The results suggested that the vaccine caused, at most, only a low-level viremia. results indicated that 1 day after passive transfer of the immune sera, an approximate 4-fold reduction in circulating nAb titers was detected in the mice. The presence of RVFV nAb titers in the range of 1 1:5 to 1 1:20 were generally protective (75100% survival). These results suggested that circulating titers of 1 1:5 or higher offer a high degree of protection by MP-12-elicited antibody in human volunteers. Also, the findings highlighted the value of using the BALB/c Levistilide A mouse RVFV challenge model as a Levistilide A surrogate for evaluating the protective nAb responses elicited by MP-12 and possible use for evaluating the efficacy of other RVFV vaccine candidates. == INTRODUCTION == Rift Valley fever virus (RVFV) causes devastating epizootics of Rift Valley fever (RVF) disease among domestic ruminants and epidemics among humans exposed to infected mosquitoes or come in contact with blood from infected ruminants.13Several studies have indicated that RVF can be prevented in domestic animals by the use of vaccines to elicit neutralizing antibody (nAb) and that vaccination is the best approach for controlling RVF outbreaks.48Although a human RVFV vaccine has not been approved, a formalin inactivated candidate vaccine designated as NDBR 103 was developed and evaluated clinically.4,911This candidate vaccine was used to vaccinate 500 human volunteers and 963 United Nations soldiers using a three-dose regimen that resulted in seroconversions in most volunteers.12,13The NDBR 103 vaccine candidate was modified by the Salk Government Services Division and designated TSI GSD 200 and was evaluated as a formalin-inactivated vaccine under an approved Investigational New Drug (IND) by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).9The TSI-GSD-200 vaccine elicited 80% plaque reduction neutralizing (PRNT80) antibody titers of 1 1:40 or greater among 90% (540 of 598) of the volunteers given three 1.0-mL doses subcutaneously on days 0, 7, and 28 post-vaccination (PV).9Although the TSI-GSD-200 vaccine was safe and immunogenic, it required a boost at 6 months, and subsequent periodic boosts were believed to be required to sustain protective antibody titers.9Although the antibody titer required to afford protection among the vaccinees was unknown, the Levistilide A passive transfer of antibody elicited by the TSI-GSD-200 vaccine resulted in a titer as low as 1:12 that protected hamsters against a lethal RVFV challenge.14Therefore, a vaccine-elicited RVFV antibody titer of 1 1:40 or more was judged to be protective for personnel who would be at risk to infection with pathogenic RVFV, including laboratory workers.15Although inactivated vaccines elicited protective nAb, the shorter-term immunity and requirement for booster vaccinations makes their use difficult in resource-limited RVFV enzootic countries in Africa.16Therefore, efforts to develop an improved vaccine for humans began to focus on live-attenuated vaccines that generally elicit longer-lasting immune responses without the requirement for booster vaccinations.17 Among several RVFV vaccine candidates under development, the RVFV MP-12 live-attenuated virus vaccine is among the most promising, both as a human and a veterinary vaccine.8The vaccine was derived by 12 serial mutagenesis passages (MP) of ZH548 RVFV human isolate in human diploid MRC-5 cells in the presence of the chemical mutagen, 5-fluorouracil (5FU).18The MP-12 vaccine is thermostable for 18 years or more after storage at 35C, suggesting that it is suitable for stockpiling purposes.1921The attenuation of MP-12 was shown to be caused by mutations in the S, M, and L RNA Cd63 segments, but that the mutations in the M and L segments confer stronger attenuation than those in the S segment. These mutations indicated that the risk of MP-12 reverting to virulence was low, which was supported by the finding that multiple attenuating mutations were effective in combination. Extensive evaluations demonstrated that MP-12 was safe and efficacious in laboratory animals and domestic ruminants, including lack of neurovirulence in nonhuman primates and safety for pregnant ruminants.8Also, experimental studies indicated that the sporadic viremia produced in animals and humans by the vaccine was less than 3. 0 log10plaque-forming units/mL and therefore avoided the risk of transmission to mosquitoes.19,20,2224These data were used to obtain an IND for conducting phase I and II clinical trials that indicated that the vaccine was safe, well-tolerated, and immunogenic in healthy.