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.
Highlights
There are still a number of pathogens that cause a significant burden of disease for which limited to no vaccines or prophylaxis is available
We developed a library of synthetic alpha-branched diester trehalose derivatives (Figure 1) to evaluate the structure activity relationship of these compounds
The relative activity of trehalose dimycolate (TDM) and trehalose dibehenate (TDB) in the human and mouse human embryonic kidney (HEK) cells is consistent with the results reported by others [20]
Summary
There are still a number of pathogens that cause a significant burden of disease for which limited to no vaccines or prophylaxis is available. Among these is the gram negative bacterium Mycobacterium tuberculosis (Mtb) which infects an estimated 10 million people per year resulting in over a million deaths annually. Pre-clinical observations [5,6,7] suggest that the IL-23/IL-17 axis alone is not sufficient for protecting from Mtb infection but that it can augment the immune response directed against Mtb. Th17 offers long-term control of bacteria growth, a critical component of an effective vaccine [8, 9]. Khader and colleagues demonstrated that a successful protective vaccine strategy will rely on populating the bacterial entry areas with IL-17-expressing cells that will respond rapidly to the infection
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