Safety and immunogenicity of recombinant Rift Valley fever MP-12 vaccine candidates in sheep

The safety and immunogenicity of two authentic recombinant (ar) Rift Valley fever (RVF) viruses, one with a deletion in the NSs region of the S RNA segment (arMP-12 Delta NSs16/198) and the other with a large deletion of the NSm gene in the pre Gn region of the M RNA segment (arMP-12 Delta NSm21/384) of the RVF MP-12 vaccine virus were tested in crossbred ewes at 30-50 days of gestation. First, we evaluated the neutralizing antibody response, measured by plaque reduction neutralization (PRNT80), and clinical response of the two viruses in groups of four ewes each. The virus dose was 1 x 10(5) plaque forming units (PFU). Control groups of four ewes each were also inoculated with a similar dose of RVF MP-12 or the parent recombinant virus (arMP-12). Neutralizing antibody was first detected in 3 of 4 animals inoculated with arMP-12 Delta NSm21/384 on Day 5 post inoculation and all four animals had PRNT80 titers of >= 1:20 on Day 6. Neutralizing antibody was first detected in 2 of 4 ewes inoculated with arMP-12 Delta NSs16/198 on Day 7 and all had PRNT80 titers of >= 1:20 on Day 10. We found the mean PRNT80 response to arMP12 Delta NSs16/198 to be 16- to 25-fold lower than that of ewes inoculated with arMP-12 Delta NSm21/384, arMP-12 or RVF MP-12. No abortions occurred though a single fetal death in each of the arMP-12 and RVF MP-12 groups was found at necropsy. The poor PRNT80 response to arMP-12 Delta NSs16/198 caused us to discontinue further testing of this candidate and focus on arMP-12 Delta NSm21/384. A dose escalation study of arMP-12 Delta NSm21/384 showed that 1 x 10(3) plaque forming units (PFU) stimulate a PRNT80 response comparable to doses of up to 1 x 10(5) PFU of this virus. With further study, the arMP-12 Delta NSm21/384 virus may prove to be a safe and efficacious candidate for a livestock vaccine. The large deletion in the NSm gene may also provide a negative marker that will allow serologic differentiation of naturally infected animals from vaccinated animals. (C) 2012 Elsevier Ltd. All rights reserved.