Abstract
Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost. Post-exposure prophylaxis (PEP) is highly effective, however in patients that present with neurological symptoms the case-fatality ratio is extremely high (>99%). During the last decades several attempts to identify potent and effective antivirals were made. Only a few of these demonstrated improvement in clinical signs in animal studies and none of the trials in humans showed significant efficacy. Here we explore novel opportunities to identify more potent anti-rabies molecules. In particular important progress has been made on antivirals against other Mononegavirales (paramyxoviruses, filoviruses) which should be an impetus to test and optimize these molecules towards anti-rabies virus therapies. Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus. Antivirals for prophylactic use can also be envisaged and these should be able to prevent infection of peripheral nerve cells and should have the potential to replace the current anti-rabies immunoglobulins that are used in PEP.
Highlights
Repurposing drugs approved for other indicationsRibavirin and interferon-alpha are broad-spectrum antivirals that have significant in vitro activity against rabies but in vivo experiments and treatment of several human patients with rabies infection did not show any beneficial activity
Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost
Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus
Summary
Ribavirin and interferon-alpha are broad-spectrum antivirals that have significant in vitro activity against rabies but in vivo experiments and treatment of several human patients with rabies infection did not show any beneficial activity. Two other FDA approved drugs with some in vitro anti-rabies activity are the Nmethyl-D-aspartate (NMDA) receptor antagonist ketamine and amantadine (this last one is approved for treatment of influenza). A combination of ketamine and amantadine was explored in patients, together with other treatment interventions, in the so-called ‘Milwaukee Protocol’. While this protocol had high coverage in the media as the first patient treated recovered, it has not been repeatable and is considered to be ineffective [4].
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