The seventh “Future of the Allergists and Specific Immunotherapy (FASIT)” workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the “Therapy Allergen Ordinance” in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.

The majority of children with sustained unresponsiveness after extended egg OIT are able to successfully introduce dietary egg. OIT outcome may be predictive of frequency, type (concentrated, baked), and quantity of egg ingested in the long term.

Peanut allergy is a severe and increasingly frequent disease with high medical, psychosocial and economical burden for affected patients. A causal, safe and effective therapy is not available.

We aimed to develop an immunogenic, protective and non-reactogenic vaccine candidate against peanut allergy based on Virus-like Particles (VLPs) coupled to single peanut allergens.

To generate vaccine candidates, extracts of roasted peanut (Ara R) or the single allergens Ara h 1 or Ara h 2 were coupled to immunologically optimized Cucumber Mosaic Virus-derived VLPs (CuMVtt). BALB/c mice were sensitized intraperitoneally with peanut extract absorbed to Alum. Immunotherapy consisted of one single subcutaneous injection of CuMVtt coupled to Ara R, Ara h 1 or Ara h 2.

The vaccines CuMVtt-Ara R, CuMVtt-Ara h 1 and CuMVtt-Ara h 2 protected peanut sensitized mice against anaphylaxis after i.v. challenge with the whole peanut extract. Vaccines did not cause allergic reactions in sensitized mice. CuMVtt-Ara h 1 was able to induce specific IgG antibodies, diminished local reactions after skin-prick-tests and reduced the infiltration of the gastrointestinal tract by eosinophils and mast cells after oral challenge with peanut. The ability of CuMVtt-Ara h 1 to protect against challenge with the whole extract was mediated by IgG, as shown via passive IgG transfer. FcγRIIb was required for protection, indicating that immune-complexes with single allergens were able to block the allergic response against the whole extract, consisting of a complex allergen mixture.

Our data suggest that vaccination using single peanut allergens displayed on CuMVtt may represent a novel and safe therapy against peanut allergy.

Oral immunotherapy (OIT) can successfully desensitize many peanut-allergic subjects, but clinical tolerance diminishes over time on discontinuation, or low-dose maintenance, of peanut. Therefore, to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses.

We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT.

We longitudinally measured, before, during, and after OIT, basophil activation in whole blood ex vivo in response to peanut stimulation, and peanut-specific IgE (sIgE) and peanut-specific IgG4 (sIgG4), in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut-specific immunoglobulins between those who were clinically reactive and those who were tolerant to peanut oral challenges.

Peanut OIT significantly decreased basophil activation, peanut sIgE, Ara h 1, Ara h 2, and Ara h 3 IgE levels, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation ex vivo and higher peanut sIgE levels and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT.

Assessments of peanut-induced basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization versus sustained unresponsiveness after OIT.

Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.

Immunoglobulin E (IgE) are least abundant, tightly regulated and IgE producing B cells are rare. The cellular origin and evolution of IgE responses are poorly understood.

To investigate the cellular and clonal origin of IgE memory responses following mucosal allergen exposure by sublingual immunotherapy (SLIT).

In a randomized double-blind, placebo-controlled, time-course SLIT study, peripheral blood mononuclear cells (PBMCs) and nasal biopsies were collected from forty adults with seasonal allergic rhinitis at baseline, 4, 8, 16, 28 and 52 weeks. RNA was extracted from PBMCs, sorted B cells and nasal biopsies for VH repertoire sequencing. Moreover, monoclonal antibodies were derived from single B cell transcriptomes.

Combining VH repertoire sequencing and single cell transcriptomics yielded direct evidence of a parallel boost of two clonally and functionally related B cell subsets of short-lived IgE+ plasmablasts and IgG+ memory B cells (termed IgGE). Mucosal grass pollen allergen exposure by SLIT resulted in highly diverse IgE and IgGE repertoires. These were extensively mutated and appeared relative stable as per heavy chain isotype, somatic hypermutations and clonal composition. Single IgGE + memory B cell and IgE+ pre-plasmablast transcriptomes encoded antibodies that were specific for major grass pollen allergens and were able to elicit basophil activation at very low allergen concentrations.

For the first time, we have shown that upon mucosal allergen exposure, human IgE memory resides in allergen-specific IgG+ memory B cells. These rapidly switch isotype and expand into short-lived IgE+ plasmablasts and serve as a potential target for therapeutic intervention.

Allergen immunotherapy (AIT) is an effective treatment for allergic diseases. We investigate whether treatment-initiation during the pollen season is safe.

RCT-IIIb-trial of 6-grass-pollen-allergoid (Allergovit®) in grass pollen-allergic patients (18-65 years) with moderate-severe rhinitis/rhinoconjunctivitis (± controlled asthma), randomized 2:1 to treatment-initiation during (Group-A) versus outside the pollen season (Group-B).

Of 240 patients (32.8 ± 9.9 years, 19.5% asthma) treated, 84.9% (Group-A) and 86.6% (Group-B) reached maintenance dose without delay. Treatment-emergent adverse events occurred in 108 (68.4%/Group-A) and 41 patients (56.2%/Group-B) leading to premature trial-termination in 11 patients (7%/A) versus 3 (4.1%/B). Across groups, physicians (for 190 patients; 85.2%) and patients (192; 86.1%) rated the tolerability as ‘very good’-‘good’. Phleum pratense-specific IgG4 increased in both groups (p < 0.0001).

Year-round allergen immunotherapy-initiation with this preparation is safe.

To systematically review the effect and safety of epicutaneous immunotherapy (EPIT) for allergic diseases.

We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, CQ VIP Database, Wanfang Data, and international trial register from their inception to July 29, 2019, without language restrictions, for randomized controlled trials (RCTs) that compared EPIT versus no EPIT for allergen-triggered allergic reactions. We assessed certainty of evidence by the GRADE approach.

Ten RCTs with 1,085 participants (aged from 10 months to 65 years) comparing EPIT with placebo for peanut, cow milk, or grass-pollen allergy met the eligibility criteria. A substantial benefit in terms of desensitization in EPIT group was more likely for peanut or cow milk protein allergy (risk ratio [RR] 2.34, 95% CI 1.69-3.23; I2 = 0%; high certainty evidence). EPIT increased local-treatment-related adverse events (L-TRAE; RR 1.56, 95% CI 1.03-2.36; I2 = 82%; moderate certainty evidence). But there were no significantly increased risk of any TRAEs (low certainty evidence) or systemic-TRAEs (S-TRAEs; very low certainty evidence) in EPIT group. The incidence rate of serious AEs, the use of rescue medications, and anaphylactic reactions stratified by organ systems including skin and mucosa, eyes and upper respiratory, lower respiratory, and gastrointestinal system in EPIT group were similar to placebo group. In subgroup analysis, desensitization of EPIT was significantly effective in peanut allergy (RR 2.29, 95% CI 1.64-3.21; I2 = 0%) and children <12 years (RR 2.85, 95% CI 1.92-4.24; I2 = 0%) with high certainty evidence. Only epicutaneous grass-pollen immunotherapy significantly increased the risk of S-TRAE (RR 4.65, 95% CI 1.10-19.64; I2 = 0%).

The systematic review suggests that EPIT might induce desensitization in peanut allergy and an increased risk of local AEs. These findings should be interpreted with caution owing to the limited study and heterogeneity. More data in the older (children ≥12 years and adults) and other allergic diseases are needed.

Venom immunotherapy (VIT) is an established and effective treatment for patients with Hymenoptera venom allergies. Especially during the build-up of VIT, systemic allergic reactions are a key issue.

To investigate the safety and effectiveness of a 3-day rush insect VIT protocol and a strategy for the management of individuals with VIT-induced anaphylaxis.

In this retrospective monocentric study, 11-year data regarding build-up cycles of VIT were retrieved from institutional records. The following parameters of VIT-induced anaphylaxis were analyzed: frequency, severity, time of occurrence within the build-up cycle, and impact on the success of VIT. The effectiveness of VIT was assessed by the results of sting challenges (SCs) by the culprit insect.

In total, 1,317 initial build-up cycles of VIT were evaluated in this study, and the frequency of VIT-induced anaphylaxis was 6.6%. Anaphylaxis occurred most frequently when the daily cumulative venom dose was ≥100 µg. A group (n = 65) of patients with VIT-induced anaphylaxis in this dose range temporarily received a reduced maintenance dose, and without additional co-medications or complications, the target dose was reached after a second build-up in 91% of the cycles. After completing the VIT build-up, SCs were performed in 76.9% of the cohort, and the effectiveness of VIT was confirmed by 98.5% of the tests.

In this study, we report a 3-day VIT rush protocol with a reasonable rate of VIT-induced anaphylaxis and excellent effectiveness of VIT.

Venom immunotherapy (VIT) is an established and effective treatment for patients with Hymenoptera venom allergies. Especially during the build-up of VIT, systemic allergic reactions are a key issue.

To investigate the safety and effectiveness of a 3-day rush insect VIT protocol and a strategy for the management of individuals with VIT-induced anaphylaxis.

In this retrospective monocentric study, 11-year data regarding build-up cycles of VIT were retrieved from institutional records. The following parameters of VIT-induced anaphylaxis were analyzed: frequency, severity, time of occurrence within the build-up cycle, and impact on the success of VIT. The effectiveness of VIT was assessed by the results of sting challenges (SCs) by the culprit insect.

In total, 1,317 initial build-up cycles of VIT were evaluated in this study, and the frequency of VIT-induced anaphylaxis was 6.6%. Anaphylaxis occurred most frequently when the daily cumulative venom dose was ≥100 µg. A group (n = 65) of patients with VIT-induced anaphylaxis in this dose range temporarily received a reduced maintenance dose, and without additional co-medications or complications, the target dose was reached after a second build-up in 91% of the cycles. After completing the VIT build-up, SCs were performed in 76.9% of the cohort, and the effectiveness of VIT was confirmed by 98.5% of the tests.

In this study, we report a 3-day VIT rush protocol with a reasonable rate of VIT-induced anaphylaxis and excellent effectiveness of VIT.