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The US Food and Drug Administration has just approved one of the most sought-after vaccines in recent decades. It is the first vaccine in the world to prevent dengue fever – a disease so painful that its nickname is "bone fever".
The vaccine, called Dengvaxia, aims to help children in Puerto Rico and other US territories where dengue fever is a serious disease. problem.
But this vaccine has a dark – and deadly – history. One has resulted in criminal prosecution in the Philippines, triggered national panic and fueled a mbadive measles epidemic that has already killed more than 355 people.
Preoccupation
This story begins on a stage in Manila in 2016.
A girl of about 9 or 10 years old was sitting in a chair surrounded by health workers. She wore a bright yellow t-shirt with the words "Dengue is dangerous". She pressed her eyes and bit her lip as the health secretary of the Philippines, Dr. Janette Garin, shot her in the arm.
This shot launched a mbadive vaccination campaign to vaccinate nearly one million schoolchildren against Dengvaxia. The goal was to save thousands of children's lives and avoid about 10,000 hospitalizations over a five-year period.
But in the end, it is estimated that more than 100,000 Filipino children have received a vaccine that, according to health authorities, increases their risk of developing a serious and sometimes fatal disease. In addition, other children who received the vaccine might have been endangered because, according to their parents, they were not in good health.
The French pharmaceutical company Sanofi Pasteur has spent 20 years – and about 2 billion dollars – on the development of dengvaxie. The company has tested it in several major trials involving more than 30,000 children worldwide and has published the results in the prestigious New England Journal of Medicine.
But on the other side of the world from the Philippines, in a suburb of Washington, DC, a scientist worried about the new vaccine.
"When I read the New England newspaper article, I almost fell off my chair, "says Dr. Scott Halstead, who has been studying dengue fever for over 50 years with the US military.
When Halstead reviewed the vaccine safety data during the clinical trial, he immediately realized that there was a problem.
For some children, the vaccine did not seem to work. In fact, says Halstead, it seemed harmful. When these children got dengue after being vaccinated, the vaccine seemed to make the disease worse in some cases. Specifically, in children who had never been exposed to dengue fever, the vaccine appeared to increase the risk of a life-threatening complication called plasma leak syndrome, in which blood vessels began to leak yellow blood fluid.
"Then all empire and maybe it's impossible to save your life," says Halstead. "A child can go into shock."
"The problem is that the disease occurs very quickly, in just a few hours," he adds. "And nothing on the outside of the body means that the person has a leak of liquid inside."
Complication is rare, Halstead says. But he was still so concerned about security issues that he had written at least six editorials for scientific journals. He even made a video to warn the Philippine government of the problem.
"I just think," No, you can not give the vaccine to a perfectly normal and healthy person, and then put him at increased risk of plasma leakage syndrome for the rest of his life, "Halstead said. "You can not do that."
The vaccine manufacturer did not agree with Halstead's interpretation of the results of the study. The company wrote a rebuttal claiming that the regulators had approved dengvaxie "based on the proven protection of the vaccine and its acceptable safety profile".
The company also announced that it would carry out additional studies to "strengthen access to the safety, efficacy, and effectiveness" of the vaccine.
Despite these concerns, in July 2016, the World Health Organization decided to recommend the vaccine against all children from 9 to 16 years old.
"Yes, we did." This is what we call a "conditional recommendation" that focuses on minimizing potential risks, "said Dr. Joachim Hombach, who led Vaccine review by WHO. "We have seen the problems, we have also clearly highlighted the data gaps."
The WHO has recommended that Sanofi multiply the experiments to better understand the vaccine's safety issues. In its evaluation, WHO emphasized that the vaccine "may be ineffective or even theoretically increase the future risk of [being] dengue hospitalized or severe "in people who have never been exposed to dengue fever – which represents about 10 to 20% of Filipino children.
The WHO recommendation came three months after the Philippines launched its mbad vaccination campaign in April 2016.
A year and a half later, this campaign was interrupted.
The problem
In November 2017, Sanofi posted an announcement on its website indicating new information on the security of Dengvaxia.
Halstead's fears have been confirmed. Sanofi had found evidence that the vaccine increased the risk of hospitalization and cytoplasmic leak syndrome in children who had never been exposed to dengue fever, regardless of age.
"For people who have never been infected with the dengue virus, vaccination should not be recommended," the company wrote.
Panic hit the Philippines. In the reports, the parents claimed that the vaccine had contributed to the deaths of ten children. Demonstrations broke out. The Philippine Congress has opened investigations into the purchase of the vaccine and the vaccination campaign. And Philippine health authorities have started performing autopsies on children who died after receiving the vaccine. "In total, the prosecutor's office opened an investigation into the death of about 600 children who received dengvaxie," said the president. Morning of South China reported last month. The investigators have not yet published their results.
Here is the problem with Dengvaxia.
Generally, a vaccine works by causing the immune system to make antibodies against the virus. These antibodies then fight the virus during an infection.
But dengue fever is a delicate virus. Dengue antibodies do not always protect a person. In fact, these antibodies can make the infection worse. The dengue virus actually uses antibodies to promote its spread in the body. Thus, a second dengue infection – when your blood already contains antibodies – may actually be worse than the first one; a person has a higher risk of serious complications such as plasma leakage syndrome.
In his follow-up study, Sanofi found that Dengvaxia acts as the first infection in a person who has never been infected before. The body produces antibodies against the vaccine, which have a similar danger potential.
The increased risk seems low. The vaccine increases the risk of hospitalization after dengue infection by about 1.1% to 1.6%, according to Sanofi's follow-up study. Thus, on one million children in the Philippines, the vaccine would result in the hospitalization of about 1,000 people over five years, Sanofi said. (On the other hand, the vaccine would prevent about 12,000 hospitalizations in children with a new dengue infection who already had dengue infection during that same period.)
But in the world of vaccines, this is not an acceptable risk. A risk must be extremely low to be tolerated. For example, with measles vaccine, the risk of encephalitis is about one in a million, a thousand times less than the risk of a measles infection, according to WHO.
The WHO has finally changed its recommendation. The agency now says that the vaccine is safe only for children who have already had a dengue infection.
By the time Sanofi recognized the problem with the vaccine, about 800,000 Filipino children had been vaccinated. The Sanofi study found that more than 100,000 of them had never been infected with dengue fever and should not have been shot, according to the revised recommendation of l & # 39; WHO.
Given Halstead's concerns and initial unknowns about the safety of the vaccine, Filipino parents should have been warned of a potential risk, said Dr. Isabel Rodriguez of the University of California at San Francisco.
"What bothers me most in this story is risk communication," says Rodriquez, who is studying dengue fever in South America. "There was a lot of uncertainty from the beginning [about the vaccine’s safety]. This had to be communicated explicitly. You must be honest about what the evidence is out there. "
Dr. Su-Peing Ng is the Global Medical Director of Sanofi Pasteur. She added that the company had followed all World Health Organization guidelines when developing the vaccine and that it had communicated honestly throughout the process.
"We have always been very transparent in sharing the results of our research," Ng said. "And I just want to stress that we have full confidence in our vaccine because it has been approved by regulatory agencies in more than 20 countries."
In hindsight, Ng added, Sanofi would not do anything else with vaccine development: "No, we have been very close to the world of research and have been working closely with them over the last 20 years to find a solution to public health needs ".
The repercussions
In April, the Philippine government indicted 14 government officials for the deaths of ten children vaccinated against dengvaxia. The government said the officials acted with "excessive haste" in procuring the vaccine and launching the mbad vaccination campaign. The Philippines The Department of Justice said the campaign had begun before the end of clinical trials
In some cases, the vaccine has been administered to children by untrained health workers and allegedly without physical fitness. Some children would have had pre-existing medical conditions that made the vaccination dangerous. But the government found that these children were still vaccinated.
Six Sanofi officials were also accused of failing to properly help the children who had reacted seriously to the shot. Sanofi disputes this allegation and others, adding in a written statement to NPR: "We do not strongly endorse the DOJ's findings against Sanofi officials (past and present) and we will vigorously defend them. clinical evidence indicating that reported deaths were causal related to vaccination.
"We are diligently monitoring the safety of those involved in clinical trials, we are also conducting pharmacovigilance activities and are constantly monitoring the safety profile of the vaccine in a real environment, including in the Philippines."
No matter how successful these tests are, The debacle in the Philippines is a great lesson for governments and manufacturers when it comes to approving and selling new vaccines: Slow down, says physician and bioethicist Keymanthri Moodley. Vaccine errors can undermine public confidence and have long-term health consequences for an entire country.
"When a vaccine is wrong, it creates fear and anxiety among the public, especially among parents," said Moodley, who heads the Center for Ethics and Law. of Medicine at the University of Stellenbosch in South Africa. "This fear can have a negative impact on established immune programs – they are actually safe and work very well."
Since the controversy over Dengvaxia, Filipino parents' confidence in vaccines has fallen from 82% in 2015 to only 21% in 2018, according to a recent study. Over the same period, the percentage of parents who strongly believe that vaccines are important has dropped from 93% to 32%.
As a result, immunization coverage against childhood diseases in the Philippines, such as measles, has been reduced, according to the WHO. And the Philippines is now facing a major measles epidemic, with more than 26,000 cases and more than 355 deaths in 2019.
And here in the United States, the approval of the vaccine – to be used in Puerto Rico, the British Virgin Islands and Guam – is subject to a significant restriction: doctors must have evidence of an earlier infection by dengue to make sure the vaccine is safe. to the child. This is a guarantee that Filipino families have never had.
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