Abstract

BackgroundThe Ebola virus is transmitted by direct contact with bodily fluids of infected individuals, eliciting death rates as high as 90% among infected humans. Currently, replication defective adenovirus-based Ebola vaccine is being studied in a phase I clinical trial. Another Ebola vaccine, based on an attenuated vesicular stomatitis virus has shown efficacy in post-exposure treatment of nonhuman primates to Ebola infection. In this report, we modified the common recombinant adenovirus serotype 5-based Ebola vaccine expressing the wild-type ZEBOV glycoprotein sequence from a CMV promoter (Ad-CMVZGP). The immune response elicited by this improved expression cassette vector (Ad-CAGoptZGP) and its ability to afford protection against lethal ZEBOV challenge in mice was compared to the standard Ad-CMVZGP vector.Methodology/Principal FindingsAd-CMVZGP was previously shown to protect mice, guinea pigs and nonhuman primates from an otherwise lethal challenge of Zaire ebolavirus. The antigenic expression cassette of this vector was improved through codon optimization, inclusion of a consensus Kozak sequence and reconfiguration of a CAG promoter (Ad-CAGoptZGP). Expression of GP from Ad-CAGoptZGP was substantially higher than from Ad-CMVZGP. Ad-CAGoptZGP significantly improved T and B cell responses at doses 10 to 100-fold lower than that needed with Ad-CMVZGP. Additionally, Ad-CAGoptZGP afforded full protections in mice against lethal challenge at a dose 100 times lower than the dose required for Ad-CMVZGP. Finally, Ad-CAGoptZGP induced full protection to mice when given 30 minutes post-challenge.Conclusions/SignificanceWe describe an improved adenovirus-based Ebola vaccine capable of affording post-exposure protection against lethal challenge in mice. The molecular modifications of the new improved vaccine also translated in the induction of significantly enhanced immune responses and complete protection at a dose 100 times lower than with the previous generation adenovirus-based Ebola vaccine. Understanding and improving the molecular components of adenovirus-based vaccines can produce potent, optimized product, useful for vaccination and post-exposure therapy.

Highlights

  • Ebola virus (EBOV) is a member of the Filoviridae family causing a viral hemorrhagic fever with a lethality that can reach beyond 90% [1,2]

  • Western blot analysis using a ZGP monoclonal antibody showed a single band corresponding to the predicted molecular weight of glycosylated ZGP at substantially higher levels in cell lysates infected with the adenovirus serotype 5 (Ad)-CAGoptZGP than with the AdCMVZGP vector at each time point (Figure 2)

  • The present study systematically analyzed the effect of increasing antigenic expression from an adenovirus-based vaccine on immune responses and protective efficacy in mice against mouse-adapted Zaire ebolavirus (ZEBOV)

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Summary

Introduction

Ebola virus (EBOV) is a member of the Filoviridae family causing a viral hemorrhagic fever with a lethality that can reach beyond 90% [1,2]. EBOV causes hemorrhagic fever following virus entry in susceptible organisms where the virus appears to initially infect monocytes, macrophages, and dendritic cells leading to deregulated activation of innate immunity and a systemic inflammatory response syndrome. This results in massive destruction of critical organs, vascular damage and haemorrhage within 5–7 days postexposure [4,5]. Replication defective adenovirus-based Ebola vaccine is being studied in a phase I clinical trial Another Ebola vaccine, based on an attenuated vesicular stomatitis virus has shown efficacy in postexposure treatment of nonhuman primates to Ebola infection. The immune response elicited by this improved expression cassette vector (Ad-CAGoptZGP) and its ability to afford protection against lethal ZEBOV challenge in mice was compared to the standard Ad-CMVZGP vector

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