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Fight to Eradicate Dengue Fever Faces Another Setback

 

Dengue fever is the world’s most pernicious mosquito-borne virus, afflicting as many as 400 million people a year — making the latest setback in the effort to stop the scourge all the more frustrating.

The vaccine Sanofi spent more than two decades and $1.8 billion developing should be given only to people who have already been infected with the virus pending a full safety review, the World Health Organization said last month.

That’s raising the stakes for vaccine candidates from Takeda Pharmaceutical Co. and the U.S. National Institutes of Health. Both products are in end-stage clinical trials, and developers are hoping to avoid the problems that caused Sanofi to cut the value of its vaccine inventory last month.

People who have never had dengue before being immunized with the Paris company’s Dengvaxia shot had a greater risk of developing severe disease if they were later infected naturally, an analysis of six years of data showed.

“It’s a real fly in the ointment for everything that’s ahead,” said Cameron Simmons, a professor of microbiology and immunology at the University of Melbourne, who was involved in early Dengvaxia research and studies dengue at the Peter Doherty Institute for Infection and Immunity. “The next generation of vaccines is going to take longer. The hoops to demonstrate safety are going to be more stringent.”

Besides Dengvaxia, which is approved for use in 19 countries, there are no other licensed vaccines or specific medicines to fight dengue, and efforts to control its mosquito vector haven’t stopped the virus extending its reach from the tropics of Asia and the Americas to southern France and Madeira, Portugal.

Almost 400 million infections occur worldwide annually, Simmons and colleagues estimated in 2013, and there’s been a 30-fold increase in the number of cases over the past 50 years, according to the World Health Organization.

“We recently received disappointing clinical news on Dengvaxia, which will constrain the outlook for the vaccine,” Sanofi Chief Executive Officer Olivier Brandicourt told analysts recently.

Dengue is caused by one of four distinct strains, or serotypes, of dengue virus that typically cause a sudden onset of fever, as well as headache, rash and muscle aches and pains so severe that the disease is known as breakbone fever. In a small subset of cases, sufferers can develop potentially fatal bleeding and shock.

Severe dengue is thought to occur more frequently from subsequent infections caused by a serotype different from the one that caused the initial illness, due to a phenomenon known as antibody-dependent enhancement. A similar pattern may occur in some vaccinated people, researchers Scott Halstead and Philip Russell wrote in a review paper last year.

Dengvaxia, which is administered in a three-shot regimen over 12 months, is what is known as a chimeric vaccine, one that uses components of all four dengue serotypes on a yellow fever vaccine backbone. Takeda’s experimental two-shot immunization uses a dengue serotype-2 backbone on which components of the three other serotypes are attached.

Immunization with that vaccine may expose the body’s immune cells to additional parts of the dengue virus that may elicit broader adaptive immune responses, according to a paper published in the journal Science last month.

An independent data-monitoring committee evaluating its safety hasn’t raised any concerns and studies so far show the vaccine achieves sustained responses to all four serotypes regardless of previous dengue exposure, said Rajeev Venkayya, president of Takeda’s vaccines unit. Results are slated late for 2018, the company said last month.

“We are very confident in the program, and that confidence has not changed at all in light of the most recent news about Sanofi’s Dengvaxia,” Venkayya said in an interview. “We are fully committed.”

The Philippines halted its Dengvaxia immunization program pending a review and consultation with groups including the World Health Organization, the country’s health department said on Dec. 1.

Analysts at Credit Suisse have cut their peak sales estimates for Dengvaxia to $10 million from $300 million, seeing a serious impact on its potential in nationwide vaccination programs, even in countries at high risk of dengue.

Sanofi said the vaccine had sales of just $26 million in the first nine months of the year, citing a difficult political and economic environment among other factors.

Even so, the company said it is committed to reducing the threat of dengue and it will continue monitoring the long-term impact of vaccination while investing in reliable, rapid and cost-effective tests to support the use of vaccines.

The next generation of dengue vaccines are expected to be superior to Dengvaxia and provide broader protection, yet it’s unclear whether it will correct the problems Sanofi has encountered, said Duane Gubler, professor emeritus at the Duke-NUS Medical School in Singapore.

The National Institutes of Health-produced vaccine, which requires a single shot, is being evaluated in an advanced trial in Brazil that is due to wind up next May.

A partially effective Dengvaxia, meanwhile, can still be a useful weapon, said Gubler, who wrote the main medical text on dengue in 1997 and is a Takeda vaccine patent holder.

“One thing we’ve learned is that cellular immunity is going to be a lot more important than we thought it was,” he said. Given the difficulty in developing a dengue vaccine with balance for all four strains, another “lesson is that we should not wait until we get the perfect vaccine before we introduce them.”

By James Paton is a Bloomberg writer
Email: jpaton4@bloomberg.net

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