Estimation of the Minimal Rift Valley Fever Virus Protective Neutralizing Antibody Titer in Human Volunteers Immunized with MP-12 Vaccine Based on Protection in a Mouse Model of Disease.

The Rift Valley fever virus (RVFV) MP-12 vaccine is a promising human and veterinary vaccine. Although the vaccine elicited neutralizing antibody (nAb) in human volunteers, the minimal antibody titer that is needed to afford protection is unknown. Therefore, this study was conducted to determine the minimal nAb titer elicited by the RVFV MP-12 vaccine in human volunteers that protected mice against lethal RVFV challenge as a surrogate assessment of the protective efficacy of the vaccine. Among volunteers who were vaccinated with the MP-12 vaccine during a phase II trial, sera with antibody titers of 1:20 collected 5 years post-vaccination (PV), 1:40 titer collected 2 years PV, and 1:80 titer collected 1 year PV was passively transferred to groups of BALB/c mice. Blood samples were obtained 1 day after passive transfer to determine the RVFV neutralizing nAb titer before challenge with pathogenic RVFV (strain ZH501). Our 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 1:5 to 1:20 were generally protective (75-100% survival). These results suggested that circulating titers of 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 mouse RVFV challenge model as a surrogate for evaluating the protective nAb responses elicited by MP-12 and possible use for evaluating the efficacy of other RVFV vaccine candidates.

Safety and immunogenicity of Rift Valley fever MP-12 and arMP-12ΔNSm21/384 vaccine candidates in goats (Capra aegagrus hircus) from Tanzania.

Vaccination of domestic ruminants is considered to be an effective strategy for protecting these animals against Rift Valley fever (RVF), but available vaccines have limitations. Therefore, the aim of this study was to determine the safety and immunogenicity of RVF virus (RVFV) mutagenesis passage 12 (MP-12) and arMP-12ΔNSm21/384 vaccine candidates in goats (Capra aegagrus hircus) in Tanzania. Goats were vaccinated intramuscularly with RVFV MP-12 or arMP-12ΔNSm21/384, and then on Day 87 post-vaccination (PV) all animals were revaccinated using the RVFV MP-12 vaccine candidate. Serum samples were collected from the animals before and after vaccination at various intervals to test for RVFV using a Vero cell culture assay and reverse transcription polymerase chain reaction and for RVFV-neutralising antibody using a plaque reduction neutralisation assay. Serum samples collected before vaccination on Days -14 and 0, and on Days 3, 4 and 5 PV were negative for RVFV and neutralising antibody. All animals remained healthy, and viremia was not detected in any of the animals. Rift Valley fever virus antibody was first detected on Day 5 PV at a 1:10 dilution in five of five animals vaccinated with the MP-12 vaccine and in five of eight animals vaccinated with arMP-12ΔNSm21/384. Titres then increased and were sustained at 1:40 to 1:640 through to Day 87 PV. All animals that were revaccinated on Day 87 PV with MP-12 developed antibody titres ranging from 1:160 to as high as 1:10 240 on Days 14 and 21 PV. Although the antibody titres for goats vaccinated with RVF MP-12 were slightly higher than titres elicited by the arMP-12ΔNSm21/384 vaccine, these findings demonstrated that both vaccines are promising candidates for the prevention of RVF among Tansanian goats.

Rift Valley fever MP-12 vaccine Phase 2 clinical trial: Safety, immunogenicity, and genetic characterization of virus isolates.

An outbreak or deliberate release of Rift Valley fever (RVF) virus could have serious public health and socioeconomic consequences. A safe RVF vaccine capable of eliciting long-lasting immunity after a single injection is urgently needed. The live attenuated RVF MP-12 vaccine candidate has shown promise in Phase 1 clinical trials; no evidence of reversion to virulence has been identified in numerous animal studies. The objective of this Phase 2 clinical trial was to (a) further examine the safety and immunogenicity of RVF MP-12 in RVF virus-naïve humans and (b) characterize isolates of RVF MP-12 virus recovered from the blood of vaccinated subjects to evaluate the genetic stability of MP-12 attenuation. We found that RVF MP-12 was well tolerated, causing mostly mild reactions that resolved without sequelae. Of 19 subjects, 18 (95%) and 19 (100%) achieved, respectively, 80% and 50% plaque reduction neutralization titers (PRNT80 and PRNT50)≥1:20 by postvaccination day 28. All 18 PRNT80 responders maintained PRNT80 and PRNT50≥1:40 until at least postvaccination month 12. Viremia was undetectable in the plasma of any subject by direct plaque assay techniques. However, 5 of 19 vaccinees were positive for MP-12 isolates in plasma by blind passage of plasma on Vero cells. Vaccine virus was also recovered from buffy coat material from one of those vaccinees and from one additional vaccinee. Through RNA sequencing of MP-12 isolates, we found no reversions of amino acids to those of the parent virulent virus (strain ZH548). Five years after a single dose of RVF MP-12 vaccine, 8 of 9 vaccinees (89%) maintained a PRNT80≥1:20. These findings support the continued development of RVF MP-12 as a countermeasure against RVF virus in humans.

Efficacy of a recombinant Rift Valley fever virus MP-12 with NSm deletion as a vaccine candidate in sheep.

Rift Valley fever virus (RVFV), a mosquito-borne virus in the Bunyaviridae family and Phlebovirus genus, causes RVF, a disease of ruminants and man, endemic in Sub-Saharan African countries. However, outbreaks in Yemen and Saudi Arabia demonstrate the ability for RVFV to spread into virgin territory and thus the need exists to develop safe and efficacious vaccines that can be used outside the endemic zones. Commercial RVFV vaccines are available but have limitations that prevent their use in disease-free countries. Consequently, there are ongoing efforts to develop and/or improve RVFV vaccines with global acceptability. In this study a previously developed MP-12-derived vaccine candidate with a large deletion of the NSm gene in the pre Gn region of the M segment (arMP-12-ΔNSm21/384) developed by T. Ikegami, that was already shown to be safe in pregnant sheep causing neither abortion nor fetal malformation was further evaluated. This vaccine was tested for protection of sheep from viremia and fever following challenge with virulent RVFV ZH501 strain. A single vaccination with arMP-12-ΔNSm21/384 fully protected sheep when challenged four weeks post vaccination, thereby demonstrating that this vaccine is efficacious in protecting these animals from RVFV infection.