Epidemic of Fear: How the Trouble-Ridden Debut of a Breakthrough Vaccine Sparked a Panic

This post was originally published on this site

The scene is quiet, eerily so. A camera moves over a motionless child—dressed in church clothes, laid out on a metal table—and then pans over a huddle of grieving family members. There is another video just like it, and another, and another—an entire series that, collectively, offers a startling amount of footage showing children lying dead in a morgue in the Philippines. 

Two stoic-looking women figure prominently in the videos. One of them, Annie Gabito, has a stern and commanding presence. The other, ­Persida Acosta, is typically at the center of the scene. Acosta, the chief public attorney of the Philippines, offers a word or hand to the grief-stricken family and, in one instance, with a look of serious inquiry prods the child’s lifeless body.

Broadcast live on Facebook over the past two years, the videos have together been viewed millions of times. They were filmed after a forensic team assembled by the public attorney’s office—rather than by the government’s regular medical examiners—conducted autopsies of the children as part of its investigation into the deaths of 148 children.

Citing these autopsy results, Acosta and the family members all point to the same culprit for the children’s deaths: Dengvaxia, made by French pharmaceutical giant Sanofi, the first and only vaccine approved to protect against the dengue virus, which infects an estimated 390 million people around the world each year.

A boy suffering from dengue fever rests under a mosquito net in a gymnasium in the town of Maasin in the Philippines in July 2019.
Leo Solinap—EPA-EHE/Shutterstock

I met the parents of 18 of these children this July. They had come from all over the chaotic, gridlocked megacity of Manila one Saturday to the modest two-story home of Gabito, who works unpaid for a Filipino nonprofit called Volunteers Against Crime and Corruption and who now spends much of her time focusing on the families of the 148 dead children she calls the “Dengvaxia Victims.”

While Gabito made lunch, I sat at a table in the upstairs kitchen as parents filed up, one by one, to share their stories. They each wore a T-shirt with a picture of their deceased child framed by name and the Dengvaxia Victim number assigned to them by Gabito’s organization. Many of them came with their child’s Dengvaxia card, documenting the dates of vaccination and a sleeve or two of photographs, before-and-after-inoculation pictures that showed their kids healthy (fourth grade graduation, family photos, a selfie with a pet cat) and sick (swollen body parts or tethered to a hospital bed and an IV drip). A few volunteered photos from their child’s autopsy, an image of a brain or internal organs, which they said showed the telltale signs of Dengvaxia’s horrific effects.

Sumachen Dominguez, a lead organizer of the group, told me, “Nobody is listening to our anguish.”

Subscribe to Fortune’s Brainstorm Health Daily newsletter, where we monitor advances in healthcare and biopharma.

And there is some truth to that now. Last year, the story of the Dengvaxia Victims was the stuff of government hearings and wall-to-wall TV coverage—a made-for-the-movies narrative about dozens upon dozens of schoolkids dying, like sacrificial guinea pigs, as the Philippine government prematurely pushed its dengue immunization drive. There was even a fitting corporate villain—a foreign pharmaceutical giant, with $42 billion in annual revenue, that appeared to confess that its vaccine had a serious flaw.

But while the Philippine news media and most of the politicians involved have moved on, the Dengvaxia controversy continues to have a profound and lasting impact. A handful of Sanofi executives and employees have been charged with “reckless imprudence resulting in homicide,” as have numerous Filipino government health officers and a couple of scientific researchers, for their alleged roles in the Dengvaxia immunization program. Those trials are planned for next year.

Parents holding pictures of deceased children who had received the Dengvaxia vaccine at a hearing in the Senate building in Manila on Feb. 21, 2018.
Noel Celis—AFP via Getty Images

For Sanofi, it has been devastating financially as well. Right up through Dengvaxia’s 2016 launch, the Paris–based company, one of the premier vaccine makers in the world, had projected booming sales and a major win in terms of global goodwill. It is struggling to sell Dengvaxia anywhere now—despite its regulatory approval in the U.S., the EU, and an additional 20 countries—and the vaccine’s inclusion on the World Health Organization’s Essential Medicines List. (Sanofi took a $186 million write-down on Dengvaxia in 2017, but the total loss—counting everything the company spent on development and infrastructure, plus vanishing sales and damage to its reputation—is likely several times that.)

Much worse is the damage that has been done to public confidence in vaccines: In the Philippines, where immunization coverage was already dangerously low, the Dengvaxia scare caused vaccination rates to fall even further, opening the door to infectious diseases once believed to be on the wane. Over the past two years, there have been new outbreaks of measles and polio. When it comes to combating dengue itself—a scourge that can be bone-crushingly painful for some and deadly for others, and which in recent decades has emerged as the world’s fastest-spreading and most common mosquito-borne illness—the opportunity cost has been grave as well. 

Which brings up the first of this tale’s tragic, even Shakespearean twists: the fact that the Dengvaxia controversy may well bury forever a vaccine that actually works—not for everyone but for huge swaths of populations in countries where dengue is an urgent and growing public health problem. Indeed, if the vaccine were an active part of global health campaigns, it would likely save many lives annually. That’s plain to see, given that devastating dengue outbreaks have tested governments this year from Pakistan to Honduras to, yes, the Philippines. 

Twist No. 2 is this: There is a good chance that Dengvaxia didn’t cause the tragic deaths of those 148 children in the Facebook videos.

A fiasco foretold

Innocuously titled “Sanofi updates information on dengue vaccine,” the press release went out to the world, in both French and English, at 11:36 a.m. Eastern Time on Nov. 29, 2017. In the Philippines, the country where the most doses of the world’s first dengue vaccine, Dengvaxia, had been administered, it was just after midnight on Nov. 30.

Twenty months earlier, the Philippines had proudly been the first country to launch a public immunization program involving Sanofi’s vaccine, boldly taking aim at a disease that perennially caused agony for its citizens and taxed its overburdened health care system.

Dengvaxia, which the Filipino government gave to roughly 890,000 children, had been feted globally as a public health triumph. The development of Sanofi’s vaccine was as complicated and technically challenging as they come. And it was the culmination of a broader effort that spanned decades and took billions of public and private dollars. Plus, in an admirably altruistic inversion of the Big Pharma playbook, the vaccine was being delivered first not to the rich Western countries that could pay the most but to a poorer one that needed it more. It was a story to celebrate.

But here in Sanofi’s press release, buried in the middle of a dense paragraph of highly technical language, was a sentence that would surely give anyone in the Philippines pause: 

“For those not previously infected by dengue virus, however, the analysis found that in the longer term, more cases of severe disease could occur following vaccination upon a subsequent dengue infection.” In other words, there were some people who wouldn’t be protected from dengue by Dengvaxia. In fact, the opposite: It put them at risk for getting sicker. 

The statement, which Sanofi had sweated over and planned around for days, lacked context, local or otherwise. It didn’t offer probabilities or degrees of risk; it didn’t explain what “severe dengue” meant, or give people in the Philippines or Brazil, where another mass immunization drive was underway, or in any of the other 15 countries where Dengvaxia was licensed, any clue how worried they should be. It just recommended that people who had never previously had dengue not get the vaccine.

That was the moment the Dengvaxia fiasco began. It was also a fiasco foretold. While the vaccine had many boosters, a handful of scientists saw problems ahead. The most vocal of the critics was one of Sanofi’s own consultants, who warned the world that the vaccine would work—but only with a critical asterisk that health officials and the public needed to understand. Which meant the news that jolted the Philippines into a spiraling calamity on Nov. 30 was, among researchers, the subject of ongoing study and a much-discussed possibility.

“It seemed like a surprise, though it wasn’t a surprise,” says In-Kyu Yoon, a senior adviser for the International Vaccine Institute.

“The communication around this was difficult,” says Gundo Weiler, a director with the World Health Organization (WHO) based in Manila. The intricacies of vaccine science and dengue, especially in an environment of fear, he adds, “are not so easy to understand—that was the problem of the whole situation.”

Eric Domingo, who serves as undersecretary for the Department of Health of the Philippines, sums up the Dengvaxia tale best of all: “It just turned into this gigantic monster,” he tells Fortune. But what’s truly frightening is how quickly this monster formed, and how easily. What happened to Dengvaxia could happen to any imperfect medical innovation in the age of social media—for here, in the emotional gyre of politics, anxiety, and misinformation, the rational questions and doubts of science can quickly be branded as crimes and conspiracies.

Nothing about the development or administration of Dengvaxia was intentionally reckless, it should be said—though its story does contain elements of hubris, blind optimism, and questionable haste.

That was clear from the start, when Chris Viehbacher became CEO of Sanofi in December 2008. Almost right away, he green-lit the building of a $398 million plant to produce Dengvaxia outside Lyon, France. The company was more than a decade into its dengue clinical development program, but this was a next-level, we’re-in-it-to-win-it commitment. Or gamble, perhaps. At the time, the vaccine candidate was still in clinical trials and years from reaching the market. There was a decent chance it could fail outright—but then, the potential was enormous. On an earnings call in 2010, Viehbacher told analysts that the drug “promises to be potentially the biggest vaccine we’ve ever sold.” 

Preventing dengue, which epidemiologists call a “neglected tropical disease,” was an enormous unmet need. There was no drug to prevent, treat, or cure the illness. And in the past half-century, as the virus swept from Southeast Asia to 128 countries, or roughly half the globe, cases had increased 30-fold.

Dengue is carried by the female Aedes ­aegypti mosquito, a resilient, disease-­spreading pest—it also efficiently transmits yellow fever, chikungunya, and Zika, among other viruses—that has thrived in the modern, globalized world. The flying menace moves around on cargo ships and breeds in water that collects in, say, plastic waste and used tires. “It’s beautifully adapted to densely populated urban environments,” says Jeremy Farrar, director of the Wellcome Trust, a U.K.-based charity focused on global health. 

Sanofi executives expected that with a warming climate, the dengue-carrying mosquito’s reach would expand, too, spreading the miserable disease.

Once commonly called breakbone fever, dengue is painful to endure. (The origin of the name “dengue” is not certain but is thought by some to come from the Swahili phrase ka-­dinga pepo, meaning a cramplike seizure caused by an evil spirit.) Patients suffer debilitating spells of headaches, fever, and severe joint pain that can send them to the hospital with symptoms that can linger for two weeks. In the worst cases, patients experience “plasma leakage,” a life-threatening process in which the protein-rich fluid of the blood seeps out of vessels and into surrounding tissues.

Most cases of dengue are not so severe (the majority are asymptomatic), but up to 5% of them are—resulting in patients who may in frighteningly abrupt fashion go into shock or suffer hemorrhagic fever that can lead to death. 

Experts contend no one should die of dengue. There’s a way to manage cases so that even the most severely ill recover, but that requires early detection and involves close monitoring and maintenance of a patient’s fluid levels over a period of days. That’s not easy for resource-strapped health systems, especially during outbreaks when dengue patients pile up in hospital wards. For that reason, dengue kills about 20,000 people a year.

Given all that, Sanofi expected governments, not to mention donors like the Gates Foundation and GAVI, an international vaccine alliance, to happily shell out dollars to prevent the disease. But the potential market was even bigger than that. Viehbacher envisioned that Dengvaxia could one day be a vaccine for everyone—not just for the people who live in dengue-endemic countries but also for those in rich, Western countries who travel to them.

That was exactly the sort of game-changing product Sanofi’s new CEO needed in order to transform the storied but doddering French pharmaceutical firm. Three of Sanofi’s top-selling drugs were soon to lose patent protection—and with them, a good chunk of the company’s revenues. 

An employee working on a vaccine assembly line in Sanofi Pasteur’s vaccine production facility outside Lyon.
Philippe Desmazes—AFP via Getty Images

Viehbacher himself symbolized change. The German-born Canadian was the first non-Frenchman to helm the company (which this year ranked No. 288 on the Fortune Global 500), and many hoped he’d rev up Sanofi’s slow-moving and rigidly hierarchical culture. (Viehbacher, who did not respond to requests for comment on this story, was ousted in 2014.)

Sanofi had grown into one of the world’s largest pharmaceutical firms through acquisitions. But it traces its history back to the days of Louis Pasteur, the renowned French scientist who, among other things, invented the rabies and anthrax vaccines. He founded the Pasteur Institute, the respected biomedical research institute—part of which became Sanofi Pasteur, Sanofi’s $6-billion-in-revenue Lyon-based vaccine business. Today Sanofi Pasteur produces much of the world’s supply of inoculations against flu, polio, and meningitis. Viehbacher saw huge potential in the business.

Backed by Viehbacher, the dengue vaccine became a marquee project for the company, one that earned ink in Sanofi’s annual reports and regular mentions on earnings calls as the sort of innovative, globally relevant product that could power the company’s growth.

Sanofi had to move quickly though. A number of other organizations had their own dengue vaccines in the works.

Being first and fast to this potentially multi­billion dollar market would be critical, and Sanofi tried to establish an edge by wringing excess time from the clinical and commercial development processes. Its trials ran on a compressed schedule, with Dengvaxia’s expensive Phase III studies beginning before Phase IIb had ended. The company also ramped up manufacturing years in advance so that it would have a ready supply when the vaccine was eventually approved.

Determined to do everything possible to ensure the vaccine would become a commercial success, Sanofi created a new internal structure, the Lyon-based Dengue Company, that was designed to be an agile and all-encompassing “team of teams.” Every function—regulatory, marketing, distribution—was represented in the unit to more quickly coordinate work.

In May 2013, Viehbacher painted a rosy picture: “We’ve got ourselves a robust dengue vaccine,” he told analysts. He predicted the company would be producing 100 million doses annually by 2015. “This is a major not only public health issue but I think a commercial opportunity,” he said. “This affects half the world’s population.”

Sanofi’s optimism, though, wasn’t fully supported by the drug’s test results: The company had already begun its two Phase III trials when the results from the Phase IIb trial came in. They were disappointing: Tested on 4,000 children in Thailand, the vaccine had reduced dengue infections in kids by just 30% in the two-year follow-up period. In short, the vaccine had fallen far short of expectations.

But the Phase III results—based on two studies of 31,000 children in 10 countries—were more promising. Dengvaxia didn’t work perfectly. But Sanofi and the scientific community believed they had a vaccine that could make a difference against dengue. 

Tackling a year-round killer 

“Dengue is really, really difficult,” says Stephen J. Thomas, a professor at SUNY Upstate Medical University who started studying the virus as a doctor with the U.S. Army a couple of decades ago. Questions that were raised about the virus in the early 1950s remain unanswered today. “Half of the world lives at daily risk of being infected with dengue,” says Thomas, “but we don’t know why some people get sick and some people don’t. We don’t know why some people get very sick and some don’t. A lot of the questions that have plagued dengue researchers are the exact questions that have been so problematic to vaccine developers.” There’s not an animal model that comprehensively mimics the disease in humans, explains Thomas, who has been a paid adviser to numerous dengue vaccine developers, including Sanofi. 

What we do know about dengue is that it’s insidiously complicated. Its basic epidemiology reads like a Mensa logic problem.

Dengue virus comes in four similar but distinct varieties, known as Dengue serotypes 1 through 4. When individuals get a first dengue infection, they develop lifelong immunity from the infecting strain. For a brief period of time, they also enjoy protection from the other three. But that cross-protection wears off—after a period of anywhere from two months to two years—and the individual becomes vulnerable to getting more severely ill on a second infection. 

That’s why it’s the second infection that health officials worry about. People tend to get only mildly sick or not sick at all after their first dengue infection, and for some reason, they hardly ever get sick on their third or fourth. The worst, life-threatening cases of dengue, the ones with plasma leakage that can lead to hemorrhagic fever or shock, almost always result from a second exposure. 

To make matters more complicated, all four serotypes are constantly comingling in most dengue-endemic countries, meaning the chances are higher for a second infection to occur. (So is the likelihood of a genetic mutation, which could produce a more virulent virus.) That wasn’t the case in most places even a couple of decades ago, and it helps explain why the number of dengue cases has risen so dramatically. Given these facts, virologists decided that the best strategy for beating dengue, along with mosquito control, was to develop a tetravalent vaccine—one that provided balanced protection, in the form of neutralizing antibodies, against all four serotypes.

That’s what Sanofi was going for in Dengvaxia. 

The global health and dengue research communities were, for all the right reasons, rooting for it. For decades, they had watched the virus creep around the world; they had seen old-school methods of mosquito control fail; they had seen the body count grow. The Dengue Vaccine Initiative (DVI), a collaboration of scientists, had worked to identify clinical trial sites and develop surveillance programs for viral outbreaks. Any vaccine, the DVI estimated, would require up to an eye-popping 3.5 billion doses in the first five years to meet demand. The WHO, meanwhile, wrote guidelines on how to design a dengue vaccine trial. And together the WHO and DVI hosted regulators from seven dengue-prone countries (the Philippines among them) for a technical consultation on the Dengvaxia data.

When Thomas Triomphe arrived as Sanofi Pasteur’s new head of Asia-Pacific in January 2015, one of his top concerns about Dengvaxia was simple: Would there be enough? His territory was vast, 19 countries from India to Australia, and just about every one of them was a potential market for the company’s new dengue vaccine. 

The Philippines was an obvious place to launch the vaccine. The virus had become a year-round killer there and was an estimated $345 million annual drag on the economy. That year, 2015, was an especially costly one, with 200,000 reported cases of the disease and 600 deaths. And Filipinos were frustrated that the government seemed to do little to stop it—with each epidemic “viewed by the public as a symbol of how the government is really taking care of its people,” says Julius Lecciones, the executive director of the Philippine Children’s Medical Center, which gets the country’s most severe cases involving children. Beyond warning the public to stay vigilant, however, there wasn’t a lot the government could do. Local officials could make a show of spraying against mosquitoes, but that was merely “political fogging,” as some dengue experts call it.

As 2015 came to a close, the Filipino government saw its chance to act. There were unused funds in the budget that needed to be spent by year’s end. Some $70 million was quickly allocated for Dengvaxia in December. That same month, the Philippines joined Brazil and Mexico in approving the drug.

The government moved fast to implement its mass vaccination program—a pilot targeting 9-year-olds in three regions of the Philippines. The nation’s school-based dengue immunization effort began on April 4, 2016, the first day of summer break.

That struck some as odd timing. But the campaign’s launch at a grade school in Manila drew a large crowd and some VIP attendees. The president of Sanofi Pasteur’s Dengue Company, Guillaume LeRoy, was there as was Janette Garin, then the Philippine’s health secretary and a trained physician, who jabbed one of the first little arms with an inaugural syringe. Later that day, Garin, who is now a congresswoman, showed up at another launch event in a province outside Manila, this time with then-President Benigno Aquino III. They wore yellow shirts, the color of the Liberal Party, and before a large, cheering crowd, Garin administered a shot, and Aquino gave a speech. The optics led some to other questions about timing: A general election was a month away. Aquino had served his maximum term and was not up for reelection, but some read the staging as a campaign event—the Liberal Party saving the nation from a miserable disease. 

“You’ve got to monitor this closely”

Though Dengvaxia was now on the market in the Philippines, a debate continued among researchers about the effectiveness of the vaccine and how it should be administered.

In July 2015, a study had been published in the New England Journal of Medicine that caused dengue experts to reconsider the results of Dengvaxia’s clinical trials. Drawing on three years of follow-up data from Phase IIb and III trials, the analysis validated much of Sanofi’s optimism. But it also raised a red flag.

The banner headline: The vaccine worked—not for everyone, but for many. It appeared to work to some degree against all four strains of dengue (though more effectively against types 3 and 4), and it seemed to work both in children who had previously been infected with dengue and those who had not (though poorly in the latter). 

Among children ages 2 to 16, there was a 60% reduction in dengue cases during the first 25 months following vaccination. That rate was higher—nearly 66%—for children age 9 and above. Incidents of hospitalization and cases of severe dengue were significantly reduced in the vaccinated population, though the data did indicate a curious, if clear, trend—one, moreover, that only emerged in the third year of the study: Very young kids who had been vaccinated and did get dengue were more likely to be hospitalized. 

Children ages 2 to 5 who received Dengvaxia in the company’s Phase III trial were, in fact, more than seven times as likely to be hospitalized for dengue as those who had not. The overall numbers were small: 19 children of the 3,598, or 0.6% of kids age 2 through 8 who were vaccinated, were hospitalized owing to dengue versus 0.4% in the control population. The data did not show the same risk for vaccinated children ages 9 and above, however.

A school worker tries to exterminate dengue causing mosquitoes in a defogging operation inside a class room in Manila, September 13, 2010.
Romeo Ranoco—Reuters

The researchers didn’t have definitive conclusions to explain the trend, but they posited a few theories that related to age (younger children were not as physically and immunologically robust) and serostatus—that is, whether or not the child had suffered a previous dengue infection. In the best-case scenario, Sanofi would have marketed the vaccine to kids as young as age 2. The data analysis made that impossible. From now on, only children as old as 9 would be given the drug.

When Scott Halstead read the New England Journal report in the summer of 2015, he says, he nearly fell off his chair. Halstead, now 89, is a towering figure in the dengue research community. He started studying the virus in 1957, when he was a young Army doctor stationed in Asia. His career coincided with dengue’s flourishing, and one way or another, he’s had a hand in many of the foundational and pivotal findings in the field.

It was Halstead who opened Asia’s first dengue laboratory. He was in Bangkok (in the 1960s) to help develop the standards of dengue diagnosis and case management. He was in a lab in New Haven (in the 1970s) to study the pathogenesis of dengue infections in monkeys. And he was in Cuba (in the 1980s) to help study the first-ever dengue hemorrhagic fever epidemic in the Americas, and in Geneva (in the 1990s) to help establish the WHO’s dengue case classification system that Sanofi used in its Dengvaxia trials. Halstead founded the Pediatric Dengue Vaccine Initiative (later, DVI), an organization that received $55 million in Gates Foundation funding in 2003.

But perhaps Halstead’s signature if controversial contribution is “antibody-dependent enhancement,” the theory he developed in the 1970s—based in part from his study of dengue in monkeys—that aims to explain why people typically get more sick the second time they get dengue.

Guillaume Leroy meets a Filipino school girl during a nationwide vaccination at a School in Marikina, East of Manila, Philippines, April 4, 2016.
Francis R Malasig—EPA/Shutterstoc

Halstead had been enlisted by Sanofi as a consultant on Dengvaxia. He says he flew to Paris for meetings a few times but found them pointless: “We never discussed anything!” Still, he says, he didn’t anticipate problems with the vaccine. Halstead believed Dengvaxia had gotten around the problem of antibody-dependent enhancement by exposing people to all four strains at once. But as he pored over the new data in the New England Journal study about higher hospitalization rates of younger vaccinees, he had a sinking feeling. Halstead says he knew instantly that he had been wrong. He was sure this was his old theory in action: For those who hadn’t been exposed to the virus, the vaccine acted like a first dengue infection, priming them for a potentially more severe infection when they later got dengue from a mosquito bite.

In February 2016, two months before the Philippines launched its school-based Dengvaxia program, Halstead and a former colleague published an article in the medical journal Vaccine warning that people not previously exposed to dengue would be at risk of a more severe case later if vaccinated. (He’s since written more than a dozen papers outlining issues related to Dengvaxia.)

Halstead’s argument didn’t sway Sanofi, which challenged it in a published response. But it did get the attention of the Strategic Advisory Group of Experts (SAGE), the WHO-affiliated committee that makes recommendations to the international community on vaccine use.

SAGE’s pronouncements carry weight. While governments make their own decisions about whether to approve a drug or implement it in a national scheme, many take their cues from SAGE, as does the all-important vaccine buyer, GAVI. Because Dengvaxia was geared toward lower-income countries, SAGE felt even greater responsibility to get this one right. 

A child in the Philippines being injected with Sanofi’s Dengvaxia vaccine in April 2016 as part of the government’s drive to vaccinate 1 million schoolchildren.
Noel Celis—AFP via Getty Images

“When we first saw the [trial] results, we were all a bit disappointed,” says Terry Nolan, who cochaired the SAGE Working Group (he is now a consultant for Sanofi). “It had definite effectiveness, but it was modest.” Beyond that, though, was the question concerning the children who had gotten more severe infections. Was this age-related and limited to younger kids? Or did it have something to do with serostatus, as experts like Halstead vociferously argued, and so older children were also at risk? 

In the end, the committee hedged its bets: SAGE’s experts relied on models that assumed Dengvaxia was both less effective and more likely to cause severe disease in kids who’d never been exposed to a dengue infection. So SAGE recommended that the vaccine be used in places where infection rates of dengue in children were 70% or higher. But Dengvaxia should not be administered anyplace where less than half the population had been exposed to dengue. (The modeling projected vaccination of early adolescents would yield a 10% to 30% reduction in dengue hospitalizations over 30 years.) The goal was to apply the vaccine where its benefits would outweigh any possible risk involved—a challenge given the lack of quality data about infection rates.

Still, says Nolan, “we were very nervous about it, and we were very cautious in our initial recommendation and saying, ‘Look, you’ve got to monitor this closely.’ ”

Cautious or not, though, the recommendation was interpreted as an endorsement of the Filipino government’s Dengvaxia program. The vast majority of children in the Philippines have experienced at least one dengue infection by age 9, making them great candidates for the vaccine. 

Halstead sniffs at the WHO committee’s conclusion. (“They sort of gave Sanofi the green light,” he says.) But he spreads some blame as well to the international dengue research community—the one he practically nursed from birth—and Sanofi especially for failing to acknowledge Dengvaxia’s flaws sooner and for not doing enough to help the Philippines manage the vaccine scare and its aftermath. “It wasn’t purposeful, it wasn’t done with any malice,” he says, “but we shouldn’t just stand by and say, ‘Gosh, isn’t this too bad?’”

#DenGate goes viral

It was 1:20 a.m. when Antonio Dans, a professor at the University of the Philippines’ College of Medicine, saw Sanofi’s Nov. 29, 2017, press release. He read the statement and promptly punched out a Facebook post, tagging 25 colleagues:

Read this news alert from Sanofi.  =(

Our heart bleeds for more than 600,000 Filipino children who received dengue vaccine without assessment for prior infection.

Sanofi, WHO, DOH—what happens to them now???

The post was soon shared more than a thousand times, and in the wee hours of Nov. 30 it generated a number of comments and red-faced emojis. He and his wife, Leonila, who also teaches at UP, started a separate Facebook page, “Health Care Geeks,” to handle Dengvaxia-related questions and commentary a few weeks later.

Many in the Filipino scientific community—including some of Sanofi’s local leaders—point to the Danses’ dramatic social media post as one of the Dengvaxia saga’s igniting sparks. It pinged around the social media feeds of the Filipino medical community.

The couple were already highly visible and controversial critics of the country’s Dengvaxia program and had been raising questions about the Sanofi vaccine even before the country’s immunization drive began. A number of medical colleagues now refer to them as “anti-vaxxers.”

The Danses, both of whom are clinical epidemiologists, physicians, and public health advocates, got concerned after reading about the soon-to-launch immunization program in the newspaper. They then turned to the analysis of the dengue vaccine trials in the New England Journal of Medicine. Worried the drug might cause harm to some children, the couple quickly dispatched a four-page letter, signed by 11 peers, to the Philippines’ health secretary, Garin. In it, they also noted that the duration of the vaccine’s protective benefit was unknown. And they argued that a three-dose vaccine would be hard to implement, and that the supply of the vaccine for 1 million children—at a cost of $70 million, greater than the budget for all other vaccines in the public program combined—was very expensive.

Antonio and Leonila Dans at their home in Manila. The couple, both of whom are physicians and public health advocates, have been outspoken critics of the Dengvaxia immunization program.
Photograph by Jes Aznar for Fortune

The couple encouraged the government to put its vaccination program on hold, at least until the WHO weighed in. The Danses met with Garin and a roomful of experts the following morning. Garin assured them that the health department was well prepared for the launch and that the WHO had told her that its official recommendation was imminent.

The vaccination campaign began a week later.

The Danses decided they couldn’t sit idly by. They found Halstead’s paper and got in touch. They felt certain that the curious (if not statistically significant) “safety signals” in the trial data were due to the theoretical phenomenon that Halstead had outlined, and that Sanofi was willfully ignoring those signs.

They gave a handful of media interviews. Then, in October 2016, the couple posted a six-minute video on Facebook, warning parents that Dengvaxia could be harmful to kids who hadn’t had dengue before. Colleagues objected to the public way in which they were undermining a government health campaign. 

Sanofi—which had twice sent scientists to review the clinical trial data with the couple—was frustrated as well, firing off a letter to the Danses to correct their “misleading communications.” The couple wouldn’t budge.

By then, the political atmosphere in the Philippines had changed as well. That summer, Aquino’s party had lost the presidential election to the controversial populist Rodrigo Duterte. Garin was no longer health secretary, and her successor had taken a suspicious view of the Dengvaxia program. Congress and the senate, meanwhile, launched an inquiry into what some thought was the vaccination program’s hasty implementation. But the trouble wouldn’t really start until a year later, when Sanofi released its Nov. 29, 2017, update on Dengvaxia.

Thomas Triomphe was at his office in Singapore on the morning of Dec. 1 when that became absolutely clear. His attention was called to the television, which was showing a press conference underway in the Philippines—the government was suspending the vaccination program.

The news came as a shock to Triomphe. His team had been in touch with the Department of Health before and after Sanofi’s Nov. 29 press statement. “There were no red signals,” says Triomphe. “Of course, when you present the data, it’s complicated,” he says. “It’s not something you grasp in 20 seconds.” The regulators wanted to understand what the finding meant for the Philippines, and Triomphe says the company invited an ongoing conversation.

But the story was no longer just a dialogue between Sanofi and government health officials. It had exploded with a raw emotional fury online.

Within days, senators were calling for investigations; #DenGate had popped up on Twitter; the word “genocide” had been invoked; political bloggers and distressed citizens alike expressed outrage that the former government had turned Filipino children into “lab rats” to test an “experimental drug.” One widely followed pundit asked, “How many will Aquino’s Dengvaxia kill before Christmas 2018?” President Duterte’s spokesman, for his part, vowed to go after those “responsible for this shameless public health scam.”

Physicians who offered levelheaded assessments of the vaccine, meanwhile, were mercilessly trolled. Edsel Salvana, an infectious disease specialist who has no ties to Sanofi and who had mixed feelings about the government’s Dengvaxia campaign, went on CNN Philippines to offer a measured take on the very modest risk that children faced getting the vaccine, compared with the benefit they’d get. His Facebook page was promptly swarmed by angry posters, some of whom called for his kids to die. “It was terrible,” he says. “I was just trying to call for sobriety.” He still gets attacked online when Dengvaxia makes the news. “A lot of us were blindsided by the vitriol.” He notes that many of the trolls had political agendas but not all of them—and it’s those people’s responses he found most disheartening and surprising: “People were willing to believe non-doctors and non-specialists over doctors and specialist scientists.”

On Dec. 4, Sanofi executives held a press conference to try to calm the storm. It didn’t work.

From Sanofi’s vantage point, the growing outrage was all a big misunderstanding. The company felt the whole mess came down to one tiny mistake, really a single word in the Nov. 29 press release: “severe.” By saying that people without previous exposure to dengue were at higher risk of getting “severe dengue” if they were given Dengvaxia, Sanofi had caused unnecessary concern. 

Sanofi had taken the word “severe” straight from the language of its clinical trial design. But out of that context, it took on a different meaning.

Ng Su Peing, Sanofi Pasteur’s global medical head, had the job of fielding questions at the company’s press conference. “The general public in the Philippines thinks of severe dengue as something that’s devastating, that could lead to death,” she says. “[The announcement] was conveyed in a way that really caused alarm.”

“Severe dengue,” by the study’s definition, covered a broad category of symptoms—from fever and gum bleeding at one end of the spectrum to the sometimes fatal hemorrhaging and shock at the other. In the clinical trial, no participants died of dengue, and reported cases of “severe dengue” fell at the milder end of the spectrum. Four out of every 1,000 children vaccinated without a previous infection had a higher risk of developing such disease over a five-year period. That compared with 1.7 per every 1,000 children without a previous infection who weren’t given the vaccine. 

In the spirit of transparency and scientific accuracy, Sanofi had crafted its press release carefully to adhere to the trial’s official terminology. But it had left out both the numbers and the nuance, leaving the public to interpret “severe dengue” as they would.

“If you were a lay person and you heard ‘severe,’ what else would you conclude?” says Anna Ong-Lim, a physician who is currently president of the Pediatric Disease Society in the Philippines.

Regulations prevented Sanofi from promoting Dengvaxia to the public directly, so the company stayed silent on social media. Instead, it continued to press its data-driven case with high-level stakeholders in the country. “Maybe it seemed overly scary, but actually it’s not scary at all,” says Triomphe, a former McKinsey consultant, recalling how frustrating it was to witness the public’s panic build. “It’s not changing at all the overall benefit/risk profile of the product.” He says in hindsight, the situation was more politicized than he realized: “Probably our voice was not hearable or understandable,” says Triomphe.

Nor was Sanofi the only one struggling to cut through the noise. So, too, was the Filipino health department. “Every day we were getting drowned out,” says Eric Domingo, undersecretary of health. “It was exhausting.”

In July 2019 I visited Domingo at his office at DOH’s leafy campus in central Manila. He was dressed in shirtsleeves and running late. The department was one week into a dengue alert, months into a measles outbreak, and managing occasional reports of diphtheria.

The affable Domingo speaks like a man who is trying to piece together the past two years, or maybe like one trying to peel himself off the pavement after being run down by a truck for the sixth or seventh time. Worn down, beat up, but not unable to appreciate the occasional absurdity of all that has happened.

The Dengvaxia mess began, more or less, on his first day on the job. He started Dec. 1, the morning the government suspended the vaccination program. The timing protected him from the accusations made against others in the department, and he became the agency’s spokesperson and point man on the matter.

“It just snowballed into this gigantic thing,” says Domingo. “We were thinking we have to communicate the risk—so sit down, now that we know this, what are the risks for these children, what are we going to do, how do we mitigate that risk, how do we take care of them and how do we tell them? I guess initially everybody just expected it to go smoothly.”

What they didn’t anticipate was the spark that would ignite the furor to come: the reports of “Dengvaxia deaths” that began bubbling up almost immediately. “It was all there on social media, and then quite a few TV stations were showing autopsies—death number one, death number two, like a countdown every day,” says Domingo. Meanwhile, protests proliferated.

The country’s health workers, typically beloved figures in their communities, were chased away as “child killers.” Parents didn’t want their vaccinations or even basic medicines like deworming pills.

The Health Department itself was struggling to get information on some of the death reports. Meanwhile, the public demanded answers. 

It was during this particularly toxic period of confusion, fear, and outrage, with allegations, misinformation, and unsubstantiated reports of Dengvaxia deaths flying around the Internet, that the Blue Ribbon Senate Committee in the Philippines conducted a series of hearings on the vaccine debacle in late 2017 and early 2018.

Ostensibly a fact-finding operation, the hearings—hours long and televised widely—served as something between popcorn-worthy political theater and a public flogging. At their center, as master of ceremonies, was Richard Gordon, a 74-year-old senator with a special gift for grandstanding. 

Gordon wasn’t especially concerned with questions of risk and what, in real terms, Sanofi’s announcement meant for the Philippines—it was a given that the country had bought a vaccine that put some children in harm’s way—he was focused on how that had happened.

A news personality and litigator, Gordon presided over the hearings—and the large cast of summoned bureaucrats, politicians, scientists, and drug company representatives—with a gravitas that frequently gave way to fits of showy outrage. He grilled. He lambasted. He flashed righteous fury. When it came to discussion, he often wouldn’t have it—barking at witnesses who tried to give more than a yes or no answer or flustered scientists who refused to reduce a complicated technical matter to one word. He admonished one trembling functionary for trying to read from a piece of paper.

He mocked everything from witnesses’ accents (especially that of the Frenchman Triomphe, whom he referred to as “Mr. L’Arc de Triomphe”) to their baldness. He made insinuations and reserved special ire for Garin, the former health secretary, despite the fact that she postponed an emergency appendectomy for four days in order to testify.

Sanofi Pasteur executives, Thomas Triomphe (right) and Yu Tan-Wen, testifying on Dec. 11, 2017, at the Philippine Senate probe into the government’s Dengvaxia immunization program.
Bullit Marquez—AP

But Gordon had also come prepared, ready to connect some dots for a public that was hungry for someone to blame. While the previous government pleaded that it had pursued an urgent public health good with resourceful, red-tape-shredding efficiency, Gordon alleged it was a sneaky and corrupt conspiracy that recklessly endangered hundreds of thousands of Filipino school kids. The political agenda gave the hearings a through-the-looking-glass quality at times where even basic realities seemed in dispute—like whether dengue was that much of a public health concern at all. 

He homed in on Garin and Aquino’s meetings with Sanofi and raised questions about the timing—making hay of the fact that a few weeks before the Philippines approved Dengvaxia in December 2015, the president had received the drug company’s executives in Paris. (Aquino had been in town for the Paris Climate Agreement and met with many other French executives as well.) He hammered on the half-truth that the government was giving out Dengvaxia before its clinical trial had even ended. (Sanofi was conducting long-term follow-up of trial participants through 2017, but it had completed its study and registered the product in accordance with WHO guidelines.) Gordon went after Sanofi, too, pointing to the company’s long history of settlements with pharmaceutical regulators around the world. 

Over the course of the hearings, the media continued to report on suspected Dengvaxia deaths, cases in which children who had gotten the vaccine later died. Some outlets—but not all of them—were careful to report that the link between the vaccine and the deaths had yet to be substantiated. The parents of those children also participated in the hearings, at one point holding their photographs up to the audience in the room.

Gordon’s committee ultimately produced a report on the Dengvaxia scandal calling for the prosecution of Aquino, Garin, and other officials, though some senators refused to sign it and wrote dissenting opinions. When I met Gordon in July, he was working late in his capacity as the chairman of the Red Cross in the Philippines. It was past 7 p.m., and he and his staff were making arrangements to send medical tents to the regions most impacted by the ongoing dengue outbreak. 

Aaron Favila—AP

As for whether or not Dengvaxia caused the deaths of the children whose photos were displayed in his hearings, Gordon said, “I have no findings sufficient for a belief or a conclusion that it can kill. I just have the finding that [Sanofi] had been forewarned by everybody and his uncle” that Dengvaxia had problems.

The Gordon hearings were winding down when it became apparent that the Philippines had an even bigger but not totally unrelated health crisis on its hands: measles. The country recorded more than 21,800 cases in 2018, up from 4,585 the previous year. The year 2019 has been even worse: through Oct. 19, the health department had tallied 42,612 reported cases and 566 deaths, many of them children under 9 months of age.

The country’s immunization coverage rates have lagged in recent years, and the Dengvaxia scare made things far worse: a survey from the U.K.-based Vaccine Confidence Project found just 32% of Filipinos thought vaccines were important in 2018, down from 93% in 2015.

Despite the sobering public health situation, the health department’s Domingo says measles just opened up another round of finger-pointing over which side was more responsible. “When you have two completely polarized groups, it doesn’t quiet down,” he told me. “It just continues.”

Indeed, the blame game was in full swing when I visited the Philippines over the summer. Few were spared, but one woman in particular came up over and over again.

A dubious assertion

Acosta, the chief public attorney, occupies a unique role in the Philippines. As part of the nation’s Department of Justice, the Public Attorney’s Office (PAO) has a charter to serve the indigent with free legal services. Acosta has led the office since being appointed to her post in 2001.

On the July day I visited the PAO, which occupies the top floor of a government building in Manila, the tiny foyer hummed with a semi-effective air-conditioning unit and was crowded with members of the public. A large photographic portrait of Acosta hung on one wall. People looked busy all around, moving with a sense of purpose among stacks of paper that were piled high on tables, chairs, and every other surface.

For parents who believe their child died or fell ill because of Dengvaxia at the hands of the government’s public immunization drive, Acosta’s advocacy has earned their loyalty. She is the rare government official they trust, their lonely crusading champion for justice.

As I waited in a small plastic chair, a security guard showed me a video on his cell phone of a man being hacked to death, his way of explaining to me the types of cases they get there. I told him I was there about Dengvaxia, and he nodded. “Oh, many cases.”

Acosta was not available to see me, but I was allowed time with two women attorneys (it was against their communications policy to give their names, they said) who had both worked for the PAO for roughly a decade. They had been leading the work on Dengvaxia cases, which at that point encompassed 144 investigations and 44 criminal cases. (PAO had filed 91 criminal and civil cases through early November.) 

The two attorneys repeated to me a dubious and controversial assertion that their office had made in court filings—that it was Dengvaxia itself that had killed the children directly rather than a severe dengue infection of the kind that Sanofi had warned about.

They explained that PAO had autopsied all the bodies and in all cases found the underlying cause of death had been “viscero- and neurotropic-like disease” caused by Dengvaxia. They did not believe dengue, or vaccine-enhanced dengue, was related to the deaths (though among the deceased, one child’s death certificate had listed dengue as the cause of death). 

The attorneys dismissed criticism of the PAO’s Dengvaxia work as “personal attacks” and defended the agency’s methods and forensic findings, saying they were confident they would prevail in court. They argue they have seen evidence—the autopsied bodies—that PAO’s many critics have not and rejected the idea that PAO was responsible for whipping up fear about vaccines in the country. That, they said, was caused by the launch of a drug, Dengvaxia, that hadn’t been fully tested. 

The stated causes of death the PAO attorneys have cited—viscerotropism and neurotropic-like disease—critics say, come not from credible autopsy findings but rather from Sanofi’s boilerplate risk disclosures for Dengvaxia.

Many of the vaccines that protect us from terrible diseases present a small risk of adverse events. On very rare occasions, the vaccine for rotavirus, for example, causes a reversible tangling of the bowel called intussusception. Likewise, there’s a one in 2.4 million chance one will contract polio from the live polio vaccine. And yellow fever vaccine very, very infrequently leads to viscerotropic disease, a deadly phenomenon involving organ failure. 

Because Dengvaxia is constructed with the viral backbone of the yellow fever vaccine, Sanofi listed viscerotropism and neurotropism as possible risks for Dengvaxia, and studied the vaccine for this effect in trials. (None was observed.)

Medical experts in the Philippines publicly decry PAO’s forensic investigators as unqualified and their findings as utterly wrong.

“They’re not even pathologists. They’ve not had a single day of training,” says Raymond Lo, an anatomical and clinical pathologist who is board certified in both the U.S. and the Philippines. “They were conducting autopsies in public, in full vision of television cameras, exhibiting all these bloody organs. You could spread disease. They made a mockery of the whole thing.” (As a former administrator at a hospital that procured Dengvaxia for the government immunization drive, Lo has been charged by the PAO with reckless imprudence resulting in homicide; he is fighting the charges.)

Lo has reviewed 33 of PAO’s forensic reports—all of which, he says, cited viscero- and neurotropic-like disease as causes of death, despite clinical notes, death certificates, and hospital pathology reports indicating the child in question died of natural causes. The Philippine Society of Pathologists has also challenged PAO’s findings, as have the Danses. Antonio Dans notes that the PAO’s forensic investigators have based their conclusions all on two basic observations—organ swelling and hemorrhaging. “Those simple things you can find in almost every child who dies,” says Dans.

The parents whose children were autopsied by the PAO offered radically different descriptions of their sicknesses and deaths. For some, the events had been sudden; in other cases, multiple hospital stays and surgical procedures were involved. Some had died weeks after vaccination, and others years. What the stories had in common was a list of general symptoms—fever, headaches, cough, dizziness, UTIs, irritability, fatigue, swollen limbs. And also a shared belief that before Dengvaxia, their child was healthy and normal—and after, he or she had died.

Many of the parents didn’t initially suspect Dengvaxia as the cause of the child’s death or illness but reached that conclusion after talking to someone—the kid’s teacher, a bystander at the funeral, a nurse at the hospital, who then connected them with the Dengvaxia Victims Facebook group. It had never made sense to these parents that their once healthy children were dead, and after hearing about other kids, it made more sense that it had been Dengvaxia than what was diagnosed or written on the death certificate: leptospirosis, rabies, leukemia, an enlarged heart, and so on.

“One death is one too many”

In March, the Filipino government indicted a wide range of individuals for their alleged roles in the so-called Dengvaxia deaths. They included former Health Secretary Garin and six Sanofi employees, but also a cast of more peripheral figures—Julius Lecciones, executive director of the Philippine Children’s Medical Center, which procured the vaccine; Rose Capeding, the researcher who investigated Sanofi’s dengue trial in the Philippines; and a handful of career employees at DOH. They were all charged with “reckless imprudence resulting in homicide,” which is punishable by up to six years in prison. All of the accused deny any guilt. Sanofi says it strongly disagrees with the DOJ’s findings and it is “vigorously defending” its employees.

When I spoke with some of the defendants in July, they were having a hard time. Many had left their jobs and were struggling to reconcile their situation with the fact that they had spent their lives serving the public. Facing a trial was expensive and stressful; it also made them public targets. One of the accused, Lyndon Lee Sy, a former Health Department spokesperson, died of a heart attack in September; his family and friends blame the weight of the case. Others noted the prosecution of researchers set a chilling precedent.

Richard Anthony Fadullon, the senior deputy state prosecutor for the Department of Justice, told Fortune that linking the deaths to the vaccine and the administration’s “rushed” implementation will be difficult. The PAO’s methods and findings, he admits, may complicate his efforts. But he says prosecuting the cases filed by the PAO is a worthy pursuit. “We cannot close our eyes to the deaths that happened,” said Fadullon. “One death is one too many. It matters a lot to the family, and it matters a lot to government.”

 So how many children died as a result of Dengvaxia? That remains a controversial question. Sanofi’s answer: “There is no clinical evidence that any reported fatalities were causally related to vaccination.”

While the PAO has been publicizing every “Dengvaxia” death and autopsy, a DOH-sanctioned task force has been quietly reviewing cases of Dengvaxia recipients who have died. Of the 891,295 individuals vaccinated in the government program, there had been 315 deaths as of Oct. 25, according to the DOH. And 41 of those cases were due to dengue. (There have been a total of 6,171 cases of dengue and 124 severe dengue among those vaccinated.) While the work is ongoing, DOH says that at present it has not directly linked any deaths to Dengvaxia itself, as the PAO asserts, or to “severe” cases of dengue precipitated by the vaccine, as Sanofi warned about. As for the 41 deaths due to dengue, there is currently no clear way to determine if they were related to the immune-enhancement effect according to the DOH and the WHO.

As for the number of people who may die from dengue without the protection of a vaccine, well, that too is unknowable for now—but the number is likely to be many, many times larger.

“You’ve got a vaccine against this disease, which has an enormous public health burden. The population benefit is clear, but there are a small number of people who would be exposed to more severe disease,” says Jeremy Farrar, the director of the Wellcome Trust, who cochaired the SAGE committee that recommended Dengvaxia’s use in 2016.

“There are people that argue the public health benefits are the most important issue, and the numbers are hugely in favor of vaccination,” he adds. That said, many people, Farrar included, believe there is an obligation to test prior to vaccination if it’s possible to identify those at risk. To not, many point out, is a violation of medicine’s do-no-harm principle.  

The seemingly easy answer is to give Dengvaxia only to those who are not at risk of harm, as in those who have suffered a previous dengue infection. This is not an easy thing to do, though.

An estimated three-fourths of dengue infections are asymptomatic—meaning the majority of people who get dengue will never know they had it. There are tests that can tell you, but they are relatively expensive, not sufficiently accurate (they can’t reliably distinguish Zika from dengue, for instance), and can take labs days or weeks to process. That’s not a feasible solution for a government that hopes to protect its population against an epidemic.

And that’s precisely what the Philippines’ dengue outbreak became this August. The escalation forced a short-lived and somewhat awkward national conversation: Was it time to bring Dengvaxia back?

Many in the medical community thought so; the vaccine could be used responsibly and benefit many in the private market. There also seemed to be demand—a smattering of Filipino celebrities and politicians had made news by visiting Singapore and Thailand for dengue inoculations.

Despite the cases the government had filed over Dengvaxia-related deaths, President Rodrigo Duterte expressed openness to the possibility. Though he had been silent on most Dengvaxia matters, he told reporters he trusted that local experts knew what to do.

The Health Department didn’t reinstate Dengvaxia’s license, but in mid-August it said Sanofi Pasteur could reapply, which the company is in the process of doing. Jean-Antoine Zinsou, Sanofi Pasteur’s general manager in the Philippines, expresses confidence that the product will be back eventually.

This year’s epidemic, meanwhile, has proved worse than any before in the country, with some 360,000 cases and 1,373 deaths through September. Among the infected was Duterte’s teenage daughter Kitty, who had reportedly received Dengvaxia. She was hospitalized in October but made a full recovery. 

A version of this article appears in the December 2019 issue of Fortune with the headline “Epidemic of Fear.”

More must-read stories from Fortune:

—Death by 1,000 clicks: Where electronic health records went wrong
—How lax oversight of electronic health records puts patients at risk
—How the maker of the world’s bestselling drug keeps prices sky-high
—How big tobacco could fill the void if vaping goes up in smoke
Laundry pod exposures are rising for the first time since 2015
Subscribe to Fortune’s Brainstorm Health Daily newsletter, where we monitor advances in healthcare and biopharma.

Add Comment