As foreign powers approve Ebola vaccines, U.S. drug makers lag in development pipeline

In the face of the West Africa Ebola crisis, U.S and Canadian government laboratories and a number of companies in Europe raced to test experimental vaccines.

A year and a half after that outbreak was declared over, the world has two licensed Ebola vaccines: One was made by scientists in Russia, the other by scientists in China.

And what of the vaccines devised in the U.S., Canada, and Europe? They are still meandering through the developmental pipeline.

It now looks like it may be 2019 at the earliest before an Ebola vaccine could be licensed by the Food and Drug Administration — nearly four years after a landmark trial showed that one of the candidates, Merck’s V920 vaccine, works. It is the only Ebola vaccine ever to have completed a crucial Phase 3 trial.

The slow pace of the process underlines just how long, complicated, and expensive vaccine development and licensure can be in the United States. In the case of Ebola, researchers had started working on vaccines years before the crisis in West Africa, in some cases more than a decade earlier.

Those efforts accelerated after the Ebola crisis, but since then, a sense of urgency over vaccine development has also dissipated.

Differences in the development and regulatory systems of the West and Russia and China may also have contributed to the speed with which those two countries were able to develop and license Ebola vaccines.

In the West, early research on vaccines is often conducted in government-funded laboratories. But at a point, the work needs a commercial partner — typically a major pharmaceutical company with the financial resources to fund the expensive trials licensure requires.

If there is little or no prospect of profits — and there is no traditional market for an Ebola vaccine — finding a partner can be tough. (Consider Sanofi Pasteur’s decision earlier this year to pull out of Zika vaccine work.) Most of the experimental Ebola vaccines designed in the West languished for years because of a lack of interest on the part of most of the pharmaceutical industry.

That work likely provided a foundation for the Russian and Chinese vaccines. Both reportedly use a human virus that causes colds to deliver a non-infectious piece of an Ebola virus to activate an immune response. Most of the Western vaccines use a similar approach, though they employ different viruses as the delivery system.

Relatively little is known about the Russian vaccine; it is still being tested in Guinea, where the 2014 outbreak began. A human study showed it was safe and triggered an immune response, though the trial was too small to prove it was protective. It isn’t clear what other data the Russian drug regulator used to approve the vaccine.

China’s regulatory agency recently approved an Ebola vaccine developed by the Chinese Academy of Military Medical Sciences’ Bioengineering Institute and Tianjin CanSino Biologics, though at this point its license restricts it to emergency use only.

Meantime, in the West, Merck and its main competitor, Janssen Vaccines — a division of pharmaceutical giant Johnson & Johnson — are working toward full licensure for their vaccines. Merck had long planned to file its application to the FDA by the end of 2017, but the company recently told STAT it would not meet that self-imposed deadline.

“It is the normal registration process,” Dr. Marie-Paule Kieny, who until last summer led World Health Organization efforts to accelerate development of Ebola vaccines and drugs, said when asked why the work on these Ebola vaccines seems to be moving more slowly.

In the event of another Ebola outbreak, the world might be able to turn to an emergency supply of vaccine. Merck and Gavi, the Vaccine Alliance, reached an agreement that established a stockpile of 300,000 doses of the Merck vaccine. (We say might because the Merck vaccine protects against one type of Ebola, the Zaire strain. If there were an epidemic caused by the Ebola Sudan virus, it would not be protective.)

There was talk of using some of the vaccine to contain an outbreak in the Democratic Republic of Congo last spring, but in the end, transmission petered out on its own.

“It’s not like there’s nothing, in the absence of registration there’s no way to use it. That is not the case,” explained Kieny, who is now research director at Inserm, the French equivalent of the National Institutes of Health.

“There is a way to use it. The framework is there. The logistics. Everything is planned. And therefore the urgency of having this registered is not that high.”

Merck took on the task of developing the vaccine in the autumn of 2014, when it became apparent that the license-holder, NewLink Genetics, did not have the expertise needed to handle an expedited approval process for what was seen to be a highly promising vaccine. The company, whose main focus is on cancer therapies, had never seen a vaccine through the licensure process.

That bit of global public service has cost Merck considerably, both in terms of money and opportunity costs. The company will, however, earn an FDA priority review voucher — which can be worth upwards of $100 million — if it completes the task of licensing the vaccine.

Merck would also be eligible for a second priority review voucher if it developed a combined vaccine to protect against several strains of Ebola and its cousin virus, Marburg. But the company seems ready to bow out of viral hemorrhagic fever vaccine work once this project is done.

“We understand, of course, that there’s a need and desire for potentially multivalent vaccines or additional vaccines to cover other types. And there are other developers who are really working on that. And we are very happy that they are working on that,” said Beth-Ann Coller, team leader on the project. “It’s certainly not our focus …. Ebola Zaire has been our focus.”

Meanwhile, Janssen Vaccines, which began working on Ebola vaccines in 2002, continues to amass the data it needs to support licensure of two Ebola products. One is a monovalent vaccine, designed to protect against a single virus, Ebola Zaire. The other, further back in its pipeline, targets two Ebola viruses, Zaire and Sudan, as well as the Marburg virus.

The company is currently conducting a clinical trial of the Ebola Zaire vaccine in children in Sierra Leone, which will serve as part of its licensure application, Dr. Johan Van Hoof, head of Janssen Vaccines, told STAT. Van Hoof said Janssen will need “some extra years” to put together the data it needs.

The company is encountering the same problem faced by all of the Ebola vaccine projects launched before the West African outbreak and since that crisis subsided. There is no way to conduct a Phase 3 trial — the large trial that shows whether a vaccine is protective — when Ebola is not spreading.

The Chinese vaccine was approved without Phase 3 data. Human data showed it was safe to use, but the studies showing the vaccine works were done in animals.

Van Hoof said Janssen expects to use this approach too — taking advantage of the so-called Animal Rule — when it applies for a license for these vaccines. The company has been in discussions with the FDA and its counterpart, the European Medicines Agency, to determine what they will require as proof the vaccine works.

Janssen wants to make sure that it can “build a bridge between the immune profile” it sees in vaccinated monkeys and the one it sees in humans, Van Hoof explained.

There is a lot of interest in the Janssen vaccine, which is given in two doses. A vaccine that needs two doses isn’t ideal in an outbreak; the Merck vaccine takes just one. But it is thought the two-dose regimen, which primes and then boosts the immune response, will induce more enduring protection.

A long-lasting Ebola vaccine administered to health care workers in at-risk countries could change the future of Ebola outbreaks. In the early days of an outbreak, before hospitals and clinics have been put on high alert, health workers often become infected and amplify spread.

Van Hoof also suggested data proving the Janssen vaccine protects people could be generated in future outbreaks, if the vaccine is given an emergency use authorization by the WHO.

But others aren’t so sure that in an outbreak, an affected country would permit Janssen or any other company with an experimental Ebola vaccine to conduct a trial, given that a vaccine with proven effectiveness already exists. Especially after that product, Merck’s vaccine, is fully licensed.

“The countries that have an outbreak will say: ‘We are not your playing ground. We want to get rid of this outbreak,’” Kieny said, noting that to even try might be deemed unethical.