Sublingual Immunotherapy For Allergy Research Articles

Sublingual immunotherapy for allergy to shrimp: the nine-year clinical experience of a Midwest Allergy-Immunology practice

BackgroundDiet restrictions and fear of adverse reactions put a significant burden on the nutrition, growth and life style of children and adults with food allergies. While various disease-modifying options are pursued, there are so far no published clinical data on immunotherapy for crustaceans. The efficacy and safety of desensitization to crustaceans by means of sublingual immunotherapy is assessed for the first time in this study with a view of validating it as a clinical-practice modality.MethodsCharts of a Midwest Allergy-Immunology practice from the period January 2014–June 2023 were reviewed to identify patients with allergy to shrimp treated with sublingual immunotherapy and to retrospectively evaluate their responses to oral challenge.ResultsSixty-six patients were identified who had been treated by sublingual immunotherapy for either systemic or localized reactions to shrimp. Demographics and relevant comorbidities were consistent with those of the atopic population. Sublingual immunotherapy with serially diluted mixtures was initiated at 64–320 ng/dose and was gradually escalated to 0.5 mg/dose three times a day. The sublingual immunotherapy course ranged from 5 to 72 months (average: 51 months), following which, 18 patients underwent shrimp oral challenge. No systemic reactions occurred upon challenge; no patient required epinephrine. Tolerance of target dose equal to or exceeding 42 g shrimp was achieved in 11 patients (61%), seven of whom had originally presented with systemic reactions to crustaceans. Seven patients (38%) developed one or more of the following localized reactions: oral itching, nasal symptoms, localized perioral hives, localized hives at pressure points, nausea, vomiting, abdominal pain upon exposure to a cumulative dose of 39.2–148.2 g of shrimp during the 4 h of the challenge. Five of these patients had originally presented with systemic reactions to crustaceans. Five of the 7 patients who developed localized symptoms during the challenge were subsequently placed on routine exposure to 12–20 g shrimp every other day. Two patients continued sublingual immunotherapy but declined routine exposure to shrimp every other day because they had no intention to incorporate crustaceans to their routine diet. On repeat challenge 6–9 months after original challenge, all five patients who had routine exposure to 12–20 g shrimp every other day tolerated the procedure to target dose without any symptoms.ConclusionsDesensitization to shrimp by sublingual immunotherapy appears to be safe and effective as shown in this study. Whether the immune modification induced by sublingual immunotherapy is permanent resulting in sustained tolerance, or the achieved degree of desensitization depends on regular exposure is not known; therefore, following challenge, regular consumption three-four times per week was recommended.

Safety and Effectiveness of Bypassing Oral Immunotherapy Buildup With an Initial Phase of Sublingual Immunotherapy for Higher-Risk Food Allergy

Because of its favorable safety, sublingual immunotherapy (SLIT) for food allergy has been proposed as an alternative treatment for those in whom oral immunotherapy (OIT) is of higher risk-older children, adolescents, adults, and those with a history of severe reactions. Although safe, SLIT has been shown to be less effective than OIT. To describe the safety of multifood SLIT in pediatric patients aged 4 to 18 years and the effectiveness of bypassing OIT buildup with an initial phase of SLIT. Patients aged 4 to 18 years were offered (multi)food SLIT. Patients built up to 2 mg protein SLIT maintenance over the course of 3 to 5 visits under nurse supervision. After 1 to 2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC) (cumulative dose, 300 mg protein) with the goal of bypassing OIT buildup. Between summer 2020 and winter 2023, 188 patients were enrolled in SLIT (median age, 11 years). Four patients (2.10%) received epinephrine during buildup and went to the emergency department, but none experienced grade 4 (severe) reaction. A subset of 20 patients had 50 low-dose OFCs to 300 mg protein and 35 (70%) OFCs were successful, thereby bypassing OIT buildup. In combination with very favorable safety of SLIT, with no life-threatening reactions and few reactions requiring epinephrine, we propose that an initial phase of SLIT to bypass supervised OIT buildup be considered for children in whom OIT is considered to be of higher risk.

RNA sequencing of single allergen-specific memory B cells after grass pollen immunotherapy: Two unique cell fates and CD29 as a biomarker for treatment effect.

Sublingual immunotherapy (SLIT) for grass pollen allergy can modify the natural history of allergic rhinitis and is associated with increased allergen-specific IgG4 . IgG4 competitively inhibits functional IgE on the surface of effector cells, such as mast cells and basophils, from binding to allergens. To further understand the important role memory B-cell (Bmem) responses play in mediating the beneficial effects of SLIT, we assessed changes in allergen-specific Bmem subsets induced by SLIT for grass pollen allergy. Blood samples were collected twice outside the pollen season from twenty-seven patients with sensitization to ryegrass pollen (RGP; Lolium perenne) and seasonal rhinoconjunctivitis. Thirteen received 4-month pre-seasonal SLIT for grass pollen allergy, and 14 received standard pharmacotherapy only. Single-cell RNA sequencing was performed on FACS-purified Lol p 1-specific Bmem before and after SLIT from four patients, and significant genes were validated by flow cytometry on the total cohort. Four months of SLIT increased RGP-specific IgE and IgG4 in serum and induced two Lol p 1-specific Bmem subsets with unique transcriptional profiles. Both subsets had upregulated expression of beta 1 integrin ITGB1 (CD29), whereas IGHE (IgE), IGHG4 (IgG4 ), FCER2 (CD23), and IL13RA1 were upregulated in one subset. There was an increase in the proportion of Lol p 1+ Bmem expressing surface IgG4 , CD23, and CD29 after SLIT. A clinically successful 4months course of SLIT for grass pollen allergy induces two transcriptionally unique Bmem fates. Associated changes in surface-expressed proteins on these Bmem subsets can be used as early biomarkers for treatment effects.

Allergen Release Profiles of Fast-Dissolving Freeze-Dried Orodispersible Sublingual Allergy Immunotherapy Tablets

BackgroundSublingual allergy immunotherapy tablets (SLIT-tablets) provide a well-tolerated and clinically efficacious treatment for allergic disease such as allergic rhinitis and allergic asthma. In SLIT, uptake of allergen by immune-competent cells in the oral mucosa activates the immune system and leads to tolerance toward the sensitizing allergen. The ability to deliver the full allergen content into solution within the recommended sublingual holding time is therefore an essential quality of SLIT-tablets that must be supported by the tablet formulation for all relevant allergen sources. SLIT-tablets based on a fast-dissolving orodispersible freeze-dried formulation (Zydis) are currently available for 5 of the most prevalent allergens: tree (birch and related species from the birch-homologous group), grass, ragweed, Japanese cedar, and house dust mite.ObjectivesThe purpose of this study was to examine the allergen release properties of three freeze-dried SLIT-tablets containing tree, ragweed, and Japanese cedar extracts, respectively. The correlation between SLIT-tablet allergen release and the level of allergen-specific T-cell activation was examined for the tree SLIT-tablet.MethodsAllergen release kinetics and tablet disintegration times for the 3 freeze-dried SLIT-tablets were examined. For all 3 tablets, the magnitude of solubilized major allergen relative to time in solution was compared to external controls to achieve a measure of the total allergen release. Additional assessments of allergen release occurring after the initial timepoint (15 or 30 seconds in solution) were done independently of external controls by linear regression analyses. For the tree SLIT-tablet, the immunological potency of the released major allergen was assessed at each experimental timepoint by a Bet v-specific T-cell activation assay.ResultsAll 3 SLIT-tablets disintegrated within 1 second after contact with assay buffer without any detectible residue. Complete release of major allergens (Bet v 1, Amb a 1, and Cry j 1, respectively) was seen at the earliest experimental time points (15 or 30 seconds). For the tree SLIT-tablet, full T-cell activation was achieved at 30 seconds (earliest experimental time point).ConclusionsThe freeze-dried SLIT-tablet formulation consistently provides rapid and complete release of allergen from a wide range of species in a standardized in vitro assay. Full release of the SLIT-tablet allergen content within the sublingual holding time is a prerequisite for maximal exposure of allergens to the sublingual mucosa immune system. The freeze-dried SLIT-tablet formulation examined here supports short sublingual holding times and furthermore offers a convenient administration form of allergy immunotherapy.

Rupatadine to prevent local allergic reactions to sublingual allergy immunotherapy: a case series

BackgroundSublingual immunotherapy tablets (SLIT-T) are an effective treatment for allergic rhinitis (AR), but some patients experience local allergic reactions (LAR) in the first few weeks of treatment that can lead to treatment discontinuation. Although oral antihistamines are recommended for the treatment and pretreatment of LAR associated with SLIT-T, there are no clinical trial data to support this recommendation. Rupatadine is an H1 antihistamine that also inhibits platelet activating factor activity. The objective of this case series is to describe real-world clinical situations in which rupatadine was used to treat or mitigate SLIT-T–related LAR.Case presentationsFive cases are presented by the managing allergist and off-label use of rupatadine is their expert opinion only. Patients in all 5 cases were treated with a SLIT-T (e.g. ragweed, tree, grass, or house dust mites) for the management of allergic rhinitis and experienced bothersome LAR with the first SLIT-T administration. In 3 cases, rupatadine 10 mg was administered for the immediate treatment of LAR (either in-office with the first SLIT-T dose or for subsequent LAR experienced at home) and the symptoms resolved. In 3 cases, pretreatment with other second-generation H1 antihistamines was unable to prevent LAR and the patients discontinued the SLIT-T. In these 3 cases, switching to pretreatment with rupatadine allowed the patients to restart and tolerate SLIT-T treatment with minimal or no LAR. In these patients with an established history of LAR, proactive pretreatment with rupatadine in subsequent seasons or with initiation of a different SLIT-T mitigated the previously experienced LARs.ConclusionsIn the cases presented, treatment with rupatadine resolved LAR associated with SLIT-T treatment and rupatadine pretreatment appeared to mitigate subsequent LAR. Rupatadine may be an option to treat or improve the tolerability of the SLIT-T, potentially improving early treatment persistence.

How important is proper dosing for subcutaneous and sublingual allergy immunotherapy?

Background: Results of surveys report that allergists use a wide range of doses for allergy immunotherapy; however, results of randomized, double-blind, placebo controlled studies suggest that the range of the optimum effective dosing is relatively narrow. Objective: To review studies that established effective or less than fully effective doses for allergy immunotherapy. Methods: Studies were reviewed that established effective and ineffective subcutaneous and sublingual immunotherapy doses. Only those studies that expressed dosing in terms of the content of a major allergen in the maintenance doses were included in defining effective and ineffective doses. Results: Studies were identified that showed effective doses for subcutaneous injection, established in randomized, double-blind, placebo controlled trials, for short ragweed, timothy grass, house-dust mites, cat and dog dander, birch, and Alternaria. For short ragweed, timothy grass, Dermatophagoides pteronyssinus, and cat and dog dander, less-effective doses were determined, along with effective doses; the less-effective doses were only one-fifth to one-tenth less in allergen content than were the effective doses. Effective doses of cockroach and all fungal extracts except Alternaria have not been established. Information is available on the mean major allergen content of U.S. standardized and a few nonstandardized extracts, which allows the information on effective and ineffective dosing to be used in prescribing subcutaneous allergy immunotherapy. With sublingual allergy immunotherapy, all the approved tablets had multidose studies that determined the optimal dose. For the U.S. liquid extracts, to my knowledge, there are no studies to define effective doses except for ragweed. Conclusions: Although a wide range of doses are prescribed by U.S. allergists, analysis of available data suggests that effective doses fall within a narrow range and that use of doses one-fifth or one-tenth of the effective doses may sacrifice most or all of the potential efficacy of the treatment.

Meta-analyses of the efficacy of pharmacotherapies and sublingual allergy immunotherapy tablets for allergic rhinitis in adults and children.

Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta-analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR. Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted. Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR. All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptom-relieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

Efficacy of Subcutaneous and Sublingual Immunotherapy for House Dust Mite Allergy: A Network Meta-Analysis–Based Comparison

Meta-analyses comparing the efficacy of sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) for house dust mite allergy are lacking. To compare the efficacy of SLIT drops, SLIT tablets, and SCIT in patients with perennial allergic rhinitis through network analysis. Frequentist network meta-analyses estimated the standardized mean difference (SMD) across the three immunotherapy modalities on allergic rhinitis symptom and medication score data from double-blind randomized clinical trials. Random effects models were investigated. We included 26 double-blind randomized clinical trials in this meta-analysis for the symptom score and 18 for the medication score. In the direct pairwise meta-analysis, a significant reduction of the symptom score was observed for all immunotherapy modalities compared with the placebo: pooled SMDs of -0.461 (95% confidence interval [CI], -0.795 to -0.127) for SLIT drop, -0.329 (95% CI, -0.426 to -0.231) for SLIT tablet, and -1.669 (95% CI, -2.753 to -0.585) for SCIT. For the medication score, a significant reduction was observed for all modalities. In network meta-analysis, the clinical efficacy of SCIT based on the symptom score was greater than for SLIT drop or SLIT tablet (SMD: -0.697, 95% CI, -1.105 to -0.288; and SMD: -0.819, 95% CI, -1.242 to -0.397). However, there was no significant difference in the symptom score between SLIT drop and SLIT tablet. This study demonstrated the clinical efficacy of all house dust mite immunotherapy modalities and suggests that SCIT may be more effective than SLIT drops or tablets in controlling symptoms of allergic rhinitis.

Successful sublingual immunotherapy for severe egg allergy in children: a case report

BackgroundEgg allergy is one of the most common food allergies in children. To date, oral immunotherapy (OIT) has been considered as a promising treatment option for egg allergy. However, safety issues remain concerning severe adverse events requiring epinephrine injection. Hence, establishing a safer method to treat egg allergy would be beneficial. We report here two children with egg allergy who were safely treated with sublingual immunotherapy (SLIT) before transitioning to OIT.Case presentationPatient 1 was a 7-year-old girl and Patient 2 was a 5-year-old girl. Although OIT for egg had been attempted in both patients, severe anaphylactic symptoms were induced by ingesting only 0.1 g of heated whole egg. Therefore, SLIT was conducted with aqueous suspensions consisting of water and heated whole egg powder. Suspensions were administered sublingually, kept in the mouth for 2 min, and spat out immediately thereafter. SLIT was continued for 7 months for Patient 1 and 8 months for Patient 2 due to the exploratory character of the study. Afterwards, the patients successfully transferred to low-dose OIT with 1 g of heated whole egg (≒170 mg of egg protein) daily, and are continuing the therapy as of June 2020. As for adverse reactions, Patient 1 expressed oral cavity itchiness once at the beginning of SLIT. Patient 2 had no adverse reaction. The levels of antigen-specific IgE decreased in both patients after SLIT, and further decreased after switching to OIT.ConclusionsFew clinical studies have evaluated the efficacy and safety of SLIT for egg allergy. Although the treatment was conducted in only two patients, our results have shown that SLIT is a promising treatment procedure for egg allergy. Further clinical trials will be needed to additionally assess the efficacy and safety of SLIT in children with food allergy.

Sublingual immunotherapy for food allergy and its future directions.

Food allergy is an important medical problem with increasing prevalence throughout the world. Different approaches of food immunotherapy are being investigated including oral, epicutaneous and sublingual routes. Sublingual immunotherapy (SLIT) for food allergy involves placement of glycerinated allergen under the tongue daily to achieve allergen-specific desensitization. SLIT has been studied in the treatment of hazelnut, peach, apple, milk and peanut allergies with substantial focus on the treatment of peanut allergy. Phase II studies have shown SLIT for treatment of peanut allergy increases the tolerated dose of peanut by a substantial margin with fewer and less severe side effects than other modalities. This review discusses the mechanisms of SLIT, early studies of its use in food allergy and larger randomized controlled trials for treatment of peanut allergy. Future directions using the mechanisms involved in SLIT include oral mucosal immunotherapy for peanut allergy.

State of the Art: Development of a Sublingual Allergy Immunotherapy Tablet for Allergic Rhinitis in Japan.

Allergic rhinitis (AR) caused by house dust mite (HDM) and Japanese cedar pollen (JCP) represents a significant, expanding health problem in Japan. Allergic symptoms often have a severe impact on the QOL such as sleep disturbance and reduced school and work performance. In addition to the classical symptoms, AR is known to be a risk factor for the development of allergic asthma, a potentially life-threatening condition. Allergy immunotherapy (AIT) is a well-documented, safe, effective treatment option for respiratory allergic disease. It has been demonstrated that AIT can provide relief from clinical symptoms and that AIT has the potential to provide long-term post-treatment effect. Although the mechanism of AIT is not fully understood, it can actively modulate protective allergen-reactive pathways of the immune system and alter the natural course of disease. Unlike pharmacotherapy, AIT addresses the basic immunological mechanisms that are responsible for the development and persistence of allergic conditions. Currently two main routes of AIT administration are commonly available, subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). Both SCIT and SLIT are clinically effective, and SLIT is particularly well tolerated, with a lower risk of systemic allergic reactions compared with SCIT. To date, SLIT tablets have been developed for a range of different allergies including HDM and JCP and are the best-documented AIT treatment form. Here we introduce the current status of development of a SLIT tablet in Japan for AR, examine the clinical aspects and mechanism of action of AIT, and discuss the future directions of SLIT.

Oral and sublingual immunotherapy for food allergy.

To critically appraise the recent most relevant studies in the rapidly advancing field of food oral and sublingual immunotherapy. Food allergen-specific immunotherapy via oral (OIT) and sublingual route (SLIT) increases the threshold of reactivity to peanut, cow's milk, egg, wheat, and many other foods in the majority of the treated individuals. This desensitized state is contingent upon the continued ingestion of the maintenance doses of the food. Permanent oral tolerance is achievable in a smaller subset of the treated individuals. The optimal duration of therapy has not been firmly established but is likely dependent on the phenotype (severity and persistence). Efficacy of food-OIT is superior compared with SLIT, whereas the safety of OIT is less favorable. Standardization of treatment protocols, maintenance dosing, duration of therapy, target populations and harmonization of the outcomes are top priorities at this stage. OIT and SLIT represent two different routes of food allergen-specific immunotherapy. Although significant progress has been made in the last decade, both treatment modalities are still in the very early stages of development and further investigations are necessary to optimize the protocols and improve safety while maximizing efficacy.

Induction of IgG2 and IgG4 B-cell memory following sublingual immunotherapy for ryegrass pollen allergy.

BackgroundWhile treatment for atopic rhinitis is aimed mostly to relieve symptoms, only allergen‐specific immunotherapy (AIT) is targeted to modify the natural history of allergic diseases. This results in sustained clinical tolerance, even when treatment has stopped. The immunomodulatory effects of AIT are attributed mainly to increased regulatory T‐cell function and increased allergen‐specific IgG4, yet little is known about the effect on the memory B‐cell compartment.ObjectiveWe aimed to examine the effects of AIT on the IgE‐ and IgG subclass‐expressing memory B cells.MethodsWe recruited 29 patients with atopic seasonal rhinoconjunctivitis and performed a longitudinal analysis of the peripheral immune compartment before, during, and after sublingual immunotherapy (SLIT) for allergy to temperate grass pollen, predominantly to ryegrass pollen (RGP; Lolium perenne). Using flow cytometry on peripheral blood mononuclear cells and serum immunoassays, we analyzed the effects of a 4 months preseasonal treatment regimen comprising two or three courses in consecutive years on circulating IgE+ and IgG+ memory B cells and allergen‐specific Ig levels.ResultsSLIT increased RGP‐specific serum IgG2 and IgG4, as well as the frequencies of IgG2 + and IgG4 + memory B cells, whereas no effect was observed on the IgE+ memory B‐cell compartment. Furthermore, SLIT enhanced proportions of regulatory T cells specific to RGP. These changes were associated with clinical improvement.ConclusionOur data provide evidence for immunological effects of SLIT on B‐cell memory. Skewing responses toward IgG2 and IgG4 subclasses might be a mechanism to suppress IgE‐mediated allergic responses.

SQ house dust mite sublingual immunotherapy for the treatment of adults with house dust mite-induced allergic rhinitis

ABSTRACTIntroduction: Allergic rhinitis (AR) is one of the most common chronic conditions affecting both children and adults. The house dust mites (HDM) account for a substantial part of the overall sources of allergens. In patients where allergen avoidance and symptom-relieving pharmacotherapy do not provide adequate disease control, specific allergen immunotherapy (AIT) is indicated. While subcutaneous injection (SCIT) is considered as a time-consuming and invasive treatment regimen, sublingual allergy immunotherapy (SLIT) appears as more convenient treatment strategy.Areas covered: This Drug Profile reviews the clinical data behind the development of the SQ HDM SLIT-tablet, including both the early studies and the pivotal studies, which formed the basis for regulatory approval in Europe, Japan, and the U.S.Expert opinion: The clinical trials behind the development of the SQ HDM-SLIT have demonstrated that the tablet provides a safe, well-tolerated and robust efficacy in the treatment of HDM-induced allergic rhinoconjunctivitis. Further, studies show that the SQ HDM SLIT-tablet is a cost-effective treatment option compared with SCIT.

Long-term sublingual immunotherapy for peanut allergy in children: Clinical and immunologic evidence of desensitization

Peanut sublingual immunotherapy (SLIT) for 1year has been shown to induce modest clinical desensitization in allergic children. Studies of oral immunotherapy, epicutaneous immunotherapy, and SLIT have suggested additional benefit with extended treatment. We sought to investigate the safety, clinical effectiveness, and immunologic changes with long-term SLIT in children with peanut allergy. Children with peanut allergy aged 1 to 11years underwent extended maintenance SLIT with 2mg/d peanut protein for up to 5years. Subjects with peanut skin test wheals of less than 5mm and peanut-specific IgE levels of less than 15 kU/L were allowed to discontinue therapy early. Desensitization was assessed through a double-blind, placebo-controlled food challenge (DBPCFC) with up to 5000mg of peanut protein after completion of SLIT dosing. Sustained unresponsiveness was further assessed by using identical DBPCFCs after 2 to 4weeks without peanut exposure. Thirty-seven of 48 subjects completed 3 to 5years of peanut SLIT, with 67% (32/48) successfully consuming 750mg or more during DBPCFCs. Furthermore, 25% (12/48) passed the 5000-mg DBPCFC without clinical symptoms, with 10 of these 12 demonstrating sustained unresponsiveness after 2 to 4weeks. Side effects were reported with 4.8% of doses, with transient oropharyngeal itching reported most commonly. Side effects requiring antihistamine treatment were uncommon (0.21%), and no epinephrine was administered. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT. Extended-therapy peanut SLIT provided clinically meaningful desensitization in the majority of children with peanut allergy that was balanced with ease of administration and a favorable safety profile.

The Importance of Tablet Formulation on Allergen Release Kinetics and Efficiency: Comparison of Freeze-dried and Compressed Grass Pollen Sublingual Allergy Immunotherapy Tablet Formulations

PurposeEfficient delivery of allergens to the sublingual mucosa is a prerequisite for successful sublingual immunotherapy (SLIT) for allergy, and in order to become available to immune-competent cells embedded in the sublingual mucosa, allergens need to be delivered in a soluble form. Delivery of solubilized allergens poses a particular challenge for tablet-based allergy immunotherapy, in which allergens are administered under the tongue in the form of dry tablets and need to be dissolved rapidly in a small volume of saliva, with little or no agitation. The purposes of this article were to compare the properties of 2 different pharmaceutical SLIT-tablet formulations, freeze-dried and compressed, and to examine how the tablet formulation affects the efficiency with which allergen is delivered from the dry state of the tablet into soluble form. MethodsTwo SLIT-tablet formulations, both indicated for grass pollen allergic rhinitis and containing grass pollen extract as the active ingredient, were examined with regard to tablet disintegration times, allergen dissolution kinetics, dependency on solvent volume and agitation, and the achieved recovery of the grass allergen content in soluble form with each tablet. FindingsThe freeze-dried and the compressed SLIT-tablet formulations differed markedly with respect to efficiency of allergen release. The freeze-dried tablet disintegrated faster and released grass allergen into solution with a release rate higher than that of the compressed formulation and, in contrast to the compressed formulation, achieved full recovery of the allergen content in soluble form in a small volume of solvent. ImplicationsRapid and complete release of soluble allergen in a small volume of solvent, as demonstrated by the freeze-dried formulation, are key elements of efficient sublingual allergen delivery by SLIT-tablets. Complete allergen release means that the full allergen dose of the tablet is recovered from the tablet and made available to the sublingual immune system in soluble form, and rapid release ensures that the immune system becomes exposed to the highest possible dose of soluble allergen for the maximal duration before swallowing. In contrast, a SLIT-tablet formulation that provides incomplete and slower allergen release will likely require a higher allergen content compared to the more efficient formulation, in order to achieve the same dose of soluble allergen, consequently leading to an excess load of allergen that becomes swallowed without having been made immunologically available.

Glycosylated nanostructures in sublingual immunotherapy induce long-lasting tolerance in LTP allergy mouse model

An effective specific immunotherapy should contain elements to generate specific recognition (T-cell peptides) and to modulate the immunological response towards a Th1/Treg pattern by enhancing dendritic cells (DCs). We propose a novel sublingual immunotherapy for peach allergy, using systems, that combine Prup3-T-cell peptides with mannose dendrons (D1ManPrup3 and D4ManPrup3). Peach anaphylactic mice were treated 1, 2 and 5 nM concentrations. Tolerance was assessed one/five weeks after finishing treatment by determining in vivo/in vitro parameters after challenge with Prup3. Only mice receiving D1ManPrup3 at 2 nM were protected from anaphylaxis (no temperature changes, decrease in Prup3-sIgE and -sIgG1 antibody levels, and secreting cells) compared to PBS-treated mice. Moreover, an increase of Treg-cells and regulatory cytokines (IL-10+/IFN-γ+) in CD4+-T-cells and DCs were found. These changes were maintained at least five weeks after stopping treatment. D1ManPrup3 is an effective new approach of immunotherapy inducing protection from anaphylaxis which persists after finishing treatment.

The Consortium for Food Allergy Research (CoFAR): The first generation

The Consortium for Food Allergy Research (CoFAR) was established by the National Institute of Allergy and Infectious Diseases in 2005 as a collaborative research program bringing together centers focused on the study of food allergy. CoFAR was charged with developing studies to better understand the pathogenesis and natural history of food allergy, as well as potential approaches to the treatment of food allergy. In its first iteration an observational study of infants with milk and egg allergy was established, and studies of oral immunotherapy for egg allergy and sublingual immunotherapy for peanut allergy were initiated, as was a phase 1 study of a recombinant peanut protein vaccine. CoFAR was renewed in 2010 for an additional 5-year period during which the initial observational study was continued, a study of eosinophilic esophagitis was initiated, and new therapeutic trials were established to study epicutaneous immunotherapy for peanut allergy and to compare the safety and efficacy of egg oral immunotherapy to the ingestion of baked egg for the treatment of egg allergy. The results of these efforts will be reviewed in this rostrum, with a brief look to the future of CoFAR.

Current and future challenges of subcutaneous and sublingual allergy immunotherapy for allergists in the United States

Current and future challenges of subcutaneous and sublingual allergy immunotherapy for allergists in the United States

Oral and sublingual immunotherapy for egg allergy.

Clinical egg allergy is a common food allergy. Current management relies upon strict allergen avoidance. Oral immunotherapy might be an optional treatment, through desensitization to egg allergen. To determine the efficacy and safety of oral and sublingual immunotherapy in children and adults with immunoglobulin E (IgE)-mediated egg allergy as compared to a placebo treatment or an avoidance strategy. We searched 13 databases for journal articles, conference proceedings, theses and trials registers using a combination of subject headings and text words (last search 31 March 2017). We included randomized controlled trials (RCTs) comparing oral immunotherapy or sublingual immunotherapy administered by any protocol with placebo or an elimination diet. Participants were children or adults with clinical egg allergy. We retrieved 97 studies from the electronic searches. We selected studies, extracted data and assessed the methodological quality. We attempted to contact the study investigators to obtain the unpublished data, wherever possible. We used the I² statistic to assess statistical heterogeneity. We estimated a pooled risk ratio (RR) with 95% confidence interval (CI) for each outcome using a Mantel-Haenzel fixed-effect model if statistical heterogeneity was low (I² value less than 50%). We rated the quality of evidence for all outcomes using GRADE. We included 10 RCTs that met our inclusion criteria, that involved a total of 439 children (oral immunotherapy 249; control intervention 190), aged 1 year to 18 years. Each study used a different oral immunotherapy protocol; none used sublingual immunotherapy. Three studies used placebo and seven used an egg avoidance diet as the control. Primary outcomes were: an increased amount of egg that can be ingested and tolerated without adverse events while receiving allergen-specific oral immunotherapy or sublingual immunotherapy, compared to control; and a complete recovery from egg allergy after completion of oral immunotherapy or sublingual immunotherapy, compared to control. Most children (82%) in the oral immunotherapy group could ingest a partial serving of egg (1 g to 7.5 g) compared to 10% of control group children (RR 7.48, 95% CI 4.91 to 11.38; RD 0.73, 95% CI 0.67 to 0.80). Fewer than half (45%) of children receiving oral immunotherapy were able to tolerate a full serving of egg compared to 10% of the control group (RR 4.25, 95% CI 2.77 to 6.53; RD 0.35, 95% CI 0.28 to 0.43). All 10 trials reported numbers of children with serious adverse events (SAEs) and numbers of children with mild-to-severe adverse events. SAEs requiring epinephrine/adrenaline presented in 21/249 (8.4%) of children in the oral immunotherapy group, and none in the control group. Mild-to-severe adverse events were frequent; 75% of children presented mild-to-severe adverse events during oral immunotherapy treatment versus 6.8% of the control group (RR 8.35, 95% CI 5.31 to 13.12). Of note, seven studies used an egg avoidance diet as the control. Adverse events occurred in 4.2% of children, which may relate to accidental ingestion of egg-containing food. Three studies used a placebo control with adverse events present in 2.6% of children. Overall, there was inconsistent methodological rigour in the trials. All studies enrolled small numbers of children and used different methods to provide oral immunotherapy. Eight included studies were judged to be at high risk of bias in at least one domain. Furthermore, the quality of evidence was judged to be low due to small numbers of participants and events, and possible biases. Frequent and increasing exposure to egg over one to two years in people who are allergic to egg builds tolerance, with almost everyone becoming more tolerant compared with a minority in the control group and almost half of people being totally tolerant of egg by the end of treatment compared with 1 in 10 people who avoid egg. However, nearly all who received treatment experienced adverse events, mainly allergy-related. We found that 1 in 12 children had serious allergic reactions requiring adrenaline, and some people gave up oral immunotherapy. It appears that oral immunotherapy for egg allergy is effective, but confidence in the trade-off between benefits and harms is low; because there was a small number of trials with few participants, and methodological problems with some trials.