Recent Advances in the Development of Mincle-Targeting Vaccine Adjuvants

Abstract

The Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor (PRR), which has shown much promise as a molecular target for the development of T_H1/T_H17-skewing vaccine adjuvants. In 2009, the first non-proteinaceous Mincle ligands, trehalose dimycolate (TDM) and trehalose dibehenate (TDB), were identified. This prompted a search for other Mincle agonists and the exploration of Mincle agonists as vaccine adjuvants for both preventative and therapeutic (anti-cancer) vaccines. In this review, we discuss those classes of Mincle agonists that have been explored for their adjuvant potential. These Mincle agonists have been used as stand-alone adjuvants or in combination with other pathogen-associated molecular patterns (PAMPs) or immunomodulatory agents. We will also highlight recently identified Mincle ligands with hitherto unknown adjuvanticity. Conjugate vaccines that contain covalently linked adjuvants and/or adjuvant-antigen combinations are also presented, as well as the different formulations (e.g., oil-in-water emulsions, liposomes, and particulate delivery systems) that have been used for the codelivery of antigens and adjuvants. Insofar the reader is presented with a thorough review of the potential of Mincle-mediated vaccine adjuvants, including historical context, present-day research and clinical trials, and outstanding research questions, such as the role of ligand presentation and Mincle clustering, which, if better understood, will aid in the development of the much-needed T_H1/T_H17-skewing vaccine adjuvants.

Keywords: C-type lectin; Mincle; adjuvant; formulation; ligand; vaccine.

Figure 1

(A) Structures of Mincle ligands TDM (1) and TDB (2). (B) The activation of Mincle on antigen-presenting cells by ligands leads to the induction of the FcRγ-Syk-Card9 pathway and NF-κB mediated gene expression. (C) Crystal structure of human Mincle (pdb ID: 3WH3), with the carbohydrate recognition domain (CRD) EPN motif in yellow, the lipophilic region in green, and the cholesterol recognition/interaction amino acid consensus (CRAC)-like motif in purple.

Figure 2

Classes of Mincle agonists with demonstrated activity as vaccine adjuvants.

Figure 3

Mincle agonists identified post-2017 with unknown adjuvant activity.

Figure 4

Representative formulations of Mincle agonists for vaccine delivery. (A) Trehalose diesters have historically been administered in emulsions (i) [28] or liposomes (ii) [130], with more recent applications in polymer-based microspheres (iii) [131] and lipid nanoparticles (iv) [89]. (B) Brartemicin derivatives can be coated on silica nanoparticles (SNPs) with antigens for codelivery in vaccines [48]. (C) Recent advances in the delivery of non-TDE Mincle agonists involve the development of emulsion-based adjuvant systems for the delivery of TMM (i) [91] and MMG (ii) [132].

Figure 5

Representative formulations of Mincle agonists with other immunomodulators for vaccine delivery. (A) Liposomal adjuvant systems CAF01 [130] and CAF04 [148] can be modified with different TLR ligands to form CAF08 [195], CAF06 [196], CAF05 [197], CAF09 [198], CAF11 [199], and CAF10 [199] for the codelivery of PAMPs. (B) Nanoemulsion CAF formulations can be modified for the codelivery of PAMPs (CAF19 [149] and CAF23 [200]). (C) Liposomes can be used for the delivery of other immunostimulants, such as retinoic acid [201].

Figure 6

Chimeric adjuvants in which Mincle ligands are covalently linked to MDP [242].

Figure 7

Adjuvant–antigen conjugates.

Figure 8

Adjuvant–antigen conjugates (therapeutic).