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Single low-dose VSV-EBOV vaccination protects cynomolgus macaques from lethal Ebola challenge.

ABSTRACT: BACKGROUND:Ebola virus (EBOV), variant Makona, was the causative agent of the 2013-2016 West African epidemic responsible for almost 30,000 human infections and over 11,000 fatalities. During the epidemic, the development of several experimental vaccines was accelerated through human clinical trials. One of them, the vesicular stomatitis virus (VSV)-based vaccine VSV-EBOV, showed promising efficacy in a phase 3 clinical trial in Guinea and is currently used in the ongoing EBOV outbreak in the northeastern part of the Democratic Republic of the Congo (DRC). This vaccine expresses the EBOV-Kikwit glycoprotein from the 1995 outbreak as the immunogen. METHODS:Here we generated a VSV-based vaccine expressing the contemporary EBOV-Makona glycoprotein. We characterized the vaccine in tissue culture and analyzed vaccine efficacy in the cynomolgus macaque model. Subsequently, we determined the dose-dependent protective efficacy in nonhuman primates against lethal EBOV challenge. FINDINGS:We observed complete protection from disease with VSV-EBOV doses ranging from 1?×?107 to 1?×?101 plaque-forming units. Some protected animals receiving lower vaccine doses developed temporary low-level EBOV viremia. Control animals developed classical EBOV disease and reached euthanasia criteria within a week after challenge. This study demonstrates that very low doses of VSV-EBOV uniformly protect macaques against lethal EBOV challenge. INTERPRETATION:Our study provides missing pre-clinical data supporting the use of reduced VSV-EBOV vaccine doses without decreasing protective efficacy and at the same time increase vaccine safety and availability - two critical concerns in public health response. FUNDING:Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

SUBMITTER: Marzi A

PROVIDER: S-EPMC6945200 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Single low-dose VSV-EBOV vaccination protects cynomolgus macaques from lethal Ebola challenge.

Marzi Andrea A Reynolds Pierce P Mercado-Hernandez Reinaldo R Callison Julie J Feldmann Friederike F Rosenke Rebecca R Thomas Tina T Scott Dana P DP Hanley Patrick W PW Haddock Elaine E Feldmann Heinz H

EBioMedicine 20191017

<h4>Background</h4>Ebola virus (EBOV), variant Makona, was the causative agent of the 2013-2016 West African epidemic responsible for almost 30,000 human infections and over 11,000 fatalities. During the epidemic, the development of several experimental vaccines was accelerated through human clinical trials. One of them, the vesicular stomatitis virus (VSV)-based vaccine VSV-EBOV, showed promising efficacy in a phase 3 clinical trial in Guinea and is currently used in the ongoing EBOV outbreak i ...[more]

PMID: 31631035

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Project description:Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV), and the Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa.IMPORTANCE The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens.

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Single low-dose VSV-EBOV vaccination protects cynomolgus macaques from lethal Ebola challenge.

Publications

Single low-dose VSV-EBOV vaccination protects cynomolgus macaques from lethal Ebola challenge.

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