Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)3) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre-existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is pre-sensitized to the allergen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response toward Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three-to-five-year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.

Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence, and was then accepted as a viable "alternative" option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and post-marketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not "class-related", as derived from meta-analyses, but restricted to each specific product. The 30-year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (e.g. food allergy, atopic dermatitis). In addition, the introduction of molecular-based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles. The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities.

Four intralymphatic allergen injections for treatment of pollen allergy reduce medication use, improve symptoms and have immune modulating effects in adolescents and young adults with rhinoconjunctivitis and mild asthma due to birch or grass pollen.

Oral immunotherapy (OIT) protects patients with IgE-mediated food allergies from food-induced allergic reactions due to accidental exposure and may improve their quality of life. This approach has never been evaluated for hazelnut, a major cause of food allergy in Europe.

We sought to determine the proportion of hazelnut-desensitized patients after 6 months of OIT and to identify predictors of successful desensitization.

In a retrospective single-center study, we included patients under 18 years of age who underwent at least 6 months of hazelnut OIT for IgE-mediated allergy, defined by history of hypersensitivity reaction after hazelnut ingestion, positive hazelnut skin prick test (SPT) or specific IgE, and positive double-blind, placebo-controlled food challenge (DBPCFC). Patients able to tolerate 1635 mg of hazelnut protein (approximately 8 hazelnuts) were considered to be hazelnut desensitized. We determined the proportion of desensitized patients after 6 months of OIT, searched for associations between baseline variables and successful desensitization, and estimated the frequency and severity of OIT-related adverse reactions.

One hundred patients were included (64% male, median age 5 years). History of severe reactions was noted in 7% of cases. At 6 months, the proportion of desensitized patients was 34% (95%CI: 25-44). The median eliciting dose (defined as the amount of hazelnut protein provoking a hypersensitivity reaction during the DBPCFC) increased from 106 mg [IQR: 51-249] at baseline to 523 mg [IQR: 190-1635] after 6 months of OIT (p<0.0001). With longer therapy, the proportion of desensitized patients increased. Using multivariate analysis, successful desensitization was associated with older age (OR: 1.5, 95%CI: 1.2-2.2), smaller hazelnut SPT wheal diameter (OR: 0.61, 95%CI: 0.4-0.8), lower hazelnut specific IgE level (OR: 0.86, 95%CI: 0.72-0.98), and absence of cashew allergy (OR: 0.42, 95%CI: 0.12-0.64). Adverse reactions occurred in 30% of patients; none were severe.

In a cohort of 100 patients aged 3-9 years, our results show for the first time that hazelnut OIT is associated with hazelnut desensitization and may be safe in the majority of patients undergoing this therapy.

Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose.

Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31-41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship.

In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature.

PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.

Olive-pollen allergy is one of the leading causes of respiratory allergy in Mediterranean countries and some areas of North America. Currently, allergen-specific immunotherapy is the only etiophatogenic treatment. However, this approach is not fully optimal, safe, or effective. Thus, efforts continue in the search for novel immunotherapy strategies, being one of the most promising the use of peptides derived from major allergens. This work tries to determine the therapeutic potential and safety of 5 dodecapeptides derived from the main allergen of olive-pollen allergy, Ole e 1. The immunomodulatory capacity of these peptides was studied using peripheral blood mononuclear cells (PBMCs) obtained from 19 olive-pollen-allergic patients and 10 healthy controls. We determined the capacity of these peptides to inhibit the proliferative response toward olive-pollen allergenic extract and to induce the regulatory cytokines, IL-10 and IL-35. To test the safety and absence of allergenicity of the peptides, the basophil activation was analyzed by flow-cytometry, using peripheral blood. The results showed that two of five peptides inhibited near to 30% the proliferative response against the total olive-pollen allergenic extract in olive-pollen-allergic patients. Inhibition increased to nearly 35% when the 5 peptides were used in combination. In both cases, a statistically significant induction of IL-10 and IL-35 secretion was observed in the supernatants of allergic patients PBMCs cultures. None of the 5 peptides induced basophil activation and cross-link inflammatory cell-bound IgE. In conclusion, these results open up new possibilities in the treatment of olive-pollen allergy, which could solve some of the problems facing current therapy approaches.

Few studies have directly compared the immunologic responses to specific subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT).

We aimed to directly compare clinical efficacy and immunological responses between SLIT and SCIT in allergic rhinitis (AR) sensitized to house dust mites.

Sixty-seven patients (age 5-55 years) with moderate-severe Dermatophagoides pteronyssinus (Der-p) and Dermatophagoides farinae AR with or without asthma were randomized (2:2:1) into SLIT (n = 27), SCIT (n = 26) and placebo (n = 14) groups. Symptom and medication scores, visual analogue score, serum Der-p specific immunoglobulin G4 (Der-p-sIgG4), CD4+CD25+FoxP3+ regulatory T cells (Tregs) and serum cytokines were measured.

After 1-year treatment, a significant improvement of total rhinitis score (TRS), total rhinitis medication score (TRMS) and visual analogue score occurred in both SLIT and SCIT. There were no differences in clinical efficacy except for TRMS (p = 0.026) when SLIT and SCIT were directly compared. CD4+CD25+FoxP3+ Tregs had a trend towards upregulation in the 2 modes and inversely correlated with TRS (p = 0.024) only in SLIT. Der-p-sIgG4 significantly increased in SLIT and SCIT (p < 0.05), and it was 30 times higher in SCIT than SLIT after the treatment (p < 0.05). Serum interferon-γ significantly increased only in SCIT after 1 (p = 0.008), 6 (p = 0.007) and 12 (p = 0.008) months of treatment and inversely correlated with TRS (p = 0.032).

While SCIT and SLIT have similar rates of clinical improvement, the 2 modes reveal heterogeneous changes of CD4+CD25+Foxp3+ Tregs, sIgG4 and cytokines.

Bronchial asthma remains one of the most common chronic diseases with a high degree of morbidity and still a considerable mortality with an increasing prevalence in many countries. Although remarkable progress has been made in the past decades in the medical treatment for asthma, curative or disease modifying approaches are still limited to allergen immunotherapy (AIT). Despite a plethora of potential immunological actions observed during AIT, the precise mechamisms that might exert beneficial effects especially in asthma remain unclear. Clinical studies in the past have suggested clinical benefits in symptom control and medication use with a small reduction in allergen-specific and non-specific bronchial hyperresponsiveness but these results were mainly derived from small, frequently suboptimally designed studies which were poorly comparable. Only recently have larger, dose ranging studies with well standardized allergens with patient relevant endpoints such as corticosteroid requirements for asthma control or the onset of exacerbations following inhaled corticosteroid (ICS) withdrawal corroborated the potential clinical effects of AIT in asthma, suggesting that it might replace some of the controller effects of ICS. In addition, newer, up-do-date designed studies support previous data that in patient populations at risk to develop asthma AIT might have a role in secondary prevention. Further studies on the long term effects as well as comparative studies are needed to further corroborate the role of AIT in the prevention and the control of asthma are needed.

Oral immunotherapy (OIT) for food allergy entails a risk of adverse reactions, including anaphylaxis. This safety concern is the major barrier for OIT to become a therapeutic option in clinical practice. The high heterogeneity in safety reporting of OIT studies prevents setting the safety profile accurately. An international consensus is needed to facilitate the analysis of large pooled clinical data with homogeneous safety reporting, that together with integrated omics, and patients/families’ opinions, may help stratify the patients’ risk and needs, and help developing safe(r) individualized care pathways. This will give OIT the right place in the food allergy therapy.

The aim of this study was to investigate the clinical outcomes of sublingual immunotherapy (SLIT) using 2 kinds of SLIT medications (LAIS and Staloral) in patients with allergic rhinitis for Dermatophagoides pteronyssinus and Dermatophagoides farinae. We have evaluated the patient’s characteristics, safety, and compliance in 293 patients and also analyzed the symptom score, medication score, satisfaction rate, and immunologic measurement in 84 patients who have continued the treatment over 1 year. The symptom scores were significantly improved in both treatment groups, 51% versus 44% (LAIS vs Starloral) at 1 year (P < .05). The medication score was also significantly decreased in both treatment groups (P < .05), 50.8% versus 60%. The subjective improvement score was 44.4% versus 46.1%, and satisfaction rate was 29% versus 40% (P < .05). The serum immunoglobulin G4 (IgG4) level was significantly increased in Staloral group (P < .05). The adverse events were 6.2% versus 33.3% and the compliance was 37.7% versus 25.1%. In conclusion, the improvements in symptom score and medication scores were not significant different between 2 SLIT medications at 1 year. LAIS was more compliant, less side effects and Staloral has shown increased satisfaction rate and IgG4 level.