Stephen R. Durham

Background: Allergen immunotherapy (AIT) is the only disease‐modifying therapeutic approach for cat allergy, though it requires at least three years of treatment and can potentially induce severe systemic reactions. Plant‐derived bioparticles expressing Fel d 1 allergen (Fel d 1 e BP) have been developed as a novel therapeutic candidate for cat allergy. We aimed to investigate the allergenicity and immunogenicity profile of Fel d 1 e BP. Methods: Fel d 1 e BP was synthesised in vivo in Nicotiana benthamiana and confirmed by cryo‐electron microscopy and tomography. Immune modulatory properties of purified natural Fel d 1 (nFel d 1) and Fel d 1 e BP were assessed at T and B cells by flow cytometry in 12 cat‐allergic subjects (CA) and 12 non‐atopic controls (NAC). Single‐cell RNA‐seq was used to assess molecular mechanisms of Fel d 1 e BP immune skewing. The safety of Fel d 1 e BP was assessed by measuring basophil responsiveness in whole blood and further confirmed in vivo by its administration as a skin prick test (SPT) in 20 cat‐allergic individuals. Results: Fel d 1 e BP was shown to be a strong inducer of Th1 cells ( p < 0.05) and IL‐10 ⁺ non‐Th2 cells ( p < 0.05) in CA subjects. Fel d 1 e BP showed a stronger trend for inducing IL‐10 ⁺ Breg cells compared to nFel d 1, peaking at 3 μg/mL. scRNA‐seq analyses demonstrated that Fel d 1 e BP targets the induction of protective metallothionein genes, CCL18 ⁺ monocytes and naïve B cells that are interferon responsive and metabolically activated. Moreover, Fel d 1 e BP demonstrated reduced capacity to elicit basophil activation ( p < 0.001) and histamine release ( p < 0.01), indicating their hypoallergenic nature. Administration of titrated doses of Fel d 1 e BP through skin prick test revealed that they are well‐tolerated with reduced mean wheal compared to native Fel d 1 in an open‐label Phase 0 study (all, p < 0.001). Conclusions: We demonstrate that Fel d 1 e BP is hypoallergenic and demonstrates tolerogenic properties, making it a novel candidate for use in AIT for cat allergy.

Summary: Compared to placebo, Dupilumab and Stapokibart (CM310) demonstrate the most significant therapeutic efficacy in treating CRSwNP. All biologics demonstrated favourable safety profiles, with Dupilumab exhibiting the lowest risk of adverse events.

Allergen immunotherapy (AIT) is the only disease-modifying therapeutic approach for cat allergy, though it requires at least three years of treatment and can potentially induce severe systemic reactions. Plant-derived bioparticles expressing Fel d 1 allergen (Fel d 1 e BP) have been developed as a novel therapeutic candidate for cat allergy. Cellular and scRNA-seq analyses reveal that Fel d 1 e BP induce Th1 and IL-10 ⁺ T cells. We also demonstrate that Fel d 1 e BP targets the induction of protective metallothionine genes, CCL18 ⁺ monocytes and naïve B cells that are interferon responsive. Moreover, Fel d 1 e BP demonstrated reduced capacity to elicit basophil activation and histamine release, indicating their hypoallergenic nature. Administration of titrated doses of Fel d 1 e BP through skin prick test revealed that they are well-tolerated with reduced mean wheal compared to native Fel d 1 in open-label Phase 0 study. Altogether, we demonstrate that Fel d 1 e BP is hypo-allergenic and demonstrate tolerogenic properties making them a novel candidate for use in AIT for cat allergy.

Purpose of the Review: To analyse the evidence regarding the optimal duration of subcutaneous and sublingual immunotherapies to induce long-lasting benefits after treatment cessation for allergic rhinitis and asthma and to identify unmet needs. Recent Findings: Subcutaneous and sublingual immunotherapies are highly effective in desensitising selected subjects with allergic rhinitis and allergic asthma. Double-blind, placebo-controlled, randomised clinical trials of both routes of immunotherapy support international guidelines that recommend their use for at least three years to achieve disease modification and continued clinical and immunological tolerance for allergic rhinitis. Evidence of the long-term effects of allergen immunotherapy in the context of randomised controlled trials for allergic asthma as opposed to rhinitis is limited. Nonetheless, real-world studies suggest the long-lasting benefits of allergen immunotherapy for allergic asthma, as this reduces prescriptions for pharmacotherapy and decreases the risk of asthma exacerbations and hospitalisations. The GINA guideline 2023 recommends the use of house dust mite sublingual immunotherapy as an add-on therapy in subjects with suboptimally controlled asthma, despite the use of low to high doses of inhaled corticosteroids, provided that the FEV₁ is > 70% predicted. Summary: Robust clinical trials of subcutaneous and sublingual immunotherapies have shown that 3 years of continuous treatment modifies the underlying course of allergic rhinitis with long-lasting clinical effects years after withdrawal. Further evaluations of the long-lasting effects of novel routes of allergen immunotherapy for allergic rhinitis and long-term studies for allergic asthma are needed in the context of randomised clinical trials.

Background: During the COVID‐19 pandemic, novel nanoparticle‐based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined.Methods: To understand COVID‐19 vaccine‐mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure.Results: Vaccine‐mediated complement activation correlated with anti‐polyethelyne glycol (PEG) IgG (but not IgM) levels while anti‐PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine‐mediated basophil activation. Single‐cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll‐like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL‐13 and IL‐1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions.Conclusion: These findings provide insights into the mechanisms underlying allergic reactions to COVID‐19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy.

Background: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients.Methods: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG₄, IgA₁ and IgA₂) and their inhibitory capacity were measured at multiple timepoints.Results: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA₁ to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71‐fold, p = .027). A significant induction in sIgG₄ to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA₂ to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen–IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra‐nasally in Group A (serum; 𝜌 = −.47, p = .0006, nasal; 𝜌 = −.38, p = .0294).Conclusions: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR.

Allergen-specific immunotherapy for inhalant allergies, using allergen extracts of proven value, is highly effective in selected patients with allergic rhinoconjunctivitis and allergic asthma. Both subcutaneous and sublingual immunotherapy (SLIT) have been shown to modify the underlying cause of the disease, with long-term clinical benefits that persist for years after their discontinuation. Real-world studies have confirmed the long-term efficacy of allergen immunotherapy in allergic rhinitis (AR) and asthma and shown a reduction in the incidence of lower respiratory tract infections. Sublingual house dust mite (HDM) immunotherapy has been suggested to improve innate antiviral immunity—a likely explanation for this finding. Based on robust randomized controlled trials, the Global Initiative for Asthma (GINA) guideline has incorporated the use of SILT for the treatment of adults with HDM-driven asthma and concomitant AR, with sub-optimal control, regardless of the use of low-to-high doses of inhaled corticosteroids, as long as the patient’s forced expiratory volume in 1 second (FEV1) is > 70%.