Oral 4′-fluorouridine rescues nonhuman primates from advanced Lassa fever

There are no approved treatments for Lassa fever, which is estimated to cause 100,000 to 300,000 infections and 5,000 deaths annually in West Africa1,2. Recently, it was shown that 4′-fluorouridine (also known as EIDD-2749), an orally available ribonucleoside analogue, protected guinea pigs from lethal challenge with the lineage IV prototype Josiah strain of Lassa virus when treatment was delayed beyond the onset of clinical signs of disease3. Here we assessed the therapeutic efficacy of 4′-fluorouridine in an African green monkey model of Lassa fever using the contemporary and apparently more pathogenic lineage VII Togo strain of Lassa virus. Daily treatment with 4′-fluorouridine beginning 6 days after Lassa virus infection, when the monkeys were viraemic and clinically ill, resulted in rapid and complete clearance of infectious virus in 4 out of 5 monkeys, and all treated monkeys survived to the pre-determined study end-point. Targeted transcriptomics showed that cellular responses and control of cytokinaemia contributed to the development of immunity. Our findings support the further development of 4′-fluorouridine both as a post-exposure prophylaxis to control outbreaks and as a therapeutic agent to treat symptomatic patients. Treatment with 4′-fluorouridine (also known as EIDD-2749) in an African green monkey (Chlorocebus aethiops) model of Lassa disease resulted in complete clearance of infectious virus in a high proportion of cases and prolonged survival to the pre-determined study end-point in all cases.