Dengue vaccine in sight

A child suffering from dengue fever lies on a bed at the Kantha Bopha hospital in Phnom Penh. Dengue causes fever, headaches and agonising muscle and joint pains. Photograph: Reuters

Thursday, 07 June 2012
Ben Hirschler/Reuters

One of the grimmest legacies of the war in the Pacific is still being fought 70 years on, but a victory over dengue, the intensely painful “breakbone fever” that conflict helped spread around the world, may be in sight.

Paris-based drug company Sanofi hopes for positive results in September from a key trial among children in Thailand that would set it on course to market a shot in 2015 that would prevent an estimated 100 million cases of dengue infection each year. Of the 20,000 who die annually, many are children.

For Sanofi, which has invested 350 million euros (about US$438 million) in a new French factory to make the three-dose vaccine, it could mean a billion euros in yearly sales, as half the world is exposed to the disease, notably in tropical cities from Rio and Mexico City to Manila and Phnom Penh.

World Health Organization epidemiologist Steven Bjorge told the Post yesterday that a medicinal measure to prevent the spread of dengue would be instrumental in countries like Cambodia.

“If the trials prove that it is effective, then it would be a real step forward, because the control of dengue is very difficult. There is no medical treatment and there is no vaccine, so we have to fall back on mosquito control, which is very imperfect,” Bjorge said.

“I’m sure the trial would be run well, but it would be another year before we have usable data. [I] don’t see that there would be any results anytime soon, to ensure safety as well as effectiveness,” he said, adding that the Thailand trial was the furthest progressed of any drug-development trials in the world.

It has been long wait. Identified in local outbreaks in Asia, the Americas and Africa since the 18th century – and noted as a serious military hindrance by US generals in their 1898 war against Spain in Cuba and the Philippines – dengue was spread to global pandemic proportions in part due to the mass movements of armies through the Pacific in World War II.

In the past 50 years, there has been a 30-fold jump in cases. The World Health Organization officially puts infections at 50 million to 100 million a year, although many experts think this assessment from the 1990s badly under-estimates the disease. Most patients survive, but it is estimated to kill about 20,000 every year, many of them children less able to fight it off.

WHO’s Bjorge emphasised the urgency of a vaccine for dengue.

“The vaccine’s been needed for 30 to 40 years. We’ve just been waiting and waiting and waiting. The technical problem is that there are four different viruses that produce the same disease,” he said. “It’s been necessary to produce four separate vaccines and make a cocktail. Complicating the problem is that the second or third time you get dengue, you can get complications.”

The good news for countries like Cambodia, is that like competitor GlaxoSmithKline, whose new malaria shot has shown promise, Sanofi is preparing for pressure to make its drug accessible to billions too poor to pay the market price.

“Everyone is aware of the fact that the vaccine has to be cheap enough for ordinary people to purchase, for the government to vaccinate large numbers,” Bjorge said.

“If you don’t vaccinate large numbers, you’re going to have outbreaks and epidemics.”

Its estimate of more than a billion euros (about US$1.25 billion) in annual sales assumes that it is added to routine immunisation schedules in Asia and Latin America and is also adopted by travellers from farther afield as well as military medics in the US and Europe.

Meeting that sales potential – while getting the vaccine to hundreds of millions who need it across the tropics – will require a careful balancing act on pricing and supply of a product that has yet to be given a commercial brand name.

Orin Levine, executive director of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health, says the new vaccine is a potential breakthrough, but warned its rollout may not be straightforward.

First, the vaccine needs to be given in three installments over the course of a year in order to counter the threat from four different types of dengue virus, none of which confers immunity for the others.

“There are going to be some challenges,” said Levine. “There’s really good economic potential from this vaccine, but I think it may take a ramp-up of three to five years.”

In an ideal world, healthcare experts would like a single-dose or, at most, a two-dose vaccine for mass immunisation.

A simpler regimen would also be better for travellers, although Pascal Barollier of Sanofi Pasteur, Sanofi’s vaccine arm, says many users will be people making regular trips to see families in Asia or Latin America who have time to plan ahead. The military, too, often has lead time for troop movements.

In any case, Sanofi is putting its money where its mouth is by spending 350 million euros on a new dengue vaccine factory near Lyon, which is already in test production.

It is a substantial gamble, since Sanofi will only learn whether the vaccine really works when it analyses data from a first study of its efficacy on 4,000 Thai children.

Results from that clinical study, in what is known as the Phase IIb of the international standard three-stage process of assessment, are expected in the third quarter – most likely September. They will also be presented for scientific scrutiny at the annual meeting of the American Society of Tropical Medicine and Hygiene in Atlanta in November.

If the data is good, Sanofi will file for market approval in countries where dengue is endemic like Australia, Malaysia, Singapore, Thailand and Mexico in 2013, suggesting a regulatory green light in 2014 and commercial launch in early 2015.

Early tests have shown a balanced immune response against all four dengue types, and Duane Gubler of the Duke-NUS Graduate Medical School, who has researched dengue for four decades, is optimistic.

“Everything they’ve done so far looks very good,” he says. “I think it will be a much better vaccine than [the one created for] malaria.”

He expects Sanofi’s vaccine will show an efficacy rate of at least 75 to 80 per cent, well above the 50 per cent or so seen with GSK’s malaria shot, which faces the added technical problem of fighting a complex parasite rather than a virus.

In Cambodia, there were 2,579 dengue cases, with 14 deaths, in the first 18 weeks of the year – an increase of 353 per cent when compared to the same period last year.

Char Meng Chuor, director of the National Centre for Parasitology, Entomology and Malaria Control, pointed out that the similarity of the dengue and CHIKIV viruses and the rise in CHIKIV cases had partly contributed to the fourfold increase in reported dengue numbers.