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 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 analyzed 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 immunization 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 judgments 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.
REJECTED SUGGESTIONS
Sanofi has rejected suggestions it ignored any risks or took any
short-cuts. 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.
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CONDITIONAL GUIDANCE
Dr. Joachim Hombach, senior health adviser in WHO's vaccine
department, said he understood Halstead's concerns but the
organization could only work with data generated by research.
He told Reuters that WHO "strongly encouraged" Sanofi to conduct
follow-up studies to clarify whether children who had never had
dengue before being vaccinated were more prone to severe dengue.
"It was recognized it was something that would be important to
follow as part of our long-term program," said Sanofi's Ng. "This is
exactly what we've done with our recent analysis."
In the end, WHO issued its conditional guidance on Dengvaxia in
July, 2016, after a year of deliberations, favoring use of the
vaccine only in countries with a high burden of dengue, and
stipulated that it only be given to children aged 9 and older.
Ferguson, at Imperial College, also raised concerns about the
vaccine in a paper published in the journal Science in September
2016, suggesting the vaccine could increase severe dengue in some
places with low transmission of dengue.
But until last month, many other scientists were on the fence about
whether the signals in Sanofi's trials were evidence of true ADE.
"I'm not sure it was nailed down until now," Jeremy Farrar, director
of the Wellcome Trust medical charity who has served on WHO's
working group on dengue vaccines, told Reuters.
A paper in PLOS Medicine in November 2016 described a "split" among
dengue experts between those like Farrar who supported the WHO
recommendations on cautious use of Dengvaxia and those such as
Halstead who said it was too risky.
To do the follow-up study, Sanofi had to solve a major problem. The
company said it had only collected blood samples that would have
revealed prior exposure to dengue in 10 percent of the more than
30,000 children in its clinical trials before they had been
vaccinated.
Sanofi did have blood samples from nearly all of the children but
only after they had been vaccinated. So it would be hard to tell
from those samples whether the antibodies in their blood were
produced in response to a natural dengue infection or the vaccine
itself.
Responding to questions from Reuters, the company said in an email
it would have been considered 'unethical' to take blood samples from
all the kids prior to vaccination, because there wasn't a clear
reason to do so when it set up the protocols for the trial.
SHEER MOMENTUM
In 2014, Sanofi had entered into a scientific collaboration with the
University of Pittsburgh Center for Vaccine Research to measure
responses to the vaccine in its trials. At the time, the company had
no reason to suspect that the vaccine would increase risks in
children who had never had dengue, Ng said, but this test ultimately
proved critical in allowing the company to differentiate those who
had been infected before vaccination from those who had not.
That test only became ready to use this past July, said Dr. Ernesto
Marques, an infectious disease specialist at the University of
Pittsburgh, who helped develop the test.
Sanofi used the test to re-analyze blood samples collected in its
trials and alerted public health officials last month that there was
an increased risk of severe dengue in people who had not been
previously infected, even among the children 9 and older who had
been recommended for the vaccine.
By the time Sanofi announced findings from its follow-up study at
the end of last month, the vaccine had been given to over 830,000
children in the Philippines, and about 300,000 people in Brazil.
One factor in decision-making was the sheer momentum behind the
project, said Ferguson, the unpaid adviser, referring to the surge
in the incidence of dengue and the fact that Dengvaxia was the first
vaccine developed to contain the disease.
The WHO says dengue is now endemic in more than 100 countries, up
from 9 countries before 1970. An estimated half a million people
suffering from dengue require hospitalization each year and about
12,500 die.
"Clearly, in retrospect, it was a mistake" not to have taken
baseline blood samples, said Ferguson, "The question is, could it
(the need to do so) have been anticipated?"
(Reporting by Julie Steenhuysen in Chicago; additional reporting by
Ben Hirschler in London and Stephanie Nebehay in Geneva; Editing by
Raju Gopalakrishnan)
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