic activity by basophil activation. Seven overlapping, surface-exposed peptides (P1–P7) with a length of 27 to 37 amino acids, which spanned the Der p 7 sequence, were synthesized and tested for IgE reactivity and allergenic activity by basophil activation assay. Carrier-bound peptides were studied for their ability to induce allergen-specific IgG antibodies in rabbits. Peptide-specific antibodies were used to inhibit allergic patients` IgE binding to Der p 7 by ELISA for mapping of IgE epitopes.
Results
rDer p 7 showed high allergenic activity comparable with Der p 5, Der p 21, and Der p 23. None of the seven tested peptides showed any IgE reactivity or allergenic activity when tested with HDM- allergic patients indicating lack of sequential IgE epitopes on Der p 7. IgE inhibition experiments using anti-peptide specific IgGs and molecular modeling enabled us to identify discontinuous, conformational IgE epitopes of Der p 7.
Conclusion and Clinical Relevance
IgE epitopes of Der p 7 belong to the conformational and discontinuous type whereas sequential Der p 7 peptides lack IgE reactivity. It should thus be possible to construct hypoallergenic vaccines for Der p 7 based on carrier-bound allergen peptides.
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