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Every few years an alarming disease launches a furious, out-of-the-blue attack on people, triggering a high-level emergency response. SARS. The H1N1 flu pandemic. West Nile and Zika. The nightmarish West African Ebola epidemic.

In nearly each case, major vaccine producers have risen to the challenge, setting aside their day-to-day profit-making activities to try to meet a pressing societal need. With each successive crisis, they have done so despite mounting concerns that the threat will dissipate and with it the demand for the vaccine they are racing to develop.

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Now, manufacturers are expressing concern about their ability to afford these costly disruptions to their profit-seeking operations. As a result, when the bat-signal next flares against the night sky, there may not be anyone to respond.

GSK has made a corporate decision that while it wants to help in public health emergencies, it cannot continue to do so in the way it has in the past. Sanofi Pasteur has said its attempt to respond to Zika has served only to mar the company’s reputation. Merck has said while it is committed to getting its Ebola vaccine across the finish line it will not try to develop a vaccine that protects against other strains of Ebola and the related Marburg virus.

Drug makers “have very clearly articulated that … the current way of approaching this — to call them during an emergency and demand that they do this and that they reallocate resources, disrupt their daily operations in order to respond to these events — is completely unsustainable,” said Richard Hatchett, CEO of CEPI, an organization set up after the Ebola crisis to fund early-stage development of vaccines to protect against emerging disease threats.

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Hatchett and others who plan for disease emergencies worry that, without the involvement of these types of companies, there will be no emergency response vaccines.

“The only real expertise in the world to make these vaccines in a quantity and a safety environment is in the private sector,” said Michael Osterholm, director of the Center for Infectious Diseases Research and Policy. “If the private sector isn’t fully engaged and involved, it’s a show stopper.”

Nearly all the major pharmaceutical companies that work on these vaccines have found themselves holding the bag after at least one of these outbreaks.

GSK stepped up during the Ebola crisis, but has since essentially shelved the experimental vaccine it once raced to try to test and license. Two other vaccines — Merck’s and one being developed by Janssen, the vaccines division of Johnson & Johnson — are still slowly wending their ways through difficult and costly development processes. Neither company harbors any hope of earning back in sales the money it spent on development.

A number of flu vaccine manufacturers were left on the hook with ordered but unpaid for vaccine during the mild 2009 H1N1 flu pandemic. By the time the vaccine was ready — after the peak of the outbreak — public fear of the new flu had subsided. Many people didn’t want the vaccine, and some countries refused to take their full orders. GSK, Sanofi Pasteur, and Novartis — which has since shed its vaccines operation — produced flu vaccine in that pandemic.

Dr. Rip Ballou, who heads the U.S. research and development center for GSK Global Vaccines, told STAT it’s not in the “company’s DNA” to say “no” to pleas to respond to appeals in an emergency. But the way it has responded in the past is no longer tenable.

“We do not want to have these activities compete with in-house programs,” said Ballou. “And our learnings from Ebola, from pandemic flu, from SARS previously, is that it’s very disruptive and that’s not the way that we want to do business going forward.”

GSK has proposed using a facility it has in Rockville, Md., as a production plant for vaccines needed in emergencies, but the funding commitments that would be needed to turn that idea into reality haven’t materialized.

And as Ebola and Zika recede ever further in the rearview mirror, the chances governments and philanthropy institutions will seize on this type of paradigm-shifting proposal appear to be slight. The threat of new outbreaks is still top of mind for organizations in this area, like BARDA and CEPI — the U.S. government’s Biomedical Advanced Research and Development Authority and the Oslo, Norway-based Coalition for Epidemic Preparedness Innovations. But there appears to be little discussion of the issue among governments facing perennial funding shortfalls.

“The people that are concerned about this haven’t lost focus,” Ballou said. “We’re still very concerned about it. I know BARDA hasn’t lost focus. CEPI hasn’t lost focus. But the rest of the world probably has.”

Sanofi Pasteur has also taken several enormous hits in the successive rounds of disease emergency responses. In the early 2000s, the company worked on a West Nile virus vaccine. Though the disease still causes hundreds of cases of severe illness in the U.S. every year and is estimated to have been responsible for over 2,000 deaths from 1999 to 2016, public fear abated, taking with it the prospects for sales of a vaccine. Sanofi eventually pulled the plug.

In 2016, Sanofi was the only major manufacturer to commit to trying to make a Zika vaccine on an expedited basis. But BARDA, which had been helping to fund the work, told Sanofi last year that it would not support the company’s Phase 3 trial – the large and expensive study needed to prove a vaccine works — and instead backed an effort by Takeda Pharmaceuticals.

At the same time, the company bore the brunt of a barrage of criticism for not publicly committing to a low-price guarantee for developing countries. Facing horrible PR and no sales prospects, Sanofi announced late last summer that it was out.

“It was a bruising experience,” admitted John Shiver, Sanofi’s head of vaccine research and development. “Honestly, we really were trying to be good citizens.”

As was the case with Zika, emergency vaccine development efforts are often at least partially funded from government coffers. But Hatchett said the sacrifices of pharmaceutical companies in outbreak response work are still underappreciated.

“If you look at the performance of the vaccine companies, it’s hard to think of an example going back 30 or 40 or 50 years where they haven’t stepped up to the plate. I think their record of corporate social responsibility is a story that they don’t get nearly enough credit for, given the risks and what they take on and how little they get out of responding,” he said.

Even if governments help fund vaccine work, money can dry up and costs can add up. Scientists reassigned to work on emergency vaccines have to put aside other work that their company — and its shareholders — hope will earn profits.

“There are opportunity costs, especially if you’re trying to do something fast. I mean, we put the equivalent of a couple of programs worth of people on Zika,” Shiver said. “They were all working on high-priority projects for us and we switched them off those projects. … And those programs slowed down or stopped.”

Shiver said particularly problematic for vaccine manufacturers is the fact that it is extraordinarily difficult to run the clinical trials needed to persuade regulatory agencies that emergency vaccines are safe and effective. Conducting research during a crisis is notoriously tough and, with diseases like these, after outbreaks end, there’s typically no way to mount a standard Phase 3 trial.

In an emergency, regulatory agencies may be willing to bend some rules. But once the crisis subsides, they revert to normal operating procedures — as Merck has found out as it tries to persuade regulators to accept data from an innovative ring-vaccination trial conducted on its Ebola vaccine.

“This is sort of a human nature problem. People pay attention to the burning house, and maybe not the one that’s got bad wiring, right, that’s down the street,” Shiver said.

Finding a way that allows vaccine makers to help without sustaining these kinds of operational costs is critical to the success of future disease outbreak responses, experts say. Because the reality is that even if a government or academic laboratory designs and tests a promising vaccine for a dangerous pathogen, someone has to make it — and potentially make large amounts of it.

“These repeated incidences where people were left hanging is going to make it a lot harder for companies to be able to make the case internally that they should get involved. And if that happens — which I think it is happening — the world is going to be in a much riskier place,” said Dr. Mark Feinberg, president of the International AIDS Vaccine Initiative and formerly Merck’s chief science officer.

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