Sanofi’s belated admission of a lethal Dengvaxia threat came long after multiple high-profile warnings

Philippine health officials administering Dengvaxia earlier this year Sipa, AP Images

Late last week, the Philippine government woke up to a public health crisis it had played a major role in creating.

It began on April 4 last year, when health officials launched a dengue vaccination program that would aggressively seek out more than 700,000 people — including tens of thousands of children 9 and up — for $70 million worth of Sanofi’s newly approved Dengvaxia.

But last week, Sanofi — which heralded Phase III data in 2015 that CEO Olivier Brandicourt declared was an “historic” achievement for a likely blockbuster product — said there was a problem with its vaccine. The pharma giant announced something that had already been clearly foretold in two studies by noted dengue experts before and right after the Philippine Department of Health began inoculating children and adults.

Any of the hundreds of thousands of kids and adults who were vaccinated with Dengvaxia who had not already been infected by one of the four different serotypes of the virus faced a potentially life-threatening fever if they went on to be infected. Their bodies would likely treat the first real dengue infection as their second, in light of the vaccine. And second infections are often the most severe.

The DOH then suspended the vaccination campaign as a nationwide controversy erupted, triggering headlines throughout the country. Former DOH undersecretary Susan Pineda Mercado ripped health officials and Sanofi for exposing people to a severe infection. On her Facebook page, she wrote:

This is the biggest government funded clinical-trial-masked-as-a-public-health-program scam of an experimental drug in the history of the DOH. And it cost the Philippines P3 B (3 billion pesos, or about $70 million) for the vaccines and so much more now for the risks, anxiety and even lives that are now endangered. This was reckless and irresponsible from the start and the public was deceived into thinking this vaccine would protect children from dengue.

On Sunday, the Philippine government responded to the uproar, vowing to get to the bottom of who was responsible for it.

“We will leave no stone unturned in making those responsible for this shameless public health scam which puts hundreds of thousands of young lives at risk accountable,” said Harry Roque, the chief spokesperson for President Rodrigo Duterte, in a statement.

For its part, the WHO launched an emergency probe of the vaccine on Monday, warning countries against injecting anyone who hadn’t been infected earlier.

Why are second infections worse?

In the first dengue infection, people typically get mild flu-like symptoms as their body generates antibodies that fight off the virus, which the vaccine is also designed to kick up. Close to two years ago, Scott Halstead and Philip Russell — both leading figures in the dengue field — pointed to those antibodies as a severe threat to anyone who then is exposed to wild type dengue for the first time. At that point they assist the virus in a process called antibody-dependent enhancement, or ADE. And the most severe cases can lead to internal bleeding, a respiratory crisis, organ failure and death.

For people who had already been infected, the vaccine could prove extraordinarily helpful, getting them past the risk of a second infection and on to lower-risk third or fourth infections. But for any virus-naïve patients, including the unexposed children it was used on in the Philippines, it could be a disaster.

The threat Dengvaxia poses was also spotlighted in a major study published in Science just a few weeks after the Philippines got busy vaccinating people. And the researchers, including Neil Ferguson, director of the MRC Center for Outbreak Analysis and Modeling at Imperial College London, offered some widely discussed, stark warnings of ADE.

Derek Cummings

“You’d have increases in hospitalized dengue cases,” co-author Derek Cummings, a professor at the University of Florida, told CNN last fall. “It would be exactly the opposite of what you intend to do.”

The authors underscored that the vaccine should be used only in areas where dengue is endemic, which is what the Philippines was doing.

The most effective solution to eliminating the risk, Cummings and his colleagues proposed, would be to develop a simple test to see who had been exposed so they could exclude anyone who would be left vulnerable to a second attack. And instead of the three doses recommended by Sanofi for each subject, you could probably get the best effect with one dose.

“I do not believe … anybody should be going forward using this vaccine without testing the individual recipient to be sure they’re already seropositive. Because that’s the group that can benefit from this vaccine,” Halstead, founder of the Children’s Vaccine Initiative, told STAT at the time the Science report came out.

And he had good reason to.

In February, 2016, before the Philippine campaign began, Halstead and Russell, former director of the Walter Reed Army Institute of Research, published a piece in Vaccine in which they drew a direct line between the vaccine and the extraordinary likelihood it would trigger hospitalizations in a subsequent wild type outbreak. The threat grows as time passes between infections, they said, citing a Cuban case from 1975 and a subsequent 1995 epidemic — leaving any of the unexposed children who were vaccinated at risk for the rest of their lives. And Halstead spotted the issue in Sanofi’s own data, just as Cummings and his colleagues did.

In a report by The Center for Infectious Disease Research and Policy at the University of Minnesota, Halstead says:

It’s clear as the nose on my face: Vaccine recipients less than 5 years old had five to seven times more rates of hospitalizations for severe dengue virus than placebo controls.

“What the company has done is say, ‘Well, we only vaccinate kids over the age 9,’ ” said Russell in the CIDRAP report. “But age is only a surrogate here for being dengue naïve. They need to directly address ADE in Phase IV studies.”

Last April, Malaysian authorities demanded a Phase IV study before allowing a vaccination campaign, specifically citing the threat posed by a post-vaccination case of severe infection.

“It was designed to fail”

Halstead tells me his discovery of ADE in his lab dates back 60 years.

“This is a group of viruses that evolved in monkeys,” Halstead tells me, but separated into 4 distinct viruses over time. The first exposure makes antibodies against the dengue infection, but those same antibodies interact differently when they subsequently encounter any of the other three viruses — not in a way that kills the virus. Instead, they effectively disarm the immune system while spurring the growth of the virus.

“Just that attachment of that immune complex is sufficient to send a signal to the root of the receptor that begins a process of switching off the macrophages in the immune defense system,” he says.

In 1963, Scott Halstead was living in Thailand and studying dengue and chikungunya in children. Scott Halstead

In newborns to mothers who have had first exposures, he adds, you can see how the babies with their transferred immune response suddenly develop the most severe, lethal reaction to dengue.

Those children who were seronegative at the time they were vaccinated “are running around now with this enhancing antibody that they can’t get rid of,” says the scientist. “They can’t get rid of it for the rest of their lives.”

From Halstead’s perspective, there are two main culprits: Sanofi for developing and marketing the vaccine without gaining a basic understanding of the biology of dengue, and the WHO for validating their conclusions.

“It was designed to fail,” says Halstead about the vaccine. “It doesn’t have the ability to produce strong T cell responses.” But he’s hopeful that another vaccine in development at the NIH can do just that, and fix the problem Sanofi created. In the meantime, he says, Sanofi needs to step in and identify which children were left at risk, so they can be the first to be vaccinated with something that does work.

Sanofi execs knew full well about the Science study, and shrugged it off at the time.

Cesar Mascareñas

In an interview with FiercePharma a few days after the study came out, Cesar Mascareñas, Sanofi Pasteur’s director of global medical affairs for dengue, discounted the report. That study, he reportedly said, was a:

…“mathematical model” and not “evidence-based.” Plus, he said, it was one of 8 models considered by the WHO in making its recommendation that the vaccine be used in countries where the virus is more than 50% prevalent.

“It’s not new information for the experts,” he said. “It has been taken into account by the experts at the WHO.”

A few months later, in early January, government regulators cited Sanofi for ignoring warnings that it was violating Philippine law by promoting Dengvaxia to the general public through TV and radio ads.

“Since Sanofi has not complied, we have issued summons directing them to cease and desist from airing the advertisements and Show Cause why they should not be penalized for violating the law,” FDA director General Nela Charade Puno said.

By last Wednesday, Sanofi had a set of longterm data to look at. And they concluded from it that the risks highlighted by the earlier studies was real.

For those not previously infected by dengue virus…the analysis found that in the longer term, more cases of severe disease could occur following vaccination upon a subsequent dengue infection.

And the pharma company suggested a label change, asking healthcare officials to determine the “likelihood” of whether or not someone had been previously infected before providing the vaccination.

Sanofi’s response: “ADE cannot be the whole story”

The bulk of the information for this story was easily gleaned from a short period of Googling. For a company that took 20 years and spent $1.6 billion in development, priding itself on keeping close contact with KOLs and experts in their field, it couldn’t be any kind of surprise. So I asked Sanofi what took them so long to announce a conclusion others had reached before the big vaccination campaigns had even begun, laying the foundation for the botched rollout that exposed kids to the risk of severe dengue.

A spokesman for Sanofi, Laurence Bollack, replied by disputing the specific concern about ADE, noting that “ADE is one hypothesis proposed to explain this aspect of dengue infection but people can get severely ill also at the first, third and fourth infection with dengue so ADE cannot be the whole story. Rather severe dengue is likely multifactorial due to factors relating to both the virus and person infected.”

She also stated:

“The new study that we conducted was not designed to prove nor disprove the ADE hypothesis but rather to further evaluate the performance of vaccination in two subgroups of the original study population: those with and those without a prior dengue infection before vaccination.”

“(S)evere dengue is rare – about 0.5% or 1 in every 800 dengue cases,” added Bollack.

I asked if Sanofi is responsible to the children and adults who were unexposed at the time they were vaccinated. Bollack said subjects of vaccination will continue to be monitored, adding:

The advice for vaccinated people is the same as for all people living in an endemic setting is to continue to protect against mosquito bites and to seek medical care immediately if they experience signs or symptoms of dengue whether they have received the vaccine or not.

Why not develop a test that can determine prior exposure?

Sanofi intends to do that now, she says, but adds that there are a variety of ways of determining a prior infection, including “documentation of dengue in a patient’s medical records, and also considering available epidemiological data on seroprevalence/dengue disease burden in their community.”

By early October, 2016, long after expert warnings had been sounded in dengue circles and beyond, Dengvaxia had been approved in 11 countries, with the support of the WHO. Sanofi’s lofty sales goals, though, ran straight into trouble. Last year, it brought in only €55 million. And this year, the take was down to €22 million in the first 9 months. Third quarter sales registered at a minuscule €4 million.

Sanofi, which has struggled to produce any major new therapies in-house, topped that with a €100 million write-off for the program, just a fraction of their investment so far. The company’s primary concern now is managing a controversy that is spreading around the world.

Like a virus.

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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