Ebola, still ravaging West Africa and killing up to 90% of its victims, is as yet unmolested by any vaccine or therapeutic. It may, however, prove vulnerable to antibody cocktails, which have shown some promise as a postexposure treatment. Monoclonal antibodies, for example, have been shown efficacy against otherwise lethal Ebola virus infection in nonhuman primates. A cocktail of monoclonal antibodies called ZMapp, which appeared to be especially efficacious in early evaluations, was even administered to several Ebola patients, on a compassionate basis.
It is still unclear whether ZMapp helped the human patients. A recently released study, however, suggests that it may have been. This study was led by Andrew Ward, Ph.D., and Erica Ollmann Saphire, Ph.D., researchers at The Scripps Research Institute (TSRI). They decided to sound an optimistic note after examining the structural biology of ZMapp’s interactions with the Ebola virus. In fact, the researchers were able to assemble 3D images of how ZMapp antibodies bind to Ebola.
“The structural images of Ebola virus are like enemy reconnaissance,” said Dr. Saphire. “They tell us exactly where to target antibodies or drugs.” Dr. Ward added, “Now that we know how ZMapp targets Ebola, we can compare all newly discovered anti-Ebola antibodies as we try to formulate an even better immunotherapeutic cocktail.”
The TSRI team led by Drs. Ward and Saphire published their results November 17 in the Proceedings of the National Academy of Sciences, in an article entited, “Structures of protective antibodies reveal sites of vulnerability on Ebola virus.”
“We provide single-particle [electron microscope] reconstructions of every [monoclonal antibody] in the ZMapp cocktail, as well as additional antibodies [that were evaluated in work that lead up to the ZMapp formulation],” wrote the authors. “Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp.”
The researchers found that two of the ZMapp antibodies bind near the base of virus, appearing to prevent the virus from entering cells. A third antibody binds near the top of the virus, possibly acting as a beacon to call the body's immune system to the site of infection.
The new picture of ZMapp reveals the two antibodies that bind near the base of the virus seem to be competing for the same site. While this appears to be a particularly vulnerable spot on Ebola virus' surface as identified in previous studies, one question now is whether future cocktails should continue to use two antibodies to target this site or try to attack the virus from a third angle.
“This information helps guide decisions about how to formulate these life-saving therapies,” said C. Daniel Murin, a graduate student in the labs of Drs. Ward and Saphire and first author of the new study. “Instead of including two different antibodies that do the same thing, why not use twice as much of the more effective one instead? Or include a third antibody against a different site to stop the virus a third way?”
Luckily, while the Ebola virus has undergone more than 300 genetic changes in the current outbreak (according to research published in the journal Science in August), the new study indicates the sites where the ZMapp antibodies bind have been unaffected so far.
“Going forward,” the authors concluded, “[our work] provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.”