Abstract
Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) is a mosquito-borne zoonotic pathogen which can cause hemorrhagic fever, neurological disorders or blindness in humans, and a high rate of abortion in ruminants. MP-12 strain, a live-attenuated candidate vaccine, is attenuated in the M- and L-segments, but the S-segment retains the virulent phenotype. MP-12 was manufactured as an Investigational New Drug vaccine by using MRC-5 cells and encodes a functional NSs gene, the major virulence factor of RVFV which 1) induces a shutoff of the host transcription, 2) inhibits interferon (IFN)-β promoter activation, and 3) promotes the degradation of dsRNA-dependent protein kinase (PKR). MP-12 lacks a marker for differentiation of infected from vaccinated animals (DIVA). Although MP-12 lacking NSs works for DIVA, it does not replicate efficiently in type-I IFN-competent MRC-5 cells, while the use of type-I IFN-incompetent cells may negatively affect its genetic stability. To generate modified MP-12 vaccine candidates encoding a DIVA marker, while still replicating efficiently in MRC-5 cells, we generated recombinant MP-12 encoding Punta Toro virus Adames strain NSs (rMP12-PTNSs) or Sandfly fever Sicilian virus NSs (rMP12-SFSNSs) in place of MP-12 NSs. We have demonstrated that those recombinant MP-12 viruses inhibit IFN-β mRNA synthesis, yet do not promote the degradation of PKR. The rMP12-PTNSs, but not rMP12-SFSNSs, replicated more efficiently than recombinant MP-12 lacking NSs in MRC-5 cells. Mice vaccinated with rMP12-PTNSs or rMP12-SFSNSs induced neutralizing antibodies at a level equivalent to those vaccinated with MP-12, and were efficiently protected from wild-type RVFV challenge. The rMP12-PTNSs and rMP12-SFSNSs did not induce antibodies cross-reactive to anti-RVFV NSs antibody and are therefore applicable to DIVA. Thus, rMP12-PTNSs is highly efficacious, replicates efficiently in MRC-5 cells, and encodes a DIVA marker, all of which are important for vaccine development for Rift Valley fever.
Highlights
Rift Valley fever virus (RVFV), which belongs to the family Bunyaviridae, genus Phlebovirus, is a zoonotic pathogen transmitted by mosquitoes, and the causative agent for Rift Valley fever (RVF)
We developed and characterized improved MP-12 viruses which encode a differentiate infected from vaccinated animals (DIVA) marker by replacing the virulence gene with that of serologically distinct viruses belonging to the same genera
Our results suggested that rMP12-PTNSs, but not rMP12-SFSNSs, replicates efficiently in MRC-5 cells, while both are as efficacious as parental MP-12, and did not induce antibodies cross-reactive to RVFV NSs
Summary
Rift Valley fever virus (RVFV), which belongs to the family Bunyaviridae, genus Phlebovirus, is a zoonotic pathogen transmitted by mosquitoes, and the causative agent for Rift Valley fever (RVF). RVF is characterized by a high rate of abortion and fetal malformation in pregnant ruminants, febrile illness in adult ruminants, and lethal acute hepatitis in newborn lambs [1]. Patients suffer an acute febrile illness with occasional complications including partial or complete blindness, hemorrhagic fever, or neurological disorders [2,3,4,5]. RVFV can be transmitted through the drought-resistant eggs of infected floodwater Aedes mosquitoes which play a role in maintaining RVFV in endemic areas. The development of an effective vaccine against RVF is important for non-endemic countries to prevent further spread of RVFV. RVFV is transmitted via aerosol, and the handling of virus should be done in biosafety level (BSL) 3+ or 4 laboratories
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