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Background No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. Methods We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Results Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P

Oral immunotherapy (OIT) leads to suppression of mast cell and basophil degranulation along with changes in the adaptive immune response.This study aimed to determine how rapidly these effects occur during OIT and more broadly, the kinetics of basophil and mast cell suppression throughout the course of therapy.Twenty participants, age 4 to 12 years, were enrolled in a peanut OIT trial and assessed for desensitization and sustained unresponsiveness after 9 months of therapy. Blood was collected 5 times in the first month and then intermittently throughout to quantify immunoglobulins and assess basophil activation by CD63, CD203c, and phosphorylated SYK (pSYK).Twelve of 16 participants that completed the trial were desensitized after OIT, with 9 achieving sustained unresponsiveness after discontinuing OIT for 4 weeks. Basophil hyporesponsiveness, defined by lower CD63 expression, was detected as early as day 90. pSYK was correlated with CD63 expression, and there was a significant decrease in pSYK by day 250. CD203c expression remained unchanged throughout therapy. Interestingly, although basophil activation was decreased across the cohort during OIT, basophil activation did not correlate with individual clinical outcomes. Serum peanut-specific IgGSuppression of basophil activation occurs within the first 90 days of peanut OIT, ultimately leading to suppression of signaling through pSYK.

Allergen-specific immunotherapy for the treatment of immunoglobulin E mediated food allergies, specifically oral, epicutaneous, and sublingual immunotherapies, are promising options that may provide an alternative to strict avoidance of the dietary allergen. Of these potential therapies, oral immunotherapy is the furthest along in development, with strong evidence of efficacy in clinical trials, and has achieved regulatory approval. Nevertheless, oral immunotherapy may not be a suitable therapy for some patients due to the risk of adverse effects. In contrast to oral immunotherapy, epicutaneous and sublingual immunotherapies have demonstrated modest efficacy in clinical trials, with a favorable adverse effect profile, which suggests that these therapies may be possible contenders to oral immunotherapy in certain clinical situations. Familiarity with the various treatment approaches is vital for guiding patients and families as more therapeutic modalities become available for use outside of the research setting.

To provide an overview of key points and helpful tips related to engaging learners in different medical education settings, including the virtual education environment.Searches were conducted in PubMed and Google Scholar for articles and review papers on the topic of medical education.There was a focus on articles that reviewed best practices on a variety of topics related to medical education.Medical education is a critical part of any students' or trainees' educational curriculum or training program. There are different settings where medical education is provided, and both general and type-specific best practices can be considered. Those who spend time in medical education are continuously working on innovative ideas to enhance and improve how educators teach in both large and small group settings. More recently, the presenter must also consider whether the event will occur in a live or virtual setting as e-learning has become more popular and at times required, which has both benefits and challenges in medical education.It is the responsibility of all those who work in medical education to provide interactive and engaging education to learners at all levels of training.

ImmunoglobulinA (IgA) is the predominant antibody isotype in the gut, where it regulates commensal flora and neutralizes toxins and pathogens. The function of food-specific IgA in the gut is unknown but is presumed to protect from food allergy. Specifically, it has been hypothesized that food-specific IgA binds ingested allergens and promotes tolerance by immune exclusion; however, the evidence to support this hypothesis is indirect and mixed. Although it is known that healthy adults have peanut-specific IgA in the gut, it is unclear whether children also have gut peanut-specific IgA. We found in a cohort of non–food-allergic infants ( n = 112) that there is detectable stool peanut-specific IgA that is similar to adult quantities of gut peanut-specific IgA. To investigate whether this peanut-specific IgA is associated with peanut tolerance, we examined a separate cohort of atopic children ( n = 441) and found that gut peanut-specific IgA does not predict protection from development of future peanut allergy in infants nor does it correlate with concurrent oral tolerance of peanut in older children. We observed higher plasma peanut-specific IgA in those with peanut allergy. Similarly, egg white–specific IgA was detectable in infant stools and did not predict egg tolerance or outgrowth of egg allergy. Bead-based epitope assay analysis of gut peanut-specific IgA revealed similar epitope specificity between children with peanut allergy and those without; however, gut peanut-specific IgA and plasma peanut-specific IgE had different epitope specificities. These findings call into question the presumed protective role of food-specific IgA in food allergy.

The recent approval of the first commercial peanut oral immunotherapy formulation ushered a new era of clinical food allergy treatment. With different options for peanut immunotherapy available, it is important review the evidence of efficacy, risks, and unique considerations for the individual modalities. Oral immunotherapy (OIT), epicutaneous immunotherapy (EPIT), and sublingual immunotherapy (SLIT) for peanut allergy have risen as possible treatments for peanut allergy. Numerous studies indicate that OIT effectively desensitizes by increasing the amount of peanut protein than can be consumed without symptoms. While this desensitization is to increased amounts of peanut protein when compared to SLIT or EPIT, OIT appears to have greater risk for anaphylaxis and other adverse events. EPIT has the unique benefit of a single-dose patch without the need for in-clinic visits for dose escalation, and it bypasses the oral route which may be advantageous in certain patients. The impact of peanut immunotherapy on health-related quality of life is not well studied and current data is conflicting, but suggests that improvement in certain domains of QOL, especially for caregivers of children with peanut allergy, may be an important target for immunotherapy. This review focuses on the data for efficacy, safety, and tolerability of OIT, SLIT, and EPIT with the aim of presenting information that will assist allergy practitioners in choosing an immunotherapy modality when indicated.

Food allergy presents a significant global health concern with up to 10% of the population affected in developed nations and a steadily increasing prevalence. In many cases, particularly with peanut, tree nut and shellfish, food allergy is a lifelong and potentially life-threatening diagnosis. While no “cure” for IgE-mediated food allergy exists, oral immunotherapy (OIT) is a promising treatment modality with the peanut OIT drug Palforzia (Aimmune Therapeutics) the only treatment for food allergy that is currently approved by the United States Food and Drug Administration. OIT primarily induces a state of desensitization with only a minority of subjects achieving sustained unresponsiveness, a state of limited clinical remission that appears to be immunologically distinct from natural tolerance. Early humoral changes during OIT include an initial increase in allergen-specific IgE, which eventually decreases to below baseline levels as OIT progresses, and a gradual increase in allergen-specific IgA and IgG4 that continues throughout the course of OIT. Basophil hyporesponsiveness and decreased skin prick test wheal size are observed within the first year of OIT, and persistence after completion of therapy has been associated with sustained unresponsiveness. In the T-cell compartment, there is an initial expansion followed by a decline in the number and activity of T helper 2 (T(H)2) cells, the latter of which may be dependent on an expansion of IL-10 producing cells, including regulatory T-cells. Our understanding of the immunomodulatory effects of OIT continues to evolve, with new technologies such as single-cell transcriptional profiling and antibody epitope analysis allowing for more detailed study of T-cell and B-cell responses to OIT. In this review, we present evidence to illustrate what is currently known about the immunologic changes induced by OIT, explore potential mechanisms, and emphasize knowledge gaps where future research is needed.

The treatment of food allergy has traditionally relied on avoidance of the offending food(s) and use of emergency medications in the event of accidental exposures. However, this long-standing paradigm is beginning to shift, as a variety of treatment approaches have been and are being developed. This report provides an overview of the past, present, and future landscape of interventional clinical trials for the treatment of food allergy. It focuses on specific issues related to participant characteristics, protocol design, and study end points in the key clinical trials in the literature and examine how differences between studies may impact the clinical significance of the study results. Recommendations are provided for the optimization of future trial designs and focus on specific unmet needs in this rapidly evolving field.

Antigen-specific immunoglobulin responses have yet to be studied at the oral mucosal surface during peanut oral immunotherapy (PnOIT).We aimed to quantify salivary peanut-specific IgG4 (PNsIgG4) and IgA (PNsIgA) and total IgG4 and IgA in participants from the Immune Tolerance Network's IMPACT study, a phase 2 PnOIT trial.Peanut-allergic children, aged 12 months to younger than 48 months at screening, were enrolled and randomized to PnOIT or placebo oral immunotherapy (OIT) for 134 weeks. Per-protocol analysis included 69 PnOIT and 23 placebo participants. Double-blind, placebo-controlled food challenges were conducted at weeks 134 and 160 to assess desensitization and remission, respectively. Saliva samples were collected at baseline and 30, 82, 134, and 160 weeks to quantify PNsIgG4, PNsIgA, and total IgG4 and IgA.Participants who received PnOIT experienced significant increases in PNsIgG4 in saliva, whereas participants on placebo did not (P.01 at all time points). The PNsIgA/total IgA ratio was also significantly increased in participants treated with PnOIT when compared with those receiving placebo at 30 and 82 weeks (P.05). During PnOIT, desensitized participants had increased PNsIgA that plateaued, whereas the not desensitized/no remission group did not change over time. Interestingly, when the PnOIT group was evaluated by clinical outcome, PNsIgA was higher at baseline in the not desensitized/no remission group than in the desensitized/remission group (P.05).PnOIT induces substantial increases in allergen-specific IgG4 and IgA in saliva. These data provide insight into OIT-induced mucosal responses and suggest the utility of these easily obtained samples for biomarker development.

Background The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg). Objective We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. Methods Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. Results Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). Conclusions These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

The most clinically relevant food allergens are cow’s milk, hen’s egg, peanut, tree nuts, wheat, soy, fish, shellfish, and seeds. Heat-stable food allergens have molecular characteristics that enhance protein stability and gastrointestinal absorption and thus are more likely to cause systemic reactions on ingestion. In contrast, heat-labile food allergens lack these characteristics and do not typically elicit reactions if sufficiently altered by heat or acid. Immunologic cross-sensitization between food allergens is more common than clinical cross-reactivity. However, certain groups of food allergens, such as tree nuts, fish, and shellfish, are associated with high rates of clinical cross-reactivity. Knowing the rates of clinical cross-reactivity is important when providing guidance to patients with food allergy and families on what foods can be safely added to the diet and what foods should be avoided.

Background Shared decision making (SDM) is the process through which patients and their medical provider mutually explore therapy goals, risk/benefit, and treatment options regarding medical care. Decision aids are tools that aid in the process of values clarification and help assess decisional needs and potential decisional conflicts. Objective To develop and assess acceptability of a decision aid for commercial peanut allergy therapies. Methods The creation of this decision aid occurred in 3 stages, including a qualitative study to assess decisional needs, development of a draft decision aid through multiple iterations in accordance with international guidelines and decision aid experts, and assessment of decisional acceptability, decisional conflict, and decisional self-efficacy related to using the decision aid. Results The decision aid went through 9 iterations, resulting in a 4-page aid with 7 parts, explaining the therapies, key risks and benefits of therapy choices, relative importance of key attributes of the therapies, and a self-check assessment regarding informational adequacy and how to take the next steps. A total of 24 subjects assessed the decision aid, noting it had good acceptability, high decisional self-efficacy (mean score 91.9/100), and low decisional conflict (mean score 20.2/100). Respondents rated the information content as adequate and sufficient and the information regarding the therapy choices as fair and balanced without a clear bias or presenting a “best choice.” Conclusion We have developed this decision aid as a tool to help caregivers navigate the complexity of decision making for peanut allergy treatment options. The decision aid was noted to have good acceptability, with scores reflective of the instrument enhancing decisional self-efficacy and reducing decisional conflict.

Introduction: Peanut allergy has continued to increase in prevalence and despite efforts to prevent the allergy with early peanut introduction, treatments for those already with the allergy have been lacking. While the physical effects of peanut allergy have been well known, what has more recently begun to be discussed are the broad psychosocial and financial implications that are also related to the allergy. Oral (OIT), epicutaneous (EPIT), and sublingual (SLIT) immunotherapy have been developed as potential treatments for peanut allergy.Areas covered: Pivotal clinical trials in OIT, EPIT, and SLIT from the past 10 years are reviewed in this manuscript. Peanut OIT has been shown to induce strong desensitization; however, side effects and safety of the treatment have remained a concern. Peanut EPIT has demonstrated a reassuring safety profile but with a more modest protective effect. Peanut SLIT has remained behind in development but recent studies have suggested a balance of desensitization, safety, and convenience.Expert opinion: There are no perfect treatments for peanut allergy and OIT, EPIT, and SLIT each has its unique pros and cons. Shared decision-making between patients and providers will be essential to achieve optimal care for patients with peanut allergy.

BACKGROUND: Immunotherapy is promising as an efficacious treatment for food allergy. Other food allergy treatments are also under development. However, adverse allergic events (AE) during treatment, as well as during oral food challenges (OFC) are common and reporting is not standardized. OBJECTIVE: A more nuanced grading scale is needed to create a comprehensive and universal system to categorize AEs and their severity for food allergy clinical trials. METHODS: Starting with the 2012 Consortium for Food Allergy Research (CoFAR) Grading Scale and the World Allergy Organization (WAO) Grading System, we developed the CoFAR Grading Scale for Systemic Allergic Reactions, Version 3.0, in collaboration with industry partners with expert opinion. RESULTS: The revised CoFAR Grading Scale for Systemic Allergic Reactions has five levels of increasing severity, ranging from generalized urticaria, localized angioedema, rhinitis, and abdominal pain (Grade 1) to death (Grade 5). Systemic reactions are further categorized within each grade by relevant organ system. Mild, single-system reactions are differentiated from mild, multi-system reactions. Lower respiratory symptoms are graded based on response to therapy; those that are refractory to standard treatment (e.g., requiring >3 doses of IM epinephrine, continuous IV epinephrine infusion, continuous albuterol nebulization) and respiratory compromise requiring mechanical ventilation are classified as Grade 4, life-threatening reactions. CONCLUSION: Universal and consistent use of the revised CoFAR Grading Scale beyond the CoFAR centers would allow for better data aggregation and safety comparisons in clinical trials for food allergy.

Peanut allergy reaction severity correlates with increased intestinal epithelial cell (IEC) barrier permeability. CC027/GeniUnc mice develop peanut allergy by intragastric administration of peanut proteins without adjuvant. We report that peanut-allergic CC027/GeniUnc mice showed increased IEC barrier permeability and systemic peanut allergen Ara h 2 after challenge. Jejunal epithelial cell transcriptomics showed effects of peanut allergy on IEC proliferation, survival, and metabolism, and revealed IEC-predominant angiopoietin like-4 (Angptl4) as a unique feature of CC027/GeniUnc peanut allergy. CC027/GeniUnc mice and peanut-allergic pediatric patients demonstrated significantly higher serum Angptl4 and ANGPTL4 compared to control C3H/HeJ mice and non-peanut-allergic but atopic patients, respectively, highlighting its potential as a biomarker of peanut allergy.

Background Treatment options for peanut allergy are limited. In previous clinical trials, epicutaneous immunotherapy with a patch containing 250-μg peanut protein (Viaskin™ Peanut 250 μg [VP250]) was well tolerated and statistically superior to placebo in desensitizing peanut-allergic children. Objective To examine the safety of VP250 in children, using a study design approximating potential real-world use. Methods REALISE is a phase 3 multicenter study consisting of a 6-month, randomized, double-blind, placebo-controlled period followed by open-label active treatment. Children aged 4 to 11 years with physician diagnosis of peanut allergy received daily treatment with placebo (6 months) or VP250 (up to 36 months). Data from the 6-month, randomized, controlled phase of REALISE are reported. Results Three hundred ninety-three children were randomized 3:1 to receive VP250 (n=294) or placebo (n=99) for 6 months; 284 (72.3%) children had a history of peanut anaphylaxis. According to parent diary, all participants receiving VP250 and 83.8% receiving placebo reported at least 1 episode of local skin reaction, with frequency decreasing over time. Only 4 participants (1.4%) receiving VP250 discontinued due to adverse events. Epinephrine was administered for allergic reactions attributed to VP250 in 7 children (2.4%), of whom 5 remained in the study; none involved severe anaphylaxis. Overall adverse event rates were similar among participants with and without history of peanut anaphylaxis. Conclusions In a study designed to mirror real-world use, VP250 was observed to be well tolerated in peanut-allergic children, consistent with previous phase 2b and 3 studies.

Background Allergen-specific IL-4+ and IL-13+ CD4+ cells (type 2 cells) are essential for helping B cells to class-switch to IgE and establishing an allergic milieu in the gastrointestinal tract. The role of T cells in established food allergy is less clear. Objective We examined the food allergen–specific T-cell response in participants of 2 food allergen immunotherapy trials to assess the relationship of the T-cell response to clinical phenotypes, including response to immunotherapy. Methods Blood was obtained from 84 participants with peanut allergy and 142 participants with egg allergy who underwent double-blind placebo-controlled food challenges. Peanut- and egg-responsive T cells were identified by CD154 upregulation after stimulation with the respective extract. Intracellular cytokines and chemokine receptors were also detected. The response to peanut epicutaneous immunotherapy (Peanut Epicutaneous Phase II Immunotherapy Clinical Trial [CoFAR6]; 49 participants receiving epicutaneous immunotherapy) and egg oral immunotherapy or a baked egg diet (Baked Egg or Egg Oral Immunotherapy for Children With Egg Allergy [CoFAR7]; 92 participants) was monitored over time. Results Peanut-specific type 2 and CCR6+ T cells were negatively correlated with each other and differently associated with immune parameters, including specific IgE level and basophil activation test result. At baseline, type 2 cells, but not CCR6+ cells, were predictive of clinical parameters, including a successfully consumed dose of peanut and baked egg tolerance. Exposure to peanut or egg immunotherapy was associated with a decrease in type 2 cell frequency. At baseline, high egg-specific type 2 cell frequency was the immune feature most predictive of oral immunotherapy failure. Conclusion Food-specific type 2 T cells at baseline are informative of threshold of reactivity and response to immunotherapy.

Introduction AR101, an investigational oral biologic drug for peanut oral immunotherapy, was studied in PALISADE and ARTEMIS phase 3 trials. Efficacy and safety are compared. Methods Subjects demonstrated clinical history of peanut allergy; peanut-specific immunoglobulin E ≥ 0.35 kUA/L and/or skin-prick test ≥ 3 mm; reacted to ≤ 100 mg (PALISADE)/≤ 300 mg peanut protein (ARTEMIS) at screening double-blind, placebo-controlled food challenge (DBPCFC). After dose escalation to 300 mg/day (6 months), 300 mg/day dosing continued (PALISADE, 6 months; ARTEMIS, 3 months). Results are reported in subjects 4-17-years-old (intention-to-treat/safety populations). Results A total of 496 PALISADE (AR101 n = 372, placebo n = 124) and 175 ARTEMIS (n = 132, n = 43) subjects were treated. Ability to tolerate 300 mg, 600 mg or 1000 mg peanut protein at exit DBPCFC was similar (PALISADE vs ARTEMIS; AR101 : 76.6% vs 73.5%, 67.2% vs 68.2%, 50.3% vs 58.3%; placebo : 8.1% vs 16.3%, 4.0% vs 9.3%, 2.4% vs 2.3%). Most treatment-emergent adverse events (TEAEs) were mild/moderate (AR101, placebo : PALISADE 94.4%, 94.4%; ARTEMIS 97.7%, 97.7%); frequency decreased from dose-escalation to 300 mg/day dosing (X). For dose-escalation in-clinic TEAEs, range of median times to symptom onset following ingestion and times from first symptom onset to last symptom resolution were similar (AR101, placebo: PALISADE onset 4.0–5.5 min, 8.0–38.5 min; resolution 16.0–32.5 min, 15.0–38.0 min; ARTEMIS onset 2.0–10.0 min, 1.5–15.0 min; resolution 14.0–47.8 min, 7.0–85.0 min) ( Fig. 1 ). Conclusion AR101 efficacy and safety results are consistent across trials despite different entry criteria. Most TEAEs were mild/moderate and transient. AR101 has a readily manageable safety profile with high desensitization rates possible as early as 3 months after 300 mg/day dosing.

Background Recently developed peanut desensitization treatment reduces the incidence of allergic reactions, the anxiety associated with the risk of accidental exposure, and the burden of precautionary behavior. Eliciting parent preferences for tradeoffs involving treatment effectiveness, tolerability, costs, and convenience quantifies the burden of juvenile peanut allergy and the perceived value of peanut desensitization therapies. Objective To understand heterogeneity in parents' treatment preferences and the role of personal characteristics in explaining differences. Methods An Internet-based, discrete-choice experiment survey was administered to a national sample of 500 parents of children aged 4 to 17 years with peanut allergy to quantify parents' preferences for peanut desensitization therapies for their children. Latent-class, mixed-logit analysis estimated relative importance coefficients for groups of participants with distinctly different preferences. Results Parents' choice patterns fell into 1 of 4 preference subgroups: (1) Cost-sensitive, (2) Protreatment (but Side-Effect–Averse), (3) Trader, and (4) Inconsistent. Mode of administration had little relative importance across all subgroups. Characteristics associated with belonging to a given preference subgroup included parent age, child age, income, parent perception of child risk and ability to manage allergic reactions, past allergic reactions, and changes in precautionary behaviors posttreatment. Conclusions We found distinct differences in parent preferences for tradeoffs involving effectiveness, tolerability, and costs of peanut desensitization treatments. Parents' treatment preferences help quantify the burden of juvenile peanut allergy and the perceived value of new therapies. Such information can inform patient-centric clinical and regulatory decision making.

For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population.We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160.Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy.In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy.National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

In the last decade, there has been increasing research dedicated to food immunotherapy to induce clinical desensitization and provide protection by increasing clinical reaction thresholds. Results from recent food immunotherapy studies with differing routes of administration (oral, sublingual, and epicutaneous) suggest that food immunotherapy can induce clinical desensitization with varying levels of safety, however lasting tolerance has not been demonstrated. Furthermore, treatment side effects and dosing logistics may make the therapies difficult for some supporting the need for alternative treatment approaches. Peptide immunotherapy and DNA vaccine approaches should in theory allow for safer administration by decreasing allergenicity but proof of their clinical efficacy and immunogenicity remains to be proven. Biologic agents may allow for increased safety and rapid up-dosing of immunotherapy with the added benefit of treating multiple allergens simultaneously.

Background Tree nut allergies affect an estimated 1% of the US population and is lifelong in 90% of allergic individuals. Oral immunotherapy (OIT) for food allergies is an effective method to induce desensitization in a majority of participants in trials of peanut, egg, and milk OIT. Limited trials using tree nut OIT have been reported, possibly due to the lack of standardized drug products. Objective Food products used in OIT are considered drugs by the Food and Drug Administration (FDA) because they are intended to modulate the individuals' immune responses to the food allergens. As such, OIT drug products must meet FDA standards for acceptable levels of microbes and undergo testing for allergenic proteins. We aimed to determine the suitability of walnut, cashew, hazelnut, and almond flours for use in OIT trials. Methods We employed gamma irradiation on commercially available walnut, cashew, hazelnut, and almond flours and tested their levels of microbial contamination, total protein, and allergen content, along with stability of these parameters over time. Results Our results demonstrate that irradiation of tree nut flours greatly diminishes the levels of total aerobic bacteria, mold, yeast, Escherichia coli, and Salmonella, whereas there are no substantial changes in total protein or allergen content. Importantly, the microbial levels, protein, and allergen content remained stable over a 24-month period. Conclusion Irradiation of tree nut flours is a safe and effective method of processing to allow tree nut products to meet the FDA standards for OIT drug products.

Food allergy is an important medical problem with increasing prevalence throughout the world. Different approaches of food immunotherapy are being investigated including oral, epicutaneous and sublingual routes. Sublingual immunotherapy (SLIT) for food allergy involves placement of glycerinated allergen under the tongue daily to achieve allergen-specific desensitization. SLIT has been studied in the treatment of hazelnut, peach, apple, milk and peanut allergies with substantial focus on the treatment of peanut allergy. Phase II studies have shown SLIT for treatment of peanut allergy increases the tolerated dose of peanut by a substantial margin with fewer and less severe side effects than other modalities. This review discusses the mechanisms of SLIT, early studies of its use in food allergy and larger randomized controlled trials for treatment of peanut allergy. Future directions using the mechanisms involved in SLIT include oral mucosal immunotherapy for peanut allergy.

Background: Epicutaneous immunotherapy is a potential novel immunotherapy that utilizes unique cutaneous immunologic properties. In a phase III, randomized, double-blind, placebo controlled clinical trial, an epicutaneous patch (DBV712) with 250 µg of peanut protein applied once daily for 12-months was statistically superior to placebo in desensitizing children with peanut allergy (ages 4‐11 years) (N = 356). Objective: To assess the relationship between the hours of daily application time and the efficacy of DBV712 250 µg. Methods: DBV712 250 µg was applied to 30 nonallergic volunteers for various durations from 2 to 24 hours and then assayed for residual peanut protein. Patch application data from the phase III clinical trial were analyzed post hoc according to prespecified responder rates and changes in the eliciting dose (ED), as measured by the geometric mean (GM) ED ratio (12 months/baseline). Results: Following application, there was a marked decrease in peanut protein on the patches from 2 to 12 hours. After 12 hours, the median peanut protein recovered was below quantification limits. The median daily patch application duration in subjects from the phase III clinical trial was 21.1 hours (DBV712 250 µg) and 22.4 hours (placebo). Ninety-five percent of the treated population achieved >10 hours per day mean application. Response rates and GM ED ratios were similar among subjects across a range of application durations; e.g., in those with a mean duration of >10 hours, the response rate was 36.6% and the GM ED ratio was 3.8, comparable with 42.6% and 4.0, respectively, in those with a mean duration of >20 hours. In DBV712 250 µg subjects with >16 hours mean application duration (84.5% of the treated population), the response rate was 38.8% versus 13.4% for placebo (difference, 24.4% [95% confidence interval, 15.5‐34.0%]; p < 0.001). Conclusion: An evaluation of residual peanut protein on patches following application and post hoc analysis of phase III data strongly suggest that allergen delivery is attained with 12‐16 hours of daily patch application time, sufficient to drive clinically meaningful desensitization to peanut after 12 months.

Many exciting food allergy therapies, including allergen-specific and non-specific treatment techniques, are currently under clinical investigation. The most well-studied treatment modality is food immunotherapy, which comes in several types including oral (OIT), epicutaneous (EPIT), and sublingual (SLIT). As a follow-up to the prior discussions on OIT and EPIT, this chapter focuses on emerging therapies that are earlier in development. With its growing body of evidence, this chapter begins with a general overview of SLIT, including its proposed mechanism of action, efficacy, and side effects. Advantages and disadvantages of SLIT when compared to OIT and EPIT are also highlighted. Other food-specific therapies reviewed in this chapter include peptide-based vaccines, recombinant allergen vaccines, allergen DNA vaccinations, and transgenic plants, which have less supportive clinical study data available but which present exciting possible treatment modalities. Studies evaluating the use of non-allergen-specific therapies in the treatment of food allergy, including anti-IgE treatment (used as monotherapy or as an adjunct to food-specific therapies), traditional Chinese medicine, and probiotics are also reviewed. Finally, understanding that food immunotherapy may become a standard part of clinical practice in the very near future, this chapter concludes with a discussion about patient-specific factors and preferences for the clinician to consider when deciding on the optimal treatment modality for an individual patient.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; PCONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Background Mechanisms underlying oral immunotherapy (OIT) are unclear and the effects on immune cells at varying maintenance doses are unknown. Objective We aimed to determine the immunologic changes caused by peanut OIT in preschool aged children and determine the effect on these immune responses in groups ingesting low or high-dose peanut OIT (300 mg or 3000 mg, respectively) as maintenance therapy. Methods Blood was drawn at several time-points throughout the OIT protocol and PBMCs isolated and cultured with peanut antigens. Secreted cytokines were quantified via multiplex assay, whereas Treg and peanut-responsive CD4 T cells were studied with flow cytometry. Basophil activation assays were also conducted. Results Th2-, Th1-, Th9- and Tr1-type cytokines decreased over the course of OIT in groups on high- and low-dose OIT. There were no significant differences detected in cytokine changes between the high- and low-dose groups. The initial increase in both the number of peanut-responsive CD4 T cells and the number of Tregs was transient and no significant differences were found between groups. Basophil activation following peanut stimulation was decreased over the course of OIT and associated with increased peanut-IgG4/IgE ratios. No differences were found between high- and low-dose groups in basophil activation at the time of desensitization or sustained unresponsiveness oral food challenges. Conclusions and clinical relevance Peanut OIT leads to decreases in pro-allergic cytokines, including IL-5, IL-13, and IL-9 and decreased basophil activation. No differences in T cell or basophil responses were found between subjects on low or high-dose maintenance OIT, which has implications for clinical dosing strategies.

In this work, we delineate an altered study design of a pre-existing clinical trial that is currently being implemented in the Department of Pediatrics at the University of North Carolina at Chapel Hill. The purpose of the ongoing investigation of the desensitized pediatric cohort is to address the effectiveness of sublingual immunotherapy in achieving sustained unresponsiveness (SU) as assessed by repeated double-blind placebo-controlled food challenges (DBPCFC). With scarce published literature characterizing SU, the length of time off-therapy that would represent clinically meaningful benefit remains undefined. We use the new design features to assess time to loss of SU, an important efficacy endpoint, that to our knowledge, no prior study has investigated. Our work has two-fold objectives: first is to propose and discuss aspects of the altered design that would allow us to study SU and second is to explore methodology to evaluate the time to loss of SU and its association with risk factors in the context of the data originating from the trial. The salient feature of the new design is the allocation scheme of study subjects to staggered sampling timepoints when a subsequent DBPCFC is administered. Due to this feature, the time to loss of SU is either left or right censored. Additionally, some participants at study entry fail the DBPCFC, leading to what can be construed as an instantaneous failure. Through in-depth numerical studies, we examine the performance and power of a recently proposed mixture proportional hazards model specifically designed for the analysis of interval-censored data subject to instantaneous failures.

Treatment of IgE-mediated food allergies is limited to allergen avoidance and emergency treatment on accidental ingestion, which is not uncommon. In recent years, interest in interventional therapies to treat food allergy has increased significantly. Although oral, sublingual, and epicutaneous immunotherapy have shown promise in studies, none is approved as therapy for food allergy to date and questions remain regarding efficacy, safety, dosing, and duration of therapy.

This article reviews research advances for sublingual and patch immunotherapy for food allergy with a focus on peanut allergy. Published studies on sublingual immunotherapy (SLIT) and epicutaneous immunotherapy (EPIT) were summarized in this review. Sublingual and epicutaneous methods have emerged as alternatives to oral immunotherapy. SLIT studies have shown modest desensitization with a robust safety profile. EPIT studies have high adherence rates, an excellent safety profile, and potential for desensitization in children. Advances in food immunotherapy with SLIT and EPIT studies have shown promise as viable alternatives to oral immunotherapy for treatment of patients with peanut food allergy.

IgE-mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk, and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies; however, its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable; however, the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march toward regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.

Background: Peanut allergy is a generally persistent, sometimes life-threatening food allergy. With no treatments demonstrating the ability to cure a food allergy, the focus of drugs in development has been on providing a level of protection against accidental exposure reactions. However, no study has estimated the relative risk reduction of a food-allergic population receiving a specific immunotherapeutic treatment for their allergies. Objective: To estimate the relative risk reduction when consuming peanut-contaminated packaged food products in a double-blind, placebo-controlled Phase 3 study population of children treated with epicutaneous immunotherapy (EPIT) for 12 months with either a patch containing 250 μg peanut protein (250-μg patch) or a placebo patch. Methods: The probability of an allergic reaction due to the unintended presence of peanut protein in packaged food products was modeled per study group and food category combination using Monte Carlo simulations. Risks per eating occasion of a contaminated packaged food product and the number of individuals per study population predicted to react on a yearly basis were investigated. Results: The population treated with the 250-μg patch demonstrated a significantly increased dose-response distribution after 12 months of treatment, which resulted in a relative risk reduction of 73.2% to 78.4% when consuming peanut-contaminated packaged food products. In contrast, no statistically significant change was observed for the placebo group at the 12-month point. Conclusion: Our study estimates a substantial relative risk reduction for allergic reactions among peanut-allergic children after 12 months of EPIT with the 250-μg patch, supporting the potential real-world clinical relevance of this investigational immunotherapy and its possible role as a future therapy for peanut-allergic children. ClinicalTrials.gov Identifier: NCT02636699 © 2019 The Authors

Background Peanut sublingual immunotherapy (SLIT) for 1 year has been shown to induce modest clinical desensitization in allergic children. Studies of oral immunotherapy, epicutaneous immunotherapy, and SLIT have suggested additional benefit with extended treatment. Objective We sought to investigate the safety, clinical effectiveness, and immunologic changes with long-term SLIT in children with peanut allergy. Methods Children with peanut allergy aged 1 to 11 years underwent extended maintenance SLIT with 2 mg/d peanut protein for up to 5 years. Subjects with peanut skin test wheals of less than 5 mm and peanut-specific IgE levels of less than 15 kU/L were allowed to discontinue therapy early. Desensitization was assessed through a double-blind, placebo-controlled food challenge (DBPCFC) with up to 5000 mg of peanut protein after completion of SLIT dosing. Sustained unresponsiveness was further assessed by using identical DBPCFCs after 2 to 4 weeks without peanut exposure. Results Thirty-seven of 48 subjects completed 3 to 5 years of peanut SLIT, with 67% (32/48) successfully consuming 750 mg or more during DBPCFCs. Furthermore, 25% (12/48) passed the 5000-mg DBPCFC without clinical symptoms, with 10 of these 12 demonstrating sustained unresponsiveness after 2 to 4 weeks. Side effects were reported with 4.8% of doses, with transient oropharyngeal itching reported most commonly. Side effects requiring antihistamine treatment were uncommon (0.21%), and no epinephrine was administered. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT. Conclusion Extended-therapy peanut SLIT provided clinically meaningful desensitization in the majority of children with peanut allergy that was balanced with ease of administration and a favorable safety profile.

Background The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. Objective ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. Methods Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non–daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. Results Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non–daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non–daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. Conclusions Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.