The Fight to Eradicate Dengue Faces Another Setback

Break-bone 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 dengue scourge all the more frustrating.

The vaccine Sanofi spent more than two decades and 1.5 billion euros ($1.8 billion) developing should only be given 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 aim 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-based 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.

An aedes aegypti mosquito.

Photographer: Miguel Schincariol/AFP via Getty Images

“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.”

Growing Threat

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 WHO.

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

Dengue is caused by one of four distinct strains, or serotypes, of dengue virus which 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 break-bone fever. In a small subset of cases, sufferers can develop potentially fatal bleeding and shock.

A health worker fumigate a neighborhood to control dengue fever in Aceh province, Indonesia on Nov. 17.

Photographer: Fachrul Reza/NurPhoto via Getty Images

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 K. Russell wrote in a review paper last year.

Dengvaxia, which is administered in a three-shot regimen over 12 months, is a so-called chimeric vaccine 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.

Sanofi’s dengue vaccine Dengvaxia.

Photographer: Ted Aljibe/AFP via Getty Images

Better Protection?

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 WHO, the country’s health department said on Dec. 1.

Analysts at Credit Suisse last month 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 22 million euros in the first nine months of the year, citing a difficult political and economic environment among other factors.

Next Generation

Even so, the company 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, it said in a statement last week.

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

A nurse draws blood from a volunteer for the NIH vaccine tests in Recife, northeastern Brazil, in Nov. 2016.

Photographer: Diego Herculano/NurPhoto via Getty Images

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.”