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Improving the safety of oral immunotherapy for cow's milk allergy in children

Periodic Reporting for period 1 - SO-CMA (Improving the safety of oral immunotherapy for cow's milk allergy in children)

Reporting period: 2016-03-07 to 2018-03-06

Cow’s Milk allergy (CMA) is the most common food allergy in young children. After nuts, it is also the most common cause of death due to allergic reactions in children in the UK. Food allergy has a major impact on quality of life, due to the fear of having an unpredictable life-threatening reaction, and the dietary restrictions needed to reduce this risk. Milk is a common ingredient in our diets, so avoidance can be very difficult.
There is no treatment for CMA- day-to-day management involves avoiding all dairy and having rescue medication (such as an adrenaline ‘pen’) available. Many children outgrow their CMA by school age, but recent reports show that up to half will continue to be allergic in adulthood. Children with persisting CMA often have more severe reactions.
A different approach to managing CMA is immunotherapy. This involves trying to “re-train” the immune system not to react to milk. One way to do this is to give increasing amounts of milk every day for several months, known as oral immunotherapy (OIT). An alternative is to keep the milk under the tongue for a few minutes every day, rather than simply swallow it. This approach, known as sublingual immunotherapy (SLIT), is very effective for non-food allergies, such as hayfever. OIT can be effective for CMA, but it can cause frequent reactions. SLIT causes very few reactions but it doesn’t have as big an effect in changing the amount of milk tolerated after treatment.
The main objective of this action was to develop a safe and effective treatment for children with persistent CMA. Specifically, to explore whether using SLIT followed by OIT is a better way of doing immunotherapy, without causing significant reactions. A number specific objectives was established (see below). The action duration was 24 months. Early termination occurred in month 7 due the fellow being appointed to a substantive clinical/academic position.
Work performed for the planned aims/objectives

1. Scientific aims.
1.1. To provide evidence that SLIT can improve OI safety in CMA children.
A clinical trial was designed to address this (work package 3, months 5-22). As early termination was notified in month 4, the trial start (and documentation submission for Ethics approval) was withheld until alternative funding had been secured. the fellow optimized the trial methodology through experts’ advice and literature search. the fellow analysed candidate products for protein content, allergenicity and taste (results presented in the European EAACI congress 2017) to identify the most suitable product for SLIT. the fellow produced the documentation required for Ethics approval and contributed to securing funding, including obtaining two research grants to fund mechanistic work. Full funding to conduct the trial at ICL has now been secured. The expected start date is in early 2018. the fellow will be co-principal investigator alongside her supervisor.

1.2. To provide the fellow with the skills, expertise and collaborations to design, manage and execute a multicentre clinical OIT trial for CM allergy, potentially using modified proteins.
the fellow has developed further her knowledge and skills to conduct high quality clinical trials in children through: a) formal courses, b) ongoing research at ICL (particularly the BOPI immunotherapy study using modified peanut), c) a one-week attachment at UMC Utrecht to learn about a multicenter trial on epicutaneous food immunotherapy, d) new scientific collaborations at ICL and Madrid, Spain, to expand research on biomarkers for safe and effective OIT for CMA.

2. Scientific objectives:

2.1. To explore options to improve the existing OIT protocols safety.
As output of work package 1, the fellow and her supervisor published a review paper in the world leading journal in Paediatric Allergy (Pediatr Allergy Imm 2016;27(2):117). This was the third most downloaded paper of the Journal in 2016. It contributed to raise awareness about the limitations of OIT and potential strategies to improve safety.

2.2. To assess the utility of laboratory tests to predict response to OIT.
The results of the SOCMA trial are not available as it has not started. However, new collaborations have been established –and funding secured- to expand the research on biomarkers to predict OIT responses. This includes IgE binding to milk peptides, saliva biomarkers, IgE-Facilitated antibody-binding test, basophil and mast cell activation tests.

3. Training objectives
The action has provided invaluable training to the fellow in the following areas:
3.1. Knowledge: a) Conducting systematic reviews (the fellow has completed specific courses and is finalizing a Cochrane systematic review update on milk immunotherapy); b) Clinical trials methodology/governance (through hands-on experience (BOPI study) and formal training); c) Statistics (through access to a Statistician to discuss study analysis planning and power calculation).
3.2. Specific skills: a) Novel Laboratory techniques. the fellow could not perform the planned 3 months laboratory secondment in Utrecht in months 2-4 due to pregnancy. Instead a one-week observership was organized in Nutricia/Utrecht where the fellow joined meetings on ongoing research on hypo-allergenic milk proteins development. the fellow learned about techniques to assess protein allergenicity in vitro, such as Immunoblot. This collaboration materialized in an abstract at the EAACI annual congress 2017. b) Management skills: through hands-on experience supervising junior staff in the BOPI trial and MSc students conducting research in ICL.
3.3. Transferable skills: the fellow has completed 15 courses at the ICL’s Postdoc Development Centre on management and communication, postdoctoral supervision and teaching, applying for funding, regulation and ethics.
3.4. Clinical opportunities: the fellow had access to weekly multidisciplinary allergy meetings for complex case discussion and other research studies in a dedicated Paediatric Research Unit.
3.5 Existing collaborations. the fellow has collaborated with international experts to explore the impact of milk immunotherapy on quality of life, nutrition and diet in children in the SOCMA trial.
In summary, as a result of this action, despite its early termination, the beneficiaries have done a significant contribution to the scientific community through a high impact review article on strategies to improve OIT safety. The SOCMA trial exploring a safer treatment for CMA will be conducted with improved methodology and outcomes through new research collaborations, covering mechanisms underlying OIT, impact on quality of life and nutrition. Funding has been secured and the requirement documentation has been produced. Finally, the action has enhanced ICL’s position as a reference for food immunotherapy in Europe as well as the fellow’s career perspectives and research opportunities. the fellow has been invited to a number of research collaborations and to speak at National/International Allergy meetings focusing on safer treatments for food allergy. the fellow is now a Board member of the Paediatric Section of EAACI, where she is co-leading a European registry on centres performing OIT with a focus on ensuring patients’ safety.