A Recombinant Rift Valley Fever Virus Glycoprotein Subunit Vaccine Confers Full Protection against Rift Valley Fever Challenge in Sheep

Faburay, Bonto; Wilson, William C.; Gaudreault, Natasha N.; Davis, A. Sally; Shivanna, Vinay; Bawa, Bhupinder; Sunwoo, Sun Young; Ma, Wenjun; Drolet, Barbara S.; Morozov, Igor; McVey, D. Scott; Richt, Jüergen A.

doi:10.1038/srep27719

Cited by 45 publications

(64 citation statements)

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“…Since those vaccine strains replicate in vaccinated animals, residual virulence might be a concern for vulnerable populations, including pregnant or newborn animals [13, 20]. Although subunit vaccines, DNA vaccines, viral vectors, and single-cycle RVF replicons are highly safe in animals due to a lack of viral spread, the vaccine immunogenicity of these novel candidates is not as high as traditional live-attenuated vaccines, and a booster dose and/or the use of adjuvant might be required to induce a long-term protective immunity [21–24]. Recently, we created a recombinant MP-12 strain, which encodes hundreds of silent mutations throughout the open reading frame (ORF) of genomic RNA (rMP12-GM50 strain)[25].…”

Section: Introductionmentioning

confidence: 99%

Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain

Ly¹,

Nishiyama²,

Lokugamage³

et al. 2017

Vaccine

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Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Arabian Peninsula that affects sheep, cattle, goats, camels, and humans. Effective vaccination of susceptible ruminants is important for the prevention of RVF outbreaks. Live-attenuated RVF vaccines are in general highly immunogenic in ruminants, whereas residual virulence might be a concern for vulnerable populations. It is also important for live-attenuated strains to encode unique genetic markers for the differentiation from wild-type RVFV strains. In this study, we aimed to strengthen the attenuation profile of the MP-12 vaccine strain via the introduction of 584 silent mutations. To minimize the impact on protective efficacy, codon usage and codon pair bias were not de-optimized. The resulting rMP12-GM50 strain showed 100% protective efficacy with a single intramuscular dose, raising a 1:853 mean titer of plaque reduction neutralization test. Moreover, outbred mice infected with one of three pathogenic reassortant ZH501 strains, which encoded rMP12-GM50 L-, M-, or S-segments, showed 90%, 50%, or 30% survival, respectively. These results indicate that attenuation of the rMP12-GM50 strain is significantly attenuated via the L-, M-, and S-segments. Recombinant RVFV vaccine strains encoding similar silent mutations will be also useful for the surveillance of reassortant strains derived from vaccine strains in endemic countries.

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Section: Introductionmentioning

confidence: 99%

Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain

Ly¹,

Nishiyama²,

Lokugamage³

et al. 2017

Vaccine

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Section: Introductionmentioning

confidence: 99%

“…RNA interference is one of the most promising platform for the development of therapeutics against viral pathogens (Faburay et al, 2016). RNAi can be triggered experimentally by exogenous introduction of dsRNA or using DNA-based vectors, which express short hairpin RNA (shRNA) in the cytoplasm that are processed by Dicer into siRNAs (Swamy et al, 2016;McGinnis, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, concerted efforts in search for safe antiviral therapies that will offer effective treatment and prevention strategies are needed. Research on recombinant subunit vaccine development based on the RVFV surface glycoproteins is currently underway (Faburay et al, 2016).The RVFV possesses a tripartite genome, which is composed of three negative-sense, and single-stranded RNA segments designated as large (L), medium (M) and small (S) where the L and M are of negative polarity while S is of ambisense polarity (Elliott, 1990;Muller et al, 1994;Giorgi, 1996). The L segment (6,404 nucleotides, nt) codes for a 237-kDa L protein, which is the viral RNAdependent RNA polymerase in a single ORF (Muller et al, 1994).…”

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Silencing of the rift valley fever virus s-genome segment transcripts using RNA interference in Sf21 insect cells

Ongus¹,

Rono²,

Wamunyokoli³

2017

Afr. J. Biotechnol.

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Rift Valley fever (RVF) is a mosquito-borne disease that affects humans and livestock. It results in economically disastrous livestock deaths in Africa. The causative agent is RVF virus (RVFV), which possesses a tripartite negative-sense, single-stranded RNA genome, with large (L), medium (M) and small (S) segments. The lack of effective vaccines and anti-RVFV therapies motivates concerted efforts in search for safe and effective remedies. Recent advances in the RNA interference (RNAi) may provide promising tools to control RVFV. This study aimed to use the Baculovirus Expression Vector System to demonstrate that the RVFV S-genome segment is susceptible to RNAi. A multiplex short hairpin RNA (shRNA) transcription cassette was constructed for generating small interfering RNA (siRNA) that target both the RVFV genomic RNA transcripts and the Green Fluorescent Protein (GFP) which was used as a reporter gene. Two expression vectors were constructed; one for expressing the RVFV S-genome alone and the other one for simultaneous expression of both the RVFV S-genome and the shRNA cassette. A separate transiently expressed GFP only vector was included as an internal positive control to be expressed simultaneously when co-transfected into Sf21 insect cells with each RVFV-S construct to monitor the effectiveness of the shRNA to trigger RNAi. By design, the RNAi effect on both the RVFV-S and the GFP transcripts was driven from the same shRNA. A statistically significant reduction in the relative GFP fluorescence (P< 0.05) was demonstrated and a drop in GFP and the RVFV S transcript levels observed. Collectively, these results suggest the potential application of RNAi as an antiviral strategy against RVFV.Key words: Baculovirus Expression, rift valley fever, RNA interference, green fluorescent protein. INTRODUCTIONRift Valley fever virus (RVFV) (genus: Phlebovirus, family: Bunyaviridae) is an enveloped virus (Muller et al., 1994;Giorgi, 1996;Ellis et al., 1988;Nichol et al., 2005;Sindato et al., 2015). The primary vectors of the virus are transovarially-infected floodwater mosquitoes of the Aedes species (Linthicum et al., 1999;Nichol et al., 2005; *Corresponding author. E-mail: julietteongus@jkuat.ac.ke. Tel: +254 722 339682. Sang et al., 2017). The virus causes an arthropod-borne RVF disease, which is a major public health threat due to its serious epizootics and epidemics in sub-Saharan Africa (WHO, 2007;Breiman et al., 2008;Boshra et al., 2011). The epizootics result in devastating abortions in pregnant animals (Swanepoel and Coetzer, 2004) and up to 100% mortality rates in domestic animals (Easterday et al., 1962;Meegan et al., 1979;Meegan et al., 1981). Author(s) agree that this article remains permanently open access under the terms of the Creative Commons Attribution License 4.0 International LicenseIn Kenya, the virus was first isolated in 1930 along Lake Naivasha in the greater Rift Valley, during which sweeping deaths and abortion storms among sheep were reported (Daubney et al., 1931). The 2006/2007 RVFV outbre...

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“…There are no therapies approved for human use. Significant efforts have been directed at vaccine development including development of ΔNSs-ΔNSm recombinant RVFV (Bird et al, 2011) and recombinant RVFV G n/ G c (Faburay et al, 2016) vaccines. Although both vaccines have shown to be safe and efficacious in animals, neither is approved for human use; and in the case ΔNSs-ΔNSm recombinant RVFV, which is a modified live attenuated virus, there are concerns about its use in non-endemic areas.…”

Section: Introductionmentioning

confidence: 99%

Short Interfering RNA Inhibits Rift Valley Fever Virus Replication and Degradation of Protein Kinase R in Human Cells

Faburay

Richt

2016

Front. Microbiol.

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Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing severe outbreaks in humans and livestock in sub-Saharan Africa and the Arabian Peninsula. Human infections are characterized by fever, sometimes leading to encephalitis, retinitis, hemorrhagic fever, and occasionally death. There are currently no fully licensed vaccines or effective therapies for human use. Gene silencing mediated by double-stranded short interfering RNA (siRNA) is a sequence-specific, highly conserved mechanism in eukaryotes, which serves as an antiviral defense mechanism. Here, we demonstrate that siRNA duplexes directed against the RVFV nucleoprotein can effectively inhibit RVFV replication in human (MRC5 cells) and African green monkey cells (Vero E6 cells). Using these cells, we demonstrate that individual or complex siRNAs, targeting the RVFV nucleoprotein gene completely abrogate viral protein expression and prevent degradation of the host innate antiviral factor, protein kinase R (PKR). Importantly, pre-treatment of cells with the nucleoprotein-specific siRNAs markedly reduces the virus titer. The antiviral effect of the siRNAs was not attributable to interferon or the interferon response effector molecule, PKR. Thus, the antiviral activity of RVFV nucleoprotein-specific siRNAs may provide novel therapeutic strategy against RVFV infections in animals and humans.

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A Recombinant Rift Valley Fever Virus Glycoprotein Subunit Vaccine Confers Full Protection against Rift Valley Fever Challenge in Sheep

Cited by 45 publications

References 49 publications

Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain

Attenuation and protective efficacy of Rift Valley fever phlebovirus rMP12-GM50 strain

Silencing of the rift valley fever virus s-genome segment transcripts using RNA interference in Sf21 insect cells

Short Interfering RNA Inhibits Rift Valley Fever Virus Replication and Degradation of Protein Kinase R in Human Cells

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