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Published on: January 7, 2019
An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a
Stefanie A Krumm1, Dan Yan, Elise S Hovingh
1Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
Abstract:
Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.
Insights
A new oral antiviral drug effectively treats canine distemper virus (CDV) in ferrets, offering hope for a pan-morbillivirus therapy to combat measles and other related diseases.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Measles virus causes significant human morbidity and mortality.
- Canine distemper virus (CDV), a related zoonotic morbillivirus, is lethal in ferrets.
Purpose of the Study:
- To develop and evaluate an orally available, shelf-stable pan-morbillivirus inhibitor.
- To assess the therapeutic potential of this inhibitor against CDV infection in a ferret model.
Main Methods:
- Administered an oral pan-morbillivirus inhibitor prophylactically and post-infection to ferrets challenged with lethal CDV.
- Monitored viremia, survival rates, and immune responses.
- Generated and characterized drug-resistant viral recombinants.
Main Results:
- Prophylactic treatment reduced viremia and prolonged survival.
- Post-infection treatment led to low viral loads, asymptomatic infection, and recovery.
- Recovered animals showed robust immunity and protection against rechallenge.
- Drug-resistant viruses were attenuated and impaired in transmission.
Conclusions:
- An orally administered pan-morbillivirus inhibitor demonstrates significant efficacy against lethal CDV infection in ferrets.
- This therapeutic approach shows promise for treating morbillivirus infections, potentially aiding measles eradication efforts by complementing vaccination strategies.
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