ABSTRACT This proposal seeks to develop a novel vaccine against pathogens transmitted by the blacklegged tick, Ixodes scapularis, by targeting tick salivary proteins (Salps) critical for tick feeding. I. scapularis Salps provide functions critical for evading host defense responses detrimental to the tick. Further, these salivary functions are also co-opted by tick-transmitted pathogens to ensure their survival in the host. We reason that tick Salps critical for tick feeding might serve as vaccine targets to impair tick feeding and consequently, also thwart the transmission of multiple tick-borne pathogens. Our hypothesis is validated by the phenomenon of acquired tick-resistance wherein, upon repeated tick infestations non-permissive hosts such as rabbits, and guinea pigs mount a robust immune response against tick Salps critical for tick feeding and this results in rapid rejection of ticks. Tick-resistance has also been shown to prevent transmission of B. burgdorferi. Exploiting this phenomenon, we have identified several Salps that are avidly recognized by tick-resistant animal sera. Since tick-resistant sera recognize multiple Salps it is reasonable to expect that multiple immunodominant Salps might have to be targeted simultaneously to recapitulate tick-resistance and achieve robust tick rejection. In this research study, we will: 1. Assess the vaccine potential of a combination of immunodominant Salps to prevent tick feeding in conjunction with adjuvants approved for human use. 2. Examine the utility of simultaneously targeting multiple immunodominant tick Salps to prevent the transmission of two tick-transmitted pathogens, B. burgdorferi and A. phagocytophilum. This combination strategy targeting multiple Salps simultaneously has the potential to result in a vaccine that might block the transmission of multiple I. scapularis- borne pathogens.