In natural infections, the immune system is triggered by several pathogen associated molecular patterns (PAMPs). Thus, during vaccine design, adjuvants or immunostimulants that activate multiple pattern recognition receptors (PRRs), are added to an antigen to elicit a stronger immune response to vaccination. Toll-like receptor (TLR) agonists, and NOD-like receptor (NLR) agonists are two such widely explored classes of immunostimulants. Dual activation of these agonists is a critical feature in immune-activation (for pathogen clearance) and immune-response (to whole-cell vaccines). However, most studies are limited to mixing these agonists together, thus removing the defined spatial arrangement of native agonists in a pathogen. In this study we will explore how unexplored combinations of spatially organized triple PRR agonists, affect immune-stimulation.  We will also explore whether synergistic immune-activation can be achieved. Specifically, we have synthesized two novel trivalent ligands; one targeting TLR4, TLR7 and NOD2 and the other targeting TLR4, TLR9 and NOD2 simultaneously. We will also explore whether NOD2 activation affects the TLR4-TLR7 and TLR4-TLR9 synergies. Moreover, we wish to investigate the effect of TLR4 and TLR9/TLR7 on the NOD2-TLR9 and NOD2-TLR4 synergies respectively.<br/>By covalently linking the agonists to a core, we have been able to account for the different retention kinetics of the adjuvants resulting in altered adjuvant ratios, as well as the defined spatial arrangement of native agonists in the pathogen. We believe the new adjuvant (linked tri-agonist) will have improved PK/PD profile, which otherwise would have led to early diffusion of the agonists. This would affect dosage and cause adverse systemic immune activation and subsequent immunotoxicity. So far, we have observed that spatial organization of PRR agonists can alter the resulting immune response, with each combination resulting in a distinct immune response.<br/>

Spatially organized pattern recognition receptor tri-agonists: NOD2 agonist in combination with two TLR agonists

2019 Fall National Meeting

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