A randomized, double‐blind, placebo‐controlled trial with mannan‐conjugated birch pollen allergoids

Abstract

BackgroundThere is still great need to develop new strategies to improve the efficacy of allergen immunotherapies with optimal safety standards for patients. A new promising approach is to couple allergoids to mannan. The objective of this phase IIa/IIb study was to identify the optimal dose of mannan‐conjugated birch pollen allergoids for the short‐course treatment of birch pollen–induced allergic rhinoconjunctivitis.MethodsFor this prospective, randomized, double‐blind, placebo‐controlled, dose‐finding study, 246 birch pollen–allergic adults received 0.5 mL placebo or 1000, 3000 or 10,000 mTU/mL of mannan‐conjugated birch pollen allergoids at five pre‐seasonal visits. Efficacy was assessed by comparing allergic rhinoconjunctivitis symptoms and use of anti‐allergic medication during the peak of the birch pollen season 2020. Immunologic, tolerability and safety effects were also analysed.ResultsThe highest dose of mannan‐conjugated birch pollen allergoids reduced the combined symptom and medication score during the peak birch pollen season by a median of 24.7% compared to placebo. The production of Bet v 1 specific IgG4 significantly increased in a dose‐dependent manner (3.6‐ and 4.5‐fold) in the 3000 and 10,000 mTU/mL groups. The Bet v 1 specific IgE/IgG4 ratio was also strongly reduced (up to −70%). No fatalities nor serious adverse events were reported, and no adrenaline was used. In total, four systemic reactions occurred (two grade I and two grade II).ConclusionAll doses of mannan‐conjugated birch pollen allergoids can be considered as safe. Since the application of 10,000 mTU/mL resulted in the highest efficacy, this dose qualifies for further investigation.

Grass pollen allergoids conjugated with mannan for subcutaneous and sublingual immunotherapy: a dose-finding study

“…Immunogenicity studies indicated that both the 3,000 and 5,000 mTU/mL doses led to a significant increase in serum levels of allergen specific IgG4 when administered subcutaneously. This increase aligns with findings from previous studies on mannan-allergoid conjugates from mites or birch pollen ( 17 , 18 ). Moreover, the ability of IgG induced by grass or birch pollen allergoids conjugated with mannan to compete with specific IgE has been confirmed in both preclinical ( 13 ) and clinical settings ( 18 ).…”

“…Recently, placebo-controlled dose-finding studies have been performed with mannan allergoids derived from mites and birch pollen ( 17 , 18 ). Here, we present the results of the first-in-human study, designed to evaluate the safety and efficacy of escalating doses of mannan-conjugated grass pollen allergoids ( Phleum pratense and Dactylis glomerata ).…”

Purified Free Mannan Promotes Tolerogenic Responses in Peanut-Stimulated Human Dendritic Cells

“…Previous in vitro and in vivo studies have demonstrated that allergoid-mannan conjugates are effective vaccines in the context of grass pollen, birch pollen, and mite allergy, able to induce the upregulation of PD-L1 and IL-10 production in human DCs, which is associated to the generation of functional FOXP3 + Tregs [11,13,28]. Importantly, phase II clinical trials demonstrated that allergoid-mannan conjugates show efficacy and safety after subcutaneous and sublingual administration for allergic rhinitis [9,10]. Herein, we show that purified free mannan retains the capacity to generate tolerogenic DCs able to polarize functional Tregs also in the presence of peanut allergens, pointing out mannan as a potential suitable adjuvant also for peanut OIT.…”

“…In this regard, the identification of novel adjuvants targeting dendritic cells (DCs) represents a promising approach. Non-oxidized mannan from Saccharomyces cerevisiae conjugated to polymerized allergoids are next-generation vaccines targeting DCs that have shown clinical efficacy and safety in phase II clinical trials for house dust mite and birch pollen allergic rhinitis [9,10]. Mechanistically, allergoid-mannan conjugates are hypoallergenic molecules recognized by the mannose receptor (CD206) and dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) that promote the generation of functional forkhead box 3 (FOXP3)-positive regulatory T cells (Tregs) through programmed death ligand 1 (PD-L1) both in vitro and in vivo and reprogram monocytes into tolerogenic DCs via epigenetic and metabolic rewiring [11][12][13].…”

IgG in the control of FcεRI activation: a battle on multiple fronts

“…The challenge here is to modify the allergens in a way that reduces FcεRI cross-linking but enhances the induction of allergen-specific IgG. Others have reviewed the current landscape of vaccination strategies for improving AIT ( 73 – 79 ). We have focused on using allergens displayed on virus-like particles (VLP), which can reduce allergen reactivity while boosting IgG responses that increase protection via FcγRIIb ( 80 , 81 ).…”