The U.S. Food and Drug Administration just approved one of the most sought after vaccines in recent decades. It's the world's first vaccine to prevent dengue fever — a disease so painful that its nickname is "breakbone fever."
The vaccine, called Dengvaxia, is aimed at helping children in Puerto Rico and other U.S. territories where dengue is a problem.
But this vaccine has a dark — and deadly — history. One that has led to criminal charges in the Philippines, sparked national panic and fueled a massive measles outbreak that has already killed more than 355 people.
That story begins on a stage in Manila in 2016.
A young girl, about age 9 or 10, sat on a chair surrounded by health officials. She wore a bright yellow T-shirt with the words "Dengue is dangerous" across it. She squeezed her eyes and bit her lip as the health secretary of the Philippines, Dr. Janette Garin, gave her a shot in the arm.
That shot launched a massive vaccine campaign to inoculate nearly 1 million schoolchildren with Dengvaxia. The goal was to save thousands of kids' lives and prevent an estimated 10,000 hospitalizations over a five-year period.
But in the end, estimates are that more than 100,000 Philippine children received a vaccine that health officials say increased their risk of a severe and sometimes deadly condition. In addition, other children who received the vaccine may have been endangered because, their parents alleged, they were not in good health.
The French pharmaceutical company Sanofi Pasteur spent 20 years — and about $2 billion — to develop Dengvaxia. The company tested it in several large trials with more than 30,000 kids globally and published the results in the prestigious New England Journal of Medicine.
But halfway around the world from the Philippines, in a Washington, D.C., suburb, one scientist was worried about the new vaccine.
"When I read the New England Journal article, I almost fell out of my chair," says Dr. Scott Halstead, who has studied dengue for more than 50 years with the U.S. military. When Halstead looked at the vaccine's safety data in the clinical trial, he knew right away there was a problem.
For some children, the vaccine didn't seem to work. In fact, Halstead says, it appeared to be harmful. When those kids caught dengue after being vaccinated, the vaccine appeared to worsen the disease in some instances. Specifically, for children who had never been exposed to dengue, the vaccine seemed to increase the risk of a deadly complication called plasma leakage syndrome, in which blood vessels start to leak the yellow fluid of the blood.
"Then everything gets worse, and maybe it's impossible to save your life," Halstead says. "A child can go into shock."
"The trouble is that the disease occurs very rapidly, just in a matter of a few hours," he adds. "And there's nothing on the outside of the body to signify the person is leaking fluid on the inside."
The complication is rare, says Halstead. Still, he was so worried about the safety concerns that he wrote at least six editorials for scientific journals. He even made a video to warn the Philippine government about the problem.
"I just think, 'No, you can't give a vaccine to a perfectly normal, healthy person and then put them at an increased risk for the rest of their lives for plasma leakage syndrome,' " Halstead says. "You can't do that."
The vaccine manufacturer disagreed with Halstead's interpretation of the study's results. The company wrote a rebuttal, asserting that regulatory agencies had approved Dengvaxia "on the basis of the vaccine's proven protection and acceptable safety profile."
The company also said it would perform additional studies to "further access the safety, efficacy and effectiveness" of the vaccine.
Despite these concerns, in July 2016, the World Health Organization went ahead and recommended the vaccine for all children ages 9 to 16.
"Yes, we did. It was what we call a 'conditional recommendation' with the emphasis to minimize potential risks," says Dr. Joachim Hombach, who led WHO's review of the vaccine. "We saw the problems. We also clearly pointed to the data gaps."
WHO recommended that Sanofi do more experiments to better understand the vaccine's safety issues. In its assessment, WHO pointed out that the vaccine "may be ineffective or may theoretically even increase the future risk of [being] hospitalized or severe dengue illness" in people who have never been exposed to dengue — which is about 10% to 20% of Philippine children.
WHO's recommendation came three months after the Philippines launched its mass vaccination campaign in April 2016.
A year and half later, that campaign came to a screeching halt.
In November 2017, Sanofi published an announcement on its website saying it had new information about Dengvaxia's safety.
Halstead's fears were confirmed. Sanofi had found evidence that the vaccine increases the risk of hospitalization and cytoplasmic leakage syndrome in children who had no prior exposure to dengue, regardless of age.
"For individuals who have not been previously infected by dengue virus, vaccination should not be recommended," the company wrote.
Panic hit the Philippines. In news reports, parents said that the vaccine contributed to the deaths of 10 children. Protests erupted. The Congress of the Philippines launched investigations into the vaccine's purchase and the immunization campaign. And Philippine health officials started performing autopsies on children who died after receiving the vaccine. "In total, the deaths of about 600 children who received Dengvaxia are under investigation by the Public Attorney's Office, " the South China Morning Post reported last month. Investigators have not yet released their results.
Here's the problem with Dengvaxia.
Typically, a vaccine works by triggering the immune system to make antibodies against the virus. These antibodies then fight off the virus during an infection.
But dengue is a tricky virus. Dengue antibodies don't always protect a person. In fact, these antibodies can make an infection worse. The dengue virus actually uses the antibodies to help it spread through the body. So a second infection with dengue — when your blood already has antibodies in it — can actually be worse than the first; a person is at a higher risk of severe complications like plasma leakage syndrome.
In its follow-up study, Sanofi found evidence that Dengvaxia acts like the first infection for a person who has not been previously infected. The body produces antibodies against the vaccine, which have a similar potential for harm.
The increased risk seems small. The vaccine raises the risk of hospitalization after a dengue infection from about 1.1% to 1.6%, the follow-up study from Sanofi found. So out of 1 million kids in the Philippines, the vaccine would cause about 1,000 to be hospitalized over five years, Sanofi estimated. (On the other hand, the vaccine would prevent about 12,000 hospitalizations for a new dengue infection in children who have had a prior dengue infection during this same time period.)
But in the world of vaccines, that's not an acceptable risk. A risk needs to be exceedingly small to be tolerated. For example, with the measles vaccine, the risk of encephalitis is about 1 in 1 million, or 1,000 times less than the risk from a measles infection, WHO says.
WHO eventually changed its recommendation. The agency now says the vaccine is safe only for children who have had a prior dengue infection.
By the time Sanofi acknowledged this problem with the vaccine, about 800,000 Philippine children had been vaccinated. The Sanofi study estimated that more than 100,000 of them had never been infected with dengue and should not have received the shot, according to WHO's revised recommendation.
Given the concerns by Halstead and the initial unknowns about the vaccine's safety, Philippine parents should have been warned about a potential risk, says Dr. Isabel Rodriguez at the University of California, San Francisco.
"What bothers me most about this story is risk communication," says Rodriguez, who studies dengue in South America. "There was a lot of uncertainty from the beginning [about the vaccine's safety]. That needed to be communicated explicitly. You need to be honest about what evidence is out there."
Dr. Su-Peing Ng, global medical head of Sanofi Pasteur, says the company followed all World Health Organization guidelines while developing the vaccine and communicated honestly throughout the process. "We've always been very transparent in sharing the results of our research," Ng says. "And I just want to stress that we have full confidence in our vaccine as it's been approved by regulatory agencies in over 20 countries."
In hindsight, Ng says, Sanofi wouldn't do anything differently with the development of the vaccine: "No, we have been very, very close to the research community, working closely with them over the last 20 years in the effort to find a solution for public health needs."
In April, the Philippine government indicted 14 government officials over the deaths of 10 children who received the Dengvaxia vaccine. The government said the officials acted with "undue haste" in procuring the vaccine and launching the mass immunization campaign. The Philippine Department of Justice said the campaign started before the clinical trials were finished
In some instances children were given the vaccine by untrained health workers and allegedly without a proper physical beforehand. Some children allegedly had preexisting medical conditions that made the immunization dangerous. But these children were still inoculated, the government found.
Six Sanofi officials were also indicted for not properly helping children who had serious reactions to the shot. Sanofi disputes this and other allegations, adding in a written statement to NPR: "We strongly disagree with the DOJ's findings made against Sanofi's officials (current and past) and we will vigorously defend them. There is no clinical evidence that any reported fatalities were causally related to vaccination.
"We diligently monitor the safety of people participating in clinical studies. We are also performing pharmacovigilance activities and continuously monitoring the safety profile of the vaccine in a real-world setting, including the Philippines."
Regardless of how these trials turn out, the debacle in the Philippines offers a key lesson for governments and manufacturers when it comes to approving and selling new vaccines: Slow down, says physician and bioethicist Keymanthri Moodley. Mistakes with vaccines can erode the public's trust and have long-term consequences for the health of an entire country.
"When a vaccine goes wrong, it creates fear and anxiety in terms of the public, especially the parents," says Moodley, who directs the Centre for Medical Ethics & Law at Stellenbosch University in South Africa. "That fear can impact negatively on the established immune programs that are actually safe and work very well."
Since the Dengvaxia controversy, the confidence in vaccines among Philippine parents has plummeted from 82% in 2015 to only 21% in 2018, a recent study found. Over that same time span, the proportion of parents who strongly believe vaccines are important has fallen from 93% to 32%.
As result, vaccine coverage for childhood diseases in the Philippines, such as the measles, has dropped, WHO says. And the Philippines is now facing a large measles outbreak, with more than 26,000 cases and more than 355 deaths during 2019.
Here in the U.S., the approval of the vaccine — to be used in Puerto Rico, U.S. British Virgin Islands and Guam — comes with an important restriction: Doctors must have proof of a prior dengue infection to ensure the vaccine will not pose any risks to the child. That's a safeguard Philippine families never had.