Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques

Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern – causing severe respiratory illness with 97 confirmed cases and 46 deaths1. Therapeutic interventions have not been evaluated in vivo, thus patient management relies exclusively on supportive care, which given the high case-fatality rate is not highly effective. The rhesus macaque is the only known disease model for MERS-CoV, developing an acute localized-to-widespread pneumonia with transient clinical disease2,3 that recapitulates mild-to-moderate human MERS-CoV cases4,5. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro6; therefore, this strategy was initiated 8 h post-infection in the rhesus macaque model. Treated animals did not develop breathing abnormalities and showed no-to-very mild radiographic evidence of pneumonia. Moreover, treated animals showed reduced levels of systemic (serum) and local (lung) proinflammatory markers in addition to reduced viral genome copies, altered gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic, IFN-α2b and ribavirin should be considered for management of MERS-CoV cases.

What are our pharmacotherapeutic options for MERS-CoV?

“…In vitro activity of interferon was further enhanced by the addition of ribavirin [30]. Recently, animal studies utilizing Rhesus Macaque monkeys infected with MERS-CoV were published [31][32][33]. Using intratracheal, ocular, oral and intranasal inoculation of MERS-CoV, Rhesus macaques developed a transient lower respiratory tract infection and had histopathologic changes of the disease and developed neutralizing antibodies [33].…”

“…From these studies, the pathogenesis of the disease revealed that MERS-CoV results in clinical disease, promotes virus shedding and replication in respiratory tissues, and that cytokines and chemokines peaked early in infection and decreased over time [33]. An earlier rhesus macaque model of MERS-CoV infection showed that both IFN-a2b and ribavirin combinations was effective in limiting MERS-CoV disease, clinically and radiographically [31]. In a recent observational study of five MERS-CoV patients treated with a combination of interferon and ribavirin, the median time from admission to therapy was 19 (range 10-22) days.…”

“…In the animal model, the combination of ribavirin and interferon was given within 8 h of infection [31].…”

An opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus

“…Their practical use in humans is challenging because, if not infected while in a healthcare setting, humans usually present for care with well advanced disease. [107,108] Combined treatments which reduce viral replication and the host immune response to it are likely to be valuable developments. [15] A wide range of repurposed or novel potential antivirals including polymerase, nucleotide synthesis and protease inhibitors and fusion-inhibiting peptides [64,87,[109][110][111][112][113] have been investigated.…”

Ortadoğu Solunum Yetmezliği Sendromu Koronavirüsü

“…Tip 1 interferonların insan akciğer doku kültürlerinde MERS-CoV replikasyonunu inhibe ettiği göste-rilmiştir. Yine yapılan bir çalışmada ribavirin ve interferon-alfa 2b'nin Vero and LLC-MK2 hücre kültürlerinde replikasyonu azalttığı gösterilmiş-tir (24)(25)(26).…”