Rift Valley Fever Vaccine Development of Animal Models and Optimize Production

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DESCRIPTION (provided by applicant): Rift-Valley fever is a viral disease endemic to sub-Saharan Africa and has been the cause of several recent epizootics and epidemics in Egypt. It is a mosquito borne enveloped RNA virus that is infectious via the aerosol route. Following a 2-6 day incubation, it typically causes acute febrile illness, and about 10% of those develop a retinitis, and about 1% of those infected develop a fulminant course with up to 50% mortality. It has the potential to amplify and be transmitted by a wide species range, including domestic livestock and mosquito species found in the United States. Prior vaccination efforts in humans have included an IND formalin inactivated vaccine. It produced neutralizing antibodies but it required a three-shot primary series and repeated boosters. To enhance immunogenicity, USAMRIID created a live, attenuated vaccine designated MP12 This was grown and a limited number of volunteers immunized under an IND prepared in the early 1980s, and this lyophilized vaccine was found to retain full potency nearly 20 years later. A total of 62 volunteers have received the vaccine, with the latest cohort of 19 subjects being vaccinated beginning in September, 2006 (supported by grant AI-062636). Results are promising in that protective antibodies were formed following one injection, and all patients responded, many with high liters not seen previous. In the initial studies, antibodies were present after one year and remain at desired levels after 6 months in the recent trial. There were minimal side effects observed in all patients. The vaccine strain MP-12 was demonstrated to be stable to reversion and genetic analysis of the genome during 34 serial passages showed no mutations in the attenuating regions. Attempts to recover MP-12 virus from vaccinees proved difficult, again demonstrating the ability to control the administration of the vaccine to an individual. This vaccine has long been considered a prime candidate for a licensed Rift Valley Fever vaccine. This project will continue vaccine development by transferring the optimized manufacturing conditions to a cGMP, FDA registered contract facility and validating the process. Three vaccine lots suitable for pre-clinical toxicology testing in support of a new IND and later usable for a new clinical trial will be produced. We will develop a small animal surrogate model necessary to support efficacy tests under the FDA Animal Rule for diseases where controlled clinical trials are difficult, and to demonstrate protective efficacy in a non-human primate of human antibody to MP-12 from volunteers recently immunized and obtained from NIH under their protocol to collect human samples of research interest. No clinical trials are in this proposal.