Pathogenesis of Chikungunya virus

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Alphaviruses are a group of over 25 mosquito transmitted single-stranded RNA viruses that cause severe human disease on all continents except Antarctica. Three of these are Category B select agents (Venezuelan, Eastern and Western Encephalitis viruses), and at least one (VEE) has been weaponized in the past by both the U.S. and the Soviet Union. The most recent large VEE epidemic occurred in 1995 with massive equine mortality and over 100,000 human cases with an approximately 1% case mortality rate. Chikungunya (CHIK) is a Category C agent and the cause of endemic severe febrile illness in Africa characterized by acute and debilitating joint pain which can persist for months after viral clearance. The virus has emerged as an epidemic of over 2 million cases currently engulfing the Indian subcontinent and Indonesia, and through an infected traveler, it now has spread to Italy. There are neither therapeutics nor licensed human vaccines for any alphavirus. We propose 1) to examine the pathogenesis of CHIK in a recently established mouse model that recapitulates its human clinical manifestations, and 2) to produce a candidate vaccine for this important emerging infection. Moreover, we will extend published results on cross-protective alphavirus B-cell epitopes and recent observations of T-cell mediated protection against alphavirus challenge to design a vaccine broadly effective against multiple members of the alphavirus genus. This practical approach conforms to the NIH mandate of designing vaccines and therapeutics effective against multiple agents.