The path towards effective antivirals against rabies

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.