Allergen immunotherapy is highly effective for seasonal pollinosis. 3 years treatment results in long-term efficacy. This disease modification is accompanied by downregulation of allergen-specific Th2 responses and the induction of persistent specific IgG and IgA- associated IgE-blocking activity. In children with seasonal rhinitis, both subcutaneous and sublingual pollen immunotherapy have been shown to reduce development of asthma symptoms and asthma medication requirements. House dust mite tablet allergen immunotherapy has been shown to be effective for perennial mite-driven rhinitis in adults and children and may suppress asthma exacerbations, whereas its long-term efficacy has yet to be explored. The success of primary prevention of peanut allergy in childhood by introduction of peanut into the diet during infancy provides a strong rationale to explore whether primary prevention of inhalant allergies and asthma may also be possible. House dust mite allergy is a major risk factor for developing asthma. Preliminary data in at-risk children suggests that sublingual house dust mite immunotherapy initiated during infancy could reduce onset of multiple allergen sensitisations and prevent development of asthma at age 6 years. This possibility should now be explored in an adequately powered prospective randomised controlled trial.

Food allergy is an increasing public health problem in children and adults. In addition to the risk of potentially severe reactions, food allergy can have a significant burden on quality of life, nutrition, cost of living, and social activities. Traditionally, treatment has primarily included strict food allergen avoidance and use of emergency medications to treat an allergic reaction. However, in recent years, there have been significant strides in the advancement of food allergy treatment, including the approval of the first and only approved therapy (peanut oral immunotherapy) for food allergy in 2020. Clinical trials have primarily focused on food allergen immunotherapy (oral, epicutaneous, sublingual). Building off of a foundation of promising data supporting the efficacy of food oral immunotherapy and our greater understanding of the underlying mechanism of immunotherapy, newer approaches, including alternative routes of delivery, adjuncts to therapy, modified allergens, and utilization in younger patients, aim to provide safer and more effective treatment approaches to the millions of patients burdened by food allergy.

Virus-like particle (VLP) Peanut is a novel immunotherapeutic vaccine candidate for the treatment of peanut allergy. The active pharmaceutical ingredient represents cucumber mosaic VLPs (CuMVTT -VLPs) that are genetically fused with one of the major peanut allergens, Ara h 2 (CuMVTT -Ara h 2). We previously demonstrated the immunogenicity and the protective capacity of VLP Peanut-based immunization in a murine model for peanut allergy. Moreover, a Phase I clinical trial has bee initiated using VLP Peanut material manufactured following a GMP compliant manufacturing process. Key product characterization studies were undertaken here to understand the role and contribution of critical quality attributes that translate as predictive markers of immunogenicity and protective efficacy for clinical vaccine development.

The role of prokaryotic RNA encapsulated within VLP Peanut on vaccine immunogenicity was assessed by producing a VLP Peanut batch with a reduced RNA content (VLP Peanut low RNA). Immunogenicity and peanut allergen challenge studies were conducted with VLP Peanut low RNA, as well as with VLP Peanut in WT and TLR 7 KO mice. Furthermore, mass spectrometry and SDS-PAGE based methods were used to determine Ara h 2 antigen density on the surface of VLP Peanut particles. This methodology was subsequently applied to investigate the relationship between Ara h 2 antigen density and immunogenicity of VLP Peanut.

A TLR 7 dependent formation of Ara h 2 specific high-avidity IgG antibodies, as well as a TLR 7 dependent change in the dominant IgG subclass, was observed following VLP Peanut vaccination, while total allergen-specific IgG remained relatively unaffected. Consistently, a missing TLR 7 signal caused only a weak decrease in allergen tolerability after vaccination. In contrast, a reduced RNA content for VLP Peanut resulted in diminished total Ara h 2 specific IgG responses, followed by a significant impairment in peanut allergen tolerability. The discrepant effect on allergen tolerance caused by an absent TLR 7 signal versus a reduced RNA content is explained by the observation that VLP Peanut-derived RNA not only stimulates TLR 7 but also TLR 3. Additionally, a strong correlation was observed between the number of Ara h 2 antigens displayed on the surface of VLP Peanut particles and the vaccine's immunogenicity and protective capacity.

Our findings demonstrate that prokaryotic RNA encapsulated within VLP Peanut, including antigen density of Ara h 2 on viral particles, are key contributors to the immunogenicity and protective capacity of the vaccine. Thus, antigenicity and RNA content are two critical quality attributes that need to be determined at the stage of manufacturing, providing robust information regarding the immunogenicity and protective capacity of VLP Peanut in the mouse which has translational relevance to the human setting.

A lower adherence rate existed in patients received allergen specific immunotherapy (AIT) due to its lengthy period and side effects even though it is the only curative treatment for IgE-mediated allergies. Therefore, exploring innovative AIT routes are necessary.

This study was designed to explore the efficacy and safety of the intratonsillar injection of house dust mite (HDM) extract in patients with HDM-induced allergic rhinitis.

A randomized double-blind placebo-controlled clinical trial was conducted. Eighty patients with HDM-induced AR were randomized to receive 6 intratonsillar injections with HDM extract or placebo over 3 months. The total nasal symptom score (TNSS), Visual Analogue Scale (VAS) of nasal symptoms, combined symptom and medication score (CSMS), Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ), and serum allergen-specific IgG4 to D. pteronyssinus were all monitored at baseline, 3, 6, and 12 months after the treatment finished. The intent to-treat (ITT) and per protocol set (PPS) are both analyzed.

The primary endpoints TNSS and ΔTNSS were improved significantly at 3 months after AR patients finished a 3-month 6 injection intratonsillar immunotherapy (ITIT) by comparing to the placebo treatment in both ITT and PPS. VAS, CSMS and MiniRQLQ were also improved significantly at 3 months after treatment in PPS. However, the improvement effect of ITIT at 6 and 12 months was limited and uncertain based on the data. The increase of serum Der p IgG4 in the active group was significantly higher than that in the placebo group at 3, 6, and 12 months after the treatment finished. Adverse events were monitored, and no systemic adverse reactions were observed.

The clinical trial showed that intratonsillar injection with HDM extract was safe and effective in patients with AR. Optimizing the protocol and allergen formulations is expected to increase and maintain the efficacy of this novel approach.

Intralymphatic immunotherapy (ILIT) is a novel, faster alternative to conventional allergen immunotherapy (AIT). Few previous studies have evaluated its long-term effects. The objective of the present study was to complete a 5-year follow-up of a randomized double-blind placebocontrolled trial of ILIT for a combination of birch and grass allergens.

Fifty-eight patients with allergic rhinitis were treated with either placebo or a combination of ALK Alutard Birch and Grass 1000 SQ-U administered in 3 intralymphatic injections at 1-month intervals. A year after the vaccination, the symptoms induced by nasal provocation were significantly reduced. After 5-6 years, 20 out of 26 actively treated patients were followed up with a nasal provocation test (NPT) and seasonal registration of the combined symptom and medications score (CSMS), IgE and IgG4 levels in blood, and immunological markers in blood and lymph nodes and compared with 13 unvaccinated controls.

The reduction in the NPT response with ILIT at year 1 could not be convincingly reproduced at year 5. The new CSMS scores were markedly lower among the previously treated patients than among the control group. Furthermore, grass-specific IgG4 was increased, grass specific IgE decreased, FcεR1 on basophils was reduced, and the fraction of memory T-cells in lymph nodes increased.

The combination of seasonal clinical data and immunological parameters supports the notion of a long-lasting effect of ILIT. These data support the concept of ILIT as a good alternative to traditional AIT in pollen-induced allergic rhinitis.

Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT duration. To show sustained efficacy 10 years after completion of treatment with depigmented-polymerized house dust mite (dpg-pol HDM) allergen extract in adults with asthma and/or rhinoconjunctivitis.

Patients included in a double-blind placebo-controlled AIT study with dpg-pol HDM allergen extract were reviewed at completion of the perennial treatment and 10-year follow-up (10y-FU). Change in symptom and rescue medication score was the primary objective. Visual analog scale (VAS), asthma control test (ACT), and degree of disease control were the secondary objectives. A comparative analysis between patients who underwent AIT treatment for <3 years and ≥3 years was performed.

Data from 31 patients (mean age 38 years) were available at 10y-FU. All had asthma and 29 had rhinoconjunctivitis at baseline. Twentythree patients were treated ≥3 years and 8 for <3 years. Seventeen (55%) patients were asymptomatic at completion of AIT, with significant differences for nasal, conjunctival, and bronchial symptoms (p < .0001) compared with baseline only in those patients treated ≥3 years. Nine (52.9%) patients remained completely asymptomatic at 10y-FU, all were treated for ≥3 years. Moreover, significant reduction in the number of patients with rhinitis (p = .0117), conjunctivitis (p < .0001), and bronchial (p = .0005) sym ptoms was observed at 10y-FU compared with baseline only in the ≥3 years treated. Ten (32.3%) patients did not require any rescue medication at 10y-FU, all had been treated for ≥3 years. ACT at 10y-FU showed a good control of asthma (median 23.5; 95% IC[22.0, 25.0]). No significant differences were observed between VAS at end of treatment compared with VAS at 10y-FU.

Sustained clinical efficacy is achieved 10 years after completion of depigmented-polymerized HDM, however, these findings were observed only if patients are treated for at least 3 years.

Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms remain unclear, AIT has been shown to reduce basophil activation (BA) against nontarget allergens.

The aim of this study was to assess immunological changes in Dermatophagoides farinae (Der f) after Japanese cedar pollen (JCP)- based subcutaneous immunotherapy (SCIT) monotherapy.

The data of 16 patients (age: 6-37 years) with JCP-induced allergic rhinitis who were sensitive to Der f (serum Der f-specificimmunoglobulin E [IgE] level >0.34 kUA/L) and received JCP-based SCIT for 5 years were reviewed retrospectively. BA by Der f and JCP extracts and serum-specific IgE and immunoglobulin G4 (IgG4) levels against these allergens were evaluated before and after completing 5 years of JCPbased SCIT monotherapy.

The areas under the dose-response curves of BA by Der f and JCP extracts were significantly reduced (p = 0.02 and p = 0.002, respectively). JCP-specific IgE levels decreased and JCP-specific IgG4 levels increased significantly (p < 0.001 for both), whereas Der f-specific IgE and IgG4 levels did not change significantly.

JCP-based SCIT monotherapy reduced Der f-specific BA. These findings suggest that JCP-based SCIT has the potential to modulate immune response toward nontarget allergens.

Allergic rhinitis (AR) is a common allergic disease, and SLT has shown effectiveness as a treatment method. This study focuses on the evaluation of serum TAM receptor tyrosine kinases (TYRO3, AXL, and MER) levels as potential indicators of disease severity and predictive markers for sublingual immunotherapy (SLIT) responsiveness in AR patients.

A total of 160 AR subjects, including 40 mild AR (MAR) and 120 moderate-severe AR (MSAR) patients, and 40 healthy controls (HC) were recruited. Serum concentrations of TYRO3, AXL, and MER were measured and their relationships with disease severity were examined. In the MSAR group, 102 patients underwent SLIT, and the early efficacy was evaluated. The correlations between the baseline serum concentrations of TYRO3, AXL, and MER and the early responsiveness of SLIT were analyzed.

Serum concentrations of TYRO3, AXL, and MER were significantly reduced in AR patients, particularly in those MSAR subjects. Correlation analysis results indicated that serum TYRO3 and MER levels were negatively correlated with the visual analog scale (VAS) and the total nasal symptom score (TNSS). After one year of follow-up, 80 AR patients completed the treatment and were divided into effective and ineffective groups. Serum baseline levels of TYRO3 and MER were found to be lower in the effective group compared to the ineffective group. Additionally, there was a significant increase in serum TYRO3 and MER levels compared to baseline levels. Receiver operating characteristic (ROC) analysis revealed that circulating TYRO3 and MER had potential values for reflecting AR severity and predicting early SLIT responsiveness.

Serum TYRO3 and MER concentrations were decreased in AR patients and negatively associated with disease severity. Circulating TYRO3 and MER seem to be promising indicators for monitoring the efficacy of SLIT in AR patients.

Specific IgE (sIgE) is merely a sensitization marker that cannot be used for allergy diagnosis if there are no associated clinical symptoms. As of 2023, there is still no evidence regarding the quantity of sIgE necessary to confirm or exclude clinical disease. Therefore, this study aimed to calculate cut-offs for sIgE, allowing us to effectively diagnose olive or grass pollen allergy and select allergenic immunotherapy (AIT) candidate patients in a region under high olive and grass allergenic pressure.

An observational retrospective study consisting of the review of electronic medical records from 1,172 patients diagnosed with seasonal rhino-conjunctivitis and suspected allergy to olive or grass pollen. Symptoms correlated with sIgE to Poaceae and Oleaceae whole extracts and sIgE to genuine allergenic components were evaluated. Optimal cut-off values were calculated using receiver operating characteristic curves. Relevant clinical symptoms and AIT indications were taken into consideration when determining the clinical allergy diagnosis.

sIgE to Lolium showed the best area under the curve (AUC) for both diagnosis (0.957) and an indication of AIT (0.872). The optimal cut-off values for grass diagnosis and AIT indication were 1.79 kUA/L and 8.83 kUA/L, respectively. A value of 5.62 kUA/L was associated with a positive likelihood ratio (LR) of 10.08 set for grass allergy. Olea sIgE showed the best AUC for the diagnosis (0.950). The optimal cut-off for diagnosis was 2.41 kUA/L. A value of 6.49 kUA/L was associated with a positive LR of 9.98 to confirm olive pollen allergy. In regard to immunotherapy, Ole e 1 sIgE showed the best AUC (0.860). The optimal cut-off was 14.05 kUA/L. Ole e 1 sIgE value of 4.8 kUA/L was associated with a 0.09 negative LR to exclude olive AIT indication.

The sIgE cut-offs found in this population under high olive and grass allergenic pressure reduce the gap between sensitization and clinical allergy, providing a new tool for the diagnosis of seasonal allergic rhinitis/asthma and helping to discriminate patients who will benefit from AIT.

The increasing food allergy incidence has led to significant interest in developing therapies for allergic diseases. Oral allergen-specific immunotherapy (OIT) is a recently FDA-approved therapeutic to treat peanut allergies. OIT utilizes daily allergen dosing to reduce allergic reactions to peanuts. However, there is diminished enthusiasm for daily OIT, potentially due to the strict regimen required to induce desensitization and the risks of severe adverse events. Thus, there remains a need for safe and effective food allergy treatments that are well-received by allergic individuals. Preclinical research studies investigate methods to induce allergen desensitization in animals and support clinical studies that address the limitations of current food allergy OIT. Because allergic reactions are triggered by allergen doses above an individual's activation threshold, immunotherapy regimens that induce allergen desensitization with lower allergen doses or without the requirement of daily administrations may expand the use of food allergy immunotherapy. Administering allergen immunotherapy by alternative routes is a strategy to induce desensitization using lower allergen doses than OIT. Several animal models have evaluated oral, sublingual, epicutaneous, and intranasal immunotherapy routes to treat food allergies. Each immunotherapy route may require different allergen doses, formulations, and treatment schedules to induce desensitization. This article will discuss scientific findings from food allergy immunotherapy animal studies that utilize various immunotherapy routes to induce allergen desensitization to support future clinical studies that enhance the safety and efficacy of allergen immunotherapy to treat food allergies.