A massive global collaborative effort is under way to understand how the Ebola virus affects cells, why the virus is lethal, and how to battle it. An experimental cocktail called ZMapp, from Mapp Biopharmaceutical, San Diego, appears to be an effective weapon against the disease. LabRoots speaks with Erica Ollmann Saphire, PhD, professor, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, Calif, who heads a global research consortium funded by a $28 million grant from the National Institutes of Health. The group is working to discover treatments or a vaccine for the virus.
Judy O'Rourke: Please discuss your plans/progress toward finding treatments or a vaccine for Ebola-in terms of short- and long-term goals.
Erica Ollmann Saphire: My expertise is in structural biology. It involves the molecular structures of pieces of the Ebola virus, and antibodies against it. That gives us the roadmap to understand how the virus affects cells, why it's lethal, and what you would do to defend against it. We're using those roadmaps to direct this global consortium. In 2011, a number of laboratories independently discovered that antibody cocktails could be very effective against Ebola virus. ZMapp is a reformulation of two of them. In the field, we thought we might be able to make an even better cocktail if we put all the known antibodies in the same study and tried to figure out, not "What's the best cocktail from San Diego, or the best cocktail from Canada?" but "What's the best cocktail if you considered all antibodies available in the world?" Let's say there are three different binding sites-"A," "B," and "C"-and there are 10 different antibodies known against "A," we'll pick the best among them, no matter where in the world it comes from. Twenty-five laboratories across seven countries have gotten together for this single study. The global scale in this, I think is unprecedented. We're going to do multiple rounds of this-we've collected 80 antibodies from around the world on our first round. We're going to do another one in a few months, and another one, and another one. We have blinded them all and we're going to compare them side-by-side, to map all the epitopes, and figure out which are most effective and why. We want to understand what constitutes a good protective response against Ebola virus, and then which combinations best confer protection. ZMapp is our consortium's proof of concept. Zmapp is a collaboration between Mapp Bio, the US Army Medical Research Institute of Infectious Diseases (USAMRIID), and the Public Health Agency of Canada. Those scientists got together and reformulated their best two cocktails, using the best components of each. ZMapp is tremendously efficacious. There is 100% survival in the laboratory animals even when antibodies are given as late as five days after infection. In the animals, death would typically occur around day seven, so at day five they're very, very sick. After treatment, they were all able to recover, which is incredible. It looks like it might be quite effective in humans as well.
The short-term goal of the consortium is the basic research: Understanding why ZMapp is effective and exactly how it functions. The long-term goals are to make similar cocktails against the other viruses for which there isn't any such therapy-Sudan virus, Bundibugyo virus, Marburg virus, Lassa virus... ZMapp only works against Ebola virus. So, our consortium has a basic research-discovery component understanding why antibodies are effective against Ebola virus, where they bind, which are most effective and why. The translational research component has, as its goal, discovery of therapies that can go into humans for all the different viruses like these.
JO: Why can't MappBio make ZMapp in larger quantities quickly?
EOS: They can...it's just that they were still doing research when the virus broke out. The normal course of things is test tubes, then rodents, and then primates, then you schedule the clinical trials. Test tubes, rodents, and primates have been done, and based on that efficacy data, they scheduled the human trials in 2015. Not that much human-quality material was available when the virus broke out-they gave out everything they had. Had anybody known that Ebola virus would break out on this scale, people might have started scaling things up a long time ago. But then again, the efficacy of ZMapp was only just discovered-nothing as good as ZMapp was available to scale up a long time ago. The reason it takes a long time is its expression in tobacco leaves. You have to grow the plants, and inoculate them with the vector that expresses the antibody, then purify the antibodies. It takes a couple of months.
JO: The Department of Health and Human Services has just announced it has funded the accelerated development of ZMapp-does that change any of the processes that are under way?
EOS: I think more of it will be manufactured earlier than if had there not been an outbreak-perfectly reasonable, sensible, appropriate response. However, the clinical trials still have to happen. One of the goals of the first trial is, with healthy people, to establish how much of the antibody should they give, how long does it last, are there adverse effects. They need to have that data.
JO: Is there anything you would like to add?
EOS: The important thing is that all the scientists in the world who work on this have gotten on the same page to pool our tools and resources into a single study to make the best therapeutics against these viruses that are possible. I don't know another research field where everybody who works on it on the planet has gotten in on the same study to agree on the right therapy-no matter whose lab it ultimately came from. It really speaks to the importance of the problem, and the necessity of developing these things for human health.
