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Background: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. Objectives: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1. Methods:Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product. Results: Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH) 3 -adsorbed drug product demonstrated at least 20 months of stability. Conclusion: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.

Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p  = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy. Allergen-specific immunotherapy is used to treat patients affected by acute immunoglobulin E (IgE) responses, but the function mechanism is unclear. Here the authors show that the administration of two cat allergen-specific IgGs reduces allergic responses in mouse models and helps ameliorate clinical symptoms in a phase 1b clinical trial.

For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8–44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61–80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59–79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755–5005) for peanut oral immunotherapy versus 5 mg (0–105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13–30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10–28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0–2755) for peanut oral immunotherapy and 0 mg (0–55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

A peanut-derived protein product, AR101, used in an oral desensitization protocol in children and adolescents with severe peanut allergy increased the amount of oral peanut protein tolerated in approximately two thirds of participants who received AR101, as compared with 1 of 25 controls.

Die Therapieallergene-Verordnung (TAV) hat zum Ziel, Allergen-Immuntherapie (AIT)-Produkte zur Therapie häufiger Allergien, die in Deutschland als Individualrezepturen vertrieben wurden, bei entsprechend nachgewiesener Qualität, Wirksamkeit und Sicherheit in geprüfte, zugelassene Produkte zu überführen. Die TAV gilt für alle Individualrezepturen, welche Wirkstoffe auf Basis folgender Allergenquellen enthalten: Hausstaubmilben, Bienengift, Wespengift, Pollen der Süßgräser (ohne Mais), Birke, Erle oder Hasel. Die letzten unter der TAV gewährten produktspezifischen Fristen zur Vorlage zulassungsrelevanter klinischer Daten enden im Verlauf des Jahres 2026. Die anschließende finale Bewertung der aktualisierten Zulassungsunterlagen erfolgt durch die zuständige Zulassungsbehörde, das Paul-Ehrlich-Institut. Während dieser Bearbeitungszeiten der Zulassungsbehörde bleiben die Produkte bis zur Entscheidung über den Zulassungsantrag verkehrsfähig. Aktuell (Stand 08.08.2025) sind unter den Übergangsvorschriften der TAV noch 40 AIT-Produkte verkehrsfähig (10 Präparate zur Behandlung von Allergien gegen Hausstaubmilben, 10 gegen Baumpollenallergien, 16 gegen Graspollenallergien und 4 Mischpräparate, die nicht-homologe Allergengruppen enthalten). Für 8 dieser Produkte wurde eine Rücknahme der Zulassungsanträge zum 01.10.2025 bzw. zum 31.01.2026 von Seiten der pharmazeutischen Unternehmen veranlasst. Vor der abschließenden Bewertung der aktualisierten Zulassungsdossiers ist es der Zulassungsbehörde nicht möglich, öffentliche Einschätzungen dazu abzugeben, ob für die verbliebenen 32 Produkte, deren Verfahren aktuell noch anhängig sind, die einzelnen Zulassungsanträge mit Erteilung der Zulassung oder mit einer Versagung derselben abgeschlossen werden. Mit der Bekanntgabe der Versagung einer Zulassung endet sofort die Verkehrsfähigkeit, das heißt es gibt keine zusätzliche Abverkaufsfrist für die betreffenden TAV-Produkte. Mit einer Zulassung wird die Verkehrsfähigkeit für das spezifische Produkt verstetigt.Erstpublikation in Allergologie select, mit freundlicher Genehmigung der AutorenPubMedCentralAllergologie selectZitierung:Mahler V, Hartenstein D, Lauer I, Vieths S, Ruoff C, Zimmer J, Kaul S. Therapy Allergen Ordinance (TAO): The final stretch. Allergol Select. 2025; 9: 93-99.DOI 10.5414/ALX02594E

Airway epithelial cells are the first line of defense against the constituents of the inhaled air, which include allergens, pathogens, pollutants, and toxic compounds. The epithelium not only prevents the penetration of these foreign substances into the interstitium, but also senses their presence and informs the organism's immune system of the impending assault. The epithelium accomplishes the latter through the release of inflammatory cytokines and chemokines that recruit and activate innate immune cells at the site of assault. These epithelial responses aim to eliminate the inhaled foreign substances and minimize their detrimental effects to the organism. Quite frequently, however, the innate immune responses of the epithelium to inhaled substances lead to chronic and high level release of pro-inflammatory mediators that may mediate the lung pathology seen in asthma. The interactions of airway epithelial cells with allergens will be discussed with particular focus on interactions-mediated epithelial release of cytokines and chemokines and their role in the immune response. As pollutants are other major constituents of inhaled air, we will also discuss how pollutants may alter the responses of airway epithelial cells to allergens.

Purpose of ReviewThe recent introduction of edible insects in Western countries has raised concerns about their safety in terms of allergenic reactions. The characterization of insect allergens, the sensitization and cross-reactivity mechanisms, and the effects of food processing represent crucial information for risk assessment.Recent FindingsAllergic reactions to different insects and cross-reactivity with crustacean and inhalant allergens have been described, with the identification of new IgE-binding proteins besides well-known pan-allergens. Depending on the route of sensitization, different potential allergens seem to be involved. Food processing may affect the solubility and the immunoreactivity of insect allergens, with results depending on species and type of proteins. Chemical/enzymatic hydrolysis, in some cases, abolishes immunoreactivity.SummaryMore studies based on subjects with a confirmed insect allergy are necessary to identify major and minor allergens and the role of the route of sensitization. The effects of processing need to be further investigated to assess the risk associated with the ingestion of insect-containing food products.

Die Allergen-Immuntherapie (AIT) ist die einzige kausale Therapie für allergische Erkrankungen und daher besonders wichtig. Allergenpräparate sind seit 1989 als Arzneimittel eingestuft (Richtlinie 89/342/EWG) und wurden 2001 in die Richtlinie 2001/83/EG übernommen. Darüber hinaus trat 2008 die Therapieallergene-Verordnung (TAV) in Kraft, um die Ausnahmeregelung für patientenbezogene Produkte (NPP) strenger zu regeln, indem häufige Therapieallergene von der Ausnahme ausgeschlossen wurden, als NPP vermarktet werden zu dürfen. Die TAV regelt die Anforderungen an die Prüfung der Unbedenklichkeit und Wirksamkeit für diese häufigen Therapieallergene. Aufgrund der langen Übergangsbestimmungen enden die letzten Fristen zur Behebung klinischer Mängel im Jahr 2026. Der Vorteil dieser Regelung ist, dass der Markt für häufige Allergene von Produkten ohne Wirksamkeitsnachweis bereinigt wurde und neue Präparate mit einem optimalen Dosisbereich durch Dosisfindungsstudien entwickelt werden. Die Forderung nach pädiatrischen Langzeitstudien wurde durch das Standard-Pädiatrische Prüfkonzept (PIP) für Allergenprodukte des Pädiatrieausschusses der EMA (PDCO) umrissen. Dies ist besonders problematisch, da absehbar ist, dass die Rekrutierung von Patienten begrenzt sein wird und ethische Probleme durch die verlängerte Verwendung von Placebo entstehen. Außerdem werden viele neu zugelassene Präparate auf absehbare Zeit nicht in der Pädiatrie eingesetzt werden, da für diese Altersgruppe noch keine Zulassung erteilt wurde. Dies wird zu einer ernsthaften Versorgungslücke für Kinder führen.Erstpublikation in Allergologie select, mit freundlicher Genehmigung der AutorenAllergologie selectZitierung:Vogelberg C, Gerstlauer M. AIT in pediatric allergology: Opportunities and difficulties on the home stretch of the Therapy Allergen Ordinance. Allergol Select. 2023; 7: 236-241.DOI 10.5414/ALX02443E