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Journal of Virology, March 2003, p. 3655-3668, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3655-3668.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Yellow Fever Virus/Dengue-2 Virus and Yellow Fever Virus/Dengue-4 Virus Chimeras: Biological Characterization, Immunogenicity, and Protection against Dengue Encephalitis in the Mouse Model

Thomas J. Chambers,1* Yan Liang,1 Deborah A. Droll,1 Jacob J. Schlesinger,2 Andrew D. Davidson,3 Peter J. Wright,4 and Xiaoshan Jiang1

Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, Missouri 63104,1 Infectious Diseases Unit, University of Rochester Medical Center, Rochester, New York 14642,2 Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom,3 Department of Microbiology, Monash University, Clayton, Victoria 3168, Australia4

Received 30 August 2002/ Accepted 11 December 2002

Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 105 PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, 1402 S. Grand Ave., St. Louis, MO 63104. Phone: (314) 577-8447. Fax: (314) 773-3403. E-mail: chambetj{at}slu.edu.

Journal of Virology, March 2003, p. 3655-3668, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3655-3668.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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