Chikungunya virus (CHIKV), an emerging, mosquito-borne alphavirus and potential biological weapon thathas caused debilitating and often chronic arthralgia in at least two million persons during the past two years,was recently placed on the NIAID list of priority pathogens as a recognition of it's emergence potential. Dueto difficulties with clinical diagnosis, CHIKV is grossly underreported and probably causes far more diseasethan is recognized in Africa and Asia, including occasional fatalities. Like dengue virus, CHIKV uses humansas amplifying hosts and therefore can disseminate readily in travelers, suggesting that it will eventuallybecome established the Americas. There are no licensed vaccines or effective therapies, and the only INDvaccine strain tested in humans is reactogenic. We will capitalize on our recent successes with chimericalphaviruses to develop novel CHIKV vaccine candidates that are superior to traditionally derived, cellculture-passaged mutants. Using genetic backbones derived from three relatively avirulent alphavirusstrains, and structural protein genes from CHIKV, we will generate and optimize chimeric cDNA clones toproduce candidate vaccine strains that replicate efficiently in Vero cells, and are highly attenuated yet rapidlyimmunogenic and efficacious in preventing CHIK disease. Further attenuation will be achieved by introducingmutations from the previously evaluated IND CHIKV vaccine strain, and by characterizing and inactivatingthe CHIKV mechanism of host cell gene expression shutoff. Mosquito transmissibility will also be minimizedusing several novel genetic approaches. Initially, several vaccine candidates will be evaluated for attenuationand efficacy in a murine model, and the most promising strains will then be tested extensively in mice formmunogenicity and efficacy in preventing disease, viremia and mortality. Following mosquito transmissibilityassessment and evaluation of genetic and phenotypic stability, the two leading vaccine candidates will bevaluated in Rhesus macaques for safety, immunogenicity and efficacy. The project will culminate withvaccine formulation studies, master and working seed virus preparation, formal histopathology studies,quality control and release tests, and the manufacture of a GMP lot for Phase I human trials. The resultingproduct will dramatically improve US preparedness for this important emerging virus, as well as provide theIrst effective prevention for an important arboviral disease of many developing nations.
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