BackgroundRabies is traditionally considered a uniformly fatal disease after onset of clinical manifestations. However, increasing evidence indicates that non-lethal infection as well as recovery from flaccid paralysis and encephalitis occurs in laboratory animals as well as humans.Methodology/Principal FindingsNon-lethal rabies infection in dogs experimentally infected with wild type dog rabies virus (RABV, wt DRV-Mexico) correlates with the presence of high level of virus neutralizing antibodies (VNA) in the cerebral spinal fluid (CSF) and mild immune cell accumulation in the central nervous system (CNS). By contrast, dogs that succumbed to rabies showed only little or no VNA in the serum or in the CSF and severe inflammation in the CNS. Dogs vaccinated with a rabies vaccine showed no clinical signs of rabies and survived challenge with a lethal dose of wild-type DRV. VNA was detected in the serum, but not in the CSF of immunized dogs. Thus the presence of VNA is critical for inhibiting virus spread within the CNS and eventually clearing the virus from the CNS.Conclusions/SignificanceNon-lethal infection with wt RABV correlates with the presence of VNA in the CNS. Therefore production of VNA within the CNS or invasion of VNA from the periphery into the CNS via compromised blood-brain barrier is important for clearing the virus infection from CNS, thereby preventing an otherwise lethal rabies virus infection.

Rabies virus (RABV) is a neurotropic virus that causes fatal disease in humans and animals. Currently there is no cure for rabies once clinical signs appear. It is believed that once RABV enters the central nervous system (CNS), virus neutralizing antibodies (VNAs) in the periphery cannot pass through the Blood–brain Barrier (BBB) and into the CNS. Furthermore, it has been hypothesized that VNAs produced in the CNS by invading B cells, rather than those produced in the periphery and then transported into the CNS, are important in clearing RABV from the CNS. In the present study, mouse serum containing VNA was administered intravenously into mice after infection with wild-type RABV. Our studies demonstrate that exogenous administration of VNAs is crucial in the clearance of RABV from the brain and prevent the development of rabies in both immunocompetent and immunocompromised mice as long as the BBB permeability remains enhanced. This present study therefore provides a foundation for the possibility of developing VNA therapy for clinical rabies in humans.

Rabies is a highly lethal disease caused by the neurotropic rabies virus (RABV), and it remains an important public health problem globally. Effective vaccines have been developed for pre- and post-exposure prophylaxis (PEP). PEP is only effective if it is initiated promptly after recognizing exposure. Once neurological symptoms develop, however, it is widely accepted that there is no effective treatment available. Recent studies indicate that the presence of RABV-specific immunity (i.e. Virus neutralizing antibodies, VNA) and the transient enhancement of the BBB permeability are absolutely required for effective virus clearance from the CNS. In principle, it has been shown in mice using various live-attenuated RABVs or recombinant RABVs expressing three copies of the G or expressing chemokine/cytokines, which can induce high levels of VNA in the serum and also capable of transiently enhancing the BBB permeability that it is possible to clear the virus from CNS. Also, it has been demonstrated that, intravenous administration of VNA together with MCP-1 (shown to transiently open up BBB) can clear RABV from the CNS in both immunocompetent and immunocompromised mice, as late as 5 days after lethal challenge. Novel therapeutic approaches aimed at allowing the peripheral VNA to cross the BBB by administration of the VNA in combination with biological or chemical agents that can transiently open up the BBB would be useful to establish an effective therapy for rabies in humans. In this review, we focus on the some of the approaches that can be used to meet the challenges in the field of rabies treatment.

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