Rift Valley Fever Virus Lacking the NSs and NSm Genes Is Highly Attenuated, Confers Protective Immunity from Virulent Virus Challenge, and Allows for Differential Identification of Infected and Vaccinated Animals

Bird, Brian H.; Albariño, César G.; Hartman, Amy L.; Erickson, Bobbie R.; Ksiazek, Thomas G.; Nichol, Stuart T.

doi:10.1128/jvi.02501-07

Cited by 150 publications

(212 citation statements)

References 47 publications

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“…We also showed that MP-12 was highly pathogenic for SCID mice, resulting in a median time to death of only 10 d. An additional advantage of our rVACVs is that they permit the use of a simple test to distinguish infected from vaccinated animals using the N protein of RVFV. Other attenuated vaccines, such as Clone 13, have the capability to distinguish infected from vaccinated using the NSs protein; however, NSs is not highly immunogenic as the N protein, leading to reduced sensitivity (45,46). Inactivated RVFV vaccines, such as TGI-GSD-200, are safe for use in pregnant and young animals but are less immunogenic (27).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Papin¹,

Verardi

Jones³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Rift Valley fever (RVF) is a zoonotic disease endemic in Africa and the Arabian Peninsula caused by the highly infectious Rift Valley fever virus (RVFV) that can be lethal to humans and animals and results in major losses in the livestock industry. RVF is exotic to the United States; however, mosquito species native to this region can serve as biological vectors for the virus. Thus, accidental or malicious introduction of this virus could result in RVFV becoming endemic in North America. Such an event would likely lead to significant morbidity and mortality in humans, and devastating economic effects on the livestock industry. Currently, there are no licensed vaccines for RVF that are both safe and efficacious. To address this issue, we developed two recombinant RVFV vaccines using vaccinia virus (VACV) as a vector for use in livestock. The first vaccine, vCOGnGc, was attenuated by the deletion of a VACV gene encoding an IFN-γ binding protein, insertional inactivation of the thymidine kinase gene, and expression of RVFV glycoproteins, Gn and Gc. The second vaccine, vCOGnGcγ, is identical to the first and also expresses the human IFN-γ gene to enhance safety. Both vaccines are extremely safe; neither resulted in weight loss nor death in severe combined immunodeficient mice, and pock lesions were smaller in baboons compared with the controls. Furthermore, both vaccines induced protective levels of antibody titers in vaccinated mice and baboons. Mice were protected from lethal RVFV challenge. Thus, we have developed two safe and efficacious recombinant vaccines for RVF.

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Section: Discussionmentioning

confidence: 99%

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Papin¹,

Verardi

Jones³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Owing to its recent discovery, little is known about the role of SBV's NSm protein; for other bunyaviruses, however, it was shown that NSm could also be important for virulence in mammalian and insect hosts (29,(50)(51)(52)(53). Because NSm-coding strategies of phleboviruses differ from those of the orthobunyaviruses, viable RVFV mutants completely lacking the NSm-coding region could be successfully rescued.…”

Section: Discussionmentioning

confidence: 99%

Deletion Mutants of Schmallenberg Virus Are Avirulent and Protect from Virus Challenge

Kraatz

Wernike

Hechinger

et al. 2015

J Virol

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Since its emergence, Schmallenberg virus (SBV), a novel insect-transmitted orthobunyavirus which predominantly infects ruminants, has caused a large epidemic in European livestock. Newly developed inactivated vaccines are available, but highly efficacious and safe live vaccines are still not available. Here, the properties of novel recombinant SBV mutants lacking the nonstructural protein NSs (rSBV⌬NSs) or NSm (rSBV⌬NSm) or both of these proteins (rSBV⌬NSs/⌬NSm) were tested in vitro and in vivo in type I interferon receptor knockout mice (IFNAR ؊/؊ ) and in a vaccination/challenge trial in cattle. As for other bunyaviruses, both nonstructural proteins of SBV are not essential for viral growth in vitro. In interferon-defective BHK-21 cells, rSBV⌬NSs and rSBV⌬NSm replicated to levels comparable to that of the parental rSBV; the double mutant virus, however, showed a mild growth defect, resulting in lower final virus titers. Additionally, both mutants with an NSs deletion induced high levels of interferon and showed a marked growth defect in interferon-competent sheep SFT-R cells. Nevertheless, in IFNAR ؊/؊ mice, all mutants were virulent, with the highest mortality rate for rSBV⌬NSs and a reduced virulence for the NSm-deleted virus. In cattle, SBV lacking NSm caused viremia and seroconversion comparable to those caused by the wild-type virus, while the NSs and the combined NSs/NSm deletion mutant induced no detectable virus replication or clinical disease after immunization. Furthermore, three out of four cattle immunized once with the NSs deletion mutant and all animals vaccinated with the virus lacking both nonstructural proteins were fully protected against a challenge infection. Therefore, the double deletion mutant will provide the basis for further developments of safe and efficacious modified live SBV vaccines which could be also a model for other viruses of the Simbu serogroup and related orthobunyaviruses. IMPORTANCESBV induces only mild clinical signs in adult ruminants but causes severe fetal malformation and, thereby, can have an important impact on animal welfare and production. As SBV is an insect-transmitted pathogen, vaccination will be one of the most important aspects of disease control. Here, mutant viruses lacking one or two proteins that essentially contribute to viral pathogenicity were tested as modified live vaccines in cattle. It could be demonstrated that a novel recombinant double deletion mutant is a safe and efficacious vaccine candidate. This is the first description of a putative modified live vaccine for the complete genus Orthobunyavirus, and in addition, such a vaccine type has never been tested in cattle for any virus of the entire family Bunyaviridae. Therefore, the described vaccine also represents the first model for a broad range of related viruses and is of high importance to the field.

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“…The modified virus cannot replicate in immunocompetent cells and was described to be nonpathogenic to humans and animals. 8,14 However, results published just after the primary and secondary screenings were completed, showed that RVFV lacking NSs is 100% lethal in immunocompetent mice via aerosol exposure. 15 That led us to perform the remaining experiments in BSL-3 conditions (approved by the department biosafety committee and the Swedish Work Environment Authority).…”

Section: Generation Of Recombinant Rvfv and Assay Optimizationmentioning

confidence: 99%

High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection

et al. 2016

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Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by ≥80%, with ≥50% cell viability at 50 µM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with ≥60% inhibition of RVFV infection at 3.12 µM compound concentration and ≥50% cell viability at 25 µM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.

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Rift Valley Fever Virus Lacking the NSs and NSm Genes Is Highly Attenuated, Confers Protective Immunity from Virulent Virus Challenge, and Allows for Differential Identification of Infected and Vaccinated Animals

Cited by 150 publications

References 47 publications

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Deletion Mutants of Schmallenberg Virus Are Avirulent and Protect from Virus Challenge

High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection

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