New insights into mechanisms should enable strategic improvement of allergen immunotherapy, aiming to make it safer, faster, more effective and able to induce long-term tolerance. We review novel approaches with potential to translate into clinical use.

Database searches were conducted in Pubmed, Scopus and Google Scholar.

Search terms were based on current and novel approaches in immunotherapy. Literature was selected primarily from recent randomised doubleblind placebo-controlled trials and meta-analyses.

Alum, microcrystalline tyrosine and calcium phosphate are adjuvants in current use. Toll-like receptor 4 agonists combined with allergen have potential to shorten duration of treatment. Other novel adjuvants, nano-particles and virus-like particles in combination with allergen have shown early promise. Omalizumab reduces systemic side effects, however does not improve efficacy. Intralymphatic immunotherapy for aeroallergens and epicutaneous immunotherapy for food allergens, use of modified allergens (allergoids), recombinant allergens (and hypoallergenic variants) and T and B cell peptide approaches have shown evidence of efficacy and permitted shortened courses but have only rarely been compared with conventional extracts

Novel routes of immunotherapy, the use of modified allergens and the combination of allergens with immunostimulatory adjuvants, or immune modifiers have been developed to augment down-regulation of Th2 immunity and/or induce ‘protective’ blocking antibodies. Whereas these strategies have permitted shortened courses, confirmatory phase III trials are required to confirm efficacy and safety, and head-to-head trials for comparative efficacy. At present, subcutaneous and sublingual immunotherapy using in-house standardised crude extracts remain the only approaches proven to induce long-term tolerance.

Allergen-specific immunotherapy, which is performed by subcutaneous injection or sublingual application of allergen extracts, represents an effective treatment against type I allergic diseases. However, due to the long duration and adverse reactions, only a minority of patients decides to undergo this treatment. Alternatively, early prophylactic intervention in young children has been proposed to stop the increase in patient numbers. Plasmid DNA and mRNA vaccines encoding allergens have been shown to induce T helper 1 as well as T regulatory responses, which modulate or counteract allergic T helper 2-biased reactions. With regards to prophylactic immunization, additional safety measurements are required. In contrast to crude extracts, genetic vaccines provide the allergen at high purity. Moreover, by targeting the encoded allergen to subcellular compartments for degradation, release of native allergen can be avoided. Due to inherent safety features, mRNA vaccines could be the candidates of choice for preventive allergy immunizations. The subtle priming of T helper 1 immunity induced by this vaccine type closely resembles responses of non-allergic individuals and – by boosting via natural allergen exposure – could suffice for long-term protection from type I allergy

The conjunctival provocation test (CPT) is often used to clearly identify the specific allergen causing the symptoms of allergic rhinoconjunctivitis but also to assess the clinical efficacy of an allergen immunotherapy (AIT). As there is no consensus about its predictive value, the aim of this publication is to evaluate under which conditions the CPT can predict the symptom severity during the allergy season after previous AIT.

Three out of four randomized controlled trials (RCTs) showed a correlation between CPT reactivity and symptoms occurring under natural allergen exposure after previous AIT. Furthermore, one RCT found that performing the CPT 4 weeks after initiating AIT can identify early responders who also show a benefit during the season. Another RCT suggested that conducting the CPT prior to starting AIT can be used to identify patients who may benefit more from treatment than others.

The assessment of the reviewed literature led us to the conclusion that the CPT has a predictive value and can consequently be used to assess the efficacy of an administered AIT if performed according to a standardized challenge protocol with high-quality allergen extracts.

The clinical relevance of increasing an allergic individual’s peanut sensitivity threshold by immunotherapy, i.e., eliciting dose (ED) to 300 or 1000 mg peanut protein, has not been previously characterized in a European population. In this study, we quantify the clinical benefits of an increased threshold of reaction following immunotherapy for the peanut-allergic individual.

Quantitative risk assessments incorporated numerous inputs to predict the risk of an allergic reaction after exposure to residual peanut protein in packaged foods. The three primary inputs for the risk assessment were the peanut-allergic individual’s clinical threshold value, the amount of food consumed per eating occasion of selected packaged foods and the concentration of peanut protein in the consumed product. Individual risk reductions were calculated for both children and adolescents-adults

Using available consumption and packaged food contamination data, children reaching an ED of 300 mg (if initial ED ≤ 100 mg) or 1,000 mg (if initial ED 300 mg) achieved >99.99% risk reduction. Adolescents-adults also achieved >99.99% risk reduction in all cases but one. Adolescents-adults who reached an ED of 300 mg (if initial ED ≤ 100 mg) achieved 99.3-99.9% risk reduction when consuming ice cream.

It is concluded that an increase in threshold following immunotherapy which achieves an eliciting dose of 300 or 1000 mg peanut protein is clinically relevant for the European peanut-allergic population. Benefits of an increased threshold include a significant reduction in risk due to traces of peanut protein.

The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (TO-203, Torii, Japan/ALK, Denmark) treatment has been effective against respiratory allergic diseases in patients aged ≥12 years during European, Japanese, and north American trials. This trial was conducted to investigate the efficacy and safety of this treatment in Japanese children (5-17 years) with moderate-to-severe HDM allergic rhinitis (AR).

In this randomized, double-blind, placebo-controlled trial, 458 Japanese children were randomly assigned to a daily SQ HDM SLIT-tablet [10,000 Japanese Allergy Unit (JAU), equivalent to 6 SQ-HDM in Europe and the US] or placebo (1:1) treatment for 1 year. Inclusion required an AR symptom score of ≥7 on at least 7 days during a 14-day run-in period while symptomatic treatment was withdrawn. The primary end point was the total combined rhinitis score (TCRS) comprising AR symptom and medication scores during the last 8 weeks of the treatment period.

The analysis of primary end point demonstrated statistically significant absolute reduction in TCRS of 1.22 with a relative difference of 23% (95% confidence interval, 14% to 31%) in the 10,000 JAU compared with placebo. Predefined stratified analyses revealed the same degree of efficacy of 1.11 (P = 0.002), 21% (8% to 32%) and 1.36 (P = 0.001), 26% (11% to 38%), respectively, in pediatric (5-11 years) and adolescent subjects (12-17 years). The treatment was well tolerated by both pediatric and adolescent subjects.

This trial, for the first time, demonstrated the efficacy and safety of the HDM SLIT-tablet in pediatric patients with moderate-to-severe HDM AR (JapicCTI152953).

Allergen immunotherapy represents the only disease-modifying therapy available for immunoglobulin E-mediated diseases such as allergicrhinitis and asthma. Allergen immunotherapy induces allergen tolerance by interfering with the immune-pathogenic mechanisms of the allergic response and is potentially able to provide long-term relief of symptoms of allergic rhinitis and asthma and alter the natural course of allergic diseases. Areas covered: Since allergen immunotherapy (AIT) is actually considered an individualized treatment on patient’s clinical and immunological profile, the identification of specific biomarkers, which may guide diagnosis, management, and predict response to AIT treatment in allergic rhinitis (AR) patients, is essential and is currently an active field of research. Expert commentary: The identification and validation of biomarkers of successful AIT for AR is an urgent need to definitively establish the role of AIT as a therapeutic tool of personalized medicine.

Specific immunotherapy (SIT) is used to treat asthma and allergic rhinitis, and a dose-response relationship has been found for SIT efficacy, creating a need to accurately select the allergen used in therapy. This need is especially pronounced in poly-sensitized children living in areas where different pollen allergen sources coexist in the same season, as this circumstance complicates diagnostic efforts. In such cases, component-resolved diagnosis (CRD) can increase diagnostic accuracy and aid in SIT prescription

We hypothesized that CRD results would lead to modifications in classical immunotherapy prescription based on sources such as medical history, season of symptom presentation, and skin testing. We studied a sample of children indicated for immunotherapy in whom classical methods had not pointed out the most relevant allergen due to sensitization to more than two pollens. We used a small panel of recombinant allergens, analyzing the percentage of changes to prescription considering the findings of molecular studies.

Of the 70 children included, CRD led to modified immunotherapy prescription in 54.3%. Indications of single-allergen therapy increased from 18% to 51% when CRD was included. The decision to prescribe immunotherapy was reversed following CRD in 9.3% of cases.

CRD use alters the choice of specific immunotherapy in poly-sensitized children. A wide panel of recombinant allergens may not be necessary to improve immunotherapy indication using molecular techniques; rather, a smaller panel adapted to include those allergens prevalent in the geographical area in question appears to be sufficient for more effective immunotherapy, also leading to an improved cost-benefit ratio.

IgE-mediated food allergy (FA) has been emerging as a public health priority. It is a potentially life-threatening condition with negative impact on the quality of life of patients and their family and its prevalence is increasing in westernized countries in the recent two decades. The current standard approach to FA consists of the strict avoidance of the triggering food. However, an elimination diet may be difficult and frustrating, above all for those foods (e.g. milk and egg) that are pivotal in the common diet. Oral immunotherapy (OIT) may increase the amount of food that the patient can intake without reaction and reduce the risk of potential life-threatening allergic reactions. It is currently considered the most promising treatment for FA. However, many gaps are still unsolved. Areas covered: The aim of this review is to shed light on the current evidence and the main needs in OIT in order to stimulate the development of longitudinal, prospective, and well-designed studies with the final goal of a ‘precision medicine.’ Expert commentary: Clinical trials for OIT conducted so far are extremely heterogeneous. The aim in the near future is to identify the most suitable candidates to OIT and algorithms for treatments tailored on well-characterized subpopulations of patients.

Peanut allergy is classically managed by food avoidance. Immunotherapy programmes are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers.

A retrospective, international survey of anonymized case records from seven specialist paediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analysed.

Of the 1.634 children aged 1 to 18 years old included, 525 (32%) failed their peanut challenge. 28% reacted to 25mg, while 38% only reacted after consuming 1g or more of whole peanut. Anaphylaxis (55 (11%)) was 3-times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to smaller 25-200mg whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity.

More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut was more common in older children. Tailored immunotherapy programmes might be considered not only for children with low, but also higher reaction thresholds. Whether these programmes could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study.

Allergen immunotherapy (AIT) is still the only causal treatment for allergic diseases. However, conventional subcutaneous immunotherapy (SCIT) administration schedules are time-consuming and patient nonadherence is a major barrier to achieving a satisfactory therapeutic effect. Our study aimed to analyze the causes leading to discontinuation of SCIT and to determine risk factors associated with nonadherence in respiratory allergies.

This was a prospective study. Patients with respiratory allergies who had received standardized dust mite SCIT were enrolled from January 2012 to January 2014. And a follow-up study on these subjects was conducted via telephone interviews on an interval of 3 months and online communication through social network applications. Reasons for discontinuation were documented when patients claimed to stop treatment.

A total of 311 patients were enrolled in the study. The adherence rate at year 3 was 64.6%. Fifty-nine patients (19.0%) dropped out in year 1, 31 (10.0%) in year 2, and 20 (6.4%) in year 3. Reasons for nonadherence included inconvenience (32.7%), ineffectiveness (25.5%), improvement of symptoms (22.7%), and adverse reactions (14.5%). Children had higher adherence than adults (70.7% vs 55.0%) (p < 0.05). The dropout reasons were different among the children and adults groups (p < 0.005). The follow-up work was carefully and thoroughly done. All the 311 (100%) patients accepted the telephone interview, and 296 (95.2%) patients submitted questions and got rapid replies from doctors online.

Adherence to SCIT was less than satisfactory in the real-life study. A close communication between doctors and patients is helpful in enhancing adherence with AIT in clinical practice.