Optimising the management of peanut allergy by targeting immune plasticity

Randomised controlled trials investigating the efficacy of oral tolerance induction to peanut have enabled detailed comparison of their clinical and immunological success. They have demonstrated that the regular consumption of peanut for at least 2 years by babies who are not allergic enables protection from developing peanut allergy. The LEAP study intervention tested the impact of regular peanut consumption for 4 years and demonstrated a sustained protection against the development of peanut allergy even after 12 months of peanut avoidance from 5 to 6 years of age. The PreventADALL trial introduced multiple allergens into babies' diets from early infancy and reduced the prevalence of food allergy at 3 years, especially by protecting against peanut allergy. Immunological studies from the LEAP cohort demonstrated that regular peanut consumption was associated with a prompt induction of peanut‐specific IgG4 and reduced manufacture of peanut and Ara h 2‐specific IgE. Even after stopping peanut consumption for 5 years, there continued to be a significant fall in peanut‐specific Ara h 2 IgE in the consumption group from 5 to 6 years of age (p < .01). Children who developed peanut allergy by 5 years started to develop increasing sensitisation to linear sequential peanut epitopes from 2.5 years of age, suggesting that putative disease‐modifying interventions should commence before 3 years. Data comparing clinical outcomes between children undergoing peanut immunotherapy from infancy suggest that younger children can consume higher portions of peanut without reaction on challenge whilst taking immunotherapy, have fewer side effects and are more likely to enjoy remission of PA. Peanut oral immunotherapy modulates T‐cell populations in order to bring about hypo‐responsiveness of allergy effector cells. Studies are now needed to characterise and compare different states of immunological tolerance. This will accelerate the design of interventions which can promote primary, secondary and tertiary levels of PA prevention across a range of age groups.


| INTRODUC TI ON
Food allergen tolerance, both in the context of the prevention and the treatment of food allergies, is the capacity for an individual to be symptom-free with consumption of the food months, or even years, after the cessation of allergen consumption. 1 Despite this clear pragmatic definition, the immune processes underpinning tolerance acquisition are only partially understood.Food ingestion facilitates food allergen sampling by CD103+ dendritic cells from the luminal tract, enabling their presentation to the T-cell compartment, inducing forkhead box protein 3-positive T-regulatory cells and supporting a tolerogenic cytokine milieu. 2,3A wide range of environmental factors may hinder natural tolerance acquisition, including genetic, [4][5][6] epigenetic, 7 microbial, [8][9][10][11] cutaneous [12][13][14] and gastro-intestinal mechanisms. 15Disruption of tolerance may result in activation of Th2 cells and class-switching from IgA to allergen-specific IgE antibody manufacture both in the gut-associated lymphoid tissue and mucosal compartment and the development of food allergy. 16Some risk factors may be assuaged by translational interventions.For instance, the dual-allergen exposure hypothesis posits that food allergies develop through transcutaneous exposure in infants, especially if their skin barrier is impaired through eczema. 17,18Observational evidence assessing the environmental burden of peanut protein, the integrity of the skin barrier, 4,5,19,20 eczema severity 12,21 and cutaneous staphylococcal burden 22 supports the hypothesis that transcutaneous peanut allergen exposure drives the development of peanut allergy (PA) and offers potential intervention targets.A single randomised trial has demonstrated proof of principle that reducing eczematous inflammation by applying topical steroids regularly over both eczematous and non-eczematous skin of infants with a history of eczema may reduce the prevalence of egg allergy. 23Alternatively, regular consumption of peanut (via the 'oral exposure route') may induce tolerance either thereby preventing PA or increasing the threshold at which patients show signs of reacting.
The array of candidate environmental and physiological processes influencing the pathogenesis of food allergy highlights the complexity of innate and acquired mechanisms that determine the relative likelihood of developing oral tolerance to food allergens.
Given that the pathophysiology of food allergy is multifaceted, and the prevalence is up to 10% in western countries, 24 restricting the delivery of food allergy prevention interventions to those at high risk of developing food allergy reduces their population impact. 25Dietary interventions which offer food allergy prevention as a 'universally accessible' public health intervention are likely to offer the most significant benefit.Where an IgE-mediated reaction to food allergen is suspected, children require clinical investigation to confirm allergy and counselling the family on next possible steps including immunotherapy where this is available.
The prevention of food allergy may be categorised into primary, secondary or tertiary prevention according to whether children have no sensitisation, sensitisation alone or demonstrate both sensitisation and clinical signs of an objective allergic reaction when administered food challenges.
In this review, we describe and compare immunological patterns that arise from trials modulating the natural history of peanut allergy (PA), which otherwise may persist into adulthood (Figure 1).We consider the public health and clinical context of the trials, by comparing both clinical and immunological outcomes from data that have already been published (listed in Table 1).We collated publications from contemporary systematic reviews, snowballing from the literature and our own knowledge, supplemented by informal database searching.We consider how these data reveal a window of immunological plasticity in early life, which may enable clinicians and researchers to develop future approaches for managing food allergy.

| LEAP intervention and assessment windows
In the Learning Early About Peanut (LEAP) study, children with egg allergy or moderate-severe eczema who ate standardised peanut portions (equivalent to 2 grams of dried peanut protein) 3 times weekly from before their first birthday benefitted from 81% relative risk reduction in PA at 5 years of age. 2692% of participants adhered to protocol.The prevalence of PA was 17.2% in the peanut avoidance group and 3.2% in the consumption group (p < .001).This proof-of-concept trial demonstrated that regular and sustained peanut consumption can prevent the development of PA in highrisk infants.Both arms of LEAP participants were then requested to avoid peanut consumption absolutely in the follow-up LEAP-On study from 5 years of age until they were re-assessed at 6 years, irrespective of whether they had been initially randomised to peanut consumption or avoidance.Even after 12 months of strictly avoiding peanut from 5 to 6 years of age, there remained a significantly lower prevalence of PA among the consumption group compared to the avoidance group (4.8% vs. 18.6%, respectively; p < .001),demonstrating that the LEAP intervention conferred at least 12 further months of tolerance to peanut after regular peanut consumption had ceased (Figure 1). 27

Key messages
• Oral tolerance induction to peanut is associated with production of peanut-specific IgG4 and the inhibition of peanut-and Ara h 2-specific IgE.
• Expansion of sequential epitope-specific IgE sensitisation in peanut allergy suggests that disease-modifying interventions should be undertaken before 3 years of age.
• Observational data suggest that peanut oral immunotherapy may show superior efficacy and safety when initiated in the first year of life, although trial data are required.
The LEAP-Trio study is assessing whether a further 6 years of adlibitum peanut consumption from 6 years will impact the capacity of the original peanut consumption intervention to protect these children from developing PA until 12 years of age. 28e LEAP intervention did not protect against the development of tree nut allergies, suggesting that the primary and secondary prevention of food allergy is food allergen specific and dependent upon the same allergen being regularly consumed. 29

| Consuming peanut protects against peanut allergy within trials of multiple allergen introduction
The Enquiring About Tolerance (EAT) study enrolled exclusively breastfed 3-month-old infants to test whether the regular consumption of multiple allergens alongside continued breastfeeding would enable the prevention of a wider range of food allergies. 30total of 1303 infants were randomised into either an 'earlyintroduction group' (consuming peanut, cow's milk, boiled egg, sesame, codfish and wheat from 4 months of age) or 'standardintroduction group' (continued exclusive breastfeeding until 6 months followed by standard government-recommended introduction of solids).The early-introduction group parents were recommended to offer portions (equivalent to 2 grams of the dried food protein) twice weekly of each food, alongside continued breastfeeding.The primary outcome of the study was challenge-proven food allergy to any of the study foods between 1 and 3 years of age.
Intention-to-treat analysis of the EAT trial showed an insignificant drop in the prevalence of food allergy in the intervention group (5.6% vs. 7.1%, p = .32). 30 There were no cases of PA among the 310 The prevalence of peanut allergy is shown among participants who had a negative result on the skin prick test (SPT) at the baseline visit in the LEAP Study, among those who had a positive result at the baseline visit and in both groups combined.Panel A shows the prevalence of PA at 5 years of age among only the participants in the primary trial who enrolled in the follow-up study.Panel B shows the prevalence of PA at 6 years of age among participants in the LEAP-On follow-up study who were included in the intention-to-treat analysis.

(A) (B)
TA B L E 1 Randomised controlled trials aiming to prevent and ameliorate peanut allergy in early childhood.

TA B L E 1 (Continued)
participants in the early-introduction group who ate the equivalent of at least 3 g of dried peanut protein for at least 5 weeks from 3 to 6 months of age, compared with 13 cases among 525 participants (2.5%) in the standard-introduction group (p = .003).
By combining the participants of LEAP and EAT, the dietary introduction of peanut protected children from PA irrespective of presence of eczema, severity of eczema, presence of egg allergy, sensitisation status to peanut or ethnicity. 31,32e PreventADALL trial confirmed that multiple food allergen introduction from 3 months can protect against food allergy with PA protection driving most of this significant protection.

| Following questions
The American government is the only national body to have formally endorsed recommendations for the dietary introduction of peanut among infants. 35Yet, significant questions remain unanswered by the trials to date.
It is unknown for how long peanut consumption should be recommended.The trials have assessed the efficacy of dietary peanut consumption by investigating PA from 3 to 5 years of age.The impact of consuming peanut for less than 2 years and more than 3 years in a health-normal population is currently unquantified.
The clinical stability of peanut tolerance is unknown.Forthcoming LEAP-Trio data will assess the duration of protection from PA after 4 years of regular peanut consumption from infancy.Further data will be required to assess whether intermittent peanut consumption from infancy protects infants less than regular consumption.
It is therefore relevant to examine the underlying immunological changes within the LEAP study participants to enable clinicians and researchers to measure the tolerance induction process.

| IMMUNOLOG IC OUTCOME S
Immunologic biomarkers for the development of peanut tolerance can be categorised into early, medium and medium-long-term changes.Data from serial skin and serum sensitisation measurements have been published among LEAP participants at enrolment, 1, 2.5, 5 and 6 years of age.

| Skin prick sensitisation patterns
The LEAP study control group demonstrates the natural progression of peanut skin sensitisation among participating infants at higher risk of developing PA.Incrementally larger peanut weal sizes are demonstrated in the peanut avoidance group at 1, 2.5 and 5 years (p = .002at 12 months and p < .001at both 2.5 and 5 years in intention-totreat analysis from LEAP).
In the LEAP-On study, peanut wheals continued to remain high from 5 to 6 years in the peanut avoidance group (p = .422;Figure 2); however, the peanut consumption group demonstrated lesser frequency and magnitude of skin prick test reactivity when compared to the avoidance group (p < .001) at 1 year and at all later time points, even at 6 years of age following cessation of peanut consumption for 12 months (when comparing participants meeting per protocol adherence definitions for LEAP and LEAP-On studies as in Figure 2).

| Serum-specific IgG4 (sIgG4)
Serum sIgG4 to peanut has the ability to block allergen from triggering effector cells. 36Its concentration was increased rapidly in the peanut consumption group by 1 year and remained higher than the avoidance group at 2.5 and 5 years of age (p < .001for each time point; Figure 3).Peanut-sIgG4 remained elevated at 6 years following cessation of peanut consumption (p < .001).From 2.5 years of age, serum peanut-sIgG4 falls in the peanut consumption group both to 5 years (p < .001)and then continued to fall further after 12 months of peanut avoidance to 6 years (p < .001; Figure 3).
However, peanut-sIgG4 remained significantly higher in the consumption group, even at 6 years of age, following 1 year of discontinuation of peanut consumption.
It is unclear whether these early and sustained immunological changes in peanut-sIgG4 production merely reflect exposure to peanut or active immunomodulation.

| Sequential epitope-specific IgE (ses-IgE) patterns
Suarez-Farinas and colleagues analysed the evolution of peanut sensitisation to linear epitopes across the LEAP study visits and compared the patterns of sequential epitope-specific (ses)-IgE sensitisation according to study arm to assess the impact of the intervention.
Peanut sensitisation to the 64 sequential linear epitopes from Ara h 1 to Ara h 3 was quantified using a bead-based epitope assay.A limited quantity of ses-IgE to peanut was detected across all participants at enrolment of this atopic cohort.Non-significant increases in ses-IgE occurred after 1 year in consumers and not to the same epitopes as those children who went on to develop PA. 37 The overall ses-IgE expansion was observed between 2.5 and 5 years of age in avoiding participants with challenge-confirmed allergy at 5 years of age, with no change among avoiders who had a negative challenge (Figure 4).This expansion of ses-IgE was inhibited in the group consuming peanut.was only a significant reduction in peanut-sIgE in the consumption group at 6 years of age (Figure 5).SIgE to Ara h 2 showed an earlier significant decline in the consumption group at 5 and 6 years of age (Figure 6).with every month in the first year of life to a greater extent in infants with eczema (especially severe eczema) and 'non-white' ethnicity (Figure 8).This highlights the need for even earlier peanut consumption around 4 months of age in these higher risk groups. 31

| Australian recommendations for giving peanut alongside solids introduction did not reduce the prevalence of peanut allergy
The Australasian Society of Clinical Immunology and Allergy updated their guidelines in 2016 to recommend that all infants should be given allergenic solid foods including peanut butter, cooked egg, dairy and wheat products before 12 months of age, including those at high risk of allergy. 41  which patients first demonstrate objective reactions during a peanut challenge, reduces the risks associated with anaphylaxis and improves quality of life. 424][45] It also markedly increases peanut-specific IgG4 up to 10-fold, 46 which can suppress basophil and mast cell activation to peanut. 36Successful POIT has been associated with the induction of CD4 + T cells and the shifting towards an anergic Th2 T-cell phenotype. 47,48There is a transition to basophil hyporesponsiveness after 3 months of immunotherapy, corresponding to the patients' clinical response. 49ese immune changes are associated with clinical desensitisation, which is the ability to consume a significantly higher cumulative threshold of peanut protein during an oral food challenge whilst taking daily maintenance therapy before starting treatment.This capacity to consume greater threshold of allergen is usually temporary and dependent upon taking regular maintenance doses.The durability of this desensitisation can be assessed within randomised trials by ceasing daily dosing and then performing a challenge after a standardised period of time, resulting in a percentage of patients demonstrating 'sustained unresponsiveness', usually within a period of weeks from stopping treatment. 50Few participants in POIT trials attain permanent tolerance to peanut and remission of their PA, which enables unencumbered consumption of any quantity of peanut without the development of symptoms even years after the cessation of treatment.

| Undergoing peanut oral immunotherapy during the first 3 years may enable tertiary prevention of peanut allergy and tolerance induction
Tolerance to peanut may be induced among patients undergoing POIT in the first years of life, when their immune system shows greater plasticity. 51By starting immunotherapy earlier, the manufacture of linear sequential epitopes with high avidity to peanut from F I G U R E 3 Serum peanut-sIgG4 titres to peanut according to intervention group from enrolment to 72 months.Green denoting LEAP peanut consumer group and grey peanut avoidance arm.
around 2-3 years of age may be reduced or prevented, enabling greater likelihood of outgrowing PA. (51-54).
CoFAR enrolled children aged 9-36 months onto a POIT programme randomising to maintenance dosing at either 300 mg or 3000 mg.Intention-to-treat analyses found that treating for a median of 29 months supported 78% (29 of 37 children in 300 mg arm) and 85% (17 of 20 children in 3000 mg arm) participants to achieve unresponsiveness to 5000 mg of peanut on challenge 4 weeks after ceasing daily therapy, with no significant increase in efficacy at the higher maintenance dose. 51A trial of probiotic (Lactobacillus rhamnosus) supplemented POIT at 2000 mg maintenance compared the proportion of children attaining sustained unresponsiveness 8 weeks after stopping therapy and passing a 4950 mg peanut protein challenge and showed no significant impact of the additional probiotic to POIT (46% demonstrated unresponsiveness in the probiotic POIT (PPOIT) group, 51% in the POIT only group and 5% in the placebo group). 52,53They also showed greater desensitisation (88% PPOIT, 79% POIT at 1-5 years; 66% PPOIT, 68% POIT 6-10 years) and sustained unresponsiveness at 8 weeks (61% PPOIT, 56% POIT at 1-5 years; 29% PPOIT, 45% POIT 6-10 years) among participants aged 1-5 years than 6-10 years. 53e IMPACT trial enrolled 146 children from 12 < 48 months of age and randomised 2:1 to POIT versus placebo with maintenance at 2000 mg per day for 134 weeks, 5000 mg peanut challenge and then ceasing daily therapy for 26 weeks before repeating the 5000 mg exit peanut challenge.ably with the 67% of 4-17 year olds who tolerated 600 mg after at least 3 months on maintenance. 56National case series from Canada have reported lower prevalence of adverse effects with their POIT using commercially available peanut products to attain maintenance at 300 mg.270 patients aged 9-71 months of age underwent POIT and only 4% (10/270) of these used adrenaline throughout their treatment, 57 which is less than the 10% among the original Palisade cohort, 56 and 7% among the active arms of the Artemis cohort. 447 patients from the Canadian peanut OIT programme underwent peanut challenge to 4000 mg and 78.6% (92 of 117) demonstrated no adverse reaction.Subsequently, sub-analysis showed that the 69 infants had a superior experience with fewer adverse events of compared to the 383 children aged 12-71 months (33.9% vs 53.7%; p = .002).58 These data support the hypothesis that younger children have safer treatment, greater tolerance thresholds on maintenance POIT and greater capacity for sustained unresponsiveness or even resolution of PA.These features have led to the concept of 'rescue peanut immunotherapy'.59,60 There is a need to characterise the young children who have the marker expression or promotes classes of T regulatory cells that attenuate the natural history of PA.
For infants who have PA, POIT may support remission and the reattainment of peanut tolerance if commenced in the early years.
Although desensitisation appears to modulate the T-cell compartment, and its success may depend upon T-cell immunotype, it is currently unclear how these immunological changes may relate to the ultimate goal of POIT inducing long-term peanut tolerance.
Different routes of therapy are being examined.Boiled peanut, 62 epicutaneous peanut patch 63,64 and sublingual treatment 65 may show improved safety and effectiveness of immunotherapy.A small trial of peanut sublingual immunotherapy with a top maintenance dose of 4 mg among pre-school children reported 15/25 (60%) without symptoms on double-blind challenge after 3 years of treatment. 66The highest prevalence of desensitisation was among the 1-to 2-year age group.12/25 (48%) of treated children demonstrated tolerance to a cumulative dose of 4443 mg of peanut protein after stopping their daily sublingual therapy for 3 months after their 3-year course, showing a possibility of complete remission of PA through low-dose immunotherapy.Adjunct monoclonal treatment in combination with POIT may also facilitate improved desensitisation, especially in those undergoing multiple food allergen immunotherapy. 67,68The OUtMATCH trial will evaluate the adjunctive impact of anti-IgE therapy alongside multiplefood immunotherapy and will enable the evaluation of sustained unresponsiveness after coming off multiple-OIT. 69Forthcoming

6 | 6 . 1 |
Allergic avoiders had consistent significant increases in their ses-IgE over time, with IgE binding to 19 different epitopes at 2.5 years and further broad expansion to 64 different epitopes by the 5-year visit.This supports parallel observations in the Consortium of Food Allergy Research (CoFAR) cohort, which demonstrated an increase in ses-IgE from 2 years of age, among those who developed PA after 4 years.38The absence of IgE to linear epitopes in the first year of life could potentially explain why the LEAP intervention was successful in the group of infants with small positive weal to peanut and detectable serum-specific IgE to peanut.The fact that inhibition of ses-IgE production occurred in the consumption group (which nevertheless had detectable IgE to peanut and its components) strongly suggests that the IgE detected in the consumption group was largely comprised of IgE with avidity for conformational epitopes.Moreover, the late expansion in sequential linear epitope production seen between 2 and 4 years in CoFAR and between 2.5 and 5 years of age in LEAP describes a progression in the immunological phenotype of peanut allergic patients over time.It also points to a potential window of opportunity to treat and potentially cure PA more effectively earlier in infancy, well before 5 years of age.38 Recent data have shown that ses-IgE profiling can provide probabilities of tolerating contemporaneous discrete doses of peanut protein in allergic subjects undergoing double-blind, placebo-controlled food challenges by categorising allergic children into low or high cumulative dose reactors.39MED I UM -TO LONG -TERM CHANG E S INDUCED BY REG UL AR CON SUMP TI ON Peanut-specific IgE (sIgE) and Ara h 2-sIgE patternsAlmost one third (29%) of LEAP participants showed peanut-sIgE sensitisation at baseline (≥0.1 kUA/L).Peanut-sIgE (median or mean) remains similarly elevated in the consumption group compared to the peanut avoidance group until 5 years of age.There

7. 3 |
Targeting peanut oral immunotherapy to achieve tertiary preventionPeanut oral immunotherapy (POIT) consists of administering the specific food protein within a carefully scheduled incremental dose programme to escalate the patients' daily consumption to a maintenance dose.This increases the threshold of peanut allergen at F I G U R E 2 Data are presented for participants who met both the LEAP and LEAP-On per protocol definitions for each study assessment time point divided into avoidance and consumptions groups.Black diamonds represent medians, boxes represent 25th and 75th centiles and error bars represent 2.5th and 97.5th centiles.Circles represent individual participants who were not allergic at 72 months.Filled stars represent individual participants who were allergic at 72 months.The p-values placed between the assessment time points refer to the within group changes of the LEAP avoidance and consumption groups separately.p-Values directly below each assessment time point refer to a comparison between the LEAP avoidance and LEAP consumption groups.Paired t-tests were used for the within group changes and 2 sample t-tests were used for the between group comparisons.
54 71% (58 of 96) participants tolerated the challenge at week 134, whilst only 1 tolerated the challenge in the placebo group.After 24 weeks of cessation, 21% (20 of 96) passed the challenge in the active arm with a median cumulative F I G U R E 4 Expansion of sensitisation to sequential epitopes of peanut protein over time in peanut avoiders and consumers from the LEAP trial.A, Mean Fluorescence Intensity expansion for ses-IgE and ses-IgG4 at each visit by peanut exposure.Colour bar indicates the strength of the increase based on False Discovery Rate (dark red) or nominal p-values (pink or grey).Individual peptides are represented on the y-axis from bottom to top by their position on the Ara h 1 to Ara h 3 proteins.Significant ses-IgE expansion occurred primarily in the avoidance group between 2.5 and 5 years of age.dose tolerated at 755 mg, whilst 2% (1 of 50) of the placebo group attained remission.IgG4 to peanut and Ara h 2 had significantly increased at weeks 134 and 160.Interestingly, the T-cell compartment of IMPACT participants at baseline showed two distinct immunotypes of Th2A effectors, despite there being no difference in peanut skin sensitisation readings.Those with a predominance of Th2A effector cells in peripheral blood were more likely to become desensitised followed by continued tolerance to 5000 mg of peanut after 26 weeks of avoidance.These children were younger at baseline and showed cell surface expression of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) with high levels of specific peanut Ig, corresponding to the greatest clinical impact of POIT. 55Participants with a lower frequency of Th2A effector cells at the outset showed greater expression of skinhoming molecules and less desensitisation.So, the age of children, the predominance of circulating peanut-specific T cells and effector cell populations may distinguish children who display greater immune plasticity towards peanut.The licensed Palforzia 300 mg maintenance dose enables comparison of the mean challenge dose at which no observable adverse effects are demonstrated according to participants' age.61% of children from 1 to 3 years of age tolerated 2000 mg of peanut in the exit challenge whilst taking daily maintenance,* which compares favour-

Grade 2
or more during baseline challenge or treatment when * Aimmune Therapeutics to Present Positive Results from Phase 3 POSEIDON Study of PALFORZIA® [Peanut (Arachis hypogaea) Allergen Powder-dnfp] in Peanut-Allergic Children Aged 1 to 3 Years | Business Wire F I G U R E 5 Serum whole peanut-sIgE according to LEAP study group.

F I G U R E 6 F I G U R E 8
highest chances of resolution of peanut allergy through immunotherapy.Earlier age of initiation is just one potential clinical feature of immunological plasticity.Further beneficial characteristics may include the lack of linear sequential peanut epitope sensitisation and adaptive functional parameters such as the relative predominance of circulating Th2A effector cells with CRTH2 expression.With greater understanding of these mechanisms, biologic therapies may target mechanisms to facilitate the induction of tolerance and also allow other patients to become amenable to intervention.For example, the use of anti-IgE monoclonal antibody treatment reduces adverse effects in the up-dosing of POIT and limits the proliferation of Th2 and T effector cells in the initial response to treatment.618 | SUMMARYThere is a growing body of evidence that the regular consumption of peanut is the most effective strategy for preventing PA when commenced from the time of introducing solids.This is likely to be most effective as a universal public health program, although specific measures to engage the families looking after babies with eczema and hard-to-reach communities need to be developed.If this opportunity passes, sufficient immune plasticity may also still remain in the first years of life to initiate peanut immunotherapy with a chance of tertiary prevention enabling remission of PA.The protective effect of introducing peanut regularly into the diet of babies appears to diminish if delayed into the second half of the first year of infancy.After children with atopic risk factors have consumed peanut regularly for 4 years from infancy, long-term tolerance to peanut may be maintained in the majority of children for 1 year from 5 years of age.The putative efficacy of protecting children from PA up until 12 years of age is being evaluated in the LEAP-Trio Study.Serum peanut Ara h 2-sIgE according to LEAP Study group.The protective effect of the early introduction of peanut is associated with early induction of peanut-sIgG4 and inhibition of highlevel peanut-sIgE and Ara h 2-sIgE production, and this inhibition increases over time.Oral tolerance induction to peanut also inhibits the epitope-spreading to linear IgE peptides seen in peanut allergic children between 2.5 and 5 years of age.Studies of primary and secondary prevention have not yet assessed whether oral tolerance induction from infancy modulates T-cell populations, alters surface F I G U R E 7 Proportion density plots showing relative distribution of peanut-sIgE and Ara h 2-sIgE between the LEAP consumers (shown in green) and LEAP avoiders (shown in grey) arms for participants who met both the LEAP and LEAP-On per protocol adherence definitions.The vertical reference lines indicate where the higher end of the distribution begins to significantly differ (p = .05)between the randomised arms using bootstrap sampling of 1000 replicates of the upper percentiles.The progressive divergence in the distribution over time demonstrates that very high peanut-sIgE values are disproportionately represented in the LEAP avoiders compared to LEAP consumers.Relative reduction in burden of peanut allergy in a normalised population by age at introduction for (A) raw data from each study, (B) EAT-modelled effect plus whole-population model, and (C) whole-population model by eczema severity.All relative reductions estimate the treatment effect between early peanut introduction and avoidance.(A) EAT intention-to-treat (ITT) and per protocol (PP; restricted to only those exposed to the intervention) point estimates are displayed as red squares and are calculated as relative reductions between the standard-introduction and early-introduction arms.The blue points and blue smoothed regression line using a spline term for age shows relative reduction estimates from the raw high-risk.LEAP screening population data (that is, LEAP + Peanut Allergy Sensitisation cohort with peanut >4 mm weal (PAS), with imputed treatment effect among the PAS cohortbeing 0).(B) Red dashed line shows EATmodelled estimates using the LEAP ITT treatment effect applied at 3 and 12 months.The whole-population (EAT + LEAP + PAS)-modelled ITT effect with bootstrapped 95% confidence intervals is shown in black and grey.(C) The whole-population-modelled ITT effect is shown by eczema severity.
that assess long-term clinical outcomes from POIT and compare mechanisms associated with 'natural' and 'induced' tolerance will enable the development of translational treatments with long-term patient benefit.Future studies should focus on pragmatic and acceptable interventions to prevent and minimise the development of peanut and multiple food allergy during infancy, both among those at increased risk of developing food allergies and, where possible, through pragmatic public health trials.These may be strengthened by the assessment of immunological biomarkers for the induction of oral tolerance, to help understand the parallels between treatment strategies for different food allergy treatments.AUTH O R CO NTR I B UTI O N SAN: Wrote original draft, reviewed and edited.GdT: Review.GL: Conceptualisation, writing review and editing, supervision, and resource access.TM: Conceptualisation, writing review and editing and supervision.CO N FLI C T O F I NTER E S T S TATEM ENTGdT is part of the scientific advisory board for Aimmune and Novartis, is an investigator on Aimmune and DBV sponsored peanut immunotherapy studies and is Joint Director of the Food Allergy Immunotherapy Centre.GL is part of the scientific advisory board for Aimmune, Novartis and DBV Technologies, is Joint Director of the Food Allergy Immunotherapy Centre, shareholder in DBV Technologies and Mission MightyMe, and has received grants from the National Institute of Allergy and Infectious Diseases (NIAID, NIH), the Medical Research Council and National Peanut Board.TM is an investigator for a trial sponsored by DBV Technologies and is Director of the Allergy Academy, King's College London, which has received sponsorship from Aimmune and DBV Technologies.

Study name (Journal) Population Intervention No. of participants intervention No. of participants control Outcomes reported Age at outcome Results intervention Results control Statistical significance of results (ITT)
Abbreviations: CMF, cow's milk formula; DISC, discontinuation; JACI, IP Journal of Allergy and Clinical: In Practice; JACI, Journal of Allergy and Clinical Immunology; Lancet, The Lancet; Mo, months; NEJM, New England Journal of Medicine; SCORAD, SCORing Atopic Dermatitis; Wks, weeks; Yrs, years.*same participants enrolled with subsequent clinical follow-up.

peanut with babies' first solids will likely best reduce the population-based incidence of peanut allergy
These panels report the logarithmic distribution of peanut-sIgE and Ara h 2-sIgE to facilitate visualisation of the more atopic outlier participants.High values of Contrasting differences in serum peanut sensitisation titres are more apparent when looking at the distribution of high-level IgE production by proportion density plots.Variation in clinical resources for allergy care between countries has led to differing approaches for developing interventions to prevent the development of food allergy.The National Institute for Allergy and Infectious Disease sponsored addendum recommendations to introduce PA prevention into clinical practice recommend that peanut consumption should be expedited for patients at 4-5 months of age if they have egg allergy or severe eczema.Observational data support the hypothesis that public health recommendations to prevent PA development should recommend consumption during the first half of infancy to best ensure efficacy.Keet et al. demonstrated that 11% of infants aged 4-11 months with severe eczema, egg allergy or peanut allergic family members have PA, with a median age of 8 months.The rapid development of PA was confirmed by assessing the peanut sen-