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Journal of Virology, April 2005, p. 4672-4678, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4672-4678.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Novel Rabies Virus-Neutralizing Epitope Recognized by Human Monoclonal Antibody: Fine Mapping and Escape Mutant Analysis{dagger}

Wilfred E. Marissen,1 R. Arjen Kramer,1 Amy Rice,2 William C. Weldon,3 Michael Niezgoda,3 Milosz Faber,2 Jerry W. Slootstra,4 Rob H. Meloen,4 Marieke Clijsters-van der Horst,1 Therese J. Visser,1 Mandy Jongeneelen,1 Sandra Thijsse,1 Mark Throsby,1 John de Kruif,1 Charles E. Rupprecht,3 Bernhard Dietzschold,2 Jaap Goudsmit,1 and Alexander B. H. Bakker1*

Crucell Holland BV, Leiden,1 Pepscan Systems BV, Lelystad, The Netherlands,4 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania,2 Rabies Section, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia3

Received 7 September 2004/ Accepted 12 November 2004

Anti-rabies virus immunoglobulin combined with rabies vaccine protects humans from lethal rabies infections. For cost and safety reasons, replacement of the human or equine polyclonal immunoglobulin is advocated, and the use of rabies virus-specific monoclonal antibodies (MAbs) is recommended. We produced two previously described potent rabies virus-neutralizing human MAbs, CR57 and CRJB, in human PER.C6 cells. The two MAbs competed for binding to rabies virus glycoprotein. Using CR57 and a set of 15-mer overlapping peptides covering the glycoprotein ectodomain, a neutralization domain was identified between amino acids (aa) 218 and 240. The minimal binding region was identified as KLCGVL (aa 226 to 231), with key residues K-CGV- identified by alanine replacement scanning. The critical binding region of this novel nonconformational rabies virus epitope is highly conserved within rabies viruses of genotype 1. Subsequently, we generated six rabies virus variants escaping neutralization by CR57 and six variants escaping CRJB. The CR57 escape mutants were only partially covered by CRJB, and all CRJB-resistant variants completely escaped neutralization by CR57. Without exception, the CR57-resistant variants showed a mutation at key residues within the defined minimal binding region, while the CRJB escape viruses showed a single mutation distant from the CR57 epitope (N182D) combined with mutations in the CR57 epitope. The competition between CR57 and CRJB, the in vitro escape profile, and the apparent overlap between the recognized epitopes argues against including both CR57 and CRJB in a MAb cocktail aimed at replacing classical immunoglobulin preparations.

* Corresponding author. Mailing address: Crucell Holland BV, Archimedesweg 4, P.O. Box 20482301, CA Leiden, The Netherlands. Phone: 31-71-5248780. Fax: 31-71-5248702. E-mail: l.bakker{at}crucell.com.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, April 2005, p. 4672-4678, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4672-4678.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bakker, A. B. H., Marissen, W. E., Kramer, R. A., Rice, A. B., Weldon, W. C., Niezgoda, M., Hanlon, C. A., Thijsse, S., Backus, H. H. J., de Kruif, J., Dietzschold, B., Rupprecht, C. E., Goudsmit, J. (2005). Novel Human Monoclonal Antibody Combination Effectively Neutralizing Natural Rabies Virus Variants and Individual In Vitro Escape Mutants. J. Virol. 79: 9062-9068 [Abstract] [Full Text]  


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