Okairos, a GSK subsidiary that makes the Ebola vaccine, isn't ready to make millions of doses.

Okairos, a GSK subsidiary that makes the Ebola vaccine, isn't ready to make millions of doses.

Loredana Siani, Okairos

Push to gamble big on mass production of Ebola vaccines

The world needed an Ebola vaccine months ago to stop the epidemic that has exploded in West Africa—but none existed. Now, the race is on to develop vaccines in a matter of months, instead of the years it typically takes. But even if one of the current candidates works, many questions remain. How fast can companies make millions of vaccine doses? When should they start production? And who will foot the multimillion-dollar bill?

At the end of a World Health Organization (WHO) meeting held in Geneva, Switzerland, last week to discuss Ebola vaccines, several participants were convinced that mass production of experimental products should begin in parallel with studies that aim to determine whether they actually work. “I’d pull out all the stops,” says Ira Longini, a statistician at the University of Florida at Gainesville who attended the meeting. “I’d try to make 30 to 40 million doses to cover at risk West African populations."

Jeremy Farrar, an infectious disease researcher and head of the Wellcome Trust in London—which has provided funding for Ebola vaccine testing—agrees. “We may come to regret that we have to throw those vaccines away if they prove not to be effective,” Farrar says, “but I think that is a risk we have to take.”

Pharmaceutical giant GlaxoSmithKline (GSK) of Rixensart, Belgium, is now testing an Ebola vaccine for safety in volunteers at no risk of contracting the disease. A second one, made by NewLink Genetics of Ames, Iowa, is expected to enter clinical trials later this month. If the vaccines prove safe and able to trigger the desired immune responses, an earlier WHO consultation found wide support for shortcutting the standard progression of vaccine clinical trials and jumping straight from these phase I trials to phase III efficacy tests in Liberia, Guinea, and Sierra Leone, the three hard-hit countries.

In early November, GSK expects to have enough data from the phase I studies to decide whether to launch phase III trials, says Ripley Ballou, who heads GSK's Ebola program. Health care workers—now broadly defined to include everyone from hospital janitors to burial teams—will be first in line. GSK earlier predicted it would have 10,000 doses by the end of the year that could be used in phase III trials, but Ballou says production has been going extremely well, and there may be as many as 20,000 doses by then.

But that would still be nowhere near enough doses to stop the outbreak in West Africa. That's why there’s a push to ramp up production to millions of doses as soon as the phase III trials launch. What the world can't afford, Farrar says, is “to be in a position where the vaccine proves to be safe and effective in small scale-randomized trials and then we have to wait another 3 to 6 months to produce it.” Doctors Without Borders (MSF), which has been the main provider of care from the epidemic’s start, agrees. “Production should be scaled up rapidly even before end results on efficacy because this will permit that more people can benefit faster from the vaccines once efficacy has been demonstrated,” says MSF’s Annick Antierens, who was also at last week's meeting.

How many shots are available will depend in part on how much product constitutes a “dose.” GSK is testing its vaccine at two different doses, and if the lower one works, they’ll have twice as much vaccine. NewLink Genetics, a small company with less experience in vaccines, is lagging behind GSK, but safety studies could start later this month. The doses tested in those trials will have an even greater range. “If one of the lower doses proves to be effective, every vial would yield several shots,” says Gary Kobinger, a scientist who helped develop the vaccine at the Public Health Agency of Canada in Winnipeg. If that happens, the amount of vaccine available would multiply at a stroke.

Just how fast vaccinemakers can spit out product presents a major unknown. Even a multinational company like GSK, which has large vaccine manufacturing plants, is asking itself how rapidly it can make millions of doses, given other vaccine production schedules. Money is an issue, too. Funding for the phase III trials does not yet exist, Ballou says, let alone for churning out millions of shots. “There is simply no budgeting model for this,” he says.

Ballou says a “back of the envelope” calculation based mainly on personnel expenses shows that GSK could produce up to half a million doses for $25 million, and that cost would drop with increased quantity. But the company does not yet have any reliable cost estimates for production at a larger scale, he says, especially given the fact that no one can accurately estimate how much is needed now or in the future, and what the vaccine's shelf life is. Ballou does know this much with certainty, however: “There are very substantial capital investments going from where we are now to what would be needed for millions of doses.”

Politically, ordering vaccines without knowing if they'll work is a hard sell. Marie-Paule Kieny, an assistant director-general at WHO, notes that there will be plenty of criticism if vaccine is purchased as an insurance policy and then not used. “At the end, when the analysis is made, people are always much cleverer,” she says.

Kieny should know. She led WHO's vaccine efforts during the H1N1 influenza pandemic in 2009. Then, too, vaccine manufacturers raced to provide many millions of doses, but most of them arrived after the pandemic had peaked in many places. “People said: Why did you waste all this money on this vaccine?” Kieny says, and the same could happen with an Ebola vaccine. “There will be inquiries, parliaments asking: How can you invest hundreds of millions of dollars in something that has not even been proven effective?”

Many are looking to the United States government to foot the bill, or the majority of it, but no commitment has yet been made. A U.S. government official who is involved with these discussions and asked not to be named says the government is helping to set up the efficacy studies as quickly as possible, and says their results should be awaited "before large sums of money need to be invested in scale up of production.” The official assured that “things that can be done now are being done, including technology transfer.”

Even if the vaccine works, and is produced in large quantities, rolling it out on a mass scale will be a struggle, especially in places where there is distrust of government, medical officials, big pharma, and clinical trials in general. The populations of the affected countries would need to be well-informed in advance, but even that carries an ethical risk: They might prepare for a vaccine that may never come, or may come too late. Yet there is no choice, Kieny says: A big education campaign “is very much needed and likely to start early in January.”

*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.