Vaccine-Mediated Induction of an Ebolavirus Cross-Species Antibody Binding to Conserved Epitopes on the Glycoprotein Heptad Repeat 2/Membrane-Proximal External Junction

Abstract

The membrane-proximal external regions (MPER) of the human immunodeficiency virus envelope glycoprotein (GP) generate broadly reactive antibody responses and are the focus of vaccine development efforts. The conservation of amino acids within filovirus GP heptad repeat region (HR)2/MPER suggests that it may also represent a target for a pan-filovirus vaccine. We immunized a cynomolgus macaque against Ebola virus (EBOV) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced memory B-cell receptors, and tested the antibodies for functional activity against EBOV GP. Antibody ma-C10 bound to GP with an affinity of 48 nM and was capable of inducing antibody-dependent cellular cytotoxicity. Three-dimensional reconstruction of single-particle, negative-stained, electron microscopy showed that ma-C10 bound to the HR2/MPER, and enzyme-linked immunosorbent assay reveals it binds to residues 621-631. More importantly, ma-C10 was found to bind to the GP of the 3 most clinically relevant Ebolavirus species, suggesting that a cross-species immunogen strategy targeting the residues in this region may be a feasible approach for producing a pan-filovirus vaccine.

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

“…VSV-based vaccines have been demonstrated to be generally safe and efficacious, and are currently being developed to protect individuals from other viruses, bacteria and parasites 59 . Although vaccine-induced antibodies have been isolated before 50,60 , our data highlight this opportunity for VSV-based vaccine strategies and therefore underline the potential to retrieve protecting antibodies that are of particular need in complicated outbreak scenarios and to combat emerging infections.…”

Immunotherapeutic strategies to target vulnerabilities in the Ebolavirus glycoprotein

“…The interaction of the antibody with this region appears to disrupt the normal helical secondary structure of the peptide and suggests that this interaction could disrupt protomer-protomer interactions in the stalk (King et al, 2019). This hypothesis, based on the peptide-bound structure of BDBV223, is supported by the finding that there may be transmitted allosteric changes in GP for the MPER antibody maC10 (Cagigi et al, 2018). These changes might impact binding of GP to cellular targets and/or function (Bornholdt et al, 2016;Cagigi et al, 2018;Flyak et al, 2016Flyak et al, , 2018King et al, 2019).…”

“…The prototypic antibody for this site is the Bundibugyo virus (BDBV)-targeting antibody BDBV223, which was isolated from a human survivor of BDBV disease and cross-reacts with EBOV GP (Figure 2D) (Flyak et al, 2016(Flyak et al, , 2018King et al, 2019). 2D class averages and 3D reconstructions of single-particle class averages have shown that site X antibodies bind with either a 2:1 or 3:1 stoichiometry (Bornholdt et al, 2016;Cagigi et al, 2018;Flyak et al, 2016Flyak et al, , 2018King et al, 2019). Site X epitopes are primarily linear, and there is a high degree of sequence identity in this region among Ebolaviruses, suggesting that antibodies targeting site X may be able to target more than one species of virus (Bornholdt et al, 2016;Cagigi et al, 2018;Flyak et al, 2016Flyak et al, , 2018King et al, 2019).…”

“…2D class averages and 3D reconstructions of single-particle class averages have shown that site X antibodies bind with either a 2:1 or 3:1 stoichiometry (Bornholdt et al, 2016;Cagigi et al, 2018;Flyak et al, 2016Flyak et al, , 2018King et al, 2019). Site X epitopes are primarily linear, and there is a high degree of sequence identity in this region among Ebolaviruses, suggesting that antibodies targeting site X may be able to target more than one species of virus (Bornholdt et al, 2016;Cagigi et al, 2018;Flyak et al, 2016Flyak et al, , 2018King et al, 2019). While the mechanism of action for these antibodies is not known, Xray crystallography of BDBV223 bound to its minimal peptide epitope showed that among many contacts, a critical p-stacking interaction occurs between a tyrosine of the CDRH1 and histidine 628 in the Bundibugyo GP peptide.…”

Ebola Virus and Its Immunopathogenesis - A Review

“…Many people have survived Ebola virus disease 38 . Their convalescent serum has been administered to others who were actually affected with Ebola virus disease with anecdotal success 39 . Early vaccines like AVI -7537 & AVI -7288 were used for the treatment of Ebola virus and found to be less effective for about 84% of the population 40 .…”