PROJECT SUMMARY Chikungunya is an arboviral disease transmitted to humans by infected mosquitoes, primarily the Aedes aegypti and Aedes albopictus species. The virus responsible for the disease is the chikungunya virus (CHIKV), a member of the Togaviridae family. First identified in Tanzania in 1952, chikungunya has since been reported in over 60 countries in Asia, Africa, Europe, and the Americas. The symptoms of chikungunya typically include febrile illness, joint pain, nausea, fatigue, and rash. While the fever usually subsides within a week and the disease is rarely fatal, joint pain can be severe and debilitating, often lasting for weeks or years. There is no specific antiviral treatment for chikungunya; care is based on relieving symptoms, such as with anti-pyretics, optimal analgesics, and fluids. Prevention relies on avoiding mosquito bites using repellents, wearing long sleeves and trousers, and eliminating standing water where mosquitoes breed. Vaccine against CHIKV is urgently needed. Only one vaccine has achieved approval, Valneva's IxchiqTM, which is based on a live attenuated CHIKV. This vaccine undergone an accelerated regulatory approval by FDA with limited human clinical efficacy study. Many mosquito salivary proteins were shown to have pro-viral activity and can augment virus transmission during blood feeding. We have found a mosquito salivary protein, AgBR1, that can enhance viral transmission and shown that immunization with AgBR1 is protective against several flaviviruses. Specifically, vaccination of mice with recombinant AgBR1 is protective against Zika, and passive transfer of AgBR1 antiserum is protective against West Nile disease. In this proposal, we seek to confirm that AgBR1 vaccine is also protective against Aedes- transmitted arbovirus of the alphavirus genera, the CHIKV. We will perform comparative evaluation of different AgBR1 formulation, either recombinant protein or mRNA-LNP vaccine, in preventing mosquito-borne CHIKV infection in mice. To ascertain the effectiveness of our vaccine against CHIKV transmission, we will run our test on two murine model of CHIKV infection – (1) an acute lethal infection model of immunocompromised mouse to see protective effect of the vaccine against lethal infection, and (2) adult immunocompetent mice to see protective effect of the vaccine against disease morbidity such as joint pain and arthritis. Our ultimate goal is to generate a universal vaccine against several mosquito-borne diseases.