Thomas Müller, 1WHO Collaborating Centre for Rabies Surveillance and Research, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Wusterhausen, Germany
Bernhard Dietzschold, 2WHO Collaborating Centre for Neurovirology, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PAFollow
Hildegund Ertl, WHO Collaborating Centre for Reference and Research on Rabies, Wistar Institute, Philadelphia, PA
Anthony R Fooks, 4WHO Collaborating Centre for the Characterization of Rabies and Rabies-related Viruses, Veterinary Laboratories Agency, Department of Virology, New Haw, Addlestone, Surrey, United Kingdom
Conrad Freuling, 1WHO Collaborating Centre for Rabies Surveillance and Research, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Wusterhausen, Germany
Christine Fehlner-Gardiner, WHO Collaborating Centre for Rabies Control, Pathogenesis and Epidemiology in Carnivores, Canadian Food Inspection Agency (CFIA) Centre of Expertise for Rabies, Ottawa, Ontario, Canada
Jeannette Kliemt, 1WHO Collaborating Centre for Rabies Surveillance and Research, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Wusterhausen, Germany
Francois X Meslin, Neglected Zoonotic Diseases (NZD), Department of Neglected Tropical Diseases (NTD), Cluster HIV/AIDS, Malaria, Tuberculosis and Neglected Tropical Diseases (HTM), World Health Organization, Geneva, Switzerland
Charles E Rupprecht, WHO Collaborating Centre for Reference and Research on Rabies, Rabies Section, Division of Viral and Rickettsial Diseases, Viral and Rickettsial Zoonoses Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA
Noël Tordo, Unit Antiviral Strategy, CNRS URA-3015, Institut Pasteur, Rabies Unit, Paris, France
Alexander I Wanderler, WHO Collaborating Centre for Rabies Control, Pathogenesis and Epidemiology in Carnivores, Canadian Food Inspection Agency (CFIA) Centre of Expertise for Rabies, Ottawa, Ontario, Canada
Marie Paule Kieny, Initiative for Vaccine Research, Vaccines & Biologicals, Health Technology & Pharmaceuticals, World Health Organization, Geneva, Switzerland

Document Type

Article

Publication Date

11-1-2009

Comments

This article has been peer reviewed and is published in PLoS Neglected Tropical Diseases 2009, 3(11). The published version is available at DOI: 10.1371/journal.pntd.0000542. © Public Library of Science

Abstract

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans.

PubMed ID

19888334

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