Interferon-β Therapy Prolongs Survival in Rhesus Macaque Models of Ebola and Marburg Hemorrhagic Fever

Abstract

There is a clear need for novel, effective therapeutic approaches to hemorrhagic fever due to filoviruses. Ebola virus hemorrhagic fever is associated with robust interferon (IFN)-α production, with plasma concentrations of IFN-α that greatly (60- to 100-fold) exceed those seen in other viral infections, but little IFN-β production. While all of the type I IFNs signal through the same receptor complex, both quantitative and qualitative differences in biological activity are observed after stimulation of the receptor complex with different type I IFNs. Taken together, this suggested potential for IFN-β therapy in filovirus infection. Here we show that early postexposure treatment with IFN-β significantly increased survival time of rhesus macaques infected with a lethal dose of Ebola virus, although it failed to alter mortality. Early treatment with IFN-β also significantly increased survival time after Marburg virus infection. IFN-β may have promise as an adjunctive postexposure therapy in filovirus infection.

Post-exposure treatments for Ebola and Marburg virus infections

“…Treatment of cynomolgus monkeys with recombinant human interferon-α2b (IFNα2b) 130 or treatment of rhesus monkeys with recombinant human IFNβ 200 after exposure to EBOV (Kikwit strain) offered no survival benefit. A small pilot study of IFNβ given 1 hour after exposure to MARV (Musoke strain) resulted in survival of one of three animals 200 .…”

“…As an example, EBOV (Kikwit strain)-infected rhesus monkeys that were given several doses of a mAb to IFNα/β receptor 1 (IFNAR1) not only all succumbed to infection but did so with significant decrease in the mean time to death versus untreated controls 200 . As another example, an antibody against integrin-β1 resulted in a worse outcome in EBOV (Makona strain)-infected rhesus monkeys, with a significant decrease in survival and time to death versus untreated controls (T.W.G., unpublished data).…”

Vesicular stomatitis virus (VSV) as a paradigm for predicting antiviral activity against Ebola virus (EBOV)

“…This was the case in 2003 when SARS (severe acute respiratory syndrome) emerged (4), and it happened again with the current EBOV outbreak (5). In fact, interferon-β therapy was shown to prolong the survival of rhesus macaques infected with either EBOV or Marburg virus (5). The use of interferon, and, in particular, pegylated interferon, to curtail the current EBOV epidemic should be facilitated by its increased availability now that its usefulness in the treatment of hepatitis C virus infections is dwindling down because of the growing impact of directacting antivirals (DAAs) to treat HCV infections.…”

Forty years of the war against Ebola

“…Viruses have evolved ways to inhibit the type I interferon production and responsiveness. So far animal studies have proved that the early post-exposure treatment with interferon β significantly increased the survival time, but it failed to alter the mortality (Jahrling et al, 1999;Smith et al, 2013).…”