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Background: Approved therapeutics for peanut allergy are not designed for the many patients with allergic reactions to more than one peanut., Methods: We randomly assigned (1:1) participants 4 to 14 years of age reacting to a challenge of between 443 mg and 5043 mg of peanut protein to peanut oral immunotherapy (P-OIT) using home-measured peanut butter versus peanut avoidance. The primary end point was the difference between groups in the proportion tolerating a two-dose-level increase or 9043 mg of peanut protein. For ingestion participants tolerating 9043 mg, sustained unresponsiveness (tolerance off treatment) was tested after 16 weeks of ad lib ingestion followed by 8 weeks of abstinence., Results: Of 73 participants, 38 were randomly assigned to P-OIT and 35 to avoidance. Thirty-two of 38 participants in the ingestion group (84.2%) and 30 of 35 in the avoidance group (85.7%) underwent the primary outcome food challenge. The primary analysis with prespecified multiple imputation for missing values showed 100% success for ingestion versus 21.0% for avoidance (between-group difference, 79.0 percentage points; 95% confidence interval [CI], 64.6 to 93.5; P<0.001). All 32 treated and 3 out of 30 avoiders (10%) tolerated 9043 mg. In the intention-to-treat analysis, sustained unresponsiveness occurred in 68.4% (26/38) on P-OIT versus 8.6% (3/35) tolerating 9043 mg among those avoiding (between-group difference, 59.9 percentage points; 95% CI, 42.4 to 77.3). No dosing reactions were greater than grade 1 severity, and no serious adverse events were reported., Conclusions: In this trial of P-OIT using store-bought, home-measured peanut versus peanut avoidance in high-threshold peanut allergy, those treated achieved significantly higher rates of desensitization with a durable response off treatment. (Funded by the National Center for Advancing Translational Sciences [UL1TR004419] and the National Institute of Allergy and Infectious [U19AI136053]; ClinicalTrials.gov number, NCT03907397.).

Background: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption., Methods: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months., Results: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 μg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 μg/l. Adverse events were uncommon, and the majority were related to the food challenge., Conclusions: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).

Background: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions., Objective: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT)., Methods: We first performed ex vivo T-cell profiling on peanut-reactive CD154 + CD137 + T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4 + T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT., Results: Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6 - CRT H 2 + and CCR6 + CRT H 2 - ). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of T H 2A pTeff cells. PnOIT induced elimination of T H 2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of T H 2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation., Conclusion: Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Findings: 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; p<0·0001). 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 (p<0·0001). 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 (p<0·0001). 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 (p<0·001). 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., Interpretation: 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., Funding: National Institute of Allergy and Infectious Disease, Immune Tolerance Network., Competing Interests: Declaration of interests SMJ reports grants from NIH-NIAID, Food Allergy Research & Education (FARE), Aimmune Therapeutic, DBV Technologies, Astellas, Sanofi, Regeneron, and Genentech; and personal fees from FARE, EMMES Corporation, and Aimmune Therapeutics. EHK reports personal fees from DBV Technologies, Aimmune Therapeutics, AllerGenis, Ukko, Vibrant America, Allakos, Kenota Health, and Duke Clinical Research Institute; and grants from FARE and the Wallace Research Foundation. KCN reports grants from NIAID, National Heart, Lung, and Blood Institute, National Institute of Environmental Health Sciences, and FARE; other fees from World Allergy Organization and Cour Pharma; other support from Before Brands, Alladapt, Latitude, IgGenix, Immune Tolerance Network (ITN), and NIH clinical research centres; and pending patent applications for inhibition of allergic reaction to peanut allergen using an IL-33 inhibitor (62/647,389), special oral formula for decreasing food allergy risk and treatment for food allergy (62/119,014), basophil activation based diagnostic allergy test (S10-392), granulocyte-based methods for detecting and monitoring immune system disorders (12/686,121), methods and assays for detecting and quantifying pure subpopulations of white blood cells in immune system disorders (12/610,940), mixed allergen compositions and methods for using the same (10/064,936), and microfluidic device and diagnostic methods for allergy testing based on detection of basophil activation (62/767,444). AN-W reports grants from NIH-NIAID, DBV Technologies, Astellas Pharma, and FARE; and grants and personal fees from Nestlé and Nutricia. RAW reports grants from NIAID, Aimmune, Astellas, DBV Technologies, Genentech, Regeneron, and Sanofi; and personal fees from UpToDate. HAS receives funding to his institution for grants from NIH-NIAID; consulting fees from DBV Technologies, N-Fold Therapeutics, and Siolta; and stock options from DBV Technologies and N-Fold Therapeutics. AMS reports grants from NIAID-ITN, FARE, Aimmune, DBV Technologies, Astellas, Sanofi, Regeneron, and Genentech; and personal fees from DBV Technologies. JW reports grants from NIAID and personal fees from DBV Technologies, ALK Abello, Genentech, and UpToDate. SBS reports grants from NIAID, Regeneron, DBV Technologies, Aimmune, Novartis, and Sanofi; and personal fees from AstraZeneca. MK reports grants from NIH and Department of Defence. JJ reports grants from NIAID. KS reports grants from NIH-NIAID. DCB reports grants from NIH-NIAID. HC reports grants from NIH-NIAID. DL reports grants from NIH-NIAID. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)