Are We Getting Closer to the Treatment of Rabies?

Rodney E Willoughby Jr

Disclosures

Future Virology. 2009;4(6):563-570. 

In This Article

Future Perspective

Rabies

We foresee several major advances against rabies in the next 10 years. Rabies has been vaccine-preventable since 1886. The impediments to postexposure prophylaxis remain the limited supply of rabies vaccine and rabies immunoglobulin and, therefore, high cost. Fortunately, Faber and Dietzschold engineered highly inflammatory, live recombinant vaccines capable of inducing protective immune responses with a single dose.[21] Single doses make rabies vaccination cost effective and compatible with routine childhood immunization schedules.[44] Hooper and Dietzschold earlier contributed a broadly rabies virus-neutralizing MAb, paired with an independently neutralizing MAb in current Phase II clinical trials, which will hopefully replace limited supplies of human and equine rabies immune globulin.[45]

Closer to the root cause for this zoonosis, single-dose vaccines provide the simplicity and economy required for combined rabies vaccination and fertility control of dogs and cats, the vectors that contribute most to the world's human burden of rabies.[46] It is doubtful that rabies can ever be eradicated from wildlife reservoirs (particularly bats), but other vaccine solutions, such as respiratory viruses expressing the rabies G glycoprotein, may permit secondary spread of vaccine within bat or terrestrial carnivore communities that harbor rabies.[47–50]

Delivery of vaccines to human and animal populations will always be imperfect and subject to political and economical constraints. The treatment of rabies needs to be improved. Our current approach of temporizing until the natural immune response can clear rabies can be improved through the development of effective antivirals for rabies. To be economically viable, antivirals will need to be developed that target a number of RNA viruses and not just the rabies virus.

The pattern of rabies is one exception to the rule, starting with the extraordinary incubation times recognized by Pasteur. We based our unorthodox approach on the extraordinary virological properties of rabies – high lethality, low cytopathogenicity and low immunogenicity. Another outlier is the inhibition of transcription of rabies, Sindbis, and probably other encephalitic viruses by intracellular antibody. Dietzschold et al. published a paper 17 years ago suggesting the clinical potential of this approach. A subset of MAbs were curative of rabies, when MAbs were administered at relatively low doses systemically and with the virus present in the brain after intranasal inoculation.[17] There now are rabies survivors, with more likely to follow. Engineering human 'rescue MAbs' from these patients is technically feasible.[51] Presumably, these rescue MAbs are able to suppress rabies virus at very low concentrations in brain interstitial fluid, given the poor efficiency of antibody passage across an intact blood–brain barrier. (Hooper's animal model, using highly attenuated rabies virus, requires lymphocyte translocation across the blood–brain barrier to confer recovery; systemic antibody to this virus is insufficient.[52]) The intracellular clearance reported for the rabies and Sindbis virus involves specific surface adherence of the antibodies to virus-infected cells. It is unclear whether rescue MAbs exert virological effects through transmembrane signaling or direct physical effects in the cytoplasm.

Other Encephalitides

Under 15% of the probable viral encephalitides in humans have a definite microbiological diagnosis.[53] Rabies is now a potential model for virus-induced disorders of neurotransmission. We actively investigated neurotransmitter metabolites for rabies encephalitis, and therapeutically administered cofactors to improve neurotransmitter biosynthesis. (While monoamine neurotransmitter precursors are routinely used in Parkinsonism and congenital BH4 deficiencies, we have not yet required these therapies.) There is no reason why these approaches cannot be extended to other viral encephalitides, even when the cause is not known.

We identified transient, physiological disorders of cerebral perfusion in rabies that are not clinically evident at bedside. We prophylax against and treat such disturbances in rabies. TCD or other neuroradiological studies to detect vasospasm should be considered for other encephalitides without clear cytopathic damage.

We used neuroprotectant drugs in combination, at high doses for 1 week or more, while temporizing for an immune response.[10] This is in contrast to the usual single-drug approach used for neuroprotection in humans, which has never worked.[54] We also avoid barbiturate sedation – the current standard for induced coma – because of its immunosuppressive properties.[39] Similar aggressive, nonbarbiturate, polypharmaceutical approaches to other encephalitides may be warranted, particularly when seizures prove intractable or cerebral edema occurs.

These are not novel ideas to physicians treating a variety of systemic, autoimmune and degenerative neurological disorders, but they are infrequently used in meningitis and encephalitis. Developments in rabies may provide the impetus for a more complex, physiological approach to treating infectious neurological disorders.

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