Animal models and biologics evaluation: experimental rabies virus infection and dose titration of CL184 monoclonal antibody combination in the Syrian hamster

Abstract

Rabies is an acute progressive encephalitis responsible for over 55,000 human fatalities each year. This zoonosis is preventable, if prompt medical intervention includes wound care and both active and passive immunization. Approximately 10 million people receive rabies post-exposure prophylaxis (PEP) annually. The World Health Organization recommends the administration of human and/or equine derived antirabies immune globulin (HRIG and ERIG) as well as cell culture vaccine for modern PEP in humans. However, in many developing regions where canine rabies is enzootic, alternative solutions for passive immunization are necessary due to the cost prohibitive, limited supply of HRIG and ERIG. Such disparities have prompted the development of anti-RABV monoclonal antibody (mAb) cocktails that can be produced on an industrial scale with consistent potency and decreased production costs in comparison to HRIG and ERIG. To assess the efficacy of a mAb combination in rabies PEP, we evaluated the use of CL184, a 1:1 protein mixture ratio of two human anti-RABV mAbs (CR57/CR4098) produced on the PER.C6® human cell line, in the Syrian hamster model. In separate experiments, female hamsters were divided into groups and inoculated on Day -1 into the gastrocnemius muscle with a lethal dose of a genetically distinct carnivore or bat RABV isolate (Asian dog or Parastrellus hesperus, respectively). On Day 0, HRIG at 20 IU/kg (n=21) or CL184 at 6 μg/kg, 12 μg/kg or 16 μg/kg (n=21/group) was administered to groups at the site of inoculation. In each experiment, a control group (n=12) and a vaccine only group (n=21) received a placebo inoculation. On Days 0, 3, 7, 14, and 28, hamsters in experimental groups received a 50μl dose of commercially available RABV vaccine. High mortality was observed in both placebo and vaccine only groups by Day 40. Preliminary data from the Syrian hamster experiments demonstrate these animals are a suitable model and suggest that CL184 may be a non-inferior alternative for HRIG in rabies PEP scenarios.