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While food allergy oral immunotherapy (OIT) can provide safe and effective desensitization (DS), the immune mechanisms underlying development of sustained unresponsiveness (SU) following a period of avoidance are largely unknown. Here, we compare high dimensional phenotypes of innate and adaptive immune cell subsets of participants in a previously reported, phase 2 randomized, controlled, peanut OIT trial who achieved SU vs. DS (no vs. with allergic reactions upon food challenge after a withdrawal period; n  = 21 vs. 30 respectively among total 120 intent-to-treat participants). Lower frequencies of naïve CD8 + T cells and terminally differentiated CD57 + CD8 + T cell subsets at baseline (pre-OIT) are associated with SU. Frequency of naïve CD8 + T cells shows a significant positive correlation with peanut-specific and Ara h 2-specific IgE levels at baseline. Higher frequencies of IL-4 + and IFNγ + CD4 + T cells post-OIT are negatively correlated with SU. Our findings provide evidence that an immune signature consisting of certain CD8 + T cell subset frequencies is potentially predictive of SU following OIT. Oral immunotherapy (OIT) clinical trials have helped a subset of participants achieve sustained unresponsiveness (SU) to the cognate allergen. Here the authors analyse immune cells from participants from one peanut OIT trial and show that CD8 + T cell differentiation status at baseline may help to predict the likelihood of achieving SU.

We designed an oral immunotherapy (OIT) clinical trial for cashew allergy to further our understanding of immunological responses with treatment, including changes in allergen-specific T cells. This information can further assist with the design of efficacious and safe treatments. Participants were built up to and maintained on 1 g of cashew flour protein. Double-blind, placebo-controlled food challenges (DBPCFCs) were conducted before and after dosing completion (week 52) and 6 weeks after dosing discontinuation (week 58). Desensitization (DS) and sustained unresponsiveness (SU) were defined as tolerating DBPCFC to a cumulative dose of 2043 mg of the allergen at weeks 52 and 58, respectively. ClinicalTrials.gov, number NCT03504774. We enrolled 40 cashew allergic participants. In the Intent-to-treat (ITT) population, both the DS and SU rate to cashew was 65% (26/40). Among cashew-reactive cells, CRTH2 CD4 T cells decreased at week 52 and week 58 compared to baseline. Additionally, we also saw reduced baseline expression of cytokines TARC, EGF and IP10 among participants that achieved SU at 4043mg compared to those who achieved SU at 2043mg. Cashew OIT have efficacy and safety outcomes similar to other published OIT studies. Reductions in pathogenic allergen-specific T cell populations may contribute to the immune mechanisms underlying tolerance achieved towards cashew post-treatment. ClinicalTrials.gov, identifier NCT03504774.

Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology 1 , 2 . Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer–BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14 + CD16 + inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization. Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.

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; 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. 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.

The incidence of allergic conditions has continued to rise over the past several decades, with a growing body of research dedicated toward the treatment of such conditions. By driving a complex range of changes in the underlying immune response, immunotherapy is the only therapy that modulates the immune system with long-term effects and is presently utilized for the treatment of several atopic conditions. Recent efforts have focused on identifying biomarkers associated with these changes that may be of use in predicting patients with the highest likelihood of positive clinical outcomes during allergen immunotherapy (AIT), providing guidance regarding AIT discontinuation, and predicting symptomatic relapse and the need for booster AIT after therapy. The identification of such biomarkers in food allergy has the additional benefit of replacing oral food challenges, which are presently the gold standard for diagnosing food allergies. While several markers have shown early promise, research has yet to identify a marker that can invariably predict clinical response to AIT. Skin prick testing (SPT) and specific IgE have commonly been used as inclusion criteria for the initiation of AIT and prediction of reactions during subsequent allergen challenge; however, existing data suggests that changes in these markers are not always associated with clinical improvement and can be widely variable, reducing their utility in predicting clinical response. Similar findings have been described for the use of allergen-specific functional IgG4 antibodies, basophil activation and histamine release, and type 2 innate lymphoid cells. There appears to be a promising association between changes in the expression of dendritic cell-associated markers, as well as the use of DNA promoter region methylation patterns in the prediction of allergy status following therapy. The cellular and molecular changes brought about by immunotherapy are still under investigation, but major strides in our understanding are being made.

Allergic diseases, such as food allergies, asthma, and allergic rhinitis, continue to present a significant challenge for a broad cross-section of the population, despite recent advancements in their treatment and prevention [...]

As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. FDA-authorized mRNA COVID-19 vaccines. Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.

BACKGROUNDProlonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODSAdult SARS-CoV-2 reverse transcription PCR-positive (RT-PCR-positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTSOur cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSIONWe found that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATIONClinicalTrials.gov, NCT04373148.FUNDINGNIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.