Abstract
Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally.
Highlights
IntroductionDespite significant progress in our understanding of rabies pathobiology and epidemiology, and major advancements in the development of safe and effective biologics for disease prevention, this neglected zoonosis causes approximately 60,000 human deaths annually [1,2]
Rabies is an acute progressive encephalitis caused by lyssaviruses
Twelve of the isolates were tested with CR57, CR4098, and HRIG (Imogam), and all isolates were neutralized with the exception of one, South Africa mongoose rabies virus (RABV), which was not neutralized by CR4098 (Table 1)
Summary
Despite significant progress in our understanding of rabies pathobiology and epidemiology, and major advancements in the development of safe and effective biologics for disease prevention, this neglected zoonosis causes approximately 60,000 human deaths annually [1,2]. Regardless of the source of viral exposure, human rabies is preventable with proper wound care, prompt administration of modern vaccine and rabies immune globulin (RIG) [3,4]. Over the past several decades, post-exposure prophylaxis (PEP) schedules have evolved, encompassing fewer doses of both intramuscular (i.m.) as well as dose-sparing intradermal (i.d.) routes for administration of inactivated vaccine in as few as four doses. In the absence of licensed, commercially available, live-attenuated rabies vaccines, administration of RIG remains a critical component of PEP when inactivated vaccines are used [3,5]
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