We have recently reported the preclinical characterization of a recombinant birch pollen allergy vaccine based on a fusion protein, AB-PreS, consisting of allergen-derived peptides fused to the hepatitis B virus (HBV)-derived PreS surface protein as immunological carrier.

To investigate in a clinical study the usefulness of the AB-PreS vaccine, termed GNR-127, for allergen-specific immunotherapy of birch pollen allergy.

Stage 1 of the study, an open-label Phase I study, determined among three doses (20 μg: n = 6; 40 μg: n = 6; 80 μg: n = 6) administered as Aluminum-hydroxide-adsorbed vaccines subcutaneously five times in monthly intervals, the highest tolerated doses. In the following Stage 2, randomized patients (placebo: n = 45; 40 μg: n = 43; 80 μg: n = 44) received in a single-blind, placebo-controlled Phase II study monthly up to five pre-seasonal injections. Safety monitoring followed the Medical Dictionary for Regulatory Activities (MedDRA); efficacy parameters were determined according to the European Academy for Allergy and Clinical Immunology (EAACI) guidelines; allergen-specific antibodies and basophil sensitivity were determined by ELISA and basophil activation testing, respectively.

A dose-dependent reduction of the combined symptom medication score (CSMS) (40 μg: 17.41%; 80 μg: 24.13%) over placebo was observed which was significant for the 80 μg group and accompanied by the strongest induction of Bet v 1-specific IgG (median 20-fold increase) and a blunting of the seasonally boosted IgE response and basophil sensitivity. The vaccine showed an acceptable safety profile despite high administered doses.

A pre-seasonal course of 5 monthly injections of GNR-127 80 μg improved symptoms of birch pollen allergy accompanied by a robust Bet v 1-specific IgG response, paving the road for a Phase III efficacy study. Trial registration: ClinicalTrials.gov (Identifier: NCT07155499)

Allergen-specific CD4+ T cells are a highly heterogenous population. Depletion of these cells has been proposed as essential to achieve allergen desensitization in allergen immunotherapy.

The overall aim of this study was to characterize the heterogeneity of timothy grass (Phleum pratense) allergen-specific CD4+ T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous (SCIT) immunotherapy. Correlations between frequencies of these cells with Total Nasal Symptom Score and grass-specific serum immunoglobulin were also investigated.

Mass cytometry with lanthanides-tagged peptide major histocompatibility complex class II multimers and CD154 upregulation assays were used to examine changes in the frequency and phenotype of Phl p-specific CD4+ T cells in longitudinal peripheral blood mononuclear cell samples from a randomized, double-blind, placebo-controlled trial of SLIT and SCIT. Supervised and unsupervised clustering was used for data analysis.

Phenotypes of Phl p-specific T cells were highly heterogenous but could be categorized into two major metaclusters, CRTH2ʰⁱCD27ˡᵒ and CRTH2ˡᵒCD27ʰⁱ, each with distinct phenotypic profiles. Weak positive correlations between Total Nasal Symptom Score and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2ʰⁱCD27ˡᵒ cells, whereas SLIT depleted CRTH2ˡᵒCD27ʰⁱ cells. CRTH2ʰⁱCD27ˡᵒ cell frequency correlated with Phl p-specific IgE and IgG4, but not IgA, levels.

Unsupervised clustering revealed distinct subpopulations of allergen-specific T cells that were differentially targeted and depleted by SCIT and SLIT, suggesting that SCIT and SLIT act through overlapping but distinct immunologic pathways.

We searched PubMed, Embase, and CENTRAL for double-blind, placebo-controlled randomized trials of HDM-AIT lasting at least 12 months. Interventions were classified as comprehensive-component subcutaneous immunotherapy (CC-SCIT), major-component-dominant subcutaneous immunotherapy (MCD-SCIT), or major-component-dominant sublingual immunotherapy tablet (MCD-SLIT-tablet) using a prespecified component-resolved framework in which the breadth of treatment-induced component-specific IgG4 responses served as the primary node-defining criterion, with component-specific IgG and proteomic evidence used as supportive evidence. Frequentist pairwise and Bayesian network meta-analyses were performed. The primary outcome was symptom score; secondary outcomes were medication score and combined symptom and medication score.

Sixteen trials involving 7,329 participants were included. For symptom score, CC-SCIT showed the most favorable estimated treatment effect versus placebo (standardized mean difference [SMD], -0.40; 95% credible interval [CrI], -0.73 to -0.11; surface under the cumulative ranking curve [SUCRA], 82.6%), while MCD-SLIT-tablet showed a more precise estimate supported by a larger evidence base (SMD, -0.30; 95% CrI, -0.41 to -0.20; SUCRA, 60.7%). For medication score, CC-SCIT (SMD, -0.40; 95% CrI, -0.81 to 0.00; SUCRA, 79.8%) and MCD-SCIT (SMD, -0.38; 95% CrI, -0.72 to -0.05; SUCRA, 78.5%) showed similar estimated effects, whereas MCD-SLIT-tablet showed a smaller but more precise effect (SMD, -0.15; 95% CrI, -0.28 to 0.00; SUCRA, 39.9%). For combined symptom and medication score, CC-SCIT showed the largest estimated effect versus placebo (SMD, -0.84; 95% CrI, -1.53 to -0.37; SUCRA, 99.5%). The network was star-shaped, and comparisons among non-placebo treatment nodes were indirect. Posterior rank distributions also indicated uncertainty in the relative ordering of the treatment nodes, particularly those supported by fewer trials.

Reported immunologic and compositional profiles of HDM-AIT preparations were associated with variability in trial-level efficacy estimates. These findings support product-level molecular characterization and direct comparative studies as priorities for future precision AIT. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/, CRD420261307571

In 2011, the AAAAI/ACAAI Joint Task Force published the third practice parameter on allergen immunotherapy (AIT), summarizing the contemporary understanding of AIT immunologic mechanisms. Since, major advances have substantially expanded insight into this complex field. This review briefly revisits earlier concepts and then focuses on newer mechanistic findings and emerging ideas, that yet have to be developed further to better understand AIT mechanisms.

Structural cells are now recognized as active contributors to the initiation of allergic inflammation; AIT reduces their pro-inflammatory activation. The innate immune system particularly type 2 innate lymphoid cells (ILC2s), plays an important role in initiating and sustaining allergic responses. AIT reduces the activation and/or number of the innate immune cells, potentially contributing to immune tolerance. Within the adaptive immune system Th2A and Tfh13 are the main pro-allergic effector cells, while regulatory T and B-cell subsets have been identified as key mediators of the long-term tolerance induced by AIT. Mechanistic differences between sublingual and subcutaneous AIT are also increasingly apparent: SCIT promotes serum allergen-specific IgG4 and serum blocking activity, while SLIT induces local nasal allergen-specific IgA1. Finally, AIT dose-response relationships vary between individuals, which may explain the clinical need for dose adjustments in some patients. The significance of molecular, proteomic, genetic and metabolic changes documented with AIT remains under investigation. Advances in understanding allergic immune responses and the complex immune changes (including cell plasticity) induced by AIT, might pave the way for enhanced AIT efficacy and predictive biomarkers in the future.

Allergen immunotherapy is the only potentially disease-modifying treatment for IgE-mediated respiratory allergy. Among the available routes, sublingual immunotherapy (SLIT) has gained prominence because of its favorable safety profile and greater patient acceptability.

This narrative review critically appraises the clinical efficacy, real-world effectiveness, and long-term disease-modifying potential of SLIT for seasonal and perennial respiratory allergies by integrating evidence from randomized controlled trials, large observational cohorts, and meta-analyses, with attention to allergen- and product-specific outcomes and age-related differences.

Robust RCT evidence supports clinically meaningful reductions in symptoms and medication use with grass and HDM SLIT tablets, with sustained benefits observed up to 1-2 years after a 3-year treatment course in key trials. Real-world cohorts corroborate these findings and additionally report a reduced risk of new asthma onset and lower long-term medication dispensing after SLIT. Evidence for SLIT in asthma shows reductions in exacerbation risk in some trials, although its effects on day-to-day control are less consistent. Pediatric trials generally mirror adult outcomes, with favorable safety and efficacy, particularly for standardized tablets; however, heterogeneity across trials and historical methodological limitations remain important caveats. Meta-analyses confirm overall efficacy but highlight substantial between-study heterogeneity and the importance of product-specific evaluations.

SLIT could be an effective, well-tolerated, disease-modifying option for respiratory allergic rhinitis and shows promise for selected asthma outcomes. Optimal benefits require standardized, adequately dosed formulations and sustained adherence (≥3 years). Future research should prioritize product-specific, adequately powered trials with standardized outcomes to refine patient selection and long-term disease-modification endpoints.

Oral immunotherapy (OIT) practices for food allergy vary globally. Whereas oral food challenges (OFCs) are not routinely performed before OIT, they can prevent unnecessary treatment. In 2024, the Allergy Development to an Accelerated Path to Tolerance (ADAPT) OIT program was established as the first nationally standardized model of care for treatment of peanut allergy. Threshold OFCs (TOFCs) were used to confirm peanut allergy and determine the OIT starting dose.

We evaluated the diagnostic accuracy and safety of this approach before starting OIT across the 10 ADAPT public hospital sites.

Infants aged less than 12 months with a history of Consortium for Food Allergy Research grade 1 to 2 reaction to peanut and sensitization (skin prick test result of 3 mm or greater or peanut/Ara h 2 specific IgE result 0.35 kUA/L or greater) were eligible. A TOFC involved seven escalating doses of 15-1,300 mg peanut protein). Data were collected by retrospective chart review.

Between April 2024 and October 2025, we assessed 1,275 infants; 778 underwent TOFC (median age, 13 months). The TOFCs were positive in 65.2% (507 of 778), with median eliciting dose of 120 mg. Anaphylaxis occurred in 12.0% of positive OFCs (61 of 507; 7.8% overall). Median skin prick test and Ara h 2 specific IgE results were higher in positive versus negative TOFCs but did not predict the reaction threshold or severity. Among 394 infants commencing OIT, 97.5% (384 of 394) successfully initiated treatment at a dose below the TOFC-determined threshold.

Within ADAPT, 34.8% of infants had negative TOFCs despite prior reactions and sensitization, enabling early delabeling. Although TOFCs carried an anaphylaxis risk, events were safely managed. Oral food challenge should be routinely considered in infant peanut allergy evaluation regardless of the proposed management strategy (immunotherapy or allergen avoidance).

Basophils are recognized as important effector cells during the sensitization and effector phases of IgE-mediated allergy. Besides histamine release during anaphylaxis, basophils contribute to early immune polarization as an important source of Th2-associated cytokines. Vespula spp. venom immunotherapy (VIT) represents a prime example of clinically highly effective allergen-specific immunotherapy. This study investigated functional and phenotypic changes in circulating basophils during early VIT in a homogenous case series.

Twenty-four patients eligible for VIT were examined before treatment, after 3 days, and after 1 month of therapy. Basophils were primed with interleukin-(IL-) 3 and stimulated with IgE-dependent triggers, including Vespula spp. venom and an anti-IgE antibody, as well as the IgE-independent bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Basophil activation was assessed by flow cytometric measurement of CD63 expression. In parallel, FcεRI and FcγRIIb receptor expression on basophils was quantified, and serum levels of total IgE, Vespula spp. venom-specific IgE, and venom-specific IgG4 were measured. Changes over time were tested using a mixed-effects model for repeated measures. Paired t-tests, Wilcoxon signed-rank tests, and Friedman tests were used for paired comparisons and non-parametric repeated measures.

After one month of VIT, venom-specific basophil excitability was significantly reduced. In contrast, activation by anti-IgE and fMLP remained largely unchanged. An increase of both FcεRI and FcγRIIb expression on basophils was already detectable at day 3 after starting VIT and reached statistical significance at day 28. Serologically, total IgE and Vespula spp. venom-specific IgE slightly rose during VIT, but the most pronounced increase was observed for venom-specific IgG4.

Data of this study suggest that upregulation of FcγRIIb together with venom-specific IgG4 induction drives venom-specific basophil suppression, possibly by FcγRIIb-FcεRI co-aggregation. The overall picture of venom-specific basophil activation, basophil FcγRIIb expression, and serum IgG4 may serve as a biomarker of immune modulation towards tolerance

Despite major advances in the treatment of severe asthma with biologics targeting IgE, IL-5/IL-5Rα, IL-4Rα, and thymic stromal lymphopoietin (TSLP), these agents suppress type 2 inflammation without reliably inducing durable allergen-specific tolerance. Allergen immunotherapy (AIT) remains the only disease-modifying option for IgE-mediated respiratory allergy, yet its use in severe asthma has historically been restricted by safety concerns in uncontrolled disease. We propose a "control first, tolerance second" framework, whereby biologic-induced disease control creates a window enabling safe initiation of subcutaneous or sublingual AIT. This narrative review synthesizes the immunological rationale and clinical evidence supporting sequential biologic-AIT combination, with emphasis on omalizumab as the best-studied adjunct and emerging data on dupilumab and tezepelumab. We address biomarker-guided patient selection, treatment sequencing, comorbid allergic rhinitis and chronic rhinosinusitis, corticosteroid-sparing effects, infection risk, airway antiviral immunity, and unresolved questions around long-term remission. The novelty of this framework lies in reframing biologics not merely as symptom-control agents but as facilitators that unlock a previously inaccessible disease-modifying intervention, potentially shifting severe allergic asthma management from control toward durable immunological remission. We conclude that biologic-enabled AIT is a promising but insufficiently defined strategy, and outline the prospective trials, standardized phenotyping, and safety registries needed to establish it as an evidence-based clinical pathway.

Egg allergy is one of the most common IgE-mediated food allergies. There is no treatment approved by the US Food and Drug Administration that allows the liberalization of egg into the diet. Studies have shown that oral immunotherapy (OIT) provides protection against accidental ingestion and may also allow patients to eat egg freely, but vary in terms of protocols, efficacy, and adverse effects.

To assess the safety and efficacy of three different office-based egg OIT protocols.

Describe three egg OIT protocols, specifically low-dose native egg, high-dose native egg, and baked egg. Compare the safety profiles and outcomes of the three protocols.

A total of 96 individuals underwent egg OIT. The mean age was 8.4 years, and 43% were female. Those undergoing low-dose egg OIT had lower rates of premedication and epinephrine use compared with the other 2 OIT protocols. Of the 96 patients, 25 (26%) discontinued or were lost to follow-up; 71 (74%) could freely eat baked egg plus at least 3 g of native egg; and 57 (58%) passed a full oral food challenge to 12 g of native egg protein and liberalized their diet to include egg.

By comparing the three OIT protocols, low-dose egg OIT was shown to be well tolerated and permitted the highest rate of patients to reintroduce egg into their diets. Egg OIT is a feasible, safe, and effective therapy in the outpatient setting for the management of egg allergy.

Peanut allergy is an increasingly prevalent condition without curative treatment. Oral immunotherapy (OIT) can induce desensitization, but its mechanisms are not fully understood. Administration of oral short-chain fatty acids (SCFAs) in murine models induces favorable immunomodulation that overlaps with processes observed in OIT. We hypothesized that in human populations, oral SCFA levels change during OIT and are associated with systemic downregulation of Type 2 processes.

Within a clinical trial of children age 4-14 years with high-threshold peanut allergy randomized to OIT or avoidance, we profiled oral SCFA levels, the oral microbiome, and peripheral blood transcriptome over the course of OIT or avoidance. Statistical and network analyses were carried out to test our hypotheses.

Among the 56 children in the clinical trial with complete multi-omic profiles over the trial duration, 29 were randomized to OIT and 27 to avoidance. 100% of the participants in the OIT group achieved desensitization compared to 18.5% in the avoidance group. Oral levels of the SCFA propionate increased with OIT but not avoidance (FDR=0.042) and remained elevated with sustained unresponsiveness. Oral propionate levels positively correlated with the relative abundances of several oral microbes, including known propionate producers Prevotella spp. (r=0.47, FDR 3.75x 10-3) and Veillonella (r=0.39, FDR 1.45x10-2). Oral propionate levels negatively correlated with peripheral blood transcript expression of OIT-associated Fcγ receptors (FDR≤ 0.05), IL-4 & IL-13 signaling (FDR≤ 0.05), and neutrophil degranulation pathways (FDR≤ 0.05).

This study raises the intriguing possibility of oral propionate serving as an important immunoregulatory bridge between local and systemic processes in peanut OIT.