Amid Failure and Chaos, an Ebola Vaccine

Ebola lingers. A 15-year-old boy in Monrovia, Liberia, his father and his brother are sick with the disease, the first cases in Liberia since June. How the boy caught Ebola is a mystery, but it is likely he had contact with an Ebola survivor. The virus also lingers in the body — and can sicken its host and infect others — even months after recovery.

There will most likely be more cases in this epidemic. But now, greater awareness and new tools are in place to contain them better, including a tool we have never had before: an effective vaccine.

Last year, Ebola became an international crisis that killed 11,300 people because of a failure of political will, according to a new report from Harvard and the London School of Hygiene and Tropical Medicine. Countries with the outbreak played down the initial cases and delayed reporting the outbreak to the World Health Organization until March 2014, three months after it began. The international response was unconscionably late. The W.H.O. did not declare an emergency until August, and only in September did large-scale international help reach the scene.

But since then, one thing has moved with record speed. In October 2014, researchers began Phase 1 safety trials of potential Ebola vaccines. By late March, one of them was saving lives in Guinea. A process that normally takes years had been compressed into six months.

The Ebola vaccine is a double achievement. Researchers proved the effectiveness not just of a novel vaccine, but also of a novel method of testing it rapidly, in chaotic conditions and without traditional clinical trials. Even as it was being tested, the vaccine was helping to contain Ebola.  Today, hopes are high that it will administer the coup de grace to the epidemic.

How was this achieved? And what can the world learn that will save lives and money in fighting future outbreaks of Ebola or other pathogens?

Ebola is a fearsome virus — but not to vaccine researchers. Making an Ebola vaccine has proved to be straightforward. By the time of the outbreak, in fact, several vaccine candidates had already been tested in animals and been found safe and effective. That had happened because of the very fear the disease inspires — paradoxically not in Africa, but in North America.

“None of these vaccines were designed to protect Africans during an outbreak,” said Adrian Hill, director of the Jenner Institute, a vaccine research group at the University of Oxford. “Their development was all funded to protect North Americans against bioterrorists using the Ebola virus.”

Animal testing is the easy part; what’s hard is moving beyond it. Vaccine development requires lots of money and attention, and the cruel fact is that both are always scarce for poor-country diseases. That is even more true for pathogens that begin with small outbreaks in remote areas. Vaccines may be needed only at some future day, in tiny quantities — or, hopefully, not at all.

“Everybody realizes there is no market for the industry,” said Marie-Paule Kieny, assistant director-general of the World Health Organization for Health Systems and Innovation. “You can’t just rely on the private sector to invest — there is no revenue for them. You need a coalition of the willing — philanthropists, but this is mainly the responsibility of governments.”

Outbreak pathogens include Ebola; Severe Acute Respiratory Syndrome, which caused 774 deaths 12 years ago; and its cousin, Middle East Respiratory Syndrome. They hold the world’s attention while they rage — and then are quickly forgotten.   “There were many vaccines in development for SARS, and after it ended they all stopped,” said David Heymann, head of the Center on Global Health Security at Chatham House. “If they had continued, now we would have a vaccine platform into which you could put a related virus” — like MERS, which has killed some 600 people and is not yet extinguished.

Another obstacle: Medicine’s standard of evidence is the Phase 3 clinical trial, which divides thousands of patients at random into vaccinated or vaccinated-with-placebo groups, and then counts how many get sick in each. But for that, you need a big outbreak.

Ebola was plenty big – at first. By the time a vaccine was ready to test, it wasn’t. A Phase 3 clinical trial began in Liberia last February, seeking to enroll 27,000 people to test the effectiveness of two top single-dose vaccine candidates. But less than three weeks later, new cases halted. Now only isolated outbreaks continue. It has been great news for the world — but bad news for testing a vaccine.

The Liberia trial could start so rapidly because, after September 2014, all the steps necessary to bring a vaccine to human trials were put on emergency footing by an alphabet soup of agencies, national governments, funders and research groups. “There was a clear decision that there was no choice — there must absolutely be acceleration of research and development even if we might be too late,” said Kieny. “There was enormous good will in all involved stakeholders — industry to make it, clinical investigators to drop all other clinical trials and liberate their centers to do this particular trial. Regulators and ethics review boards allowed the protocols to jump the queue.”

“The main thing that moved it forward was partnerships,” said Swati Gupta, Executive Director for Public Health and Scientific Affairs at Merck Vaccines. “There was unprecedented multinational collaboration.”

Two vaccines were tested beginning in September and October in Phase 1 trials — small trials for safety and immunogenicity (whether the vaccine provokes an immune response) in volunteers at multiple sites. One was developed by the United States National Institute of Allergy and Infectious Diseases and GlaxoSmithKline, and another by the Public Health Agency of Canada and licensed to NewLink Genetics and then Merck.

A third, two-dose vaccine followed in December: a two-stage vaccine whose development was funded by the United States National Institutes of Health and the Biomedical Advanced Research and Development Authority — the bio-threat agency Hill was describing. Johnson & Johnson’s Janssen Pharmaceuticals holds the license.

While researchers were working, logistics experts in affected countries built a chain of super-cold facilities using batteries and solar power, since both vaccines need to be held at around -80 degrees Celsius (-112 Fahrenheit) in countries without reliable electricity.

Meanwhile, researchers were getting financing. Hill, who led Oxford studies of the GSK vaccine, said that his application for funding to the Wellcome Trust, a British biomedical research foundation, was turned around in 12 days.

All this came together to enable the Phase 3 clinical trial of the Merck and GSK vaccines in Liberia — which very quickly fizzled out. The measure of a vaccine is whether it prevents infection in people exposed to a disease. With Ebola fading, how could that be tested?

Researchers turned to ring vaccination — vaccination of everyone in contact with a sick person, and the contacts of those contacts. It had been used once before, to complete the eradication of smallpox, but never to test a vaccine.

Researchers in Guinea started ring vaccination with Merck’s vaccine in late March. To test effectiveness, contacts were vaccinated in 48 Ebola cases. In a control group of 42 other cases, contacts of the sick had to wait three weeks before getting vaccine.

In the control group, 16 people developed Ebola. But of those who were vaccinated, after the few days necessary for the vaccine to take effect, no one got sick. In other words, the vaccination needed 6 days to take effect, and after that conferred 100 percent protection against Ebola. On July 24, the trial was stopped and all participants were vaccinated right away.

The other two vaccines never underwent Phase 3 trials, because Ebola cases had run out.

One potential problem with the Merck vaccine is its side effects: fever and arthritis pain that are temporary, but annoying. Another is that it might confer only very short-term protection. As with all new vaccines, we don’t know how long protection lasts; to find out if a vaccine lasts 10 years, you have to wait 10 years.

Nevertheless, the Merck vaccine does stop the transmission of Ebola. It is now being offered to contacts of the new patients in Liberia, according to the national allergy and infectious diseases institute.

The Janssen vaccine could be longer-lasting, because it consists of a prime vaccine and then a different vaccine as a booster shot. Paul Stoffels, chief scientific officer and worldwide chairman for pharmaceuticals at Johnson & Johnson, said that nine months into a trial, the vaccine was still working in those first vaccinated. A short-acting vaccine is adequate for emergencies, but a long-acting vaccine would best protect health care and burial worker.

Ebola lingers in another way. While the next pathogen to hit might be a disease we’ve never seen, it’s more likely to be a strain of Ebola. The virus lives in wild animals, and so can never be eradicated. There have been two dozen outbreaks in Africa since Ebola was discovered in 1976: last year, one in the Democratic Republic of the Congo, unrelated to the West Africa epidemic, killed 49 people while the world wasn’t looking.

Ebola is one of 15 outbreak pathogens that have emerged in the last 15 years, Hill said. All, like Ebola before last year, have potential vaccines available that have worked in animals — some better than others.

Kieny is convening meetings of researchers, funders and officials to draw up a global get-ready plan, which will begin with an attempt to identify the threats most likely to emerge, and plan for research and development.

Before being used in an outbreak, vaccine candidates must have already completed animal tests and Phase 1 and 2 clinical trials, so we know they are safe and can provoke an immune system response. They then must be manufactured to the highest standards and stockpiled in a large enough quantity for emergency use. Regulators in developed countries and countries likely to be hit must grant clearance to use the vaccine. And for all of this, there must be sustained money and attention — “in peacetime,” as Kieny puts it.

In an outbreak, a vaccine could be used as part of a clinical trial, either a standard trial or a ring vaccination trial. But there are also other ways. Luciana Borio, acting chief scientist of the United States Food and Drug Administration, said some vaccines had been licensed based on strong safety and immunogenicity data alone, without any trials of effectiveness in humans; one example is the flu vaccine, which every year covers new strains.

Another challenge is persuading pharmaceutical companies to manufacture these vaccines on a large scale. Stoffels said that Johnson & Johnson put $200 million into developing its Ebola vaccine candidate, with no guarantees of repayment. Pharmaceutical companies take risks with every drug, but these vaccines are particularly bad financial risks, and Janssen made 800,000 doses of its vaccine before knowing if it would be approved. “We can do that — once,” Stoffels said. “To do this many times, to get to a systematic response, there has to be an incentive.” He said that one option could be to give pharmaceutical companies accelerated regulatory review of another of their drugs.

“These do not look like difficult vaccines to make,” said Hill. “Ebola worked the first time.   We can do 10 in a similar fashion and they’re likely to work. It will cost tens of millions of dollars to make a small stockpile — a hundred million for a licensed product. But Ebola cost the world billions.”

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Tina Rosenberg won a Pulitzer Prize for her book “The Haunted Land: Facing Europe’s Ghosts After Communism.” She is a former editorial writer for The Times and the author, most recently, of “Join the Club: How Peer Pressure Can Transform the World” and the World War II spy story e-book “D for Deception.” She is a co-founder of the Solutions Journalism Network, which supports rigorous reporting about responses to social problems.