Project Abstract The primary objective of this project is to advance technology to improve the safety of vaccines while maintaining or boosting efficacy. By chemically conjugating our novel synthetic TLR7/8 agonists directly to recombinant antigens, our conjugate vaccines provide robust cellular and humoral immune responses with substantially less vaccine side-effects. While conjugated to antigen our adjuvant molecule is in a reduced potency prodrug form, yet still yields a strong cellular and humoral immune response because the adjuvant and antigen are always delivered to the same endosome of dendritic cells. This closely mimics the natural process of pathogen infection much more closely than traditional admixed adjuvant + antigen vaccines whereby cells can be exposed to antigen or adjuvant individually leading to no or low effective immunity and unwanted inflammation. We will further improve the therapeutic index of adjuvant-antigen conjugate vaccines by using linker technology that maintains the adjuvant potency but targeted to the immune cells where it’s needed to reduce potential side-effects.