Abstract
The 2014 Ebola virus (EBOV) outbreak in West Africa is the largest in recorded history and resulted in over 11,000 deaths. It is essential that strategies for treatment and containment be developed to avoid future epidemics of this magnitude. With the development of vaccines and antibody-based therapies using the envelope glycoprotein (GP) of the 1976 Mayinga strain, one important strategy is to anticipate how the evolution of EBOV might compromise these efforts. In this study we have initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between GP and the antibody KZ52. The watch list was generated using molecular modeling to estimate stability changes due to mutation. Every possible mutation of GP was considered and the list was generated from those that are predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. The resulting watch list contains 34 mutations (one of which has already been seen in humans) at six sites in the GP2 subunit. Should mutations from the watch list appear and spread during an epidemic, it warrants attention as these mutations may reflect an evolutionary response from the virus that could reduce the effectiveness of interventions such as vaccination. However, this watch list is incomplete and emphasizes the need for more experimental structures of EBOV interacting with antibodies in order to expand the watch list to other epitopes. We hope that this work provokes experimental research on evolutionary escape in both Ebola and other viral pathogens.
Highlights
With nearly 30,000 confirmed cases and over 11,000 deaths, the recent Ebola virus (EBOV) epidemic in West Africa has dwarfed all recorded outbreaks of the disease (Centers for Disease Control, 2015)
Two vaccines that express the EBOV envelope glycoprotein (GP) from the 1976 Mayinga strain are in phase III clinical trials: rVSV-ZEBOV and ChAd3-ZEBOV (Garbutt et al, 2004; Stanley et al, How to cite this article Miller et al (2016), Initiating a watch list for Ebola virus antibody escape mutations
We focus on the KZ52 antibody as it is one of the few with an available structure bound to EBOV GP
Summary
With nearly 30,000 confirmed cases and over 11,000 deaths, the recent Ebola virus (EBOV) epidemic in West Africa has dwarfed all recorded outbreaks of the disease (Centers for Disease Control, 2015). That the 2014 outbreak appears to be waning, it is critical to develop strategies for treatment and containment to avoid future epidemics of this magnitude. One important strategy is the development of vaccines. Two vaccines that express the EBOV envelope glycoprotein (GP) from the 1976 Mayinga strain are in phase III clinical trials: rVSV-ZEBOV and ChAd3-ZEBOV (Garbutt et al, 2004; Stanley et al., How to cite this article Miller et al (2016), Initiating a watch list for Ebola virus antibody escape mutations. The monoclonal antibodies in ZMapp were generated by vaccination of mice with GP from the 1976 Mayinga strain (Wilson et al, 2000; Qiu et al, 2011; Qiu et al, 2014)
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