Novel vaccines targeting dendritic cells by coupling allergoids to mannan

Abstract

Allergen-specific immunotherapy (AIT) is the single disease-modifying treatment for allergy. Clinical trials show AIT to be safe and effective for many patients; however, it still faces problems related to efficacy, safety, long treatment duration and low patient adherence. There has been intensive research to develop alternative strategies, including novel administration routes, adjuvants or hypoallergenic molecules. Promising results are reported for some of them, but clinical progress is still moderate. Allergoids conjugated to nonoxidized mannan from Saccharomyces cerevisiae have emerged as a novel concept of vaccine targeting dendritic cells (DCs). Preclinical human and animal models demonstrated that allergoids conjugated to mannan enhance allergen uptake, promote healthy responses to allergens by inducing Th1 and T regulatory (Treg) cells, and show clinical efficacy in veterinary medicine. Dose-finding phase II clinical trials in humans are currently ongoing. We review the current stage of allergoids conjugated to mannan as next generation vaccines for AIT.

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…29,30 This is a paradigmatic study revealing the importance of the better understanding of the molecular mechanisms driving alum adjuvanticity in the context of allergy, especially in humans, to continue improving allergen vaccine formulations for AIT. Allergoid-mannan conjugates represent a major development in the search of novel vaccine approaches to improve AIT, 6,[9][10][11] and Alum was introduced as a vaccine adjuvant in 1926 by Glenny et al, 31 and since 1937, it is used in AIT. Although there are different adjuvant preparations that can be used in AIT as immunostimulants (ie, mineral salts or TLR-targeting adjuvants) or delivery systems (ie, different types of microand nanoparticles), 11 nowadays most of the subcutaneous vaccines for AIT include alum as adjuvant.…”

“…9,10 In mice, subcutaneous or sublingual immunization with PM increases the frequency of splenic FOXP3 + Treg cells and induces healthy immune responses to allergens. 9,11,13 All these beneficial effects depend on the structural integrity of the conjugated mannan. 9,[12][13][14] Aluminium hydroxide (alum) remains the most widely used adjuvant in AIT.…”

“…Clinical trials and real‐life practice demonstrated AIT as an effective treatment; however, it still faces several drawbacks regarding the long treatment duration, patient compliance, side effects or low efficacy for some patients . Polymerized allergoids conjugated to mannan (PM) have been recently reported as next‐generation vaccines targeting dendritic cells (DCs) that might well contribute to overcome such inconveniences . PM are captured very efficiently by human DCs via mannose receptor and other C‐type lectin receptors (CLRs).…”

“…PM activates CLRs and promotes IL‐10‐producing tolerogenic DCs that generate functional forkhead box P3 (FOXP3) + Treg cells through programmed death‐ligand 1 (PD‐L1) . In mice, subcutaneous or sublingual immunization with PM increases the frequency of splenic FOXP3 + Treg cells and induces healthy immune responses to allergens . All these beneficial effects depend on the structural integrity of the conjugated mannan …”

Adjuvant Allergen Fusion Proteins as Novel Tools for the Treatment of Type I Allergies

“…Those include cytokines, bacterial toxins, and glycolipids (Reed et al 2009). Moreover, allergoid preparations conjugated to non-oxidized mannan from Saccharomyces cerevisiae were shown to have promising immune-modulating properties (reviewed in Benito-Villalvilla et al 2018). Allergoids, which are already used in the clinical practice, are allergen extracts that are chemically cross-linked with glutaraldehyde reacting with the primary amine groups of the allergen proteins to generate high molecular aggregates (Benito-Villalvilla et al 2018).…”