Did Sanofi, WHO ignore warning signals on dengue vaccine?

CHICAGO/LONDON, (Reuters) - When French drugmaker Sanofi published the results of clinical trials of children given its dengue vaccine two years ago, the overall findings were that it protected against the world’s biggest and fastest growing mosquito-borne disease.

But the trial also showed that in the third year after receiving the Dengvaxia inoculation, younger children were more likely to end up in hospital with a severe case of dengue than those who didn’t get the vaccine.

The study’s authors cited two main possibilities: the children had immature immune systems that made the vaccine less protective, or the vaccine itself made them more susceptible to severe disease if they had never had dengue and later became infected.

More than two years later, it turns out the latter was the primary factor - a revelation at the end of last month that has triggered alarm among hundreds of thousands of anxious parents in the Philippines, where the vaccine has been given to over 830,000 children.

It has also torpedoed initial expectations by analysts and the company that Dengvaxia, the first dengue vaccine to be developed, might become a $1 billion-a-year blockbuster product. Sanofi says it will take a charge of around 100 million euros ($118 million) for the fourth quarter.

Initially, to address the issue seen in younger children, Sanofi had recommended that the vaccine only be given to those aged 9 and older in areas where the disease was widespread. The World Health Organization analysed Sanofi’s data and came to the same conclusion. It made a conditional recommendation to use the vaccine.

But after a new analysis of data from the trials, Sanofi confirmed last month the vaccine could increase the risk of severe dengue in some cases in people who had not been previously exposed to the disease. The WHO has now backed a decision by the Philippines government to suspend a mass immunisation program and said it has begun reviewing safety data.

In Sanofi’s large-scale trials, blood samples were not collected from all the children before they were vaccinated, which would have identified prior exposure to the disease by showing the presence of antibodies.

“The development process around the first dengue vaccine led to a degree of momentum and judgements being made that we should learn lessons from,” Neil Ferguson, a professor at Imperial College London and an unpaid adviser to both Sanofi and the WHO, told Reuters.

The case raises questions whether Sanofi and the WHO, in their pursuit of a new weapon to fight a deadly disease, should have foreseen the risk. Their decisions on how the vaccine was rolled out could set back efforts to combat dengue by a generation, some disease experts say.

Sanofi has rejected suggestions it ignored any risks or took any shortcuts. However, it has acknowledged that clinical tests of the vaccine did not fully investigate whether a previous dengue infection could influence the outcome.

“When you are the first in class, we’re the ones having to develop and understand the science as we go,” said Dr. Su-Peing Ng, the global medical head of Sanofi Pasteur, the vaccines division of the drugmaker. “We don’t have another vaccine to follow the lead on.

“The findings we have today, we would have loved to have (earlier),” she told Reuters. “Now that we have these findings, of course it’s our responsibility again to ... share this information.”

The protocols for the tests, devised in 2009, were “thoroughly vetted by many dengue experts, including with WHO’s technical advisory group and various regulators”, Ng added.

The WHO said it acted promptly to address concerns when they arose. It has also said its recommendations on use of Dengvaxia were conditional and confined to children aged 9 and older in areas where dengue was endemic.

Complicating matters, scientists were sharply divided about the risks of the vaccine.

Four decades ago, Dr. Scott Halstead, a leading figure in dengue research, first proposed that antibodies from an initial exposure to one of four types of the disease could increase the risk of a potentially lethal complication called severe dengue when a person was infected a second time, a process know as antibody-dependent enhancement or ADE.

This phenomenon could make development of a dengue vaccine tricky.

Rather than being protective, a shot given to someone who had never had dengue could act like a first infection, increasing their risk of severe dengue when they were exposed a second time.

Halstead, an adjunct professor at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, said when he saw Sanofi’s 2015 paper, he was convinced the increased risk that some children would contract severe dengue was evidence of ADE.

Halstead wrote a series of papers published in Vaccine, the Journal of Infectious Diseases and other journals urging Sanofi and the WHO to proceed with caution in rolling out the vaccine. “It was not obvious to Sanofi and the World Health Organization, but it was obvious to me,” he told Reuters.