Effective post-exposure treatment of Ebola infection

Abstract

Ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in Central Africa and a potential for use as a biological weapon. There is no vaccine or treatment licensed for human use. In the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. In this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge. In contrast, progress in developing therapeutic interventions against Ebola virus infections has been much slower and there is clearly an urgent need to develop effective post-exposure strategies to respond to future outbreaks and acts of bioterrorism, as well as to treat laboratory exposures. Here we tested the efficacy of the vesicular stomatitis virus-based Ebola vaccine vector in post-exposure treatment in three relevant animal models. In the guinea pig and mouse models it was possible to protect 50% and 100% of the animals, respectively, following treatment as late as 24 h after lethal challenge. More important, four out of eight rhesus macaques were protected if treated 20 to 30 min following an otherwise uniformly lethal infection. Currently, this approach provides the most effective post-exposure treatment strategy for Ebola infections and is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate release.

Figure 1

Kaplan-Meier Survival Curves for Mice and Guinea Pigs Given Post-Exposure Treatment for ZEBOV Infection (A) Mice (groups of five animals) were infected with 1,000 LD₅₀ of MA-ZEBOV by i.p. injection. At various times points 24 h prior to challenge (○), 30 min after challenge (♦), or 24 h after challenge (▵) they were treated with  2 ×  10⁵ pfu of VSVΔG/ZEBOVGP by i.p. injection. The controls (▪) were left untreated and all died. All treated animals survived the challenge. (B) Guinea pigs (groups of six animals) were infected with 1,000 LD₅₀ of GA-ZEBOV by i.p. injection. At various times points 24 h prior to challenge (○), 1 h after challenge (♦), or 24 h after challenge (▵) they were treated with 2 × 10⁵ pfu of VSVΔG/ZEBOVGP by i.p. injection. The controls (▪) were left untreated and all died.

Figure 2

Survival and Plasma Viraemia for Rhesus Monkeys Given Post-Exposure Treatment for ZEBOV Infection (A) Kaplan-Meier survival curves for animals treated with ∼2 ×10⁷ pfu of VSVΔG/ZEBOVGP (subjects 1 to 8, solid line) or VSV control vectors (subjects c1 and c2, dotted line) 20–30 min after i.m. challenge with 1,000 pfu of ZEBOV. (B) Plasma viraemia of animals treated with VSVΔG/ZEBOVGP or VSV control vectors 20–30 min after i.m. challenge with 1,000 pfu of ZEBOV. Viraemia was determined by plaque assay at indicated time points. The asterisk indicates that on day 8 post-challenge viraemia levels were only determined for the control animals (subjects c1 and c2). Plasma viraemia levels at day 6 post-ZEBOV challenge could be separated into three different groups. Control animals, which received VSV control vectors (black square), developed high plasma viraemias (>6 log₁₀ pfu/ml). Animals treated with VSVΔG/ZEBOVGP, which developed fulminant EBOV HF and succumbed to ZEBOV challenge (orange square), developed moderate plasma viraemias (∼4–6 log₁₀ pfu/ml), while animals treated with VSVΔG/ZEBOVGP, which survived (green square), had low plasma viraemias (≤1.4 log₁₀ pfu/ml). Subject 6 did not develop fulminant disease consistent with EBOV HF and succumbed on day 18 from a secondary bacterial infection.

Figure 3

Serological Response Profile for Rhesus Monkeys Given Post-Exposure Treatment for ZEBOV Infection IgM (A), IgG (B), and development of EBOV-neutralizing antibodies (C) in sera of animals treated with 2 × 10⁷ pfu of VSVΔG/ZEBOVGP 20–30 min after i.m. challenge with 1,000 pfu of ZEBOV.