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Journal of Virology, July 2005, p. 9285-9295, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9285-9295.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Genetically Engineered Attenuated Coxsackievirus B3 Strain Protects Mice against Lethal Infection

M. Dan and J. K. Chantler*

Department of Pathology and Laboratory Medicine, University of British Columbia, and British Columbia Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada V5Z 4H4

Received 5 October 2004/ Accepted 8 March 2005

Coxsackievirus B3 (CVB3) is a common human pathogen that is endemic throughout the world. There is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. Previously, we showed that the virulence of CVB3 is reduced by a lysine-to-arginine substitution in the capsid protein VP2 (K2168R) or a glutamic acid-to-glycine substitution in VP3 (E3060G). In this report, we show that the double mutant virus CVB3(KR/EG) displays additional attenuation, particularly for the pancreas, in A/J mice. In addition, two other attenuating mutations have been identified in the capsid protein VP1. When either the aspartic acid residue D1155 was replaced with glutamic acid or the proline residue P1126 was replaced with methionine, the resulting mutant also possessed an attenuated phenotype. Moreover, when either of these mutations was incorporated into CVB3(KR/EG), the resulting triple mutant viruses, CVB3(KR/EG/DE) and CVB3(KR/EG/PM), were completely noncardiovirulent and caused only small foci of damage to the pancreas, even at a high dose. Both triple mutants were found to be immunogenic, and a single injection of young A/J mice with either was found to protect them from a subsequent lethal challenge with wild-type CVB3. These findings indicate that the triple mutants could be exploited for the development of a live attenuated vaccine against CVB3.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Ave., Vancouver, British Columbia, Canada V5Z4H4. Phone: (604) 875-3262. Fax: (604) 875-3674. E-mail: chantler{at}interchange.ubc.ca.

Journal of Virology, July 2005, p. 9285-9295, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9285-9295.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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