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Journal of Virology, July 2006, p. 6982-6992, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00551-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Isolation and Characterization of Human Monoclonal Antibodies from Individuals Infected with West Nile Virus§

Mark Throsby,1* Cecile Geuijen,1 Jaap Goudsmit,1 Arjen Q. Bakker,1 Jehanara Korimbocus,2 R. Arjen Kramer,1 Marieke Clijsters-van der Horst,1 Maureen de Jong,1 Mandy Jongeneelen,1 Sandra Thijsse,1 Renate Smit,1 Therese J. Visser,1 Nora Bijl,1,{dagger} Wilfred E. Marissen,1 Mark Loeb,3 David J. Kelvin,4 Wolfgang Preiser,5,{ddagger} Jan ter Meulen,1 and John de Kruif1

Crucell Holland B.V., Leiden, The Netherlands,1 National Reference Center for Arbovirus and Viral Hemorrhagic Fevers, Pasteur Institute, Lyon, France,2 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada,3 Division of Experimental Therapeutics, University Health Network, Toronto, Canada,4 Institute of Medical Virology, W. Goethe-Universität, Frankfurt, Germany5

Received 16 March 2006/ Accepted 21 April 2006

Monoclonal antibodies (MAbs) neutralizing West Nile Virus (WNV) have been shown to protect against infection in animal models and have been identified as a correlate of protection in WNV vaccine studies. In the present study, antibody repertoires from three convalescent WNV-infected patients were cloned into an scFv phage library, and 138 human MAbs binding to WNV were identified. One hundred twenty-one MAbs specifically bound to the viral envelope (E) protein and four MAbs to the premembrane (prM) protein. Enzyme-linked immunosorbent assay-based competitive-binding assays with representative E protein-specific MAbs demonstrated that 24/51 (47%) bound to domain II while only 4/51 (8%) targeted domain III. In vitro neutralizing activity was demonstrated for 12 MAbs, and two of these, CR4374 and CR4353, protected mice from lethal WNV challenge at 50% protective doses of 12.9 and 357 µg/kg of body weight, respectively. Our data analyzing three infected individuals suggest that the human anti-WNV repertoire after natural infection is dominated by nonneutralizing or weakly neutralizing MAbs binding to domain II of the E protein, while domain III-binding MAbs able to potently neutralize WNV in vitro and in vivo are rare.

* Corresponding author. Mailing address: Crucell Holland B.V., P.O. Box 2048, 2301 CA, Leiden, The Netherlands. Phone: 31 (71) 5248778. Fax: 31 (71) 5248702. E-mail: m.throsby{at}crucell.com.

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

{dagger} Present address: Department of Medical Biochemistry, Academic Medical Centre, Amsterdam, The Netherlands.

{ddagger} Present address: Department of Pathology, University of Stellenbosch, Tygerberg, South Africa.

Journal of Virology, July 2006, p. 6982-6992, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00551-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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