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#439881 - 06/06/12 08:00 AM Dengue Vaccine in Sight, After 70 Years
Marty Online   happy

(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" which that conflict helped spread around the world, may be in sight.

The U.S. Army, which like its Japanese enemy lost thousands of men to the mosquito-borne disease in the 1940s, has piled resources into defeating the tropical killer. But it may be about to see the battle to develop the first vaccine won not in the United States but by French drug company Sanofi.

The Paris-based firm 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 which would prevent an estimated 100 million cases of dengue infection each year. Of 20,000 annual deaths, many are of children.

For Sanofi, which has invested 350 million euros ($440 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 fast-expanding tropical cities from Rio and Mexico to Manila and Mumbai.

But like British rival GlaxoSmithKline, whose new malaria shot has shown promise against another mosquito-carried scourge, Sanofi is also preparing for pressure to make its drug accessible to billions too poor to pay the likely market price.

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

That conflict, in which some 90,000 American troops were put in hospital by dengue, prompted the first efforts to develop a vaccine, as U.S. and Japanese scientists isolated the virus spread by the bite of the Aedes aegypti mosquito. But the disease, which can cause intense joint and muscle pain, has gone on sapping the health of troops, from Vietnam to Somalia and Haiti, and made lives miserable for millions of civilians.

In the past 50 years there has been a thirty-fold jump in cases. The World Health Organisation officially puts infections at 50 to 100 million a year, though 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 these children less able to fight it off.


The U.S. Army's quest for a vaccine had most recently been pursued in partnership with GlaxoSmithKline. But Sanofi now seems closest to offering a viable treatment. And, unlike GSK's malaria injection designed for African babies, it promises to be the commercial blockbuster the French firm needs to refresh a portfolio weakened by expiring patents.

Its estimate of over 1 billion euros in annual sales - Sanofi's 2011 turnover was 33.4 billion euros - assumes that it is added to routine immunization schedules in Latin America and Asia and is also adopted by travelers from farther afield and by military medics in the United States 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 (IVAC) at the Johns Hopkins Bloomberg School of Public Health, says the new vaccine is a potential breakthrough but warned its roll-out may not be straightforward.

First up, 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," says 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 immunization.

A simpler regimen would also be better for travelers, although Pascal Barollier of Sanofi Pasteur, Sanofi's vaccine arm, says many users will be people making regular trips to see families in Latin America or Asia with 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.

Submissions in other countries and for the travelers market would follow in 2014 and 2015.


Early tests have shown a balanced immune response against all four dengue types and Duane Gubler of the Duke-N.U.S. 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 malaria."

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

The efficacy rate refers to the reduction in the prevalence of subsequent infection among those vaccinated.

Despite both being transmitted by mosquitoes, dengue and malaria are notably different enemies.

Malaria, which is carried by a different mosquito, typically attacks rural populations living near swamps. Dengue, by contrast, has adapted to life in the city and is one of the winners of mankind's accelerating rush to urbanize.

The number of people living in urban areas is projected to rise to 6.3 billion by 2050 from 3.4 billion today, leading to more mega-cities with poor sanitation where dengue and other diseases can thrive, according to a study in The Lancet medical journal last week.

Globalization has also brought cases of dengue into southern Europe and the United States, particularly Texas and Florida, although Gubler believes higher living standards mean it is not likely to take off in these regions.


For the middle classes of Latin America and Asia, an out-of-pocket purchase of a dengue vaccine probably seems affordable and worthwhile, especially for their children. Yet dengue takes its biggest toll among the poor, who lack money for immunization and are also less likely to get medical help when the disease leads to potentially deadly haemorrhagic fever.

Getting vaccine to them will need the involvement of international agencies like the GAVI Alliance, which provides routine childhood immunizations in poor countries with funds granted by public and private donors.

Nina Schwalbe, GAVI's managing director for policy and performance, says she is monitoring the dengue vaccine program closely but needs hard evidence that it offers value for money, based on public health impact, efficacy and price.

Sanofi is not ready to set a price before it sees the full clinical trial results and has a clearer sense of vaccine yields at its factory. But the drugmaker will embrace "tiered pricing" to make the product affordable, Barollier at the company said.

That has not stopped the guessing.

"I would expect, for middle-income countries, they would be looking at prices similar to those of other new vaccines - for example HPV (human papillomavirus), pneumococcal and rotavirus vaccines - which sell for $15 to $70 per course in countries like Brazil, South Africa, Venezuela and Thailand," said IVAC's Levine.

Setting the price will be a test for Sanofi Chief Executive Chris Viehbacher. He reckons his vaccine is about five years ahead of any others and he knows he has a major opportunity to boost his company's reputation by getting the roll-out right.

With no specific drugs to treat or prevent dengue - in contrast to malaria - the world needs a success. Likewise, Viehbacher's shareholders, who have seen the company lose top-selling drugs as patents expire, need a commercial winner.

They will be watching closely those results from Thailand in September.

($1 = 0.8089 euros)


#440271 - 06/11/12 08:24 AM Re: Dengue Vaccine in Sight, After 70 Years [Re: Marty]
Marty Online   happy

Scott O'Neill wants to rid the world of dengue fever by infecting mosquitoes with bacteria so they can't carry the virus that causes the disease.

A Scientist's 20-Year Quest To Defeat Dengue Fever

This summer, my big idea is to explore the big ideas of science. Instead of just reporting science as results — the stuff that's published in scientific journals and covered as news — I want to take you inside the world of science. I hope I'll make it easier to understand how science works, and just how cool the process of discovery and innovation really is.

A lot of science involves failure, but there are also the brilliant successes, successes that can lead to new inventions, new tools, new drugs — things that can change the world

That got me thinking that I wanted to dive deeper into the story of an Australian scientist named Scott O'Neill. Scott had come up a clever new way for combating dengue fever.

Dengue is a terrible disease. It sickens tens of millions and kills tens of thousands. There's no cure, no vaccine and pretty much no way to prevent it. It's one of those diseases transmitted by a mosquito, like malaria.

"Success for me is having a significant impact on dengue disease in communities," says Scott O'Neill, holding a container of mosquitoes.

About 20 years ago, a lot of scientists got excited about the idea of genetically modifying mosquitoes so they couldn't transmit these diseases. People are still pursuing this approach. But I thought genetically modifying mosquitoes would be really hard to do. Even if you were able to make these disease-blocking mosquitoes in the lab, I didn't see how you would ever get them to survive in the wild, and displace the disease-transmitting mosquitoes that were already there. There was also a societal problem with the scheme. Most people probably wouldn't be thrilled about having swarms of genetically modified mosquitoes released in their backyards.

But last summer, when I read about O'Neill's work, it really knocked me out. His big idea was to infect mosquitoes with a naturally occurring bacteria called Wolbachia. Turns out that by some unknown quirk of biology, Wolbachia-infected mosquitoes can't carry the dengue virus.

Let me repeat that, because this is a key point: A mosquito infected with the bacteria called Wolbachia can't transmit the virus that causes dengue. One microbe defeats the other.

When I interviewed O'Neill by phone last year, he told me the idea seemed to be working. He had released his Wolbachia-infected mosquitoes into two small communities in northeastern Australia.

"Over a very short period of time, the Wolbachia was able to invade the wild mosquito population until close to 100 percent of all mosquitoes had the Wolbachia infection — and so we presume, greatly reduced ability to transmit dengue between people," O'Neill told me.

That was enough success for me to do a short news story about O'Neill's work. But I knew there was more. I convinced my editor to let me go to Australia to learn more about O'Neill and his big idea.

'Incredibly Frustrating Work'

One of the first things I learned when I got to his lab at Monash University in Melbourne was a surprise: It had taken O'Neill 20 years to get his big idea to work.

"You know, I was incredibly persistent in not wanting to give this idea up," O'Neill said. "I thought the idea was a good idea, and I don't think you get too many ideas in your life, actually. At least I don't. I'm not smart enough. So I thought this idea was a really good idea."

The problem was that O'Neill couldn't figure out how to infect mosquitoes with Wolbachia. Remember, a Wolbachia infected mosquito can't transmit dengue.

You can't just spread Wolbachia bacteria around and hope the mosquitoes catch it. Instead, you have to puncture a mosquito egg or embryo about the size of a poppy seed with a hair-thin needle containing the bacteria, peering through a microscope the entire time so you can see what you're doing.

"It's incredibly frustrating work," O'Neill says.

His colleague Tom Walker spends hour after hour, day after day, trying to inject the embryos. Even though he's become an expert at this, Walker can do no more than 500 a day.

Then the scientists have to wait a week until the adult mosquitoes emerge to see if any are infected with Wolbachia. Walker says in this latest round of work he's injected 18,000 eggs — with nothing to show for it. "The success rate is very low," says Walker, in something of an understatement.

"We don't have any windows that can open in this building, so people like Tom can't jump out of them," O'Neill adds with a laugh. He sounds like he's only half kidding.

The good news is that if you can manage to get the bacteria into even one mosquito, nature will take care of spreading it for you. Any mommy mosquito that's infected will also infect all her darling offspring, all 100 or more of them. And when those baby mosquitoes become mature in about 10 days, the new mommies among them will pass Wolbachia to their babies. Pretty soon, everybody who's anybody in that mosquito community is infected.

Success: 'A Significant Impact On Dengue Disease In Communities'

Now as I said, O'Neill has been pushing this idea of using Wolbachia to control dengue for decades, for a most of that time without any success. I asked him what it takes to stick with something for that long.

"I think being obsessive," he replied. "Being maybe a little ill in that regard. And it's just that I seem to have focused my obsession onto Wolbachia instead of on to postage stamps or model trains."

And even though his obsession has brought him to the point where he's shown he can get his Wolbachia-infected mosquitoes to spread in the wild, that's not the success he's ultimately after. "Success for me is having a significant impact on dengue disease in communities," he says.

To do that, he'll have to release his mosquitoes in a place where there's a lot of dengue, and then see if that brings down the number of cases of the disease in humans. Those studies are being planned now.

The stakes are high. By some estimates, more than a billion people around the world are at risk for getting dengue. Even if it doesn't kill you, I'm told a case of dengue can make you feel so bad, you wish you were dead.

"[It's] pretty much the worst disease I've ever had. It was not fun," says Steven Williams, a tropical disease researcher at Smith College in Northampton, Mass. Williams was bitten by a dengue mosquito while on a trip to French Polynesia. He says for 10 days he had a high fever, horrible headache and terrible pain in his muscles and joints.

One other delightful thing about dengue: There are no specific drugs to treat it. "You basically just have to ride it out," says Williams.

Moments Of Triumph, With Trepidation

With no cure and no vaccine, O'Neill's Wolbachia-infected mosquitoes could make a huge difference. Although proving that is still years off, there have been moments of triumph in the 20-year slog that's brought him this far.

Take the day in 2006, when one of O'Neill's graduate students told him he thought he'd finally succeeded in infecting a dengue mosquito with Wolbachia.

I figured this must have been a red-letter day for O'Neill, a day of sheer elation. He told me looking back on it, it was. But at the time it didn't seem that way.

Releasing Mosquitoes To The Wild

"Because you're so used to failure that you don't believe anything when you see it," he says. "And so you can think back to when there was a Eureka moment, but at the time, you're probably, 'This looks good but I've been burnt thousands of times before. Let's go and do it again, and the do it another time, and check and check and make sure it's actually real.' "

O'Neill says the day his team really enjoyed was last year when they tested to see if their mosquitoes would take over from the other mosquitoes in the wild.

O'Neill's colleague Scott Ritchie recorded the event for posterity on his cellphone.

That got me interested in O'Neill's work last summer. He and his colleagues have now completed a second release, and the results are looking promising. But O'Neill says it's not yet time to celebrate.

"We've got some good preliminary data, and we're on the path. And it's looking good. But you know I am a realist. It could fall over at any day," he says.

'Eliminate Dengue' Team Has A Deep (Lab) Bench

Every profession has its symbols of success. For opera singers, it's performing at La Scala or the Met. For mountain climbers it's making it to the top of Everest. For scientists, if you get two papers published in the same issue of a prestigious journal like Nature, you're hot.

So when an Australian named Scott O'Neill had two papers published in Nature last year describing his big idea for combating a disease called dengue, the world took notice. O'Neill is a medical entomologist and dean of the faculty of science at Monash University in Melbourne.

"We were getting bombarded by people around the world, from different governments, wanting us to come work in their countries because people are so desperate for something to try and stop dengue," says O'Neill.

Dengue is nasty. It's transmitted by a mosquito and can be a deadly disease. But even if it doesn't kill you, it knocks you out with a week or more of high fever and a pounding headache. Billions of people around the world are at risk for getting dengue if they get bitten by a mosquito carrying the dengue virus.

O'Neill's big idea for stopping dengue didn't involve a vaccine or a medicine. Instead, it involved attacking the mosquito that transmits the disease.

There are two parts to the idea. First, find a way to treat mosquitoes in the lab so they could no longer transmit dengue. That took him more than a decade to figure out. And five years ago, O'Neill finally managed to do it.

Next, release those dengue-proof mosquitoes and show that they will not only survive outside the lab but actually drive out the native population of mosquitoes that can transmit dengue. That's what O'Neill showed in those two Nature papers last year.

Now, I say O'Neill has done this, but that's misleading, because science is now a team sport. "We don't work in isolation in any projects in science these days," he says. "The days of having someone beavering away by themselves in the backroom have long gone, I think. So we're working in large teams always."

O'Neill's team is also spread around the world — he has collaborators in the United States, Brazil, Vietnam and Thailand, and in the tiny town of Babinda in northeastern Australia, where I went to visit.

Babinda's main claim to fame is winning the Golden Gumboot. A gumboot is the Australian term for a waterproof boot, what the Brits call a Wellington. The Golden Gumboot is a tongue-in-cheek award given each year to the Australian town that gets the most rain.

O'Neill's team here drives through the community in a minivan, releasing lab-reared mosquitoes. Martin Durkan is on the mosquito release team. When his day starts, there are dozens of small plastic containers in the back of the van, each with about two dozen of O'Neill's mosquitoes. I watch as he drives up to a house, jumps out, walks over to the front yard, and pries the lid off the container. "And away they go," he says. "The little angels are flying."

The Challenge Of Managing Science

These little angels are the key to combating dengue. The mosquitoes native to Babinda can transmit dengue. Scott's little angels can't. If the angels can take over from the natives, then in theory there will be no more dengue in Babinda. Not that there was ever a lot of dengue here, but you've got to start somewhere.

So how do you know if the angels are winning? Well, you could ask, but sometimes it's hard to tell what mosquitoes are saying. So a better way is to collect mosquito eggs. By analyzing the eggs, you can tell whether they came from O'Neill's angels, or the local riffraff.

The analysis is done in O'Neill's's lab at Monash University, where the mosquito eggs are ground up and put into a machine that will show whether the eggs are from those nasty wild mosquitoes or whether they are descendants of O'Neill's's angels.

So far this year, it looks like the angels are taking over from the natives. But it just as easily could have gone the other way.

O'Neill couldn't have found that out without relying on his team. He told me he's seen a lot of science projects fall over because teams couldn't hang together. "Finding a way to manage a group of people who are all quite individualistic and having them work together towards this common goal is critical," he says. "So I think there's a big management component to science that's not fully appreciated."

By all accounts O'Neill is a pretty good manager. But that means at times telling people things they don't want to hear. Michael Turelli, who works at the University of California, Davis, and is a devoted member of O'Neill's team, says O'Neill is a great team leader, "but that means that if part of the team isn't working, that part of the team is cut off without ceremony. I've seen him do that. And he does it in a way that people aren't offended. They realize, 'Yes, you can't give me another million dollars, because I haven't produced anything.' So that's that."

O'Neill is moving into a critical stage of his project — he's got his special mosquitoes, he's shown they can take over in the wild, but he still has to show they can stop dengue. That's going to mean taking on a bigger challenge: releasing them in countries like Vietnam and Thailand, where dengue is a huge problem.

The Balance Between 'Self-Promotion' And 'Cautious Conservatism'

O'Neill's colleague Scott Ritchie old me about another challenge O'Neill faces that has nothing to do with management. It's about how you portray your work. He says take the name they have given their project: Eliminate Dengue.

Scott O'Neill is leading a global effort to rid the world of dengue fever. "Finding a way to manage a group of people who are all quite individualistic and having them work together towards this common goal is critical," he says.

"That's really putting yourself up there," says Ritchie, "to say that we're going to eliminate dengue. And I think a lot of scientists are saying, 'Yeah, you bet. I'll bet you haven't thought of this, you haven't thought of that, you're making big promises before you've got the evidence to say that you're going to do it.' On the other hand, a name like that draws attention. It's certainly generated a lot of attention in the media. I mean, you're here, Joe. So I think you need to find this balance between self-promotion, but also a bit of cautious conservatism."

It's the entrepreneur in O'Neill that made him choose a bold name like Eliminate Dengue. He knows there are risks.

"We need the exposure; we need people to know about what we're doing. We want to have communities supporting what we're doing. But at the same time we need to be careful," says O'Neill. "This has the potential be difficult for the team, if it comes across that this is all Scott's idea and it's all because of Scott."

O'Neill and his colleagues have learned a lot in the past 20 years. And a goal as big as this, to change an entire species of mosquitoes in the world, could take another 20 years.

"Success for me is having an impact on dengue disease in communities. That's what we're really looking for," says O'Neill.



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