Inhibition of novel ß coronavirus replication by a combination of interferon-a2b and ribavirin

Falzarano, Darryl; de Wit, Emmie; Martellaro, Cynthia; Callison, Julie; Munster, Vincent J.; Feldmann, Heinz

A synergistic effect of IFN-a and ribavirin has been previously reported in vitro for both SARS-CoV 27,44 and feline infectious peritonitis virus 45 ; however, we observed an additive effect against hCoV-EMC/2012 in this study. The levels of IFNa-2b and ribavirin required for inhibition of nCoV replication must be achievable in humans in order to be relevant for clinical use. In humans, an interferon concentration of 100-750 IU/ml has been observed after intravenous injection of up to 3 3 10 7 U 46,47 , while 24 mg/ml of ribavirin is achievable following a 1000 mg intravenous dose 35 . Here IFN-a2b and ribavirin alone were shown to have an antiviral effect against hCoV-EMC/2012; however, in Vero cells the concentrations required to achieve a beneficial effect are likely higher than what is achievable in humans. When combined, the inhibitory concentration of both IFNa-2b and ribavirin drops to ranges that are likely achievable in humans, suggesting that the combination is a potential treatment option. Used early in the course of infection or given prophylactically to close contacts of sick individuals (close contact transmission has been documented in infection chains) this combination may improve clinical outcomes. In addition, reduced viral load would also likely translate to reduced virus shedding; thus, reducing the risk of secondary transmission. As these two drugs are currently used together in the clinic, combination therapy including IFN-a2b and ribavirin should be considered for case patient management of new nCoV cases and possibly for prophylaxis in highly exposed individuals.