Novel vaccines targeting dendritic cells by coupling allergoids to mannan

Cristina Benito-Villalvilla, Irene Soria, José Luis Subiza, Oscar Palomares, Cristina Benito-Villalvilla, Irene Soria, José Luis Subiza, Oscar Palomares

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.

Keywords: Allergen vaccines; Allergen-specific immunotherapy; Allergoids conjugated to mannan; Dendritic cells; Immune tolerance; Regulatory T cells.

Conflict of interest statement

C. Benito-Villalvilla declares that she has no competing interests. I. Soria is employee of Inmunotek S.L. J.L. Subiza is the CEO-President of Inmunotek S.L. O. Palomares received lecture fees from Allergy Therapeutics, Amgen, AstraZeneca, Inmunotek, Novartis, Sanofi-Genzyme and Stallergenes and participated in advisory boards from Novartis and Sanofi-Genzyme.

Figures

Fig. 1
Fig. 1
Novel developments for allergen vaccines. Adjuvants can be classified as immunostimulant substances including TLR-ligands, mineral salts, amino-acids or CLR-ligands and as delivery systems including micro- or nanoparticles, VLPs or CLR-ligands. There are different ways to modify allergens to make them hypoallergenic: molecular (peptides, fusion proteins or recombinant hypoallergens) or chemical (generating allergoids) strategies. Both approaches are used in combination to generate allergoids conjugated to mannan. TLR Toll-like receptor; CLR C-type lectin receptor; VLP Viral-like particle; MPL Monophosphoryl lipid A; ODN Oligodeoxynucleotide
Fig. 2
Fig. 2
Sugar oxidation of mannan carbohydrate backbone. Mannan oxidation with sodium periodate (NaIO4) breaks the mannopyranose rings within the polymannose backbone between the adjacent hydroxyl groups at positions C3 and C4 generating highly reactive and unstable aldehyde groups
Fig. 3
Fig. 3
Steps for the generation and development of allergoids conjugated to mannan as vaccines for AIT. a Allergens are polymerized and conjugated with mannan under non-oxidative conditions in a single step using glutaraldehyde. b Preclinical experiments in human, rabbit, and mice models to establish the in vivo properties of allergoids conjugated to mannan (PM). c Dose-finding clinical trials for grass pollen and mite allergy using PM are currently ongoing. LN lymph nodes; PC Preclinical phase; SCIT subcutaneous immunotherapy; SLIT sublingual immunotherapy

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