Strong Dose-response On Immunoglobulin Makers During a Phase II Allergen Immunotherapy Study With Subcutaneously Administered Tyrosine Adsorbed Modified Grass Allergen + MPL

BackgroundObservational comparative effectiveness studies in allergen immunotherapy (AIT) represent an important evidence source answering research questions that can be challenging to obtain from randomized controlled trials (RCTs), such as long‐term benefits of AIT, the effects on asthma prevention and the onset of new allergen sensitizations. However, observational studies are prone to several sources of bias, which limit their reliability.The REal Life Evidence AssessmeNt Tool (RELEVANT) was recently developed to assist in quality appraisal of observational comparative research to enable identification of useful nonrandomized studies to be considered within guideline development.ObjectiveTo systematically appraise the quality of published observational comparative AIT studies using RELEVANT.MethodsObservational studies comparing AIT to pharmacotherapy for respiratory allergies, assessing as outcome measures reduction of symptoms and/or medication use reduction, were retrieved by computerized bibliographic searches. According to RELEVANT, a failure to meet any one of primary items (background, design, measures, analysis, results, discussion/interpretation, and conflict of interest) represents a critical flaw, significantly undermining the validity of the study results.ResultsThe 14 studies identified supported the benefit of AIT in real‐life, which persists after treatment discontinuation. However, none of them met all the 7 primary RELEVANT criteria. The main defects were reported in the design (28.6% of studies), measures and analysis (64.3% of studies), and results (78.6% of studies) items, due to selection bias and lack of methods for adjusting controls. Half of the studies did not report on conflict of interest.ConclusionThere is a need for more robust observational research in AIT. RELEVANT appears as an easy‐to‐use and sensitive tool for quality appraisal in AIT studies.

Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: Looking at the published evidence

There is evidence from epidemiologic studies, supported by more intensive study of selected groups of subjects, for the importance of allergy in initiating and contributing to the severity of bronchial asthma. Furthermore, removal of allergen exposure is followed by improvement in both symptoms and evidence of airway inflammation. Allergen immunotherapy reduces the sensitivity of the respiratory tract to allergens, blocks the influx of eosinophils and mucosal mast cells in response to allergen exposure, and alters the pattern of cytokine release by T-lymphocytes, generally decreasing Th2-related cytokines (IL-4) and increasing those related to the Th1 response (interferon-gamma, IL-2, IL-12). It would be remarkable, given these alterations in responsiveness produced by allergen immunotherapy, if this treatment were not effective in bronchial asthma. Indeed, an analysis of controlled studies of allergen immunotherapy does indicate that it is clinically effective in carefully selected, allergic asthmatics.

A prospective safety study of allergen immunotherapy in daily clinical practice

Oral immunotherapy for the treatment of food allergy

Real-life (or real-world) studies can provide information that cannot be derived from randomized controlled trials. This approach is currently becoming of relevance for many treatments. In recent years, the real-life method has been applied also to allergen immunotherapy, providing new insights on it. We reviewed herein the available literature on the argument. Several prospective and retrospective studies on allergen immunotherapy in the real-world setting have been published, mostly in the last 5 years. Most of them focused on adverse events, compliance, and the long term/preventive effects, and evidenced an overall favorable profile for different products and different allergens. Real life study provided novel information and evidenced those aspects of immunotherapy that worth a more detailed approach, without the strict limitations usually imposed by controlled randomized trials.

Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Allergy. 2007;62(11):1261–1269 PURPOSE OF THE STUDY. To evaluate the efficacy of oral tolerance induction as a treatment for cow's milk and egg allergies. STUDY POPULATION. Forty-seven children aged 0.6 to 12.9 years with positive double-blind, placebo-controlled food challenges to milk or hen's egg were included in this German study. Children with severe eczema were excluded. METHODS. Subjects were randomly assigned to specific oral tolerance induction or continued avoidance. Treatment involved home escalation over at least 67 days from a dose of 1 drop of cow's milk to 250 mL or from 5 mg of lyophilized hen egg powder to 3500 mg. Subjects continued home dosing for a median of 21 months total, after which time they underwent a secondary period of avoidance for 2 months followed by a food challenge. RESULTS. At follow-up challenge, 9 (36%) of 25 children in the specific-oral-tolerance-induction group showed permanent tolerance, 3 (12%) of 25 were tolerant with regular intake, 4 (16%) of 25 were partial responders, and 9 (36%) of 25 did not complete the treatment because of adverse effects. In the control group, 7 (35%) of 20 children were tolerant at the study end. Allergen-specific IgE levels decreased in children who developed tolerance both in the control (P < .05) and treatment (P < .001) groups. CONCLUSIONS. Specific oral tolerance induction may be a valid treatment option for patients with persistent food allergy. However, only a minority of patients had evidence of persistent tolerance once treatment was stopped, with some unable to tolerate the therapy and others seeming to be only transiently desensitized. REVIEWER COMMENTS. Allergen-specific immunotherapy with injected extracts has proven too dangerous to be a viable treatment method for food allergy. Sublingual or oral immunotherapy, as described here, is a promising alternative to strict avoidance. Although one third of the patients in this study had to withdraw because of adverse effects, the remaining patients were able to incorporate the allergen into their diet at some level. This treatment modality is highly promising, but it is still experimental, carries the potential for significant risk, and requires close monitoring by experienced physicians. Several studies of oral and sublingual immunotherapy for food allergy are ongoing in the United States and Europe.

Several recent clinical trials reported that intralymphatic immunotherapy (ILIT) for some allergens, such as cat dander and pollen, induce tolerance more rapidly than conventional subcutaneous or sublingual immunotherapy, have a comparable duration of effect after only 3 injections, and do not provoke serious local or systemic reactions. However, the efficacy and safety of ILIT are using Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), and dog, which are indoor allergens that are commonly found globally, need to be evaluated. Furthermore, use of multiple allergens in ILIT should be investigated. We assessed the clinical efficacy and adverse effects of ILIT using aqueous Df, Dp, dog, and cat allergens or mixtures thereof in patients with allergic rhinitis. A total of 11 subjects with AR sensitized to Df, Dp, cat, and/or dog allergens received 3 intralymphatic inguinal injections of sensitized allergen extract (HollisterStier, New Orleans, LA, USA). Clinical parameters were assessed before ILIT, and 4 months and 1 year after the first injection. Rhinitis symptoms were alleviated and quality of life was improved 4 months after ILIT (P=0.012 and P=0.007, respectively), and these improvements lasted for 1 year after ILIT (P=0.047 and P=0.009, respectively). However, we observed 2 cases of anaphylaxis, one case of a moderate-to-severe systemic hypersensitivity reaction and the other case of a severe local reaction at the injection site after ILIT. In conclusion, ILIT can rapidly improve allergy symptoms and quality of life, and this effect lasts for 1 year. In hypersensitized patients, however, ILIT can provoke severe systemic and/or local hypersensitivity reactions when performed using aqueous allergen extracts.

A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy

Oral immunotherapy (OIT) is a significant focus of treatment of food allergy. OIT appears to be effective in inducing desensitization, however, patients receiving OIT frequently developmild/moderate symptoms during the therapy. It has not been clearly established whether the clinical tolerance induced by OIT resembles natural tolerance. According to our data, the efficacy of OIT is different among food antigens, and it is comparatively difficult to achieve the clinical tolerance in milk OIT. Moreover, the definitive evidence of efficacy and safety with long-term therapy is limited. Further studies need to be offered to patients in clinical practice. Recently, novel treatments for food allergy, sublingual and epicutaneous immunotherapy, and combination treatment with an anti-IgE monoclonal antibody (omalizumab), have been examined in some studies. OIT combined with omalizumab increased the threshold doses of food without adverse reactions and may be of benefit in food allergy treatment. More studies are needed to demonstrate long-term safety and treatment benefits in a larger patient cohort.

About every second allergic person in Germany suffers from a so-called "early bloomer allergy," a little scientific description of the tree pollen allergy.1 And almost every allergic person knows the specific tree, which he or she is allergic to, the hazel, the alder, the birch, the ash, the plane tree and, finally the most German of all the trees, the oak. This knowledge has been burned into the minds of our patients. So, it comes to a revolution, when a German-Danish research group around the lateral thinker Jörg Kleine-Tebbe in their article "Is allergy immunotherapy with birch sufficient to treat patients allergic to pollen of tree species of the birch homologous group?" now speaks out that most trees from an allergological point of view are actually birches,2 or at least those of the Fagales homologous group. They shed light on this from various aspects, the regulatory, the immunological and finally the clinical perspective, and with this knowledge, they have the intention to give recommendations for diagnosis and change current treatment habits. Indeed, they have strong arguments on their side: Already in 2008, the European Medicine Agency EMA defined homologous allergen groups and subsumed not only birch, hazel, alder, hornbeam and oak, but also hop hornbeam, beech and sweet chestnut among the birch group. All these are based on strong scientific evidence, which comes from the field of molecular allergy, rather than from the previous botanical view of taxonomical classes. It started with the characterization of the PR-10-like molecule Bet v 1, as the major allergen in birch. All trees of the Fagales group display a high degree of structural homology in their major allergens. This is in line with results from the immunological diagnosis of numerous allergen immunotherapy studies. In these studies, high levels of cross-reactivity of birch-specific IgE towards allergens of the birch homologous trees were observed with correlation coefficients ranging from 0.83 for birch/oak to 0.98 for birch/hazel. They report similar findings also for the changes in allergen-specific IgG4, a factor which is often interpreted as a biomarker of the treatment effects of AIT. Here, the correlation coefficients reached from 0.72 for birch/oak to 0.95 for birch/alder. In their own studies from Northern and Central Europe, the overlap of birch sensitization with alder or hazel was almost complete and a patient reacting to alder or hazel but not displaying a birch sensitization was an extremely rare exception. The article quotes surprising sensitization data from the Mediterranean Italy.3 High rates of birch sensitization were also found in the Italian South. This is not just about cross-reactivity. Birch pollen can spread with the wind over thousands of kilometres and also sensitize atopic people, where a birch has never been spotted. Even there, IgE reactivity to Bet v 1 seems to be a fine marker of Fagales sensitization. But the strongest argument for the paradigm shift comes from the recently presented clinical trials with the birch tablet. "He who heals is right" said our predecessors in the pre-evident era. The birch tablet not only demonstrated symptom improvements in birch, alder and hazel patients, but also showed highly significant and clinically relevant improvements for patients who were shown to be sensitized exclusively to oak allergen. Moreover, they cite studies with recombinant Bet v 1 which were efficacious, thereby demonstrating that this major allergen is the main driver of the disease. The authors attribute the effects which they have observed to the long-term induction of birch-specific IgG4 and especially to the appearance of birch-specific IgE-blocking factor in the blood of successfully treated patients as the underlying mechanism. The work of Kleine-Tebbe and colleagues propagates a novel, minimalist approach for both, the diagnosis and the treatment of tree allergy: Their simple algorithm recommends for allergy sufferers, who develop symptoms before the grass pollen period, that it is usually sufficient to test only for birch allergen and to treat the patient in a positive case with the birch tablet. If this approach proves to be effective on a broad basis, it would at least partially reduce the continuous discussion about the constant shortage of diagnostic allergens, because then we could dispose properly of the diagnostic solutions for hazel, for alder, for beech and for oak. And space would be created in the refrigerator because the twofold and threefold combinations of tree pollen therapy allergens have become obsolete. I think this is a conceivable scenario, but I find it difficult and time-consuming to communicate these new findings to our well informed and highly motivated allergy patients polysensitized to various tree pollen. Prof. Mösges reports personal fees from ALK, grants from ASIT biotech, personal fees from allergopharma, personal fees from Allergy Therapeutics, grants and personal fees from Bencard, grants from Leti, grants, personal fees and nonfinancial support from Lofarma, nonfinancial support from Roxall, grants and personal fees from Stallergenes, grants from Optima, personal fees from Friulchem, personal fees from Hexal, personal fees from Servier, personal fees from Klosterfrau, nonfinancial support from Atmos, personal fees from Bayer, nonfinancial support from Bionorica, personal fees from FAES, personal fees from GSK, personal fees from MSD, personal fees from Johnson&Johnson, personal fees from Meda, personal fees and nonfinancial support from Novartis, nonfinancial support from Otonomy, personal fees from Stada, personal fees from UCB, nonfinancial support from Ferrero, grants from BitopAG, grants from Hulka, personal fees from Nuvo, grants from Ursapharm, personal fees from Menarini, personal fees from Mundipharma, personal fees from Pohl-Boskamp, grants from Inmunotek, personal fees from Hikma, personal fees from Sandoz, grants and personal fees from Lek, grants and personal fees from Cassella, outside the submitted work.

The Editors' Choice

Oral mucosal immunotherapy (OMIT) involves the use of a specifically formulated toothpaste to deliver allergenic proteins to immunologically active areas of the oral cavity. This represents a novel delivery mechanism with several features designed to improve food allergy desensitization. OMIT has advantages over other approaches to allergy immunotherapy due to its targeted delivery and simplified administration. To determine the safety, tolerability, and adherence to OMIT with INT301 in adults with peanut allergy. The Oral Mucosal Escalation Goal Assessment study enrolled 32 adults, aged 18 to 55 years, with peanut allergy in a 3:1 ratio to receive either an escalating dose of INT301 or a placebo. Entry criteria included a positive skin prick test result with a wheal diameter greater than or equal to 3 mm than control and/or peanut-specific IgE level greater than or equal to 0.35 kU/L. Subjects were required to fail an oral food challenge less than or equal to 100 mg dose of peanut protein. Safety and tolerability were monitored in the 48-week trial period. All active subjects (100%) tolerated the prespecified protocol at the highest dose. No moderate or severe systemic reactions were observed in the active participants. Nonsystemic adverse reactions were mostly local (oral and nasal cavities), mild and transient. Active subjects adhered to the treatment for 97% of the days in the study, with no withdrawals due to study medication. In the Oral Mucosal Escalation Goal Assessment trial, INT301 met all primary and secondary end points of safety, tolerability, and adherence. Thus, OMIT seems to be a safe and convenient option for individuals with food allergies. These results support the need for further evaluation in the pediatric population. ClinicalTrials.gov Identifier: NCT04603300.

This study aimed to determine whether baseline immunoglobulin E (IgE) binding patterns to specific peanut protein epitopes can predict which patients with peanut allergy will achieve sustained unresponsiveness or sustained high tolerance after completing peanut oral immunotherapy (OIT). Building upon findings from the POISED (Peanut Oral Immunotherapy Study: Safety, Efficacy, and Discovery) trial, the goal was to identify immunologic biomarkers that could help guide clinical decisions regarding OIT.The study included participants aged 7 to 55 years with confirmed peanut allergy, as diagnosed by a double-blind, placebo-controlled food challenge (DBPCFC) showing a reaction to 500 mg or less of peanut protein. All participants were previously enrolled in the POISED trial and were randomized to receive either placebo or 24 months of peanut OIT, during which they built up to a daily maintenance dose of 4000 mg of peanut protein. At the end of 24 months, individuals who passed a 4000-mg DBPCFC were randomized again to either continue with 300 mg of daily peanut or completely avoid peanut for an additional 12 months. At the end of this maintenance or avoidance phase, participants underwent a final DBPCFC. Based on these outcomes, participants were classified as having achieved sustained unresponsiveness if they tolerated 4000 mg after 12 months of avoidance (8/55 patients), sustained high tolerance if they tolerated 4000 mg after continued low-dose peanut exposure (13/28 patients), or transient desensitization if they passed the 24-month challenge but reacted during the final DBPCFC.This was a prospective analysis using serum samples collected at baseline and other time points, with the primary analysis focused on pretreatment data. Researchers employed high-resolution epitope mapping to measure IgE binding to linear epitopes from major peanut allergens, including Ara h 1, Ara h 2, and Ara h 3. Baseline IgE binding profiles were analyzed and compared across outcome groups. Additional immunologic markers included total peanut-specific IgE and IgG4, as well as component-specific IgE levels. Statistical methods included multivariate modeling and machine learning approaches to identify which patterns of epitope-specific IgE binding were most predictive of achieving either sustained unresponsiveness or sustained high tolerance after OIT.Participants with lower baseline IgE binding to specific peanut protein epitopes, particularly within Ara h 2, were more likely to achieve sustained unresponsiveness or tolerate higher doses of peanut after 2 years of OIT. In contrast, broader or more intense IgE responses to multiple epitopes at baseline were associated with a reduced likelihood. These findings suggest that specific IgE binding profiles at the epitope level may serve as useful biomarkers for predicting the success of peanut oral immunotherapy.The findings of this study suggest that detailed assessment of epitope-specific IgE at baseline may serve as a useful biomarker for identifying patients most likely to benefit from peanut oral immunotherapy and for guiding personalized treatment strategies. This kind of personalized immunologic assessment could improve patient selection and treatment planning, ultimately leading to better outcomes for individuals undergoing food allergy immunotherapy.Although there is a growing body of evidence on OIT, there are limited data to guide the duration of therapy. Most patients lose protection once stopping OIT, but as shown by the previous POISED study, there is a small subset of patients that do not. This study addresses a clinical need by demonstrating that detailed IgE epitope binding patterns and machine learning algorithms may help predict which patients may fall into this latter category. Future studies should include a larger patient cohort, as well as younger patients, as there may be different predictors in this age group. It is also important to note that epitope-specific IgE are not yet commercially available tests. In the future, should these become available, this machine learning model could become a useful tool for clinicians and families in shared decision-making between different therapies for food allergy.

BackgroundAllergoids are chemically modified allergen extracts administered to reduce allergenicity and to maintain immunogenicity. Oralair® (the 5-grass tablet) is a sublingual native grass allergen tablet for pre- and co-seasonal treatment. Based on a literature review, meta-analysis, and cost-effectiveness analysis the relative effects and costs of the 5-grass tablet versus a mix of subcutaneous allergoid compounds for grass pollen allergic rhinoconjunctivitis were assessed.MethodsA Markov model with a time horizon of nine years was used to assess the costs and effects of three-year immunotherapy treatment. Relative efficacy expressed as standardized mean differences was estimated using an indirect comparison on symptom scores extracted from available clinical trials. The Rhinitis Symptom Utility Index (RSUI) was applied as a proxy to estimate utility values for symptom scores. Drug acquisition and other medical costs were derived from published sources as well as estimates for resource use, immunotherapy persistence, and occurrence of asthma. The analysis was executed from the German payer’s perspective, which includes payments of the Statutory Health Insurance (SHI) and additional payments by insurants. Comprehensive deterministic and probabilistic sensitivity analyses and different scenarios were performed to test the uncertainty concerning the incremental model outcomes.ResultsThe applied model predicted a cost-utility ratio of the 5-grass tablet versus a market mix of injectable allergoid products of € 12,593 per QALY in the base case analysis. Predicted incremental costs and QALYs were € 458 (95% confidence interval, CI: € 220; € 739) and 0.036 (95% CI: 0.002; 0.078), respectively. Compared to the allergoid mix the probability of the 5-grass tablet being the most cost-effective treatment option was predicted to be 76% at a willingness-to-pay threshold of € 20,000. The results were most sensitive to changes in efficacy estimates, duration of the pollen season, and immunotherapy persistence rates.ConclusionsThis analysis suggests the sublingual native 5-grass tablet to be cost-effective relative to a mix of subcutaneous allergoid compounds. The robustness of these statements has been confirmed in extensive sensitivity and scenario analyses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13601-015-0045-z) contains supplementary material, which is available to authorized users.