How Thailand might save the world from a dengue pandemic

[dozer]

http://asia.nikkei.com/Tech-Science/Sci ... e-pandemic

BANGKOK -- Thailand is at the center of a global rush to head off the risk of a dengue fever pandemic caused by global warming.

For the past four decades, Thailand has been on the front line of the fight against the dengue virus, which infects up to 100 million people a year, killing about 15,000, mostly in tropical and sub-tropical regions. Even survivors suffer fever and acute joint pain. Finding a vaccine has proven difficult, in part because of the complex nature of the virus, but also because of a dearth of investment to combat what has been seen as a disease that mainly affects poor countries.

Next year, however, Japan's Chemo-Sero-Therapeutic Research Institute, also known as Kaketsuken, plans to begin clinical trials of a vaccine developed in Thailand. A drug could hit the market within six to eight years, according to Kaketsuken's Thai partner, Mahidol University.

The Serum Institute of India is also working on a dengue vaccine, using the same Mahidol technology; it could have a product available within a decade.

There are three other dengue candidate vaccines under research and development at Thailand's top universities -- part of a program run by Thailand's National Science and Technology Development Agency -- that could be marketable within 10 to 15 years.

Separately, Sanofi Pasteur, the vaccines division of Sanofi, the French pharmaceutical group, has succeeded in passing a candidate vaccine through the required three clinical trial phases and could soon move on to commercialization.

The dengue virus is transmitted by the Aedes aegypti and Aedes albopictus mosquitoes, which thrive in tropical urban environments and feed on humans. Global warming and increasing urbanization will give these mosquitoes much larger feeding grounds, giving governments and pharmaceutical giants good reasons to spend more on battling the virus. In the past five years, dengue outbreaks have been reported in France, Italy, Japan, Portugal and the U.S. state of Florida.

History of failure

The road toward a vaccine is littered with failures. In Asia, work started in Thailand in 1980, when the U.S. military and Mahidol combined forces. American scientists brought new cloning technology, but it failed.

Mahidol professor Natth Bhamarapravati pursued the more traditional technology of life attenuation in cell culture, which had been successfully applied elsewhere to create vaccines against polio, mumps and rubella.

Using dog kidney cells to attenuate the dengue virus to the stage where it could trigger an immune response in humans without the accompanying symptoms, Natth succeeded in creating a vaccine that worked against three out of the four dengue strains; the method failed to immunize humans against dengue strain No. 3.

Three out of four is not good enough for a dengue vaccine. One of the unique characteristics of the dengue virus is that it becomes more life threatening with each strain a victim endures. As an individual builds up immunity to one strain, he or she becomes more vulnerable to the other three. Sanofi Pasteur bought Natth's technology but failed to commercialize a vaccine because of the problem with strain No. 3. The company switched to recombination technology, splicing the dengue gene onto a yellow fever vaccine.

After 25 years and an estimated investment of $1.7 billion, Sanofi Pasteur is on the verge of releasing a vaccine, after performing tests on 40,000 people in Asia and South America. The company claims an efficacy rate of 60% against all four strains.

However, experts are divided on the vaccine's merits. Disease Daily, a medical journal, said in January that "efficacy questions linger" over the results of a final round of trials in Asia. The journal added that the vaccine "was least effective against ... the most prevalent strain in Asia." Prasert Auewarakul, chairman of the health division of the NSTDA, said the vaccine might be a hard sell. "Because the protection is not so good," he said, "it won't be successful in terms of marketing."

Natth, a legendary figure in the Thai scientific community, died in 2004 before proving his method could work on dengue strain No. 3. His colleague, professor Sutee Yoksan, the current director of Mahidol's Center for Vaccine Development, continued Natth's mission. In 2005, Sutee received a grant of 25 million baht ($739.000 at current exchange rates) from Thailand's National Research Council to continue Natth's work using life attenuation in dog kidney cells.

The breakthrough came in 2006, when Sutee managed to introduce dengue strain No. 3 in dog kidney cells by patiently waiting for the virus to emerge after several generations. Natth had assumed the process did not work, but the real problem was that the No. 3 virus produces few offspring.

"Because [Natth and his team] did not detect the progeny of the virus in the first passage, they assumed there were none at all," Sutee said. "We had to look carefully, be patient and not throw everything away when [we couldn't] detect it. To succeed in developing a dengue vaccine you have to have the right technology, and for that we have to credit Dr. Natth. I followed him and used the same technology."

The money factor

Another crucial ingredient in developing a dengue vaccine is money; clinical trials are expensive. While Thailand has funding for research and development, it lacks the financial resources to conduct clinical trials, which sometimes involve thousands of volunteers. Sutee got a 33 million baht grant from the Thailand Center of Excellence for Life Sciences from 2007 to 2009 and then another 11 million baht from the Department of Diseases Control in 2010, which allowed him to test his vaccine for all four strains on monkeys. "So we had to change cars three times to get to the end of the pre-clinical trials," he said.

Then the funding ran out. With the approval of its backers, Mahidol in October 2011 signed a licensing agreement with Kaketsuken. The dengue vaccine technology would be transferred to the Japanese pharmaceutical company, and Mahidol would continue its support for the program. In 2013, Mahidol signed a similar agreement with the Serum Institute of India, based in Pune, in the state of Maharashta. "We have nonexclusive licenses with both of them," Sutee said.

The Kaketsuken dengue vaccine project got a fillip in September, when it received a grant of 345 million yen ($2.78 million) from the Global Health Innovative Technology Fund, an international funding organization based in Tokyo. The grant was announced shortly after a dengue outbreak was reported in Tokyo, the first such outbreak in 70 years.

The licensing agreements with Kaketsuken and the Serum Institute of India do not prevent Mahidol from developing its own vaccine, but there are other constraints. "If Kaketsuken and the Serum Institute of India were not interested in my vaccine," Sutee said, "I don't think it would have proceeded further. I think in Thailand we just want to be a 'smart center.' We can create vaccines, and other companies can evaluate and produce them."

The Natth/Sutee dengue vaccine is not the only Thai candidate. The NSTDA program has been working on three dengue vaccines since 2004, using three technologies -- genetic engineering, DNA and viral proteins. The agency, part of the Ministry of Science and Technology, has its own budget and plans to move into phase one clinical trials within two years.

However, it is not clear how further trials, with their additional costs, will be financed. The government's goal is to increase both public and private sector investment in research and development from about 0.25% of gross domestic product to 1%, but there have been no increases so far.

"While they are talking and planning," Prasert said, "the budget stays more or less the same."
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[JamesWest]

"BANGKOK -- Thailand is at the center of a global rush to head off the risk of a dengue fever pandemic caused by global warming"

[charlesh]

Using dog kidney cells to attenuate the dengue virus to the stage where it could trigger an immune response in humans without the accompanying symptoms,

So that's what happens to the dogs. Kidneys extracted and infected with dengue.