Ebola Vaccine Challenge: Motorbikes and Kerosene Fridges

Deep inside a drug manufacturing plant in an industrial district of suburban Rome, vials of Ebola vaccine sit in freezers, chilled to minus 70 degrees Celsius with the help of liquid nitrogen. Much warmer -- say, the temperature in outdated kerosene-fueled fridges in some West African villages -- risks destroying the drug.

Refrigeration is just one of the myriad challenges for GlaxoSmithKline Plc and other companies racing to create vaccines to fight Ebola. They’re facing issues ranging from packaging the drug in tiny glass vials for distribution, to assembling fleets of trucks and motorbikes to transport it along potholed roads, to monitoring subjects in a Swiss lakeside city to test the vaccine ultimately destined for villages in the African jungle.

Companies, regulators, and non-profit groups worldwide are cooperating as never before to create a workable vaccine and announcing new timelines almost weekly. Typically, getting a vaccine from the lab bench to clinics where it’s injected into patients’ arms takes up to a decade. With Ebola, targeted immunization could start in the second half of next year, and field tests in health workers fighting the epidemic are likely by January -- unprecedented speed for such research.

“It is like nothing I have ever seen or anybody has ever talked about in terms of the compression of a development program,” said Ripley Ballou, the Glaxo scientist overseeing the company’s Ebola program. “I spend every minute, from the moment I wake up to the time I go to sleep, on this project.”

As scientists are pulled away from other work, the plan to bring the vaccine to market is starting to take shape. Just seven weeks ago, Ballou said it would be optimistic to expect 15,000 doses by January. A month later, Glaxo predicted it will be able to make 1 million doses a month by the end of 2015 as it continues to sort out the details of commercial production.

Lake Geneva

In August, Margaret Chan, the head of the World Health Organization, phoned Glaxo Chief Executive Officer Andrew Witty to urge him to move faster. At least a half-dozen other drugmakers, including Johnson & Johnson and NewLink Genetics Corp., are developing their own Ebola vaccines.

“Everything is now devoted to Ebola,” said Hanneke Schuitemaker, head of viral vaccine discovery for J&J in the Dutch city of Leiden, where the company grows the active ingredient for its shot in 10-liter glass vessels. “People are working 18 hours a day.”

Those hours of work don’t come cheap. Developing a new vaccine typically costs between $500 million and $1 billion, according to PATH, an organization in Seattle devoted to making medications available in developing countries. The cost for Ebola vaccines will largely depend on the dosage required, the complexity of the drug, and whether new factories must be built.

Vaccines against diseases such as pneumococcal infection and meningitis run between $2 and $5 a dose, according to the GAVI Alliance, a Geneva non-profit that pays for vaccine programs. The group is in talks with Glaxo and the WHO about Ebola and next month will decide whether to fund vaccinations against the disease.

In Lausanne, a city of 125,000 on the shores of Lake Geneva, Glaxo in October began inoculating volunteers to determine whether its vaccine causes fever or other unexpected side effects. The company is conducting similar safety tests in Britain, the U.S., and Mali. Newlink has started trials of its version in the U.S. and J&J will begin tests in January.

With new pockets of infection still breaking out -- the latest was in Mali, where more than 200 people had contact with at least five confirmed cases -- the WHO has said it won’t wait for those trials to finish before launching the next phase of testing, to see how effective the vaccines are in warding off Ebola. Those will begin by January in Liberia.

Muddy Roads

“Even if we decide not to use the vaccine during this outbreak and stockpile instead, we’d be so much better off than having nothing,” said Walter Orenstein, associate director of the Emory Vaccine Center in Atlanta.

As drugmakers prepare trials and eventually mass distribution, they must figure out how to keep the vaccines refrigerated from the moment they’re manufactured to their delivery across West Africa.

That journey could involve trucks, planes, buses, motorbikes and even bicycles as the medication makes its way from European manufacturing facilities through airports and crowded cities, then down long stretches of muddy rural roads to village clinics.

Most vaccines remain stable when cooled below 8 degrees Celsius (46 degrees Fahrenheit), but a few -- like those for polio -- must be stored at minus 15 (5 Fahrenheit) or colder. The cooling needs of the Ebola vaccine remain unknown, but some scientists fret that the gas- or kerosene-powered refrigerators and simple coolers used in remote areas of West Africa might not be reliable enough to protect it.

“Temperature stability is a really big deal,” said Kate O’Brien, a professor of public health at Johns Hopkins University in Baltimore and member of a panel of experts who advise the WHO on vaccine programs.

Past vaccination programs show the bottlenecks and gaps in delivery systems, some of them designed in the 1970s, said Bruce Lee, director of operations research at the International Vaccine Access Center at Johns Hopkins. During a recent polio campaign in Mali, a WHO team found a cold room so overstuffed that it couldn’t be closed properly. With boxes of vials spilling out the door, large quantities of vaccine had to be discarded because of heat damage.

“The lower down the chain you go, the less likely it is to be in working order,” said Michel Zaffran, the coordinator of WHO’s immunization programs. Zaffran says he expects data from the manufacturers on the stability of the vaccines at various temperature ranges will be ready in January.

Glaxo’s vaccine is being made at a factory in Pomezia, a Roman suburb near the beaches where U.S. troops landed in World War II. Inside the low-rise building, scientists grow cells in 50-liter plastic bags filled with a fluid that nurtures their development. To keep the newly grown cells from settling to the bottom, the bags rock back and forth on trays that look something like child-sized waterbeds.

Emotive Virus

The mature cells are injected with a weakened chimpanzee cold virus containing a small piece of the Ebola gene. After the virus reproduces in the cells, it is harvested and purified, then used to trigger an immune response to Ebola without actually infecting recipients with the disease.

When Glaxo has sufficient quantities, it will freeze the purified vaccine and truck it to what’s called a Biosafety Level 2 facility. There, it will be thawed and injected into tiny glass vials, which are flash-frozen for safe transport. With a limited number of such plants that aren’t already working on other vaccines, the WHO is urging regulators to allow packaging in facilities with lower-level bio-safety ratings.

In the field, health officials must ensure recipients welcome vaccination programs. While doctors, nurses, and other clinic staffers are likely to be the first to receive the drug, later recipients will include people with less understanding of the benefits and risks. With those people, building trust is “absolutely key,” said Heidi Larson, an anthropologist at the London School of Hygiene & Tropical Medicine.

“Ebola is a highly emotive virus,” Larson said. “You can never totally guess what people are going to be thinking.”

Nigerian doctor Muhammed Afolabi got a taste of that as he worked on a trial for vaccinating newborns against HIV in the Gambia. The doctor had announced it was to be a “double-blind” test, which means neither participants nor the scientists running the trial know whether a patient is getting the active drug or a placebo. One concerned mother asked whether her child might be able to participate in a single-blind trial instead.

Viral Video

“She only wanted her baby to lose sight in one eye,” Afolabi said. “She had no real idea what I was talking about.”

The experience spurred Afolabi to prepare a video for a later program to treat malaria in which he and others acted out instructions about possible side effects and when and why the medication should be taken. More than four-fifths of people who watched the video were later shown to understand the treatment, versus about half of those who only received verbal information.

The Ebola outbreak, at one point deemed out of control, proves the need for a vaccine and all the preparation work required to ensure people at risk of the disease will be protected, said Peter Piot, director of the London School of Hygiene & Tropical Medicine, as more epidemics of Ebola and of other diseases are sure to come.

“We must learn from crises,” said Piot, a participant in the discovery of the Ebola virus four decades ago in what was then called Zaire. “Crisis, for me, means problem plus opportunity, so we are prepared for the next one.”