Utilization of virus-like particles (VLPs) is considered to improve allergen-specific immunotherapy (AIT). AIT aims at the efficient uptake of the target allergen by antigen-presenting cells (APCs) subsequently inducing adaptive allergen-specific immune responses to induce tolerance. The purpose of this review is to describe the immune-modulating properties of VLPs per se and to summarize the application of VLPs as antigen carriers, preferably for Th2 cytokines or allergens, with and without simultaneous administration of adjuvants in order to modulate allergic immune responses.

Currently, a broad variety of approaches considering the origin of the VLPs, the choice of the adjuvant and antigen, and the coupling of the antigen are under preclinical investigation. The data provide evidence that VLPs used as carrier for antigens/allergens strongly increase antigen immunogenicity, and might be suitable to prevent allergies. However, systematic studies in mice showing the immunological mechanism and data from clinical studies are scarce.

The food allergy epidemic of recent years has led to the search for safe and effective methods of immunotherapy for foods. Studies of epicutaneous immunotherapy (EPIT) in mice have shown promising safety and efficacy data. Murine models have also identified probable mechanisms for the development of tolerance to food allergens, including the induction of regulatory T cells. Clinical data is lacking, but relatively small and early studies among peanut and cow’s milk allergic subjects suggest that EPIT has an excellent safety profile, particularly compared to other methods of specific allergen immunotherapy. Efficacy data are also promising for peanut allergy, among younger patients (ages 4-11 years of age), suggesting that a majority of young patients will experience an increase in reaction threshold with therapy. The goal of this therapy is the protection from accidental exposures to a known food allergen. Additional clinical data is needed to prove efficacy and further demonstrate the safety profile of EPIT for food allergy, prior to approval by the Food and Drug Administration.

Food immunotherapy has been the focus of several allergy research initiatives over the last decade. Though many questions remain unanswered, the evidence suggests that this treatment may be available in the near future outside clinical trials. Additionally, pharmaceutical companies, in light of promising early stage results, have shown interest in developing commercially available products, thus increasing the likelihood that new immunotherapy treatments will be introduced, especially for peanut allergy. Given this optimistic scenario, and given the prospect of rigorously developed products for peanut allergy treatment, each allergist will need to understand the specificities of these treatments and their expected efficacy and adverse event profiles. It is thus imperative that allergists understand the differences in efficacy between the different management options as well as how the endpoints are measured in the relevant literature. However, given the significant heterogeneity detected among food immunotherapy trials, this task may not be as straightforward as desired. This article aims to dissect how primary efficacy endpoints are defined and assessed in order to facilitate understanding of the design of these trials and the potential impact that this variation may have on the reported outcomes.

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 efficacy and safety of 300 index of reactivity (IR) tablets of house dust mite (HDM) allergen extracts in Japanese pediatric (5-16 years old) patients with allergic rhinitis (AR) were assessed in a double-blind, randomized, placebo-controlled study (JAPIC CTI-152981).

Patients were randomized 1:1 to HDM sublingual tablets or placebo once daily for 52 weeks. The primary endpoint was Average Adjusted Symptom Score (AASS; average of daily Rhinitis Total Symptom Scores, comprising sneezing, rhinorrhea, nasal congestion, and nasal pruritus, adjusted for rescue medication use), analyzed during Weeks 48-52 (mixed-effects model for repeated measures).

Of 438 patients randomized, 403 (92%; 193 active, 210 placebo) completed the study. AASS (least-squares [LS] mean [standard error]) during Weeks 48-52 was significantly (P = .0005) lower in the active group compared with placebo (6.32 [0.20] vs 7.27 [0.19]; relative LS mean difference, -13%). Immunological responses (IgE and IgG4 antibodies specific to antigens of 2 HDM species) were significantly greater in the active group compared with placebo (P < .0001). Almost all patients experienced mild or moderate adverse events (AEs). The most common treatment-related AEs were oral pruritus, mouth edema, throat irritation, and ear pruritus. One patient experienced serious pseudocroup (subglottic laryngitis) that recovered. There were no deaths or anaphylaxis requiring the use of injectable adrenaline.

The HDM tablet significantly improved symptoms of HDM-induced perennial AR and was associated with a significant immunological response. The safety profile in pediatric patients was consistent with that in adults, with no new safety concerns.

The clinical benefit of allergen-specific immunotherapy (AIT) involves induction of blocking antibodies. It is not clear if these antibodies function via steric hindrance alone or a combination of levels, avidities, and epitope specificities, and clinical outcome cannot be predicted. We aim to in-depth characterize serum antibody profiles during birch pollen AIT, investigate therapy-induced antibodies for their capacity to block IgE binding to Bet v 1 and correlate data with clinical outcomes.

Immune responses of five birch pollen allergic patients were monitored during the first year of AIT by nasal provocation tests (NPTs), ImmunoCAP, immunoblots, direct and avidity enzyme-linked immunosorbent assays, mediator release assays, facilitated antigen binding (FAB) assays, and inhibition mediator release assays.

There was no correlation between NPT results and therapy-induced changes in levels (IgE, IgG, IgA, IgM), avidities, or mediator release potency of Bet v 1- specific antibodies. In FAB assays, blocking antibodies initiated upon AIT were shown to prevent formation of Bet v 1-IgE complexes of an indicator serum pool and significantly correlated with clinical readout. Inhibition mediator release assays using patient-specific IgE for passive sensitization revealed therapy-induced blocking capacities with very good correlation to NPT results. Notably, this assay was the only one to detect a non-responder during treatment in this pilot study.

Clinical outcome of AIT depends on induction of blocking antibodies able to prevent the patient’s own IgE from allergen binding. Monitoring of clinical efficacy seems to be best achieved using the inhibition mediator release assay, as development of relevant blocking antibodies can be verified in a patienttailored manner.

So far, only a few biomarkers in allergen immunotherapy exist that are associated with a clinical benefit. We thus investigated in a pilot study whether innate molecules such as the molecule lipocalin-2 (LCN2), with implications in immune tolerance demonstrated in other fields, may discriminate A) between allergic and non-allergic individuals, and B) between patients clinically responding or non-responding to sublingual allergen immunotherapy (SLIT) with house dust mite (HDM) extract. Moreover, we assessed haematological changes potentially correlating with allergic symptoms.

LCN2-concentrations were assessed in sera of healthy and allergic subjects (n = 126) as well as of house dust mite (HDM) allergics before and during HDMsublingual immunotherapy (SLIT) in a randomized, double-blind, placebo-controlled trial for 24 weeks. Sera pre-SLIT (week 0), post-SLIT (week 24) and 9 months after SLIT were assessed for LCN2 levels and correlated with total nasal symptom scores (TNSS) obtained during chamber challenge at week 24 in patients receiving HDM- (n = 31) or placebo-SLIT (n = 10).

Allergic individuals had significantly (p < 0.0001) lower LCN2-levels than healthy controls. HDM-allergic patients who received HDM-SLIT showed a significant increase in LCN2 9 months after termination of HDM-SLIT (p < 0.001), whereas in subjects receiving placebo no increase in LCN2 was observed. Among blood parameters a lower absolute rise in the lymphocyte population (p < 0.05) negatively correlated with symptom improvement (Pearson r 0.3395), and a lower relative increase in the neutrophils were associated with improvement in TNSS (p < 0.05). LCN2 levels 9 months after immunotherapy showed a low positive correlation with the relative improvement of symptoms (Pearson r 0.3293). LCN2-levels 9 months off-SLIT were significantly higher in patients whose symptoms improved during chamber challenge than in those whose symptoms aggravated (p < 0.01).

Serum LCN2 concentrations 9 months off-SLIT correlated with clinical reactivity in allergic patients. An increase in the LCN2 levels 9 months after HDM-SLIT was associated with a clinical benefit. Serum LCN2 may thus contribute to assess clinical reactivity in allergic patients.

Today, in vivo allergy diagnosis and allergen-specific immunotherapy (AIT) are still based on allergen extracts obtained from natural allergen sources. Several studies analyzing the composition of natural allergen extracts have shown severe problems regarding their quality such as the presence of undefined non allergenic materials, contaminants as well as high variabilities regarding contents and biological activity of individual allergens. Despite the increasing availability of sophisticated analytical technologies, these problems cannot be overcome because they are inherent to allergen sources and methods of extract production. For in vitro allergy diagnosis problems related to natural allergen extracts have been largely overcome by the implementation of recombinant allergen molecules that are defined regarding purity and biological activity. However, no such advances have been made for allergen preparations to be used in vivo for diagnosis and therapy. No clinical studies have been performed for allergen extracts available for in vivo allergy diagnosis that document safety, sensitivity, and specificity of the products. Only for very few therapeutic allergen extracts state-of-the-art clinical studies have been performed that provide evidence for safety and efficacy. In this article, we discuss problems related to the inconsistent quality of products based on natural allergen extracts and share our observations that most of the products available for in vivo diagnosis and AIT do not meet the international standards for medicinal products. We argue that a replacement of natural allergen extracts by defined recombinantly produced allergen molecules and/or mixtures there of may be the only way to guarantee the supply of clinicians with state-of-the-art medicinal products for in vivo diagnosis and treatment of allergic patients in the future.

Food allergy is a significant public health problem, with no suitable treatments available for patients. Currently, patients are limited to avoidance and the use of readily available emergency medications. Immunotherapy is an appealing therapeutic strategy for inducing tolerance. Studies with whole native allergens have demonstrated the efficacy of immunotherapy for food allergy; however, the risk of IgE-mediated reactions with such treatment is significant. Advances in molecular biology techniques, including purification, sequencing, and cloning, have allowed researchers to identify specific allergen components and T cell binding epitopes. Support for the use of recombinant and peptide vaccines for food allergy comes from prior studies involving aeroallergens and hymenoptera venom. By manipulating allergenstructure and IgE binding, allergenicity can be reduced, thereby reducing systemic reactions, making recombinant and peptide vaccines a safe and effective form of immunotherapy. Pre-clinical studies using in vitro and murine models demonstrated a more tolerant state following the use of these therapies. Studies with human subjects will be necessary to characterize the effects of recombinant and peptide food allergy vaccines and to demonstrate a safe treatment option for patients.

Health-related quality of life (HRQL) is influenced by physiological, psychological, and environmental variables and can be best understood by considering the interactions of factors that cut across multiple levels. One of the most important issues relating to treatment in food allergy is to identify, describe, and define predictors that may contribute to modify HRQL outcomes. The research presented demonstrates that measures of HRQL are able to distinguish key features of known groups (e.g. relating to reaction severity, treatment, allergen type/number, expectation of outcome) and delineate impact on hitherto unknown groups (e.g. relating to personality types and coping styles). This heterogeneity may explain why HRQL or other patient-related outcomes may differ in individuals during, or following any treatment or intervention. Patient-reported outcomes are relatively poorly defined to date. Since HRQL has only been studied in relatively few oral immunotherapy trials to date, primarily looking at caregiver HRQL, it is unclear which factors, measures, or subscales are most predictive of short- and/or long-term treatment outcomes for which type of patient, and which time points for measurement are most informative. A standardized protocol that incorporates HRQL and other relevant patient-related outcome measures and agreed definitions of outcomes would allow for the comparison of efficacy of food allergy treatments between centres, trials, or countries. Further evidence-based research aimed at exploring the effects of interventions on outcomes in food allergy is needed, including the influence of patient and parent factors on protocol design. To this end, it is vital that patient-related outcomes such as improved HRQL are seen as a primary outcome and are measured at multiple intervals during the trial duration and beyond. The creative use of methods and designs (both qualitative and quantitative) to better understand the role of HRQL in immunotherapy treatment trials will enable improved modelling of the costs, risks, and benefits of any treatment. Systematic analysis and modelling of antecedent factors, mediators, and outcomes will be important to boost intervention effects and to maximise the overall benefits of treatment.