Synthesis of Chemically Modified TLR Agonists Used to Probe Innate and Adaptive Immune Responses

The development of vaccines has resulted in a dramatic decrease in the number of cases of diseases, such as measles and smallpox. With the emergence of Ebola and the Zika virus, there is a greater need for the development of more effective and safer vaccines. However, the challenge with designing new immunotherapies is that little is still known about how vaccines work, since most have been empirically determined. Thus, our group is interested in using chemical tools to probe and understand the immune response with the goal of designing more effective vaccines. Dendritic cells, a vital part of the innate immune system, contain Toll-like receptors (TLRs) that are activated by components of pathogens, such as bacterial oligonucleotides and lipopeptides. These molecules are immune agonists that can act as adjuvants, which help elicit or enhance an immune response toward a non-immunogenic protein antigen, and are commonly used in vaccines. Recent studies indicate that vaccines containing multiple TLR agonists enhance the immune response toward a target pathogen compared to the use of a single ligand. A prime example is the Yellow Fever Vaccine, one of the most successful vaccines, which activates the immune system through four different TLRs. Due to this precedence, we hypothesized that activating specific receptors in a precise spatial manner could modulate how the immune system responds by mimicking natural pathogens and therefore control downstream pathways. My research focuses on synthesizing multi-TLR agonist conjugates to study the spatial organization of multiple TLR agonists and how different combinations of agonists affect the immune response, as observed by cellular and antibody responses. To study the effect of multiple TLR agonists on the immune response, we chemically modified whole cell antigens with different TLR agonists as well as covalently conjugated multiple TLR agonists together to present them in a localized manner. As a result of chemical modification and linkage, we observed distinct changes in immune activation, via cytokine production and antibody responses, suggesting implications for downstream immune system signaling. We are applying our findings to more rationally develop safer and more effective vaccine adjuvants and immunotherapies