PROJECT SUMMARY A novel vaccine for Lyme disease Acquired resistance to Ixodes scapularis, commonly known as “tick resistance”, can prevent transmission of Borrelia burgdorferi, the Lyme disease agent. We have shown that tick resistance can be generated in guinea pigs (1) repeatedly exposed to I. scapularis, (2) immunized with I. scapularis saliva, or (3) immunized with a lipid nanoparticle containing mRNAs encoding 19 saliva proteins (19ISP). In addition, salivary protein 14 (Salp14), a component of 19ISP, elicits partial tick resistance. The goal of this proposal is to identify the specific proteins in I. scapularis saliva that elicit tick resistance and demonstrate that vaccination with these proteins can prevent B. burgdorferi infection. We will delineate the importance of Salp14 and additional saliva proteins in tick resistance, determine the host responses that are associated with tick resistance, and examine whether vaccination with saliva proteins or mRNAs encoding each saliva protein can prevent B. burgdorferi infection. These studies will lead to new knowledge to aid in the development of a novel vaccine which may prevent Lyme disease and, possibly, other tick-borne infections.