Species-Specific Structural Requirements of Alpha-Branched Trehalose Diester Mincle Agonists

Abstract

Despite the ever present need for an effective Mycobacterium tuberculosis ( Mtb ) vaccine, efforts for development have been largely unsuccessful. Correlates of immune protection against Mtb are not wholly defined, but Th1 and likely Th17 adaptive immune responses have been demonstrated to be necessary for vaccine-mediated protection. Unfortunately, no approved adjuvants are able to drive a Th17 response, though recent clinical trials with CAF01 have demonstrated proof of concept. Herein we present the discovery and characterization of a new class of potential Th17-inducing vaccine adjuvants, alpha-branched trehalose diester molecules (αTDE). Based off the Mtb immunostimulatory component trehalose dimycolate (TDM), we synthesized and evaluated the immunostimulatory capacity of a library of structural derivatives. We evaluated the structure activity relationship of the compounds in relation to chain length and engagement of the Mincle receptor, production of innate cytokines from human and murine cells, and a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells. Murine cells displayed more structural tolerance, engaging and responding to a wide array of compound chain lengths. Interestingly, human cells displayed a unique specificity for ester chains between 5 and 14 carbons for maximal immune stimulating activity. Evaluation of two distinct αTDEs, B16 and B42, in concert with a recombinant Mtb antigen demonstrated their ability to augment a Th17 immune response against a Mtb antigen in vivo . Collectively this data describes the species-specific structural requirements for maximal human activity of alpha-branched trehalose diester compounds and demonstrates their capacity to serve as potent Th17-inducing adjuvants.

CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection

“…Several infectious diseases of significant public health concerns could benefit from a Th17-inducing adjuvant system including M. tuberculosis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, and Aspergillus fumigatus (17,45,50). Cationic adjuvant formulation 1 (CAF01) and derivatives of trehalose diesters that can bind to Mincle receptor on macrophages were used with subunit vaccines against M. tuberculosis (16,51). A nanoemulsification adjuvant made of soybean oil with cetylpyridinium chloride, Tween 80, and ethanol in water has been shown to induce a Th1-and Th17-mixed immune response against mucosal viral infection (15).…”

“…Several experimental adjuvants have recently been demonstrated to stimulate IL-17 production and to augment vaccine-mediated immunity against pulmonary Mycobacterium tuberculosis infections (15)(16)(17). Glucan particles (GPs) that are primarily composed of b-1,3-D -glucans derived from Saccharomyces cerevisiae cell wall have been shown to elicit a mixed Th1 and Th17 response against fungal infections (18,19).…”

Carbohydrate Immune Adjuvants in Subunit Vaccines

“…Thus, the lipid moieties also play a role in the formulation’s immune stimulating activity [ 171 ]. The presence of two fatty acids (5–14 carbons) is crucial for TDB potency [ 172 ].…”

The coadministration of trehalose dibehenate and monosodium urate crystals promotes an antitumor phenotype in human‐derived myeloid cells

“…While the anticancer activity of MSU + TDB appears promising, species‐specific differences have been observed for Mincle ligands 17,19,23 . This raises the question as to whether the TDB effect translates to human cells—particularly as studies investigating the effect of TDB on cells of human origin are rare 19,23 .…”

“…While the anticancer activity of MSU + TDB appears promising, species‐specific differences have been observed for Mincle ligands 17,19,23 . This raises the question as to whether the TDB effect translates to human cells—particularly as studies investigating the effect of TDB on cells of human origin are rare 19,23 . To this end, we investigated how TDB and/or MSU altered the phenotype of human monocytes, macrophages and DCs, either alone or in combination with T cells, so as to determine whether MSU + TDB may be an adjuvant combination with the potential to enhance tumor regression in humans.…”