An interdisciplinary approach to characterize peanut-allergic patients-First data from the FOOD@ consortium.

Background: Peanut allergy is a frequent cause of food allergy and potentially life-threatening. Within this interdisciplinary research approach, we aim to unravel the complex mechanisms of peanut allergy. As a first step were applied in an exploratory manner the analysis of peanut allergic versus non-allergic controls. Methods: Biosamples were studied regarding DNA methylation signatures, gut microbiome, adaptive and innate immune cell populations, soluble signaling molecules and allergen-reactive antibody specificities. We applied a scalable systems medicine computational workflow to the assembled data. Results: We identified combined cellular and soluble biomarker signatures that stratify donors into peanut-allergic and non-allergic with high specificity. DNA methylation profiling revealed various genes of interest and stool microbiota differences in bacteria abundances. Conclusion: By extending our findings to a larger set of patients (e.g., children vs. adults), we will establish predictors for food allergy and tolerance and translate these as for example, indicators for interventional studies.

SARS-CoV-2 mRNA vaccinations fail to elicit humoral and cellular immune responses in patients with multiple sclerosis receiving fingolimod.

BACKGROUND: SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. METHODS: As part of a prospective cohort study, we investigated the induction, stability and boosting of vaccine-specific antibodies, B cells and T cells in patients with multiple sclerosis (MS) on different DMTs after homologous primary, secondary and booster SARS-CoV-2 mRNA vaccinations. Of 126 patients with MS analysed, 105 received either anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-ß, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and 21 were untreated MS patients for comparison. RESULTS: In contrast to all other MS patients, and even after booster, most aCD20-BCD- and fingolimod-treated patients showed no to markedly reduced anti-S1 IgG, serum neutralising activity and a lack of receptor binding domain-specific and S2-specific B cells. Patients receiving fingolimod additionally lacked spike-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether a humoral immune response was elicited. CONCLUSIONS: The lack of immunogenicity under long-term fingolimod treatment demonstrates that functional immune responses require not only immune cells themselves, but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses suggests that fingolimod-treated patients with MS are at risk for severe SARS-CoV-2 infections despite booster vaccinations, which is highly relevant for clinical decision-making and adapted protective measures, particularly considering additional recently approved sphingosine-1-phosphate receptor antagonists for MS treatment.

Tolerance induction through early feeding to prevent food allergy in infants with eczema (TEFFA): rationale, study design, and methods of a randomized controlled trial.

BACKGROUND: Up to 8% of all children in industrialized countries suffer from food allergies, whereas children with atopic eczema are affected considerably more frequently. In addition, the type and starting time of weaning foods seem to influence the development of food allergies. However, data from interventional studies on weaning are controversial. The aim of this randomized-controlled clinical trial is to investigate, whether an early introduction of hen's egg (HE), cow's milk (CM), peanut (PN), and hazelnut (HN) in children with atopic eczema can reduce the risk for developing food allergies in the first year of life. METHODS: This is a protocol for a randomized, placebo controlled, double blind, single-center clinical trial. One hundred fifty infants with atopic eczema at 4-8 months of age will be randomized in a 2:1 manner into an active group that will receive rusk-like biscuit powder with HE, CM, PN, and HN (initially approximately 2 mg of each food protein) for 6-8 months or a placebo group, whose participants will receive the same rusk-like biscuit powder without HE, CM, PN, and HN on a daily basis. During the interventional period, the amount of allergens in the study product will be increased three times, each after 6 weeks. All study participants who are sensitized to HE, CM, PN, or HN at the end of the interventional period will undergo an oral food challenge to the respective food in a further visit. Primary endpoint is IgE-mediated food allergy to at least one of the four foods (HE, CM, PN or HN) after 6-8 months of intervention (i.e., at around 1 year of age). Secondary endpoints include multiple food allergies, severity of eczema, wheezing, and sensitization levels against food allergens. DISCUSSION: This clinical trial will assess whether an early introduction of allergenic foods into the diet of children with atopic eczema can prevent the development of food allergies. This trial will contribute to update food allergy prevention guidelines. TRIAL REGISTRATION: German Clinical Trials Register DRKS00016770 . Registered on 09 January 2020.

Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study.

BACKGROUND: Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy. METHODS: The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1-67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose. DISCUSSION: This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid. TRIAL REGISTRATION: German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de .

SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4+ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4+ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4+ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.