Hypoallergenic recombinant fold-variants of major allergens have been suggested as safer and more effective AIT candidates. The Bet v 1-fold variant BM41, with confirmed preclinical hypoallergenicity and increased immunogenicity, was proposed for the treatment of birch pollen allergy.

We performed a 6-month randomized, double-blind, placebo-controlled first-in-human clinical trial with BM41, a licensed birch pollen extract-based treatment, as the active comparator (AC), and placebo (n = 16, n = 16, and n = 15, respectively). The primary endpoint was safety. Secondary outcomes were Bet v 1-specific (s)IgE, IgG, IgG1, and IgG4 responses measured by ImmunoCAP, and sIgE-blocking activity using mediator release and facilitated antigen binding assays.

Despite SPT-confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG1 levels were induced, sIgG4 levels increased 3-fold more in AC compared to the BM41 group. In AC, the sIgG4/sIgG1 ratio tripled over time, whereas for BM41 it stagnated. BM41 induced efficient serum inhibitory activity for sIgE compared to placebo but was 12%-32% less efficient than AC. Both sIgG4 and sIgG1 contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity.

Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG4 by the fold variant in the course of the treatment was less efficient in blocking sIgE-mediated responses. This is the first study providing evidence that, instead of a Th1-favored IgG1-dominated response, "modified Th2"-skewed IgG4-dominated humoral responses are beneficial in AIT vaccine design.

A short-course pre-seasonal subcutaneous injection of PQ Grass is clinically effective for the treatment of allergic rhinitis, though its mechanism remains unclear. The aim of the study was to interrogate immunological mechanisms induced by PQ Grass conventional and extended regimens.

A RDBPC exploratory field study involving participants that either received injections of PQ Grass with a cumulative dose of 27,600 SU conventional (six once weekly injections) or extended regimen (three once weekly injections followed by three once monthly injections) or placebo containing microcrystalline tyrosine (MCT) (placebo + MCT) or saline (placebo) was performed. Humoral, cellular, and molecular responses were assessed at baseline (V1), end of treatment, prior to grass pollen season (V12) and end of pollen season (V15). Immunoglobulin analyses and cellular/gene microarray analyses were performed in the sub-study cohort consisting of PQ Grass Conventional (n = 25 and n = 10, respectively), PQ Grass Extended (n = 26 and n = 10, respectively), Placebo with MCT (n = 13 and n = 5, respectively), and Placebo (saline; n = 12 and n = 5, respectively).

Both PQ Grass regimens, conventional and extended, were associated with improvement in total combined scores (TCS) with a relative difference of -35.0% (p = 0.03) and -40.8% (p = 0.01) against placebo with MCT, respectively. Both PQ Grass treatment regimens were associated with increases in the sIgG4/sIgE ratio (all, p < 0.05) and induction of IgA1 (all, p < 0.05) and IgA2 (all, p < 0.01) compared to placebo groups. Nasal fluid (p < 0.01) and serum (p < 0.05) blocking antibodies are functional and have the capacity to inhibit allergen-IgE complex formation and binding to B cells in the PQ Grass groups. In vitro cellular and microarray gene analyses demonstrated that the extended PQ Grass regimen was more proficient in modulating the immune response towards a tolerogenic milieu by dampening pro-inflammatory type 2 immune response and the associated cytokines (p < 0.05), immune deviation towards a Th1 response (p < 0.05), and induction of FOXP3+ Treg cells (p < 0.05).

For the first time, we highlight differential mechanisms of tolerance induction by PQ Grass, with the extended regimen being superior in modulating T cell compartments.

Sublingual allergen immunotherapy (SLIT) is a safe and effective treatment of allergic rhinitis, and its use has been increasing in recent years. Although several randomized and observational studies showed the effectiveness of SLIT among adults and children aged > 12 years, its extent remains unclear in nationwide routine healthcare settings for school-aged children.

We conducted a propensity score (PS)-matched cohort study using a nationwide administrative database. Data from 13,449 individuals who received SLIT for house dust mites between 2015 and 2021 were extracted and matched with data from 1,732,961 individuals who did not. The PS-matching procedure created 10,985 pairs and followed them for three years, totaling 812,795 person-months. Then, we compared healthcare costs, resource use, and prescriptions between the SLIT and control groups over the three years.

The introduction of SLIT was associated with an 8.9% reduction in antibiotic use (95% CI, 12.0% to 34.7%) and a 65.2% reduction in hospitalizations (95% CI, 52.8% to 74.4%), as well as a 44.1% increase in health resource utilization (95% CI, 40.7% to 47.6%), with minimal impact on overall healthcare costs (+8.9% [95% CI, -12.0% to +34.7%]) over the three-year follow-up period. Similar findings were observed in event-study design and intention-to-treat analyses, as well as in age-stratified analyses (ages 5-10 years and 11-19 years).

The introduction of SLIT for house dust mites was associated with a reduction in antibiotic prescriptions and hospitalizations among children aged 5-19 years with minimal impact on healthcare costs, demonstrating sustained benefits over three years.

Peanut Oral Immunotherapy (POIT) holds promise for remission of peanut allergy, though treatment is protracted and successful in only a subset of patients. Because the gut microbiome has been linked to food allergy, we sought to identify fecal predictors of POIT efficacy and mechanistic insights into treatment response. Here, we conducted a secondary analysis of the IMPACT randomized, double-blind, placebo-controlled POIT trial (NCT01867671), using longitudinal fecal samples from 90 children, and performed 16S rRNA sequencing, shotgun metagenomics, and untargeted metabolomics. Integrated multi-omics analyses revealed a relationship between gut microbiome metabolic capacity and treatment outcomes. Five fecal bile acids present prior to treatment initiation predicted POIT efficacy (AUC 0.71). Treatment failure was associated with a specific bile acid profile, enhanced amino acid utilization, and higher copy number of the ptpA gene encoding a bacterial hydrolase that cleaves tripeptides containing proline residues—a feature of immunogenic peanut Ara h 2 proteins. In vitro, peanut-supplemented fecal cultures of children for whom POIT failed to induce remission evidenced reduced Ara h 2 concentrations. Thus, distal gut microbiome metabolism appears to contribute to POIT failure.

Oral immunotherapy (OIT) induces desensitization in peanut allergy, yet 15%-30% of patients do not respond, and a significant risk of anaphylaxis due to treatment remains. In a placebo-controlled peanut OIT trial, this study identifies molecular drivers of OIT responsiveness through multi-omics profiling in immune cells.

Immunoglobulins, cytokines, transcriptome, and DNA methylome profiles were analyzed in peanut-stimulated and unstimulated peripheral blood mononuclear cells isolated from peanut-allergic children before and after treatment. Multi-omics profiling focused on OIT responsiveness within the active treatment arm. Additional subgroup analyses were performed to further elucidate molecular mechanisms and potential biomarkers.

Complete responders, tolerating 4500 mg of peanut protein, exhibited lower pre-treatment peanut-specific IgE and Th2 cytokine production (IL-4, IL-5) compared to incomplete responders who tolerated ≤ 1000 mg of peanut protein after treatment. Our primary analysis identified 184 differentially expressed genes and 1001 differentially methylated genes, enriched for innate (ILC3) and adaptive (CD8αα subset of CD8+ T cells) immune cells, alongside γδ T cells and exosomes, highlighting gastrointestinal regulatory processes as central to OIT success. We found a marked downregulation of immunoglobulin genes in patients receiving peanut compared to placebo, suggesting OIT-induced modulation of B-cell activity. Functional networks revealed a marked imbalance contrasting regulatory T-cell responses and B-cell suppression in the complete responders with innate immune signaling and metabolic stress in the incomplete responders.

This multi-omics approach underscores the importance of gastrointestinal immune mechanisms underlying the variation in peanut oral immunotherapy responses and offers potential biomarkers for improving treatment strategies. Trial registration: German Clinical Trials Register DRKS00004553.

The sting challenge test (SCT) is regarded as the most reliable method for assessing the effectiveness of venom immunotherapy (VIT). However, its predictive value in patients undergoing VIT is unclear. This study aims to evaluate the predictive value of the SCT.

A multicenter retrospective observational study was conducted on patients receiving VIT who underwent SCT. The study gathered data on patient demographics, diagnosis, immunotherapy details, outcomes of the SCT, and subsequent field stings.

A total of 261 patients were included, and 372 SCTs were recorded. Most patients (75.1%) were men. Mastocytosis was confirmed in 7.7%. The final diagnosis was allergy to Apis mellifera (48.7%), Polistes dominula (36.8%), Vespula species (2.7%), and P dominula plus Vespula species (10.7%). SCTs were performed with Apis in 61.6% overall, Polistes in 34.1%, and Vespula in 4.3%. Most of the SCT results were negative (95.7%). A total of 306 field stings were recorded for 146 patients (56.2%); of these, 95.1% were negative. Among these 146 affected patients, 137 had a negative SCT result, and 130 of these also had a subsequent negative field sting, resulting in a negative predictive value (NPV) for the SCT of 94.9%. Of the patients who experienced a field sting, 9 had a positive SCT, and only 3 had a positive field sting, resulting in a positive predictive value of 33.3%.

SCT is safe, and the high NPV emphasizes the usefulness of this test in assessing the effectiveness of VIT.

Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well-justified minimal clinically important difference (MCID).

Direct patient feedback from 1071 grass-allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS0-6. Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS0-6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE).

69% of grass-allergic patients were satisfied with a 1-point-improvement (e.g., from "severe" to "moderate") in their most severe symptom. This translated into an MCID range for CSMS0-6 of -0.23 to -0.21 points or -17% to -16%. Furthermore, a -0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS0-6 of -0.21 points (-16%) was derived using RESONATE.

Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS0-6 scale and -16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

In this uncontrolled phase II/III study, 42 apple cultivars were tested for their allergen content in vivo by skin prick tests and oral provocations. Afterwards, 36 patients consumed apples of increasing dose and allergenicity over a period of 12 months. Side effects were documented weekly in a clinical diary. Efficacy was tested before and after therapy by oral provocation and skin prick test with Golden Delicious apple. Total IgE, specific IgE, and IgG4 for Mal d 1 and inhibition of basophil activation were analyzed before and after treatment. Other cross-reactive foods were determined by a questionnaire before and after therapy.

Oral immunotherapy with apples resulted in a consistent and durable tolerance of apples and significant augmented tolerance to other Bet v 1 cross-reactive foods. After therapy, specific IgG4 antibodies to Mal d 1 increased significantly, while specific IgE to Mal d 1 and skin prick test reactivity to apples decreased significantly. Moreover, sera of treated patients displayed blocking activity to Mal d 1.

Oral allergy-specific immunotherapy with fresh apples is a promising treatment for birch pollen food allergy syndrome to apples and other Bet v 1 cross-reactive foods.

Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergic rhinitis and asthma. Sublingual immunotherapy (SLIT) is commonly used in clinical practice. Although its effectiveness has been proven in randomized controlled trials and real-world studies, poor or no responses may occur in some cases.

The present review aims to summarize the main possible factors involved in ineffective SLIT treatment, including immunological mechanisms, molecular and diagnostic errors, non-purified extracts, inadequate dosage, and patients' intrinsic and extrinsic characteristics. Possible remedies are also reported to predict and overcome poor patient response to guarantee optimal treatment efficacy.

Identifying the reason for SLIT ineffectiveness is clinically relevant. Allergologists should carefully investigate the possible cause of poor or no response to SLIT. Identification is important as the potential removal of the interfering problems might allow SLIT to continue. The most common causes of poor SLIT efficacy include diagnostic errors, incorrect allergen dosage and schedule, poor quality extract, comorbidity, impaired immune system function, and inadequate adherence.