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Leaked documents reveal behind-the-scenes Ebola vaccine issues

Extensive background documents from a meeting that took place today at the World Health Organization (WHO) have provided new details about exactly what it will take to test, produce, and bankroll Ebola vaccines, which could be a potential game changer in the epidemic.

ScienceInsider obtained materials that vaccinemakers, governments, and WHO provided to the 100 or so participants at a meeting on “access and financing” of Ebola vaccines. The documents put hard numbers on what until now have been somewhat fuzzy academic discussions. And they make clear to the attendees—who include representatives from governments, industry, philanthropies, and nongovernmental organizations—that although testing and production are moving forward at record speed, knotty issues remain.  

At the meeting, GlaxoSmithKline (GSK) of Rixensart, Belgium, which has the vaccine furthest in development, spelled out how it might scale up production in parallel with the safety and efficacy trials now under way so that the product could be ready for wider distribution by April if warranted. The company expects to have preliminary data in November from phase I studies that analyze safety and immune response in small numbers of people not at risk of contracting Ebola. If those data are positive, efficacy trials could start as early as January in Guinea, Sierra Leone, and Liberia, the three West African countries hard hit by the epidemic.

Earlier discussions suggested that efficacy trials should recruit health care workers and first-line responders like those who do burials or track contacts of known infected people. WHO estimates that there are about 12,000 health care workers in the three affected countries and another 17,500 “community” responders.

GSK is considering two efficacy trials. The largest would take place in Liberia and involve 12,000 people. This study, which could begin in mid-January, would randomize half of the participants to receive the vaccine and the other half a placebo. The study could also have a third arm, GSK said: A vaccine made by NewLink Genetics of Ames, Iowa, that has just entered phase I studies in the United States. The U.S. National Institutes of Health indicated that it was interested in leading this study.

A second trial would start simultaneously in Sierra Leone, Ripley Ballou, who is heading the GSK Ebola vaccine project, told ScienceInsider. “One of the trials may fail for logistics reasons,” he explained. “We only have one shot to get this right.” The trial in Sierra Leone would not use a placebo but instead would offer groups of health care workers the vaccine at different points in time. This “stepped-wedge” trial could involve up to 8000 people, and the U.S. Centers for Disease Control and Prevention has had preliminary discussions with affected countries about staging these studies. Although Guinea is also hard hit, it has the least infrastructure in place to do a trial, Ballou says. “It would be the most challenging place to do a phase III study.”

GSK estimates (see table below, and here) that it will have 24,000 doses of its vaccine ready by January for the efficacy trials. If it cranks up production to full capacity before the those trials are complete, the company could have 230,000 doses available in April, and then could steadily increase capacity to produce more than 1 million doses a month by December 2015.

GSK has made modest investments in scaling up production of its vaccine, and this table projects what it might be able to produce over the next year if it went all out and added several new production lines. The "at risk" noted by the asterisks refers to the company doing quality control without needing to wait for regulatory agencies to repeat the tests.

In one of the background documents, GSK noted that a “critical issue” is what’s known as fill capacity. GSK said there is a shortage of facilities that can fill vaccine vials under sterile conditions in a facility that meets what are known as biosafety level 2 conditions. It suggested the regulatory agencies relax their biosafety requirements. If GSK alone must do the filling, this will affect the company’s ability to produce other vaccines already on the market, including ones that protect against rotavirus, measles, mumps, and rubella, the document said.

The GSK document also outlines a number of proposals to make the first batches of vaccine quickly available, like running some of the quality control tests in parallel and changing the test used to prove sterility of the vaccine from one that takes 14 days to an assay that takes half the time.

Additional studies of the NewLink vaccine will start soon in Geneva, Switzerland, and Hamburg, Germany. A first lot of the vaccine arrived in Geneva on Wednesday, Marie-Paule Kieny, an assistant director-general at WHO, told ScienceInsider. The Canadian government has donated 800 vials of the vaccine to WHO, but is sending them in three separate shipments, Kieny explained. “It just felt too risky to put all eggs in one basket,” said Kieny, who has volunteered as a subject for testing the vaccine herself.

Janssen, a division of Johnson & Johnson, described its plans to speed development of yet another Ebola vaccine strategy that has yet to enter human studies. A delegation from Russia planned to discuss Ebola vaccines being made there, too.

A highly detailed, 28-page document by the Norwegian Institute of Public Health offered “crude cost estimates” for scaling up mass production of Ebola vaccines. By these calculations, 27 million doses of vaccine would cost up to $73 million, and the cost of the vaccination campaigns themselves will add another $78 million to the bill.

Several analyses laid out the complex regulatory and liability issues. The U.K. government argued that “there is a need to provide some form of relief of liability for the producers and distributors of the vaccines” and that WHO should coordinate discussions with regulators. The U.K. government also noted that “affected African countries will have the primary role of authorising or allowing use of investigational vaccines” and said “buy in” from those communities about the clinical trials must be obtained as soon as possible.

As far as financing, the U.K. government contends that a “multi-donor club” should pay for the vaccine development in “the medium term.” But for now, the United Kingdom says it will “unilaterally” cover the costs for purchasing vaccines in Sierra Leone, and it asks the governments of the United States and France to make the same commitment for Liberia and Guinea, respectively.

In a planning document, WHO pointed out multiple logistical issues, including “the ability to safely and securely transport the intervention to the delivery site, the existence of safe and secure storage facilities with appropriate cold chain capacity, the availability of sterile equipment to administer injections.” But to Ballou the greatest question hanging over the vaccine trials is the stability of the countries. “The thing that is going to have the biggest impact is what is happening to the trajectory of the epidemic curve,” he says. “If you progress the current trends 2 months into the future are we still in an environment where you can even consider doing a trial?”

*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.