Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice

Abstract

Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGPFc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use.

Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Protective, Noninfectious Vaccine against Ebola Virus Challenge in Mice

“…Given the positive association of serum neutralizing antibodies with survival against EBOV in human and animal model infections (9,34,38) and our observed correlation between survival and anti-EBOV GP antibody levels in sera from vaccinated mice, we evaluated the ability of sera from vaccinated mice to neutralize EBOV GP/VSVΔG pseudovirion infection of Vero cells, using the criterion of at least 50% inhibition of EBOV GP/VSVΔG infection as evidence of neutralization. Sera from mice vaccinated with even our highest concentrations of pseudovirions did not meet our criterion for neutralizing activity, despite providing robust protection against lethal challenge (Fig.…”

Mice Orally Immunized with a Transgenic Plant Expressing the Glycoprotein of Crimean-Congo Hemorrhagic Fever Virus

“…Therefore, immunization is considered to be essential in mitigating the high rate of mortality from viral hemorrhagic fevers. It was recently shown that Ebola virus glycoprotein can confer protection in vaccinated mice (26). Similarly, specific antibodies against CCHFV are protective in a suckling mouse animal model (6).…”

A review on the Ebola virus, outbreak history and the current research tools to control the disease

“…The apparent size of this protein in polyacrylamide electrophoresis gel is 125-140 kDa due to heavy glycosylation [61,62]. The gp gene undergoes transcription by the L protein, involving furin cleavage and disulfide-bond formation between the N-terminus and the membrane proximal portion of GP [62][63][64]. This processing yields two peptide subunits required to synthesize the surface GP [60,65].…”

“…This processing yields two peptide subunits required to synthesize the surface GP [60,65]. The membrane-anchored GP2 is covalently linked via disulfide bond to the N-terminus of GP1, which has a highly O-glycosylated mucinlike domain [63]. Upon infection, high amounts of GP1 is secreted from the cells after release from the GP2 subunit.…”

“…Upon infection, high amounts of GP1 is secreted from the cells after release from the GP2 subunit. Moreover, an additional nonstructural soluble GP deriving from GP1 (identical sequence of 295 amino acids with N-terminal GP1), is produced by EBOV-, but not Marburg virus-infected cells [63,66]. The GP (class 1 membrane GP) is arranged in trimers that forms spikes at the surface of virions [67], and it is the only surface protein in the virion, which indicates that this protein mediates virus entry through receptor binding and fusion [34,54,62,65].…”