Development of a tri-agonist compound library used to determine optimal adjuvanticity of a Q fever vaccine

Abstract

Abstract Vaccines are one of the most successful treatments for disease. However, the development of more effective vaccines is still necessary for diseases, such as malaria and HIV. Recently, researchers have demonstrated that administering a target antigen with multiple immune agonists, especially Toll-like receptor (TLR) agonists, can enhance specific immune responses. Thus, suggesting that vaccines will require synergistic activity of multiple agonists 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 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 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, where Q fever is a current bioterrorism threat, to examine changes in T and B cell populations, antibody responses, and efficacy of the tri-agonist adjuvants. From our studies, 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.