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Human Infection Study Speeds Dengue Vaccine Development

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An experimental dengue vaccine fully protected 21 healthy volunteers who were purposely infected with a mild form of dengue virus, researchers say. This type of study, known as a human infection or challenge study, may offer a valuable tool for screening candidate dengue vaccines before launching costly, and often risky, trials in a large population.

The results, which appear in the 16 March issue of Science Translational Medicine, helped advance the vaccine into phase 3 trials that started last month in Brazil, where dengue is endemic. These promising results spurred the Butantan Institute in Brazil to license the vaccine and launch a phase 3 trial, which seeks to enroll 17,000 adults and children within the next year.

"This [human infection model] is really establishing a platform upon which the vaccine can be tested. What it gives us, as a vaccine developer, is an early indication that the vaccine will be successful," said Beth Kirkpatrick of the University of Vermont College of Medicine at a 15 March press teleconference. "This really does give you a way to expedite the process, accelerate vaccine production and vaccine development."

Human challenge models have been used previously to study malaria and influenza vaccines, among others. It can potentially be applied to other emerging threats, such as the Zika virus, which is closely related to dengue, according to Anna Durbin of the Johns Hopkins Bloomberg School of Public Health.

"We hope to do this with Zika virus," said Durbin. "We believe that a safe Zika human challenge model can be developed and would be instrumental in the acceleration of Zika vaccine development."

Dengue is the most common mosquito-borne viral infection in the world, infecting 390 million people annually, often in tropical and subtropical areas. While the virus usually causes no symptoms or only mild fever, more than 2 million people each year develop life-threatening dengue fever.

The path to the clinic is particularly arduous for dengue vaccines, several of which are currently in clinical testing. One of the biggest hurdles is the fact that a vaccine must protect against all four types of dengue virus to be effective, because individuals previously infected with one type can suffer from worse disease symptoms when infected with another type. A vaccine that is only partially effective can potentially put people at even greater risk of severe dengue.

"The phase 3 efficacy trial, which is ordinarily the first time you know whether the vaccine will actually work, can take five years, thousands if not tens of thousands of volunteers, and tens of millions of dollars," said Kirkpatrick.

To better predict which vaccine will be the most promising and which should be weeded out from further testing, the team conducted a human challenge study for a candidate dengue vaccine, which was invented by Stephen Whitehead of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. The vaccine, called TV003, contains weak or attenuated forms of each of the four dengue virus types.

Forty-one healthy individuals, who had not been previously exposed to dengue, received either a single shot of the vaccine or a placebo. Six months later, they were infected, in a carefully controlled setting, with a mild version of dengue serotype 2 virus, the hardest type to prevent.

The 20 people in the placebo group showed virus circulating in their blood, a temporary drop in white blood cell count, and a mild rash. In contrast, all 21 vaccinated individuals developed none of these symptoms and were completely protected from infection.

"The vaccine appears to be 100% efficacious at preventing a dengue 2 infection," said Kirkpatrick. Human challenge studies for the other dengue virus types are already underway, she said.