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Journal of Virology, January 2003, p. 1069-1074, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1069-1074.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of Protective Epitopes on Ebola Virus Glycoprotein at the Single Amino Acid Level by Using Recombinant Vesicular Stomatitis Viruses

Ayato Takada,1,2 Heinz Feldmann,3 Ute Stroeher,3,4 Mike Bray,5 Shinji Watanabe,6 Hiroshi Ito,7 Martha McGregor,6 and Yoshihiro Kawaoka1,2,6*

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639,1 CREST, Japan Science and Technology Corporation, Saitama 332-0012,2 Department of Veterinary Public Health, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan,7 Special Pathogens Program, National Microbiology Laboratory, Canadian Science Centre for Human and Animal Health, Winnipeg, Manitoba R3E 3R2, Canada,3 Institute for Virology, Philipps-University, Marburg, Germany,4 Division of Virology and Pathology, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011,5 Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin 537066

Received 13 June 2002/ Accepted 10 October 2002

Ebola virus causes lethal hemorrhagic fever in humans, but currently there are no effective vaccines or antiviral compounds for this infectious disease. Passive transfer of monoclonal antibodies (MAbs) protects mice from lethal Ebola virus infection (J. A. Wilson, M. Hevey, R. Bakken, S. Guest, M. Bray, A. L. Schmaljohn, and M. K. Hart, Science 287:1664-1666, 2000). However, the epitopes responsible for neutralization have been only partially characterized because some of the MAbs do not recognize the short synthetic peptides used for epitope mapping. To identify the amino acids recognized by neutralizing and protective antibodies, we generated a recombinant vesicular stomatitis virus (VSV) containing the Ebola virus glycoprotein-encoding gene instead of the VSV G protein-encoding gene and used it to select escape variants by growing it in the presence of a MAb (133/3.16 or 226/8.1) that neutralizes the infectivity of the virus. All three variants selected by MAb 133/3.16 contained a single amino acid substitution at amino acid position 549 in the GP2 subunit. By contrast, MAb 226/8.1 selected three different variants containing substitutions at positions 134, 194, and 199 in the GP1 subunit, suggesting that this antibody recognized a conformational epitope. Passive transfer of each of these MAbs completely protected mice from a lethal Ebola virus infection. These data indicate that neutralizing antibody cocktails for passive prophylaxis and therapy of Ebola hemorrhagic fever can reduce the possibility of the emergence of antigenic variants in infected individuals.

* Corresponding author. Mailing address: Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 608-265-4925. Fax: 608-265-5622. E-mail: kawaoka{at}ims.u-tokyo.ac.jp.

Journal of Virology, January 2003, p. 1069-1074, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1069-1074.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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