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Journal of Virology, March 2008, p. 2681-2691, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02501-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Brian H. Bird,1,2,{dagger} César G. Albariño,1,{dagger} Amy L. Hartman,1 Bobbie Rae Erickson,1 Thomas G. Ksiazek,1 and Stuart T. Nichol1*

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, Georgia 30329,1 University of California, Davis, School of Veterinary Medicine, Davis, California 956162

Received 21 November 2007/ Accepted 21 December 2007

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 ~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 104 PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, ~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.

* Corresponding author. Mailing address: 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. Phone: (404) 639-1115. Fax: (404) 639-1118. E-mail: address: stn1{at}cdc.gov

{triangledown} Published ahead of print on 16 January 2008.

{dagger} Both of these authors contributed equally to this work.

Journal of Virology, March 2008, p. 2681-2691, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02501-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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