Although reliable figures are still largely unavailable, IgE-mediated food hypersensitivity (hereafter referred to as food allergy) is thought to affect around 1-2% of adults and 4-8% of children, i.e. roughly around 10 million EU inhabitants (reviewed in [1, 2]). Recent studies within the FP6-funded project EuroPrevall  showed tree nuts (hazelnut and walnut), fruits (apple, peach and kiwi) and peanut are the most common plant foods causing food allergy, followed by vegetables like carrot, tomato and celery. After milk and egg, fish and shrimp are most frequently causing food allergy to animal-derived foods (pers. comm. M. Fernandez-Rivas).
The clinical presentation of food allergy varies from mild local symptoms of the oral cavity, usually referred to as the oral allergy syndrome (OAS), to severe systemic reactions which can include life-threatening anaphylaxis. In the U.S., food-induced anaphylaxis is estimated to cause about 120,000 emergency room visits and 3000 hospitalizations each year .
The only available treatment for food allergy is avoidance, in conjunction with rescue medication in case of accidental exposure. However, hidden allergens in composite foods, unwanted contaminations and occasional poor adherence to dietary restrictions make avoidance difficult and ineffective. Therefore there is an urgent need to develop a treatment for food allergy that lowers the threshold significantly and makes avoidance less stringent. Allergen-specific immunotherapy (SIT) is the only treatment available that targets the immunological cause of the disease. It has proven successful in treatment of insect venom allergies and for respiratory allergies such as rhino-conjunctivitis and asthma to pollen and house dust mite [5–7], but due to the duration and invasiveness (i.e. 3-5 years of monthly subcutaneous injections) and the risk of anaphylactic side-effects, SIT is a niche treatment compared to symptomatic drugs, though new alternative routes have been recently successfully explored .
Over the past decades, major inhalant and food allergens have been identified, purified, cloned and produced as recombinant proteins. The use of recombinant allergens to replace biological extracts will contribute to enhance the efficacy of SIT by better control over the dosage and elimination of some of the disadvantages (variability in product quality, difficulty in standardization of extracts, sensitization to new allergens) inherent to biological extracts (reviewed in ). The first clinical trials using recombinant allergens of birch, grass and ragweed pollen have demonstrated that single recombinant proteins can effectively replace extracts [10, 11].
For the development of immunotherapy for food allergy, most attention has so far been given to peanut egg and milk, as these foods are important causes of severe food allergy, mainly in children. Oral immunotherapy approaches for several foods (milk, egg, peanut) show desensitization but no tolerance and commonly have side-effects (well-reviewed in ). As children with transient milk or egg allergy seem to have IgE primarily directed to conformational epitopes, sensitive to heat or processing [12, 13], two clinical trials focused on investigating tolerance to heated milk and egg products in this population [14, 15]. Preliminary studies suggested accelerated tolerance induction, so a follow-up study is ongoing. Subcutaneous allergen-specific immunotherapy (SCIT) as a treatment for peanut allergy has been evaluated using aqueous peanut extract. Although a significant level of efficacy was demonstrated, anaphylactic side-effects, caused by IgE-binding to the injected allergen, were too frequent and the project was abandoned [16, 17]. In recent years, sublingual therapy has gained a considerable share of the market for the treatment of respiratory allergies in the form of extract-based drops or tablets. Side-effects are reported to be minimal and efficacy has been demonstrated. The first reports of SLIT with food allergens, date from 2003, in kiwi [18, 19]. More recently, SLIT using hazelnut [20, 21] and peanut extract  has been reported for the treatment of hazelnut and peanut allergy and peach peel extract enriched for LTP was used in a SLIT trial to treat peach allergy [23, 24]. These treatments resulted in a significant but moderately increased tolerated dose and systemic side-effects have so far rarely been reported. Despite these quite promising results, in FAST we have decided to target SCIT, the main reason for this being the expected higher efficacy and better compliance and safety, facilitated by performing treatment in an outpatient clinical environment.
To increase safety and develop effective SCIT for the treatment of food allergy, the allergen can be modified in such way that it exhibits significantly decreased IgE-binding potency, i.e. that it becomes hypoallergenic, but retains T-cell reactivity. In addition, these hypoallergens can be absorbed to aluminium hydroxide, which increases safety due to its depot effect and furthermore increases efficacy by its adjuvant effect.
There is still some disagreement concerning the immunological basis of the beneficial effect of immunotherapy. Allergic patients can typically be distinguished from healthy subjects by the presence of allergen-specific IgE antibodies, but a (usually not observed) decrease in specific IgE can not explain the beneficial effect of SIT. The current knowledge on the characteristics of the allergic immune response and its modulation by SIT has developed dramatically beyond the level of serum IgE antibodies, in particular knowledge on other isotypes such as IgG4 and IgA, on various subsets of helper T-cells (Th-cells) and on the role of innate antigen presenting cells (like dendritic cells (DCs). Essentially there are two extremes for explaining the beneficial effect of SIT: inhibition of allergic reactions by blocking IgG4 and IgA antibodies or by a shift from Th2 to Th1/Treg. FAST aims at induction of both using hypoallergenic but immunogenic recombinant allergens. Although double-blind placebo-controlled food challenge (DBPCFC) will always remain the primary read-out for establishing efficacy, it is not an appropriate tool to use at many (early) time-points during treatment. However, reliable early (composite) biomarkers for efficacy that correlate with the outcome of the DBPCFC are not (yet) available. To improve and identify relevant (composite) biomarkers for monitoring efficacy of immunotherapy it is important to further unravel the mechanism of protection in patients responding favorably to immunotherapy. In depth monitoring of humoral and cellular immune parameters will help identify such (early) biomarkers for efficacy.
Within this context it is the objective of the EU-funded collaborative project FAST to develop a safe and effective immunotherapy against persistent and life-threatening food allergies. The project includes 15 partners from 11 different countries. To address all the main objectives indicated above, the partnership first focuses on producing and testing a number of different mutant (hypo-) allergens (and wild-type allergens for comparison). Additionally, there are three companies, two partners from the pharmaceutical industry (BIAL, Spain and HAL Allergy, The Netherlands) and one biotech company (BIOMAY, Austria) that will focus on the production of the chosen hypoallergens under good manufacturing practice (GMP) for the clinical trials. In the consortium there are six clinical centers participating in six countries, chosen on the basis of expertise and geographic background. Lastly, allergen-specific MHC class II tertramers/multimers will be developed as well as mouse models for immunotherapy with hypoallergens.