Submitted to: International Positive Strand RNA Virus Symposium
Publication Type: Abstract Only
Publication Acceptance Date: 6/9/2004
Publication Date: 6/9/2004
Citation: Pletnev, A.G., Fuller, F.J., Swayne, D.E., Hanley, K.A., Speicher, J., Putnak, R., Goggard, L., Chanock, R.M., Murphy, B.R. 2004. Pre-clinical Evaluation of a Live Attenuated Virus Vaccine Based on the Chimeric West Nile/Dengue Virus. International Positive Strand RNA Virus Symposium, CD-Rom.
Technical Abstract: We evaluated the chimeric West Nile/dengue viruses (WN/DEN4 and WN/DEN4 delta 30) bearing the structural pre-membrane (prM) and envelope (E) protein genes of West Nile virus (WN) on a backbone of dengue type 4 virus (DEN4) with or without a deletion of 30 nucleotides in the 3' noncoding region of DEN4 as a live attenuated virus vaccine for protection of mice, birds, horses, and monkeys from WN disease. We observed that both the unmodified WN/DEN4 chimera and its WN/DEN4 delta 30 deletion mutant did not cause encephalitis or death in immunodeficient mice inoculated intraperitoneally with a dose of as high as 50,000 PFU. Compared to wild-type WN parent, both chimeras were more than 108-fold restricted in their replication in the brain of suckling mice inoculated intracerebrally. Chimeric WN/DEN4 viruses were attenuated in geese, however, chimeras failed to induce a detectable WN-specific antibody response and to protect birds from WN challenge. In contrast, the WN/DEN4 vaccine candidates were immunogenic in mice, horses, and nonhuman primates. None of the WN/DEN4 delta 30-immunized rhesus monkeys developed viremia, and all these monkeys were protected from WN challenge. In addition, both chimeric viruses were also restricted in their ability to replicate in Aedes or Culex species of mosquitoes. Lack of infectivity for geese, reduced infectivity for mosquitoes, and a significant attenuation of chimeric viruses in mice, horses, and monkeys make these viruses promising vaccine candidates against disease caused by WN virus.