Targeting a ubiquitous spirochete bacteriophage to prevent Lyme disease Borrelia burgdorferi is the etiologic agent of Lyme disease, which is spread by the bite of Ixodes ticks. Lyme disease is the most common tick-borne disease in the United States with reported cases nearly tripling in the past ten years. It would be ideal to vaccinate against Lyme disease. However, there are no approved vaccines that prevent Lyme disease in humans. One major challenge is identifying microbial targets that are amenable to immunization and common across all B. burgdorferi strains. Nearly all B. burgdorferi are infected by cp32 prophages. These prophages can undergo lytic replication where they are packaged into infectious virions designated fBB-1. Recent work demonstrates that a wide range of bacteriophage species directly interact with innate pattern recognition receptors on human and mouse immune cells and modulate immune responses in ways that promote pathogenesis. Furthermore, we discovered that immunizing against a bacteriophage can prevent infection by the human pathogen Pseudomonas aeruginosa. In light of these observations, we hypothesize that a vaccine against fBB-1 bacteriophages will protect against Lyme disease. To test this hypothesis, we have established a team of microbiologists, Lyme disease experts, immunologists, and vaccine scientists. In Aim 1, we will leverage our teams experience in creating anti-bacteriophage vaccine formulations to develop and optimize an anti-fBB-1 vaccine. In Aim 2, we will demonstrate the efficacy of our vaccine in the tick-mouse model of Lyme disease. We will measure B. burgdorferi and fBB-1 loads in both mice and ticks after a bloodmeal. If successful, this work will provide a critical first step towards developing a novel anti-bacteriophage vaccine that prevents Lyme disease. Additionally, this work will further elucidate the biology underlying this fascinating phage/host/microbe interaction, which may reveal additional therapeutic targets to treat or prevent not only Lyme disease, but other spirochete-related infections such as relapsing fever.