Rabies is an inevitably fatal but preventable disease. In developing countries rabies remains a significant endemic disease burden. World-wide approximately 55,000 people die of rabies each year (WHO Expert Consultation on Rabies, 2004). Rabies is preventable with proper early post-exposure treatment. Currently, post-exposure prophylaxis includes thorough wound-washing with soap and water followed by administration of vaccine and anti-rabies virus immunoglobulin (RIG) of human or equine origin. RIG administered shortly after exposure at the wound site provides passive immunity which neutralizes rabies virus and prevents its spread until the patient's immune response following vaccination is elicited. Deaths due to post-exposure prophylaxis failure are most commonly attributed to deviations from the recommended regimen such as late initiation of post-exposure prophylaxis or no administration of RIG (Wilde, Vaccine, 25:7605-7609, 2007). In developing countries, availability of RIG is extremely low with only 1-2% of post-exposure prophylaxis being performed using RIG (Sudarshan et al., Int J Infect Dis, 11:29-35, 2007; WHO Consultation on a Monoclonal Antibody Cocktail for Rabies Post Exposure Treatment, 2002). In the United States, only human derived RIG is administered due to the risk of anaphylactic shock from exposure to equine immunoglobulins, but the concern of blood-born pathogen transmission in human RIG remains.
Human monoclonal antibodies (mAbs) that neutralize rabies virus have long been recognized as an alternative to overcome the limitations of RIG (Dietzschold et al., J Virol, 64:3087-3090, 1990). Adequate supplies of cell-cultured human mAbs could be produced in a cost-effective manner (Prosniak et al., J Infect Dis, 188:53-56, 2003). In addition, the use of human mAbs reduces the likelihood of an adverse immune response (Weiner, J Immunother, 29:1-9, 2006) and has been shown to be as effective as RIG in preventing rabies in animals (de Kruif et al., Annu Rev Med, 58:359-368, 2007). When a cocktail of two rabies-neutralizing, human mAbs was given with a rabies vaccine to animals experimentally infected with rabies, dose-dependent survival was observed, and all animals receiving the highest dose survived (Goudsmit et al., J Infect Dis, 193:796-801, 2006). The same cocktail was recently shown to be safe to administer to healthy humans in two phase-one clinical trials (Bakker et al., Vaccine, 26:5922-5927, 2008). However, selection of human monoclonal antibodies to include in such a cocktail has some limitations. The diversity of mAbs produced depends significantly on the diversity of viral antigens used to immunize human donors.
Rabies virus is a member (genotype 1) of the genus Lyssavirus. This genus also includes rabies-like viruses (genotypes 2-7) which can cause rabies disease in humans (Bourhy et al., Virology, 194:70-81, 1993; Gould et al., Virus Res, 54:165-187 1998). These viruses have a non-segmented, negative-sense, single-stranded RNA genome that encodes five proteins (Sokol et al., Virology, 38:651-665, 1969; Sokol et al., J Virol, 7:241-249, 1971). In the mature virion, RNA-dependent RNA polymerase, phosphoprotein, and nucleocapsid protein are associated with the genomic RNA while matrix protein and glycoprotein (G protein) surround it (Wiktor et al., J Immunol, 110:269-276, 1973). Trimeric G protein “spikes” coat the surface of the virion and as the only surface exposed protein, is responsible for attachment and entry into host cells. This also makes G protein the primary antigen for induction of virus-neutralizing antibodies, and G protein-specific mAbs are included in the cocktails currently being developed for post-exposure prophylaxis (Dietzschold et al., J Virol, 64:3087-3090, 1990; Kramer et al., Eur J Immunol, 35:2131-2145, 2005; Wunner et al., “Rabies Virus” in Rabies (Second Edition),” pp. 23-68, Academic Press, Oxford, 2007).