Vaccines are one of the most successful treatments for disease. However, diseases, such as malaria and HIV, do not have effective treatments, demonstrating the need to continue vaccine research. Some of the most successful vaccines, such as the yellow fever vaccine, have been empirically determined, so the mode of action is unknown. We are working to understand how the immune system functions and battles pathogens on a molecular level in order to design improved and safer vaccines. Recently, treatment with multiple pathogen-associated molecular patterns (PAMPs), especially Toll-like receptor (TLR) agonists, has enhanced or altered specific immune responses. Thus, indicating that multiple agonists will be required, instead of one agonist, in vaccine formulations to effectively activate the immune system and eliminate disease. In addition, vaccine development would greatly benefit from understanding the effect distinct combinations of immune agonists have on immune activity. This information would allow us to more rationally design vaccines that elicit directed and prolonged immune responses. Previously, we probed immune system responses by conjugating three TLR agonists (TLR4, 7, and 9 agonists) together. Testing our construct in vitro and in vivo, we were able to modulate innate immune and antibody responses, suggesting downstream changes in immune signaling and adaptive immune activation. Here, we synthesized a library of tri-agonist compounds and treated immune cells with the conjugates in vitro. We examined how different covalently linked TLR agonist combinations affected immune activation via NF-kB activity and cytokine production. We are currently testing our constructs on a Q fever vaccination model to examine T and B cell populations as well as antibody responses. Ultimately, these tri-agonist scaffolds can inform us about immune system signaling and activation in order to study immune activation mechanisms. Therefore, allowing us to potentially design more effective vaccines.

Synthesis of a tri-agonist compound library used to evaluate innate and adaptive immune responses

251st National Meeting (2016)

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