by Sid Holt
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, nineteen 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 nine-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 two to sixteen, there was a 60 percent reduction in dengue cases during the first twenty-five months following vaccination. That rate was higher—nearly 66 percent—for children age nine 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 two to five 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 percent of kids age two through eight 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 nine and above, however.
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 two. The data analysis made that impossible. From now on, only children as old as nine 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 eighty-nine, 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 Initiat
ive (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.
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.
“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 percent 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 percent to 30 percent reduction in dengue hospitalizations over thirty 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 nine, 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 November 29, 2017, press release. He read the statement and promptly punched out a Facebook post, tagging twenty-five 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 November 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 “antivaxxers.”
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 eleven 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.
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 seven-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 November 29, 2017, update on Dengvaxia.
Thomas
Triomphe was at his office in Singapore on the morning of December 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 November 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 twenty 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 nondoctors and nonspecialists over doctors and specialist scientists.”