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Zhen-Zhen Wang,1– 3,&ast; Hang Li,4,&ast; Anish R Maskey,2,&ast; Kamal Srivastava,2,5,&ast; Changda Liu,6,&ast; Nan Yang,2,5 Taoyun Xie,7 Ziyi Fu,8 Junxiong Li,9 Xiaohong Liu,10 Hugh A Sampson,6 Xiu-Min Li2,11 1Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 2Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA; 3Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou, Henan, People’s Republic of China; 4Central Lab, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People’s Republic of China; 5General Nutraceutical Technology, Elmsford, NY, USA; 6Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 8The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 9Guangdong Province Hospital of Integrated Chinese and Western Medicine, Foshan, Guangdong, People’s Republic of China; 10Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 11Department of Otolaryngology, Westchester Medical Center New York Medical College, Valhalla, NY, USA&ast;These authors contributed equally to this workCorrespondence: Xiu-Min Li, Tel +1 914-594-4197, Email XiuMin_Li@NYMC.eduIntroduction: Neutrophil predominant airway inflammation is associated with severe and steroid-resistant asthma clusters. Previously, we reported efficacy of ASHMI, a three-herb TCM asthma formula in a steroid-resistant neutrophil-dominant murine asthma model and further identified Ganoderic Acid C1 (GAC1) as a key ASHMI active compound in vitro. The objective of this study is to investigate GAC1 effect on neutrophil-dominant, steroid-resistant asthma in a murine model.Methods: In this study, Balb/c mice were systematically sensitized with ragweed (RW) and alum and intranasally challenged with ragweed. Unsensitized/PBS challenged mice served as normal controls. Post sensitization, mice were given 4 weeks of oral treatment with GAC1 or acute dexamethasone (Dex) treatment at 48 hours prior to challenge. Pulmonary cytokines were measured by ELISA, and lung sections were processed for histology by H&E staining. Furthermore, GAC1 effect on MUC5AC expression and on reactive oxygen species (ROS) production in human lung epithelial cell line (NCI-H292) was determined by qRT-PCR and ROS assay kit, respectively. Computational analysis was applied to select potential targets of GAC1 in steroid-resistant neutrophil-dominant asthma. Molecular docking was performed to predict binding modes between GAC1 and Dex with TNF-α.Results: The result of the study showed that chronic GAC1 treatment, significantly reduced pulmonary inflammation (P < 0.01– 0.001 vs Sham) and airway neutrophilia (P < 0.01 vs Sham), inhibited TNF-α, IL-4 and IL-5 levels (P < 0.05– 0.001 vs Sham). Acute Dex treatment reduced eosinophilic inflammation and IL-4, IL-5 levels, but had no effect on neutrophilia and TNF-α production. GAC1 treated H292 cells showed decreased MUC5AC gene expression and production of ROS (P < 0.001 vs stimulated/untreated cells). Molecular docking results showed binding energy of complex GAC1-TNF was − 10.8 kcal/mol.Discussion: GAC1 may be a promising anti-asthma botanical drug for treatment of steroid-resistant asthma.Keywords: asthma, mouse model, neutrophilic inflammation, Ganoderma, ganoderic acid

There is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis. In July 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened a second meeting on anaphylaxis, which included representatives from 16 different organizations or government bodies, including representatives from North America, Europe, and Australia, to continue working toward a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, further review the evidence on the most appropriate management of anaphylaxis, and outline the research needs in this area. [ABSTRACT FROM AUTHOR]

Technology has improved the food supply since the first cultivation of crops. Genetic engineering facilitates the transfer of genes among organisms. Generally, only minute amounts of a specific protein need to be expressed to obtain the desired trait. Food allergy affects only individuals with an abnormal immunologic response to food--6% of children and 1.5-2% of adults in the United States. Not all diseases caused by food allergy are mediated by IgE. A number of expert committees have advised the U.S. government and international organizations on risk assessment for allergenicity of food proteins. These committees have created decision trees largely based on assessment of IgE-mediated food allergenicity. Difficulties include the limited availability of allergen-specific IgE antisera from allergic persons as validated source material, the utility of specific IgE assays, limited characterization of food proteins, cross-reactivity between food and other allergens, and modifications of food proteins by processing. StarLink was a corn variety modified to produce a Bacillus thuringiensis (Bt) endotoxin, Cry9C. The Centers for Disease Control and Prevention investigated 51 reports of possible adverse reactions to corn that occurred after the announcement that StarLink, allowed for animal feed, was found in the human food supply. Allergic reactions were not confirmed, but tools for postmarket assessment were limited. Workers in agricultural and food preparation facilities have potential inhalation exposure to plant dusts and flours. In 1999, researchers found that migrant health workers can become sensitized to certain Bt spore extracts after exposure to Bt spraying. Thus, the potential for occupational and consumer risks needs to be assessed. [ABSTRACT FROM AUTHOR]

Food anaphylaxis is now the leading known cause of anaphylactic reactions treated in emergency departments in the United States. It is estimated that there are 30 000 anaphylactic reactions to foods treated in emergency departments and 150 to 200 deaths each year. Peanuts, tree nuts, fish, and shellfish account for most severe food anaphylactic reactions. Although clearly a form of immunoglobulin E-mediated hypersensitivity, the mechanistic details responsible for symptoms of food-induced anaphylaxis are not completely understood, and in some cases, symptoms are not seen unless the patient exercises within a few hours of the ingestion. At the present time, the mainstays of therapy include educating patients and their caregivers to strictly avoid food allergens, to recognize early symptoms of anaphylaxis, and to self-administer injectable epinephrine. However, clinical trials are now under way for the treatment of patients with peanut anaphylaxis using recombinant humanized anti-immunoglobulin E antibody therapy, and novel immunomodulatory therapies are being tested in animal models of peanut-induced anaphylaxis. [ABSTRACT FROM AUTHOR]

Background: Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc(epsilon) receptor on mast cells and basophils.Methods: We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a history of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to four weeks after the fourth dose.Results: From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated.Conclusions: A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanuts. [ABSTRACT FROM AUTHOR]

This common statement of the American Academy of Allergy, Asthma and Immunology (AAAAI) and The European Academy of Allergy and Clinical Immunology (EAACI) provides an update of the 2012 published guidelines on food challenges. The guidelines equally address food challenges in the research and the clinical settings. They first address the diagnostic tests which can guide the decision to conduct a challenge. Safety of food challenges is prime, and the various procedures and safety issues as well as medications potentially involved in challenges are extensively discussed. Challenges are suggested to be conducted with semi-logarithmic incremental doses based on the protein content, typically for IgE-mediated food allergy with intervals of 20-30 min between doses. Specific protocols for other types of reactions such atopic dermatitis or gastrointestinal food allergy are detailed separately. Proper stopping criteria are essential in order to reduce the risk of false-positive diagnoses, but also severe reactions. The guidelines recommend criteria based on "go on," "stop," or "observation." These revised guidelines will clearly provide much needed guidance for food challenges in the research and clinical settings. They will continue to evolve with new diagnostic tests or new needs in the field of food allergy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immunoglobulin E (IgE)-mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti-IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE-mediated food allergies by the US Food and Drug Administration (FDA). This GA 2 LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE-mediated food allergies, based on a systematic review and meta-analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE-mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: The bead-based epitope assay has been used to identify epitope-specific (es) antibodies and successfully used to diagnose clinical allergy to milk, egg, and peanut., Objective: We sought to identify es-IgE, es-IgG4, and es-IgG1 of wheat proteins and determine the optimal peptides to differentiate wheat-allergic from wheat-tolerant using the bead-based epitope assay., Methods: Children and adolescents who underwent an oral food challenge to confirm their wheat allergy status were enrolled. Seventy-nine peptides from α-/β-gliadin, γ-gliadin, ω-5-gliadin, and high- and low-molecular-weight glutenin were commercially synthesized and coupled to LumAvidin beads (Luminex Corporation, Austin, Tex). Machine learning methods were used to identify diagnostic epitopes, and performance was evaluated using the DeLong test., Results: The analysis included 122 children (83 wheat-allergic and 39 wheat-tolerant; 57.4% male). Machine learning coupled with simulations identified wheat es-IgE, but not es-IgG4 or es-IgG1, to be the most informative for diagnosing wheat allergy. Higher es-IgE binding intensity correlated with the severity of allergy phenotypes, with wheat anaphylaxis exhibiting the highest es-IgE binding intensity. In contrast, wheat-dependent exercise-induced anaphylaxis showed lower es-IgG1 binding intensity than did all the other groups. A set of 4 informative epitopes from ω-5-gliadin and γ-gliadin were the best predictors of wheat allergy, with an area under the curve of 0.908 (sensitivity, 83.4%; specificity, 88.4%), higher than the performance exhibited by wheat-specific IgE (area under the curve = 0.646; P < .001). The predictive ability of our model was confirmed in an external cohort of 71 patients (29 allergic, 42 nonallergic), with an area under the curve of 0.908 (sensitivity, 75.9%; specificity, 90.5%)., Conclusions: The wheat bead-based epitope assay demonstrated greater diagnostic accuracy compared with existing specific IgE tests for wheat allergy., Competing Interests: Disclosure statement This research project was supported by a grant from the Faculty of Medicine, Siriraj Hospital, Mahidol University (grant no. Internal Order [IO] R016232026) and by the David H. and Julia Koch Research Program in Food Allergy Research. Disclosure of potential conflict of interest: M. Suárez-Fariñas reports consultancy feeds from DBV Technologies. M. Suprun is currently an employee at Janssen Pharmaceutical. H. A. Sampson reports funding to his institution for grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases; has received consulting fees from DBV Technologies, N-Fold Therapeutics, LLC, and Siolta, Inc; and has received stock options from DBV Technologies and N-Fold Therapeutics, LLC. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: IgE-mediated food allergy and eosinophilic esophagitis (EoE) are diseases commonly triggered by milk. Milk-responsive CD4 + T cells producing type 2 cytokines are present in both diseases, yet the clinical manifestation of disease in milk allergy (MA) and EoE are distinct., Objective: We sought to identify differences in CD4 + T cells between EoE and MA that may be responsible for distinct disease manifestations., Method: The total and milk-specific CD4 + T-cell phenotype of children with MA, children with EoE (active or in remission), and controls was measured using spectral flow cytometry of peripheral blood (all groups) or esophageal biopsies (EoE and control)., Results: Circulating milk-responsive T cells could be identified in active EoE and MA. An increased frequency of T H 2A cells was also noted in MA and EoE. In circulating T cells, type 2 cytokine production was elevated in MA, but not EoE. Within the milk-responsive T follicular helper (T FH ) subset, a dichotomy of phenotype was noted: T FH 13 cells predominated in MA, while IL-10-producing T FH cells predominated in EoE. In the esophagus, CD4 + T cells were constitutively activated and expressed not only type 2 cytokines, but also IL-10 and IL-21 in active EoE. IgG4 was produced from CD38 + plasma cells in close proximity to CD4 + T cells. In vitro activation studies demonstrated that IL-10 and IL-21 elicited strong IgG4 responses in B lymphocytes, while IL-4 and IL-13 promoted IgE production., Conclusions: Our studies demonstrate a dichotomy of T FH responses that may be the basis for different clinical manifestations to milk in EoE and MA., Competing Interests: Disclosure statement Funding was provided by grant R01 AI151707 from the National Institute of Allergy and Infectious Diseases (to M.C.B. and M.C.d.L.) and pilot grants from the Mindich Child Health and Development Institute (one to M.C.B. and D.D. and one to D.L.-O.). D.L.-O. was partially funded by a postdoctoral fellowship from the Spanish Fundación Alfonso Martín Escudero. Disclosure of potential conflict of interest: H. A. Sampson reports funding to his institution from National Institutes of Health/National Institute of Allergy and Infectious Diseases grants and has received consulting fees from DBV Technologies SA, N-FOLD Therapeutics, Alpina Biotechnology, and Siolta Therapeutics unrelated to this work and stock options from DBV Technologies SA and N-FOLD Therapeutics. M. Curotto de Lafaille received consulting fees from Genentech, unrelated to this work. The rest of the authors declare that they have no conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Peanut allergy treatment options remain limited, but novel approaches are being studied, including epicutaneous immunotherapy (EPIT). EPIT uses the cutaneous immune system to promote tolerance to food allergens. Viaskin™ Peanut, an approach to EPIT in late-stage clinical development uses an occlusive patch with a condensation chamber that enables natural epidermal water loss to solubilize dry antigen on the patch, which is then absorbed and captured by skin Langerhans cells. This form of EPIT does not require disruption of the skin barrier, thus avoiding a proinflammatory cytokine response by targeting the nonvascularized epidermis and limiting systemic allergen exposure. Extensive preclinical research suggests that Viaskin Peanut has a distinct mechanism of desensitization, including the potential for disease modification, driven by a unique population of regulatory T cells. Numerous clinical studies of Viaskin Peanut have demonstrated desensitization and reductions in reaction severity, particularly in children aged 1 through 11 years, as well as a favorable safety profile with mostly mild-to-moderate skin reactions that were observed to decrease over time. EPIT with Viaskin Peanut may be a potential therapeutic option for peanut allergy that is clinically practical with long-term efficacy and tolerability., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The basophil activation test (BAT) has been limited to research settings owing to technical issues. Novel approaches using dry, ready-to-use reagents and streamlined protocols offer greater flexibility and may open opportunities for easier implementation in clinical research., Objective: Using a streamlined basophil activation test (sBAT) strategy and the settings of the baseline study of the Epicutaneous Immunotherapy in Toddlers with Peanut Allergy (EPITOPE) trial of EPicutaneous ImmunoTherapy, we aimed to assess the feasibility of implementing BAT in a multicenter trial and to evaluate its utility in predicting the outcomes of peanut double-blind placebo-controlled food challenge (DBPCFC)., Methods: Whole blood samples were collected from subjects aged 1 to 3 years (n = 241) undergoing baseline eligibility DBPCFC in the EPITOPE study across 15 clinical sites in North America. After preparation with sBAT reagents, processed samples were analyzed in a single central laboratory within 5 days of collection and preparation. The eliciting dose (ED) at DBPCFC was determined using, Practical Allergy (PRACTALL) criteria. Using a machine learning approach that incorporated BAT-derived features, clinical characteristics, and peanut-specific immunoglobulin E, the ability to predict outcomes of interest (ED ≤ 300 mg or > 300 mg] and use of epinephrine) was assessed using data randomly split into training (n = 182) and validation (n = 59) subsets., Results: The expression of basophil activation markers CD203c and CD63 correlated with ED and severity outcomes of DBPCFC. Most informative concentrations of peanut extract in the sBAT assay for these associations were 1 ng/mL and 10 ng/mL. Using machine learning to assess the ability to predict the outcomes of DBPCFC, the best models using only the BAT-derived features provided relatively high sensitivities of 0.86 and 0.85 for predicting ED and epinephrine use, respectively, whereas specificities were lower, ranging from 0.60 to 0.80. Although including specific immunoglobulin E and skin prick test data in addition to those from sBAT did not improve the ability to identify individuals most at risk for severe reactions, it did improve the ability to identify patients with an ED greater than 300 mg., Conclusions: In addition to facilitating implementation in multicenter trials, sBAT retains the potential of BAT to characterize allergic patients and confirms its potential to contribute to predicting the outcome of oral food challenges., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The skin is the largest immunologic organ in the body and contains immune cells that play a role in both food allergen sensitization and desensitization. The dual allergen exposure hypothesis posits that sensitization to food allergens may occur with cutaneous exposure on inflamed skin, eg, atopic dermatitis, but early oral consumption generally leads to tolerance. However, only one-third of children with atopic dermatitis develop a food allergy, suggesting that there is a more complex mechanism for allergen sensitization. Emerging evidence suggests that the outcome of cutaneous allergen exposure is context-dependent and largely influenced by the state of the skin barrier with healthy skin promoting natural tolerance. Current research supports the ability to induce desensitization through repeated application of allergens to the skin, known as epicutaneous immunotherapy. Preclinical research with an occlusive patch has demonstrated a significantly reduced T-helper cell type 2-driven immunologic response when applied to intact, uninflamed skin and induction of a unique population of regulatory T cells that express a broader range of homing receptors, which may be able to maintain sustained protection. In clinical studies of children aged 1 through 11 years with a peanut allergy, epicutaneous immunotherapy with an occlusive patch led to significant desensitization with no major differences in efficacy or safety between children with and without atopic dermatitis. These data begin to answer the conundrum of how allergens that are applied to the skin can lead to both sensitization and desensitization, and future studies should enable us to optimize the power of the skin as a complex immunologic organ to treat allergic, autoimmune, and autoinflammatory disorders., Competing Interests: Disclosures H.A.S. reports receiving funding from the National Institute of Allergy and Infectious Diseases; consulting fees from DBV Technologies, S.A., N-Fold Therapeutics, LLC, and Siolta, Inc; and stock options from DBV Technologies and N-Fold Therapeutics., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Reaction thresholds in peanut allergy are highly variable. Elucidating causal relationships between molecular and cellular processes associated with variable thresholds could point to therapeutic pathways for raising thresholds., Objective: The aim of this study was to characterize molecular and cellular systemic processes associated with reaction threshold in peanut allergy and causal relationships between them., Methods: A total of 105 children aged 4 to 14 years with suspected peanut allergy underwent double-blind, placebo-controlled food challenge to peanut. The cumulative peanut protein quantity eliciting allergic symptoms was considered the reaction threshold for each child. Peripheral blood samples collected at 0, 2, and 4 hours after challenge start were used for RNA sequencing, whole blood staining, and cytometry. Statistical and network analyses were performed to identify associations and causal mediation between the molecular and cellular profiles and peanut reaction threshold., Results: Within the cohort (N = 105), 81 children (77%) experienced allergic reactions after ingesting varying quantities of peanut, ranging from 43 to 9043 mg of cumulative peanut protein. Peripheral blood expression of transcripts (eg, IGF1R [false discovery rate (FDR) = 5.4e-5] and PADI4 [FDR = 5.4e-5]) and neutrophil abundance (FDR = 9.5e-4) were associated with peanut threshold. Coexpression network analyses revealed that the threshold-associated transcripts were enriched in modules for FcγR-mediated phagocytosis (FDR = 3.2e-3) and Toll-like receptor (FDR = 1.4e-3) signaling. Bayesian network, key driver, and causal mediation analyses identified key drivers (AP5B1, KLHL21, VASP, TPD52L2, and IGF2R) within these modules that are involved in bidirectional causal mediation relationships with neutrophil abundance., Conclusion: Key driver transcripts in FcγR-mediated phagocytosis and Toll-like receptor signaling interact bidirectionally with neutrophils in peripheral blood and are associated with reaction threshold in peanut allergy., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: DBV712 250 µg (also referred to as Viaskin Peanut or peanut patch; Viaskin is a trademark of DBV Technologies) is an innovative approach to epicutaneous immunotherapy (EPIT). The patch-based technology system facilitates peanut protein (allergen) absorption into the intact non-vascularized epidermis to promote desensitization to peanut while limiting systemic allergen exposure., Areas Covered: Efficacy and safety in children have been evaluated in four completed phase 3 studies. Overall, the results from these studies have demonstrated the peanut patch to be superior in desensitization compared with placebo and safe for daily use over multiple years., Expert Opinion: These findings, as well as supportive evidence from phase 2 studies, confirm the potential for an effective treatment of peanut allergy in children. The purpose of this review is to summarize the safety and efficacy of the peanut patch in the treatment of peanut allergy.

Competing Interests: Disclosures Dr Bird reports receiving grants from the National Institutes of Health/ National Institute of Allergy and Infectious Diseases (NIH/NIAID); grants and personal fees from Genentech; grants and personal fees from Novartis during the conduct of the study; grants from Aimmune, Astellas, Regeneron, and Siolta; grants and personal fees from DBV Technologies and Food Allergy Research and Education (FARE); personal fees from Allergenis, Allergy Therapeutics, HAL Allergy, and Nutricia; and other fees from the American Academy of Allergy, Asthma, and Immunology, the American Academy of Pediatrics, the International FPIES Association, and Vedanta outside the submitted work. Dr Fleischer has received research support from ARS Pharmaceuticals and DBV Technologies; serves as an unpaid advisory board member for Food Allergy and Anaphylaxis Connection Team and the National Peanut Board; receives royalties from UpToDate; and received personal fees as a consultant to Aquestive, ARS Pharmaceuticals, Bryn Pharma, DBV Technologies, Genentech, and Nasus outside of the submitted work. Dr Shreffler reports receiving grants from NIH/NIAID; has contract research support from Genentech, DBV, Allergy Therapeutics, Aravax, and Novartis; and received personal fees from Aimmune, DBV, Novartis, ALK, Allergy Therapeutics, FARE, and UpToDate. Dr Sampson reports receiving grants to his institution from NIH/NIAID; has received consulting fees from DBV Technologies, S.A., N-Fold Therapeutics, LLC, and Siolta, Inc; and has stock options from DBV Technologies and N-Fold Therapeutics. Dr Spergel reports receiving grants from NIH/NIAID and Novartis during the conduct of the study and received grants and personal fees from Regeneron and Sanofi; personal fees from ACAAI, Syneos, UpToDate, and Readysetfood; and grants from Allakos outside the submitted work.

Importance: No approved treatment exists for allergen-specific immunoglobulin E (IgE)-mediated cow's milk allergy (CMA), a common childhood food allergy., Objective: To assess dose, efficacy, and safety of epicutaneous immunotherapy with Viaskin milk in children with IgE-mediated CMA., Design, Setting, and Participants: A phase 1/2, 2-part, randomized, double-blind, placebo-controlled dose-ranging clinical trial in children aged 2 to 17 years with IgE-mediated CMA was conducted between November 2014 through December 2017. It took place at 17 trial sites in the US and Canada. Current CMA was confirmed by double-blind, placebo-controlled food challenge at study entry. Part A assessed the short-term safety of 150 μg, 300 μg, or 500 μg of Viaskin milk; part B evaluated the efficacy and safety of the 3 doses vs placebo over 12 months of treatment. Of the 308 screened participants with physician-diagnosed CMA, 198 met eligibility criteria (including an eliciting dose 300 mg or less) and were randomized., Intervention: Safety of Viaskin milk (150-μg, 300-μg, or 500-μg doses) was evaluated over a 3-week period (part A). In part B, 180 additional participants were randomized to receive Viaskin milk at doses of 150 μg, 300 μg, or 500 μg or placebo (1:1:1:1) for 12 months., Main Outcomes and Measures: The primary outcome was the proportion of treatment responders, defined as a 10-fold or more increase in the cumulative reactive dose of cow's milk protein (reaching at least 144 mg) or a cumulative reactive dose of cow's milk protein at 1444 mg or more at the month 12 double-blind, placebo-controlled food challenge., Results: A total of 95.5% of the randomized participants (mean [SD] age, 8 [4.17] years; 124 of 198 were male [62.6%]) completed treatment. The highest response rate was observed in participants who received Viaskin milk at the 300-μg dose with 24 of 49 responders (49.0%) overall vs 16 of 53 responders (30.2%) in the placebo group (odds ratio, 2.19; 95% CI, 0.91-5.41; P = .09), highest in the 2 to 11 years age group (22 of 38 [57.9%] vs 13 of 40 [32.5%]; P = .04). Most treatment-emergent adverse events were mild or moderate application-site reactions. One participant in the 500-μg Viaskin milk dose group experienced treatment-related anaphylaxis., Conclusions and Relevance: In this randomized clinical trial, 12 months of daily epicutaneous immunotherapy with a dose of Viaskin milk at 300 μg was associated with a statistically significant treatment response in 2- to 11-year-old children with IgE-mediated CMA. Treatment-related anaphylaxis and treatment-related discontinuation rates were low. Further research is needed to explore Viaskin milk as a viable treatment option for children with IgE-mediated CMA., Trial Registration: ClinicalTrials.gov Identifier: NCT02223182.

Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23 + IgG1 + memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of CD23 + IgG1 + memory B cells correlated with circulating concentrations of IgE in children with peanut allergy. A corresponding population of "type 2-marked" IgG1 + memory B cells was identified in single-cell RNA sequencing experiments. These cells differentially expressed interleukin-4 (IL-4)- and IL-13-regulated genes, such as FCER2 / CD23 + , IL4R , and germline IGHE , and carried highly mutated B cell receptors (BCRs). In children with high concentrations of serum peanut-specific IgE, high-affinity B cells that bind the main peanut allergen Ara h 2 mapped to the population of "type 2-marked" IgG1 + memory B cells and included clones with convergent BCRs across different individuals. Our findings indicate that CD23 + IgG1 + memory B cells transcribing germline IGHE are a unique memory population containing precursors of high-affinity pathogenic IgE-producing cells that are likely to be involved in the long-term persistence of peanut allergy.