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Journal of Virology, January 2001, p. 934-942, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.934-942.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Molecular Basis for Attenuation of Neurovirulence of a Yellow Fever Virus/Japanese Encephalitis Virus Chimera Vaccine (ChimeriVax-JE)

Juan Arroyo,1 Farshad Guirakhoo,1 Sabine Fenner,1 Zhen-Xi Zhang,1 Thomas P. Monath,1 and Thomas J. Chambers2,*

OraVax, Inc., Cambridge, Massachusetts 02139,1 and Department of Molecular Microbiology and Immunology, St. Louis University Health Sciences Center, St. Louis, Missouri 631042

Received 11 July 2000/Accepted 11 October 2000

A yellow fever virus (YFV)/Japanese encephalitis virus (JEV) chimera in which the structural proteins prM and E of YFV 17D are replaced with those of the JEV SA14-14-2 vaccine strain is under evaluation as a candidate vaccine against Japanese encephalitis. The chimera (YFV/JEV SA14-14-2, or ChimeriVax-JE) is less neurovirulent than is YFV 17D vaccine in mouse and nonhuman primate models (F. Guirakhoo et al., Virology 257:363-372, 1999; T. P. Monath et al., Vaccine 17:1869-1882, 1999). Attenuation depends on the presence of the JEV SA14-14-2 E protein, as shown by the high neurovirulence of an analogous YFV/JEV Nakayama chimera derived from the wild JEV Nakayama strain (T. J. Chambers, A. Nestorowicz, P. W. Mason, and C. M. Rice, J. Virol. 73:3095-3101, 1999). Ten amino acid differences exist between the E proteins of ChimeriVax-JE and the YFV/JEV Nakayama virus, four of which are predicted to be neurovirulence determinants based on various sequence comparisons. To identify residues that are involved in attenuation, a series of intratypic YFV/JEV chimeras containing either single or multiple amino acid substitutions were engineered and tested for mouse neurovirulence. Reversions in at least three distinct clusters were required to restore the neurovirulence typical of the YFV/JEV Nakayama virus. Different combinations of cluster-specific reversions could confer neurovirulence; however, residue 138 of the E protein (E138) exhibited a dominant effect. No single amino acid reversion produced a phenotype significantly different from that of the ChimeriVax-JE parent. Together with the known genetic stability of the virus during prolonged cell culture and mouse brain passage, these findings support the candidacy of this experimental vaccine as a novel live-attenuated viral vaccine against Japanese encephalitis.

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

Journal of Virology, January 2001, p. 934-942, Vol. 75, No. 2
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.2.934-942.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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