PUBLIC HEALTH:

Dengue re-emerges in U.S., spurring race for vaccine

For the first time in more than 65 years, dengue has returned the continental United States, according to an advisory the Centers for Disease Control and Prevention issued in late May. While a few cases were reported earlier, they were primarily in Americans who had caught the virus abroad or at the Texas-Mexico border.

The upsurge is not unexpected. Experts say more than half the world's population will be at risk by 2085 because of greater urbanization, global travel and climate change. Over the past 30 years, a global outcry against using the pesticide dichlorodiphenyltrichloroethane, or DDT, has led to the resurgence of the mosquito, a voracious consumer of human blood and carrier of infectious disease.

Epidemics have become routine in Latin America, a continent on the verge of becoming highly endemic. Outbreaks are today raging in Brazil, Guatemala and other nations. Thailand, within a week of its annual dengue season this year, has already reported 18,000 cases and 20 deaths, according to the Ministry of Public Health.

As the virus spreads in the tropics, experts are continuing to push toward an ultimate solution for the mosquito-borne illnesses: an effective and affordable vaccine. There are no drugs for the disease.

Jean Lang, associate vice-president and head of research and development for the dengue program of the deep-pocketed pharmaceuticals company Sanofi Pasteur Inc., last month presented the world's most advanced effort to vaccinate against dengue to a room full of industry insiders in Chicago. The market for a vaccine is huge, with experts pegging sales at between $700 million and $1 billion per year.

In comparison, the company's top-selling drug right now, an insulin injection called Lantus, nets $3.7 billion per year.

"If everything goes well, we will have phase 3 trials on an industrial scale by the end of the year," Lang remarked. He spoke of nearly 100 million people worldwide getting the disease and 25,000 people dying in tropical countries per year.

But the virus was closer than that. In April, a 41-year-old man in Key West, Fla., was admitted to a hospital, complaining of fever and blood in his urine, according to CDC. Tests revealed that he had antibodies to the dengue virus, which is mild in its most prevalent form. In more severe versions of the illness, called dengue hemorrhagic fever and the dengue shock syndrome, the virus can kill by significant internal bleeding.

Since August 2009, U.S. doctors have diagnosed 28 people with dengue, according to CDC. They had all caught it in Florida.

"We live in a world of world travelers, and these vectors are spreading," said Kim Knowlton, senior scientist at the Natural Resources Defense Council and assistant clinical professor at Columbia University's Mailman School of Public Health. "The need for a vaccine has never been greater."

'Very optimistic' about new vaccine

Sanofi's is the most advanced vaccine against the life-threatening disease carried by the tiger mosquito, Aedes aegypti. The company has recruited 4,000 children ages 4 to 11 in Thailand who will receive three shots of a vaccine that should protect them, if all goes well. Final trials will be conducted in an even larger group. Since vaccine development is a minefield with most attempts dying in the clinical trial phase, success is not guaranteed.

The process goes through phase 1, where safety is determined; phase 2, where researchers ensure that the body has an immune reaction to the vaccine; phase 2b, a new stage to show that the vaccine prevents disease in a smaller population; and finally phase 3, where the largest populations are tested before licensure.

Dengue is a difficult candidate to design a vaccine for, Lang explained. It belongs to the flavivirus category of microbes, so named after the virus that causes yellow fever. And there are actually four different viruses, and each can activate a separate immune response in the body. A person who is vaccinated needs to be able to ward off all the virus types.

If the vaccine acts against only one virus, an infection by a different variety can result in the more severe dengue hemorrhagic fever or shock syndrome.

"I'm very optimistic that Sanofi's product is going to work," said Lt. Col. Stephen Thomas, a U.S. Army physician at the Armed Forces Research Institute of Medical Sciences in Thailand, which is working with drugmaker GlaxoSmithKline (GSK) on a different vaccine.

"They've given the vaccine to thousands of people so far and very carefully assessed safety, and there's been no major safety signal so far," Thomas said. Other experts in the field agree.

The United States' investment in dengue started after World War II when it saw children dying of a mysterious hemorrhagic fever in Thailand. Army men and women were also contracting the disease abroad. It soon handed over research to its infectious disease unit, and the Army has been collaborating with various universities and pharmaceutical groups since then.

The latest partnership is with GSK, which is examining results from a phase 2 clinical trial to be concluded in December, according to Thomas.

"There are over 110 countries where transmission can occur," Thomas said. "Lots of countries and governments would be very interested in purchasing a dengue vaccine."

Risky research

For most of the time during the history of research into the disease, there has been no animal model for testing. While monkeys can get infected by the virus, they do not fall sick from it like humans do. This means that any advances in science would have to be tested in people. The pitfalls of an unsafe vaccine would be huge, and larger leaps in science would have to be ignored for smaller but safer attempts.

Despite the risks, a few efforts have advanced. Sanofi's is a novel attempt at engineering a cure in a field that has been around for half a century.

The vaccine is genetically modified, a mishmash of the genes of dengue pasted into the backbone of the yellow fever virus. The viruses so formed are mutated and weak.

Where injecting the normal viruses into a human can trigger a full-blown case of dengue, the weakened viruses are overtaken by the immune system. The body learns from the attack and makes antibodies that ward off future infections by naturally occurring viruses. The company expects the vaccine to be launched in 2015.

In comparison, GSK's vaccine is not man-made, but a weakened version of the naturally occurring virus.

Other initiatives include one by the National Institutes of Health, which is entering phase 1 trials, according to Anna Durbin at the department of international health at the Johns Hopkins Bloomberg School of Public Health.

Studies flourish with disease

Developing vaccines for infectious diseases that primarily afflict low- and middle-income countries has traditionally been a low priority. But with the re-emergence of the disease in the Western Hemisphere, a $55 million increase in funding by the Bill and Melinda Gates Foundation in 2003, and interest from major pharmaceutical companies, research has flourished, said Lt. Col. Thomas.

The recent upsurge in disease in the Americas has been caused by a number of factors, including careless vector control since the eradication of the mosquito in the 1970s, according to Knowlton. A report she did for the Natural Resources Defense Council found that since 1995, rates of dengue fever have increased by more than 100 percent in Bolivia, Costa Rica, El Salvador, the Caribbean and Puerto Rico.

"The mosquitoes love to live in close proximity to people and like clean water that people need," Knowlton said.

The insect's preferred habitat -- flower pot liners, stagnant but clean water stored in parched cities, rubber tires and the like -- have exploded in recent years as people flock to cities. And new infections have tended to result in more severe fevers as waves of adults catch the disease the second time around. The World Health Organization is contemplating revising its definitions of dengue hemorrhagic fever since even primary fevers can sometimes be quite severe, according to Durbin of Johns Hopkins.

The risk is set to increase. A report in the medical journal Lancet, which looked at the impact of climate change on the global distribution of dengue fever, found that nearly 5 billion to 6 billion people will be living in land suitable for transmission by 2085.

This is compared to 3 billion to 5 billion people who would be at risk without climate change.

Viral development is faster at warmer temperatures and mosquitoes survive for longer, according to Paul Epstein, associate director of the center for health and the global environment at Harvard Medical School.

"As things continue to warm, there'll be more breaches of our shores by tropical illnesses," Epstein said.