Abstract
Zaire Ebola virus (ZEBOV) is a pathogen that causes severe hemorrhagic fever in humans and non-human primates. There are currently no licensed vaccines or approved treatments available against ZEBOV infections. The goal of this work was to evaluate different treatment strategies in conjunction with a replication deficient, recombinant human adenovirus serotype 5-based vaccine expressing the Zaire Ebola virus glycoprotein (Ad-CAGoptZGP) in Ebola infected mice and guinea pigs.Guinea pigs were treated with Ad-CAGoptZGP in combination with different treatment strategies after challenge with guinea pig adapted-ZEBOV (GA-ZEBOV). B10.BR mice were used to further characterize efficacy and immune responses following co-administration of Ad-CAGoptZGP with the most effective treatment: AdHu5 expressing recombinant IFN-α (hereafter termed DEF201) after challenge with a lethal dose of mouse adapted-ZEBOV (MA-ZEBOV).In mice, DEF201 treatment was able to elicit full protection against a lethal dose of MA-ZEBOV when administered 30 minutes after infection. In guinea pigs the Ad-CAGoptZGP and DEF201 combination therapy elicited full protection when treated 30 minutes post-exposure and were a superior treatment to Ad-CAGoptZGP supplemented with recombinant IFN-α protein. Further analysis of the immune response revealed that addition of DEF201 to Ad-CAGoptZGP enhances the resulting adaptive immune response against ZGP. The results highlight the importance of the innate immune response in the prevention of ZEBOV pathogenesis and support further development of the Ad-CAGoptZGP with DEF201 treatment combination for post-exposure therapy against ZEBOV infection.
Highlights
Ebola virus (EBOV) is a member of the family Filoviridae
Survival and weight loss in guinea pigs following Ebola virus infection and treatment Complete survival was previously observed in mice administered Ad-CAGoptZGP 30 minutes after infection with 1000 × LD50 of MA-Zaire Ebola virus (ZEBOV) [33]
Guinea pigs were first infected with 100 × LD50 of GA-ZEBOV, followed 30 minutes later by a single intramuscular (I.M.) injection of 1 × 1010 infectious forming units (IFU) of AdCAGoptZGP per animal in conjunction with either dextrose, AdHu5-iMYD88.CD40 with dimer drug, CD40 ligand (CD40L), recombinant IFN-α protein (rIFN-α), DEF201 or 6 hours later with isopropanol, or azithromycin from days 1-5 post-challenge
Summary
Ebola virus (EBOV) is a member of the family Filoviridae. They are enveloped, singlestranded, negative-sense RNA viruses, which cause severe hemorrhagic fever and are associated with highly lethal infections in humans. Several strains of EBOV have been identified to date including the Zaire, Sudan, Bundibugyo, Ivory Coast and Reston Ebola virus [1]. The most aggressive strain identified is the Zaire Ebola virus (ZEBOV) with mortality rates reported to be as high as 90% [2]. Outbreaks of EBOV infection have occurred sporadically in Africa in the past and caused substantial fatalities within the affected communities. Several factors including high lethality rates in humans, the ease of in vitro propagation and the potential for aerosol dissemination make EBOV a causative agent for biological warfare [3]. The development of an effective post-exposure therapy is considered a high priority despite the limited impact of EBOV on the human population worldwide
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