As the Ebola outbreak in West Africa accelerates, the containment measures that worked in the past, such as isolating those who are infected and tracing their contacts, clearly have failed. This has spurred hopes that biomedical countermeasures, such as monoclonal antibodies and vaccines, can help save lives and slow spread. But as President Barack Obama calls for an aggressive ramp up of the U.S. government’s response, resolve is colliding with a grim reality: The epidemic is outpacing the speed with which drugs and vaccines can be produced.
Administration officials have begun working with industry to speed manufacturing of experimental drugs and vaccines. “We’re trying to do everything we can to scale up product,” says Nicole Lurie, assistant secretary for preparedness and response at the U.S. Department of Health and Human Services (HHS). But the logistical obstacles are huge, and makers are getting a late start.
An Ebola vaccine made by GlaxoSmithKline (GSK) in Rixensart, Belgium, is the furthest along, having entered phase I human trials on 2 September. GSK has committed to manufacturing up to 10,000 doses of the vaccine, which consists of an Ebola surface protein stitched into a weakened chimpanzee adenovirus, by the end of the year. If it passes muster in the early studies, it could be given to health workers as soon as November. But hundreds of thousands of doses would be needed to put a dent in the outbreak. That “would take one-and-a-half years at the scale we’re working at,” says Ripley Ballou, who heads the Ebola vaccine program for GSK.
The scientific hurdles are not particularly high. Companies have made similar vaccines at high volume, and animal studies have shown that Ebola virus is fairly easy to defeat with the proper immune response. “Although Ebola is a very scary, hemorrhagic virus, all you need is fairly modest neutralizing antibody response and you’re protected,” says John Eldridge, chief scientific officer at Profectus BioSciences, a Maryland and New York–based company making an Ebola vaccine that has struggled to attract funding.
Ballou says GSK is considering several options for speeding production. But first the company wants to be sure that there’s a market for the vaccine. He says that when the company contacted the World Health Organization at the start of this outbreak this past March, no one showed much interest. “The answer was, ‘Thanks, we’ll get back to you.’ ”
NewLink Genetics of Ames, Iowa, has a second vaccine in a phase I trial that consists of a crippled vesicular stomatitis virus (VSV), which infects livestock, with the gene for the Ebola virus surface protein. Only 1500 doses exist. Profectus makes a similar vaccine that should be ready for human testing next June. Like GSK, Profectus needs a commitment from a funder before it can scale up production from the planned 5000 to 20,000 doses, Eldridge says.
As a result, vaccinemakers have yet to confront the technical challenges of boosting production. In principle, vaccine production is straightforward: Grow a “master seed” strain of virus on a large scale, then harvest and process it. Okairos, a small company that produces the GSK vaccine at a facility near Rome,, grows its virus in a human cell line in up to 200-liter wave bags, so-called because they rock back and forth on a platform. In all, it will take about 2 months to grow, harvest, and prepare the promised 10,000 or so doses.
Company founder Riccardo Cortese says with an investment of about $10 million, they could convert their facility to process several 400-liter bags simultaneously in as little as 3 months. At that scale, he says, “I calculated we could make 100,000 doses per month.”
GSK’s Ballou is more circumspect. First, they need more master seed. “There were only so many vials made, and we’re depleting them,” he says. And mass production, he says, would work best in huge bioreactors, stainless steel fermenters that resemble beer tanks and hold 1000 liters or more. But the cell lines that produce the vaccine virus are finicky. “The driver is really the productivity of the cell line,” Ballou says. He puts the most optimistic timeline for 100,000 to 500,000 doses at 9 months—and the cost at $25 million.
Treatment is stuck in a similar rut. A cocktail of Ebola antibodies called ZMapp has shown remarkable efficacy in monkey experiments and has been given to seven people. But there’s less than one dose left. Made by Mapp Biopharmaceutical of San Diego, California, ZMapp contains three monoclonal antibodies produced in tobacco plants. The process from plants to product takes a few months and now yields just tens of doses.
HHS’s Biomedical Advanced Research and Development Authority (BARDA), which was established to speed development of treatments and vaccines for emergencies, has contacted two other outfits that can make the antibodies in tobacco plants. But this will boost production to only hundreds of doses per month. BARDA is now exploring the possibility of producing the antibodies in Chinese hamster ovary (CHO) cells—the standard system for making monoclonals. But a 2012 study suggested that the antibodies would have reduced potency if made in CHO cells. “You’re not going to make 100,000 doses anytime in the near future,” says someone familiar with the discussions who did not want to be named.
A bill now moving through the U.S. Congress would give BARDA $58 million for Ebola vaccines and treatments. That’s sure to help, but not soon enough. “I don’t know that we’re going to have these countermeasures in time to make a big dent now,” says HHS’s Lurie. “But hopefully we’ll have the countermeasures by the next time there’s an outbreak so this never, ever happens again.”
*The Ebola Files: Given the current Ebola outbreak, unprecedented in terms of number of people killed and rapid geographic spread, Science and Science Translational Medicine have made a collection of research and news articles on the viral disease freely available to researchers and the general public.