Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies

Abstract

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks.

Modeling Favipiravir Antiviral Efficacy Against Emerging Viruses: From Animal Studies to Clinical Trials

“…We modeled the virologic and PK data that had been collected in the 44 animals of different experiments conducted in the BSL4 (see above), and complemented them with additional data on the innate and the adaptive immune responses 69 . A number of cytokines were measured longitudinally in a subset of macaques ( n = 20) using Luminex technology or enzyme‐linked immunosorbent assay, in particular IFNα, IL6, and TNFα, and cytometry measures were performed in the last experiment ( n = 10, 5 untreated and 5 treated with 180 mg/kg b.i.d.)…”

“…Model predictions (median and 95% prediction interval) for the compartments of the integrated model given in Figure in animals left untreated (black) or treated with favipiravir 180 mg/kg BID 69 . The dots are the individual data in each compartment.…”

Modeling Challenges of Ebola Virus–Host Dynamics during Infection and Treatment

“…More complex models that account for EBOV viral titer kinetics, susceptible cells, EBOV-infected cells, and immune response dynamics might advance understanding of EVD pathogenesis and assist in prioritization of therapies for rigorous evaluation in randomized clinical trials (RCTs) [3]. Recently, Madelain et al [4] developed a single-anatomic compartment immuno-pathogenesis mathematical model to provide insights into EBOV-host dynamics in nonhuman primates and predict effectiveness of favipiravir and remdesivir, both viral RNA polymerase inhibitors, for post exposure prophylaxis and treatment of EVD in humans.…”

Ebola virüsüne yönelik ilaç çalışmaları: bir umut ışığı

“…Remdesivir (GS-5734) acts by RNA-dependent RNA polymerase (RdRp)-mediated mechanism and prevents its proliferation 3 , even in the setting of intact exoribonuclease (ExoN)-mediated proofreading in viruses. In non-human primates, early initiation of polymerase inhibitors Favipiravir and Remdesivir improves survival, but whether they could be effective in patients is unknown 4 . Vincent Madelain et al 4 predicts survival rates of 60% for Favipiravir and 100% for Remdesivir when treatment is initiated within 3 and 4 days post infection, respectively.…”

“…In non-human primates, early initiation of polymerase inhibitors Favipiravir and Remdesivir improves survival, but whether they could be effective in patients is unknown 4 . Vincent Madelain et al 4 predicts survival rates of 60% for Favipiravir and 100% for Remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. ZMapp is a combination of three humanized monoclonal antibodies, that was produced by the method of genetic modification of the most consumable tobacco plants,that target three Ebola virus major glycoprotein and its Epitopes.This monoclonal antibody drug has been shown survival benefit in experimental non-human primates that was infected with this Ebola virus 5 .…”