FeatureEpidemiology

Epidemic Insurance

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Science  14 Apr 2017:
Vol. 356, Issue 6334, pp. 125-127
DOI: 10.1126/science.356.6334.125

Caught short by Ebola, the world gets ready for the next outbreak.

When the next viral threat goes on the march in a remote African or Asian village, a defunct drugmaking facility in Rockville, Maryland, could be critical to the global response. The plant, a warren of clean rooms crowded with glass purifying columns and stainless steel tanks, stands sterile and empty a few weeks before Christmas 2016. But the cavernous lobby is the scene of a company party, where an amateur band plays a spirited rendition of “Johnny B. Goode.”

The tune is apt. The plant's owner, pharmaceutical giant GlaxoSmithKline (GSK), foresees a new and virtuous life for the plant, which once made a monoclonal antibody to treat the autoimmune disease lupus. Ripley Ballou, an infectious disease specialist at GSK—and the band's guitarist and lead singer—wants to rebuild it under a “no profit, no loss” model as the world's only facility dedicated to manufacturing commercially risky vaccines against future viral threats. For the conservative pharmaceutical industry, which normally develops vaccines for large, secure markets, it's a proposal as brash as a Chuck Berry song. It's also something of an insurance policy for GSK—and it comes with a public relations bonus for the company.

The London-based firm's offer to convert the plant into what it calls a Biopreparedness Organization (BPO) evolved from its frustrating attempt to rush out a vaccine during the Ebola crisis that erupted in West Africa 3 years ago and, at one point, threatened more than a million people. GSK's resource-draining, crash effort, which Ballou directed, slammed to a halt when traditional containment efforts stopped the epidemic in the summer of 2015. The company never could determine whether the vaccine worked—and whether it might help end future epidemics. “That left us with a bad taste in the mouth,” Ballou says. “There has got to be a better way of doing this.”

When Middle East respiratory syndrome (MERS) jumped to South Korea in 2015, a business complex used a thermal camera to detect possible cases. An effort is underway to speed development of a MERS vaccine.

PHOTO: CHUNG SUNG-JUN/GETTY IMAGES

BPO would draw on outside funding to retrofit and staff the plant, which would make vaccines that public health experts identify as priorities. It would move them through early phase I and II human tests for safety and immune responses so they could be ready for large-scale phase III efficacy trials the minute an outbreak occurs. With Ebola, “we were way behind the eight ball,” says Ballou, noting that phase I tests didn't start until the epidemic was raging.

BPO, which has yet to attract funding, is just one idea in a much broader, revolutionary rethink of epidemic preparedness in the wake of the devastating Ebola crisis. “The enormity and complexity of the problem that has to be addressed is not going to be solved by building a manufacturing plant,” says Julie Gerberding, an executive at Merck in Upper Gwynedd, Pennsylvania, who formerly headed the U.S. Centers for Disease Control and Prevention.

Merck also invested substantial resources into making an Ebola vaccine, and Gerberding says it faced “incredible challenges” that had nothing to do with manufacturing: securing permits to move the product and the reagents needed to test it across borders, weighing liability concerns, and staging clinical trials in the midst of an epidemic. “It was just one barrier after another,” she says. To top it off, even though Merck's vaccine worked in a phase III trial, it has not yet received approval for future use.

Gerberding, along with Ballou's boss Moncef Slaoui—an architect of the BPO idea—both sit on an interim board of a new organization that aims to, in its words, “tackle the barriers to epidemic vaccine development” and “give us the joint global insurance policy we need.” Called the Coalition for Epidemic Preparedness Innovations (CEPI) and temporarily based in Oslo, the nonprofit has raised more than half a billion dollars, which could support vaccine development at BPO or other, smaller contenders. The effort is “really energizing,” says Gerberding, a veteran of emergency responses to anthrax, severe acute respiratory syndrome, and avian flu scares. “I'm so tired of reading after-action reviews that say the same thing over and over again,” she says. “Let's do something different and figure out how we're going to solve this.”

DURING A TOUR of the would-be BPO plant, Ballou has the verve of a new homeowner imagining the possibilities. He envisions moving away from the traditional, inflexible approach to making vaccines, which relies on hard-to-clean stainless steel fermenters holding thousands of liters, which churn out disabled microbes or their proteins. “Plug-and-play vaccine production” is his mantra. The system GSK used for its Ebola vaccine is a model: A respiratory virus found in chimpanzees, which cannot harm humans, is engineered to hold the gene for an Ebola surface protein and then grown in disposable plastic bags of cell culture. The chimp virus or another “platform” could serve as the backbone for myriad other vaccines, allowing the plant to quickly switch products, Ballou says. “All of that adds to reduction of complexity, reduction of cost, and shorter time frames.”

Adel Mahmoud, who from 1999 to 2005 was president of Merck Vaccines, likes the BPO idea. But Mahmoud, an infectious disease specialist now at Princeton University, says Ballou's plug-and-play vision “is still pie in the sky,” stressing that “every vaccine we've dealt with in the last 30, 40 years is a different production process.”

Gary Nabel, chief scientific officer at Sanofi in Cambridge, Massachusetts, wonders who would own intellectual property (IP) that resulted from work at the BPO plant. “It's a thorny issue,” he says. “There could be a lot of research around the platform,” which the company might want to patent. Ballou acknowledges as much. “We can't be in a position where we lose access to critical IP that we need to be successful as a company.”

But the main stumbling block could be cost. BPO would require roughly 170 full-time staff, and GSK estimates it would cost $80 million to retrofit the plant and another $40 million a year to operate it, conduct animal studies, and run clinical trials. Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, notes the challenge. “It's very difficult to raise money for something that hasn't happened yet,” he says. “But you have to prepare for something that hasn't happened because it hasn't happened yet.”

A race against time

Vaccines already exist for many emerging threats, but most are years from being ready for full-scale testing. Several new efforts aim to shorten the timeline.

GRAPHIC: ADAPTED BY V. ALTOUNIAN/SCIENCE FROM CEPI AND WHO

The world's three other large vaccine-makers dislike the BPO model. Sanofi would prefer to receive outside funding to build extra plant space it could use for either commercial or nonprofit projects as needed. “It's a more dynamic and distributed model,” Nabel says. Merck's Gerberding says the key issue is “agility in your manufacturing prioritization process.” At Pfizer, Kathrin Jansen, who heads vaccine R&D in Pearl River, New York, says the company wants to see which vaccines move forward before it decides whether to commit manufacturing capacity. “I'm not sure having a dedicated facility [ahead of time] makes the most sense,” she says.

Slaoui, GSK's chairman of vaccines, says none of these companies has “idle capacity waiting out there,” and none can afford to shift from a commercially hot vaccine project to an unpredictable emergency outbreak. “What business can have an ideal capacity waiting to be diverted to a particular crisis?” Slaoui asks. “It's not possible.”

CEPI HOPES TO HELP sort out these dilemmas. In January it solicited proposals for the development of vaccines against three viruses earlier identified by World Health Organization expert committees as potential outbreak threats: Lassa, a hemorrhagic disease spread by rats in West Africa; Middle East respiratory syndrome (MERS)-coronavirus; and Nipah, a bat-borne virus that causes encephalitis in Asia. None of these vaccines has moved beyond phase I tests—they're stuck in the R&D “valley of death.”

CEPI over the next 5 years plans to fund two versions of each of these vaccines through phase II studies and the production of enough doses to stage phase III trials. “If we would have had that for Ebola we would not only have had certainty about the efficacy of the candidate vaccines, but we would have saved lives,” says Peter Piot, head of the London School of Hygiene & Tropical Medicine and vice chair of CEPI's interim board.

CEPI explicitly addresses the IP issues, noting that its primary objective is that the vaccines be priced “as low as possible” so there's “equitable access.” CEPI will negotiate terms on a case-by-case basis, but does not seek to own IP—only stipulating that programs “dedicated” to the mission, like BPO, must funnel profits from IP discovered under contract back to the program. If a vaccine becomes commercially viable, CEPI also wants a share of profits.

GSK, along with more than two dozen other companies and research groups, has approached CEPI for support. Funding from CEPI alone wouldn't be enough to sustain BPO, however, and GSK is also seeking support from the U.S. Biomedical Advanced Research and Development Authority (BARDA). BARDA focuses on protecting the country from bioattack, not public health threats, but Ballou says it has been “the most receptive” potential financial backer other than CEPI and is “working creatively” to see whether it can support BPO given its mission and funding constraints.

FREEZERS IN MARYLAND AND PENNSYLVANIA hold a reminder of another challenge to preparedness: 700,000 doses worth of Merck's Ebola vaccine, tested but not yet approved. Epidemiologist John-Arne Røttingen, interim CEO of CEPI, headed the steering committee of an efficacy trial of the vaccine in Guinea, and he is deeply frustrated that the road to licensure had so many twists and turns. “We don't know when the next outbreak will happen and we need a very clear and strong strategy,” he says.

The results of the 4000-person Guinea study were spectacular: Not a single person in the treatment group became infected (although even the control group had just 23 infections). But the trial's unusual design challenged the U.S. Food and Drug Administration (FDA), which is still debating whether to license the vaccine. Unlike a traditional phase III study, in which people at risk of a disease are randomly assigned to receive either the vaccine or a placebo, the study vaccinated a cluster or “ring” of people who might have had contact with a confirmed Ebola case. As a control, other rings received the vaccine after a delay of 21 days. Because the participants all had an unusually high likelihood of exposure to the virus, the ring trial promised faster results, with fewer people.

In another departure from convention, the study did not attempt to identify an immune response that correlated with protection: Worried about accidental transmission of Ebola, the researchers deemed it unsafe to take blood samples from participants. Assessing immune responses in vaccinees might have allowed investigators to bridge the human results to data from monkey studies, strengthening the case for licensure. It also might have opened the door for what's known as “accelerated approval,” which allows a product to come to market simply if a human trial provides what FDA calls a “surrogate endpoint that reasonably suggests clinical benefit.”

Accelerated approval of the Merck vaccine might have allowed both GSK and Johnson & Johnson of New Brunswick, New Jersey—which has moved its own Ebola vaccine through phase II studies—to push for licensure with the same surrogate endpoint data. But accelerated approval requires postmarketing studies during subsequent outbreaks. Vaccines that had piggybacked on Merck's approval would then face an ethical dilemma: Can you test alternatives to a vaccine with proven efficacy during the spread of such a lethal disease?

GlaxoSmithKline's Ripley Ballou wants to convert this inactive pharmaceutical plant in Rockville, Maryland, into the world's go-to facility for making vaccines against emerging diseases.

PHOTO: PAUL FETTERS

CEPI organized a closed-door meeting 22 March at the National Academy of Medicine in Washington, D.C., to address these perplexing questions. “Ebola pressure tested the system,” says the chair of CEPI's scientific advisory committee, Mark Feinberg, who headed Merck's Ebola vaccine project and now runs the International AIDS Vaccine Initiative in New York City. “It was terrible in many ways, but it's illuminating how we need to move forward.”

EPIDEMIC INSURANCE POLICIES CANNOT eliminate risks. But they can reduce the likelihood of an Ebola-scale catastrophe. “The chance that the next big problem is going to be Lassa, MERS, or Nipah isn't very high,” Merck's Gerberding says. “But we've got to start somewhere, and by continuing to plug along on this, eventually we'll have a much stronger armamentarium and enhance the probability of success.”

CEPI may not be able to finish the job alone—and it remains short of funds to complete its own agenda. Major global health donors like the U.S. and U.K. governments have yet to contribute, and CEPI so far has raised only half of the $1 billion it expects to need for the first 5 years. There's no money in reserve to pay for the expensive phase III trials that CEPI-funded vaccines ideally will receive during an outbreak. Nabel says he'd like to see a more “serious and sustainable investment” in R&D for these vaccines, for example a commitment by the G-8 countries to each contribute $100 million per year for 10 years to address these challenges. “We're all tired of seeing these fire drills, and when Ebola's gone we forget about it,” he says.

A perspective that appeared online in the 10 April issue of the Proceedings of the National Academy of Sciences—co-authored by GSK Chief Scientist Rino Rappuoli—also urges a bolder response, stressing that CEPI and BPO have “much merit” but would “still leave us short.” The perspective calls for an independent agency devoted to biopreparedness, funded by all governments, and making both vaccines and monoclonal antibodies against up to 30 threatening diseases.

Ballou says that if BPO can't find funding, “We will do the best we can, that's all I can say.” His worry is that without BPO “it's going to be very difficult to have the kind of response you saw even for Ebola.” Yes, GSK, Merck, and their many collaborators moved untested vaccines forward at unprecedented speed. But all told, the West African Ebola epidemic sickened 28,616 people, killing nearly 40% of them, and a vaccine had nothing to do with bringing it to an end.

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