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.
Rift Valley fever (RVF) virus is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and more recently the Arabian peninsula. Infection of livestock can result in sweeping "abortion storms" and high mortality among young animals. Human infection results in self-limiting febrile disease that in approximately 1 to 2% of patients progresses to more serious complications including hepatitis, encephalitis, and retinitis or a hemorrhagic syndrome with high fatality. The virus S segment-encoded NSs and the M segment-encoded NSm proteins are important virulence factors. The development of safe, effective vaccines and tools to screen and evaluate antiviral compounds is critical for future control strategies. Here, we report the successful reverse genetics generation of multiple recombinant enhanced green fluorescent protein-tagged RVF viruses containing either the full-length, complete virus genome or precise deletions of the NSs gene alone or the NSs/NSm genes in combination, thus creating attenuating deletions on multiple virus genome segments. These viruses were highly attenuated, with no detectable viremia or clinical illness observed with high challenge dosages (1.0 x 10(4) PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, approximately 1:6,400) by day 26 postvaccination. All vaccinated animals that were subsequently challenged with a high dose of virulent RVF virus survived infection and could be serologically differentiated from naïve, experimentally infected animals by the lack of NSs antibodies. These rationally designed marker RVF vaccine viruses will be useful tools for in vitro screening of therapeutic compounds and will provide a basis for further development of RVF virus marker vaccines for use in endemic regions or following the natural or intentional introduction of the virus into previously unaffected areas.
Bird
Brian H
BH
Special Pathogens Branch, Division of Viral and Rickettsial Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G-14, Atlanta, GA 30329, USA.
Albariño
César G
CG
Hartman
Amy L
AL
Erickson
Bobbie Rae
BR
Ksiazek
Thomas G
TG
Nichol
Stuart T
ST
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005814:Genes, Viral; D049452:Green Fluorescent Proteins / Q000235:genetics; D010957:Plasmids; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012296:Rift Valley fever virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014765:Viral Vaccines / Q000276:immunology*; D014774:Virulence
D000914:Antibodies, Viral; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; D049452:Green Fluorescent Proteins