La Dengue and the Sanofi disasters

La Dengue and the Sanofi disasters

This article is taken from the paper magazine of "Le Scienze" of August 2019. Le Scienze is the Italian edition of Scientific American


In December 2015, the President of the Philippines Benigno Aquino III and others negotiated an agreement with the pharmaceutical company Sanofi for the purchase of three million doses of Dengvaxia, the first approved dengue vaccine. The plan was to vaccinate one million nine-year-old pupils with three doses of the vaccine each, to protect them from the worst consequences of the disease: shock, collapse of internal organs and death.

There are four varieties of the dengue virus, all transmitted by the females of the Aedes mosquitoes, in particular A. aegypti, which suck blood during the day, when people are not protected by mosquito nets. Over the past fifty years these viruses, close relatives of those of West Nile fever, yellow fever and Zika, have spread in waves in the tropical and subtropical regions of the world, increasing the incidence of dengue by 30 times and affecting over 390 millions of people every year.

Not everyone who is infected with a dengue virus falls ill: three out of four people among those infected with mosquito bites are asymptomatic. The rest can suffer from symptoms belonging to one of three groups:

  1. a fever similar to that of many other viral diseases;
  2. "dengue fever", which is accompanied by headache, pain behind the eyes, pain in the joints and bones and, in rare cases, internal bleeding;
  3. and the severe version of the disease with dengue hemorrhagic fever and dengue shock syndrome.
Dengue is scary, and health workers in developing countries have been waiting for a vaccine for decades. But when the internist Antonio Dans and the pediatrician Leonila Dans, both clinical epidemiologists at the Manila College of Medicine of the University of the Philippines, read the news of Aquino's vaccination campaign in the Philippine Star newspaper, the first thing that got them the cost was affected. With a price of 3 billion pesos ($ 57,5 million) for the supply alone, the vaccination campaign with Dengvaxia would have cost more than the entire national vaccine program for 2015. It would have reached less than 1 percent of the country's approximately 105 million residents. And although it was estimated that on average in the Philippines about 750 people died per year, dengue was not even among the top ten causes of mortality. Among infectious diseases, pneumonia and tuberculosis claimed many more victims.

By carefully reading an interim report by researchers from Sanofi Pasteur (the vaccine department of Sanofi) on the clinical trials of Dengvaxia, Dans and Dans found other reasons for concern.

Among Asian children aged two to five, those who received the vaccine were seven times more likely than unvaccinated children to be hospitalized for severe dengue in the three years after inoculation. Careful analysis of the data revealed that although on average Dengvaxia was safer in older children, it was statistically impossible to rule out the possibility that some children worsened the situation.

In March 2016, Dans and Dans, and other medical professionals, wrote to then-health minister Janette Garin, pointing out that the vaccine could be risky for some children and that perhaps the Philippines did not have enough qualified health workers to monitor any harmful effects on so many people. A potentially safer vaccine was in development and probably worth the wait, they argued.

In the same month, however, the World Health Organization (WHO) respected advisory group on vaccines, which provides guidelines on vaccination practices to countries, stated in an information document on Dengvaxia that hospitalizations of inoculated children , if observed over several years, were not statistically significant. "No other safety signs have been identified in any age group" above the age of five, it read. There was a "theoretical possibility" that Dengvaxia could be dangerous for some children, and further studies were needed to prevent it from "compromising public trust" in the vaccine. But it was "to be introduced as part of the routine vaccination program in the appropriate settings", which included regions where 70 percent and more of the population was already affected by dengue, where pre-adolescent vaccination could reduce hospitalizations by up to 30 per year. one hundred over a period of thirty years. In a subsequent policy document the group stated that the vaccine was safe for children from the age of nine, for whom it was recommended.

Apparently the Philippine authorities were so convinced of the safety of Dengvaxia that Sanofi Pasteur was not forced to present the results of the pharmacovigilance studies. The inclusion of a new pharmaceutical product in the national health program usually took three to five years, but the dengue vaccination program was started immediately, in April 2016.

A few days later the first post-vaccination death was reported ...

Dans and Dans continued for months talking to the press and posted a video on Facebook in which, based on a highly contested theory dating back decades before called «Antibody dependent potentiation» (ADE, from English antibody-dependent enhancement), it was felt that in children who had never previously been affected by dengue the vaccine could make subsequent dengue infection more lethal than usual. The answer from science was a warning: doctors who took part in the "disinformation" about Dengvaxia would be responsible for any death from dengue that could have been prevented by the vaccine.


Things stayed that way until November 2017, when Sanofi Pasteur also issued a warning: Dengvaxia was not to be given to individuals who had never been infected with dengue.

A month later, WHO published new guidelines recommending the vaccine only to those who had it «A previous documented contagion of dengue». In December, the Philippines stopped the vaccination program, while parents and the press reacted with fury, recriminations and other reports of child deaths. By that time, more than 830.000 school-age children had already been vaccinated.

The controversy has not slowed the launch of Dengvaxia, which is currently approved in more than 20 countries. In October 2018, the U.S. Food and Drug Administration announced that it would speed up the examination procedure for Sanofi Pasteur's request for Dengvaxia's approval. This means that the vaccine could be approved in the United States for use in areas where dengue is endemic, such as Puerto Rico, before the Philippines completed the investigation into the deaths of vaccinated children and before Sanofi Pasteur published the final report. on the six years of clinical trials.


A disconcerting disease

For more than 15 years scientists who collaborated in the Nicaraguan Pediatric Dengue Cohort Study have treated sick children and went to their homes to collect data and blood samples. Out of 6684 subjects, they found 618 cases of children who had suffered from dengue and nearly 50 who had developed the disease in severe form. By studying the over 41.000 blood samples taken over more than 12 years, they made a remarkable discovery. Children with a specific antibody concentration (not low enough to be useless, not high enough to offer protection, but at an average level) had an almost eight times greater risk of contracting dengue hemorrhagic fever and dengue shock syndrome .

ADE explains these results with ease. If at first the antibodies are not present or are present with very low densities, they cannot enhance a subsequent dengue infection and cause a serious attack. If antibodies are present with high densities (as occurs immediately after the initial infection), they manage to cover any new dengue virus sufficiently to disable it and allow macrophages to kill it. But if the concentration of antibodies is in what for Harris is the "danger zone", neither low nor high, they can favor the entry of the larli with Dengvaxia, Sanofi Pasteur did it only with 10-20 percent of the subjects . The company claims to have had to move into an unexplored territory and to have followed the best protocols known to vaccine science. "Taking blood from only 10-20 percent of subjects is routine in many vaccine trials," says Su-Peing Ng, Sanofi Pasteur's global medical manager.

When the worrying hospitalization rate came to light, researchers were no longer able to take samples from the thousands of children who had participated in clinical trials to check their condition related to dengue before inoculation: the children had already been vaccinated. Sanofi Pasteur collaborated with the University of Pittsburgh to develop a method by which to test children who had received the vaccine to look for traces of a previous infection. This reassessment was the basis of the warning published by the company in November 2017, so that only those who had already suffered from dengue should have received Dengvaxia.

The previous recommendations were based on preliminary clinical trial results, according to which Dengvaxia was safe for viruses in macrophages without defusing it, speeding up its reproduction.

The article in which Harris described the results, published in "Science", was, in the words of Jean Lim, virologist of the American Icahn School of Medicine at Mount Sinai, a "champion study" that made some people change their minds of the most determined opponents of the ADE. His unexpected discoveries may also have led to the solution of the mystery of the vaccine.


A warning sign

For a strange coincidence, just a few days after the publication of Harris' article, in November 2017, Sanofi Pasteur made the announcement that sparked the anger of the Filipino parents: do not use Dengvaxia if you have not already suffered from dengue. A month later, the WHO also aligned itself on the same position, stating that only those who could prove that they had already suffered from dengue in the past had to receive the vaccine.

It was the same thing Halstead had been repeating since March 2016, when he published an analysis in "Vaccine" claiming that Dengvaxia could cause harm. The problem was that there was no way to easily understand which children were negative for dengue before receiving Dengvaxia, because Sanofi Pasteur had not collected this information on all subjects before vaccinating them.

"I don't like to say" I told you so "- says Harris - but it was to be expected." In various meetings and long teleconferences he had pointed out to the researchers of Sanofi Pasteur that they did not collect the type of data necessary to evaluate the possibility of the vaccine to endanger human lives. Instead of testing all the children to see if they had suffered from dengue before inoculating them with Dengvaxia, Sanofi Pasteur did so only with 10-20 percent of the subjects. The company claims to have had to move into an unexplored territory and to have followed the best protocols known to vaccine science. "Taking blood from only 10-20 percent of subjects is routine in many vaccine trials," says Su-Peing Ng, Sanofi Pasteur's global medical manager.

Previous recommendations were based on preliminary clinical trial results, according to which Dengvaxia was safe for older children. But as revealed by the new tests, age was a bit of an indicator of a previous infection. Nine year olds are more likely to have already contracted the disease than 2-3 year olds, especially in areas where dengue is endemic, so on average the vaccine should be safe for them. However, neither the age of the child nor the endemicity of the disease are sure indicators to determine who has already suffered from dengue: the only way to know for sure is to do blood tests. "There will always be a group of nine-year-olds who have never had dengue," says Halstead.

The expert communicated his doubts to the WHO in a public way. In an article in the December 2016 Journal of Infectious Diseases, he claimed that a statement from the leading WHO vaccine advisory group was wrong. The team said that the risk of hospitalization for children aged two to five reaches their peak in the third year after vaccination and then "vanishes". Halstead argued that the results of Sanofi Pasteur's longer-term trials contradicted that claim. After independently analyzing the trial data, Dans, Dans and others published an article in the Journal of Clinical Epidemiology stating that "there is no biological basis for setting a threshold at the age of nine" beyond which assume that Dengvaxia is safe.

However, the WHO confirmed its decision to recommend the vaccine to older children living in the countries most severely affected by the disease. "The review was extremely thorough, transparent and in accordance with our published procedures," says Joachim Hombach, senior health advisor to the Department of Immunization, Vaccines and Biological Substances of WHO. "Several possible recommendation options were discussed and the one published in 2016 was the position on which the advisory committee reached consensus."


The controversy continues

In July 2018 Sanofi Pasteur published a new analysis on the data of clinical trials with the method developed in Pittsburgh in the New England Journal of Medicine. The results confirmed a greater risk of dengue in serious form and hospitalization for "seronegative" children (those whose blood did not show traces of previous dengue infections) who had received the vaccine compared to those who did not received. "The vaccine partially mimics the first infection and increases the risk of severe dengue during subsequent infections," the researchers wrote. Although ADE supporters predicted these findings, the article said that "the immunopathogenetic mechanisms underlying these findings remain unknown."


Loss of confidence

The repercussions of the vaccination program still echo in the Philippines. Speaking to a Senate commission of inquiry, Aquino explained that the incidence of dengue fever in the country was growing at an alarming rate and that it had operated in the hope that Dengvaxia could prevent the virus from spreading in densely populated urban areas. Last February, however, both the Senate and the House of Representatives recommended that Aquino, Garin and other senior officials be charged under an anti-corruption law, for irregularities in procurement for the supply and administration of the vaccine. The families of some thirty deceased children have started criminal proceedings against Garin and other Filipino officials, accusing them of negligence and irresponsibility comparable to murder and torture.

While scientists fight each other, the parents of vaccinated children are unable to sleep at night, according to Antonio Dans. "Mothers are very worried, and wonder: was my son seronegative when he was vaccinated? Why didn't they tell us it could be dangerous? They call us and tell us: my son has a cough, should we rush him to the hospital? It seems to me that I have a little fever, is it good to go to school? And how do you keep the cold and fever of about a million children under control to find out if it is dengue or not? It's a logistical nightmare, and that's what we wanted to warn the Ministry of Health about. "

Since antibody levels in vaccinated seronegative children drop to an intermediate level where ADE becomes more likely, Halstead worries that over time those children are increasingly more likely to develop severe cases of dengue if exposed to infection. true. Based on data from Sanofi Pasteur's clinical trials (i.e. that 5 seronegative children vaccinated out of 1000 were hospitalized for dengue and, of these, 2 for the severe form of the disease), he calculated that in the Philippines they could be hospitalized for enhanced dengue from the vaccine more than 4000 children. "I can't believe my eyes," he says. "Why isn't Sanofi wondering," Now that we've made so many people sensitive to ADA, how are we going to protect them? "

This story also raises difficult questions about how pharmaceutical companies and regulatory authorities should proceed in the context of ever-changing scientific knowledge and the existence of imperfect vaccines. Is it ethical to endanger a minority to protect the majority, as the warning on Dengvaxia published by the WHO in September 2018 implies? Who is responsible for making such difficult decisions: world-wide expert organizations, national health authorities, informed doctors and parents, or a combination of the previous options? And who is responsible when things go wrong?