Dengue vaccine trial delivers promising results

In a clinical trial, all volunteers who received an experimental dengue vaccine were protected from infection.

“The findings from this trial are very encouraging to those of us who have spent many years working on vaccine candidates to protect against dengue, a disease that is a significant burden in much of the world and is now endemic in Puerto Rico,” said Stephen Whitehead, Ph.D., of NIH’s National Institute of Allergy and Infectious Diseases (NIAID). “In fact, these results informed the recent decision by officials at Brazil’s Butantan Institute to advance the TV003 vaccine into a large phase 3 efficacy trial.”

The experimental vaccine was developed primarily by Dr. Whitehead and his colleagues at NIAID’s Laboratory of Infectious Diseases. Scientists from the U.S. Food and Drug Administration also contributed to the vaccine’s development. The candidate vaccine is made from a mixture of four live, weakened (attenuated) viruses targeted to each of the four serotypes. A total of 48 healthy adult volunteers enrolled at two trial sites, the University of Vermont College of Medicine, Burlington, and Johns Hopkins Bloomberg School of Public Health, Baltimore, and were randomly assigned to receive either vaccine or placebo injection.

Six months later, 41 people returned for the challenge with dengue virus. Dr. Whitehead and colleagues also developed the challenge virus used in the trial, which is a genetically modified version of a dengue-2 serotype virus isolated in the Kingdom of Tonga in 1974. The original virus was notable for causing only mild illness. In previous human challenge trials with this modified virus, Dr. Whitehead and his coinvestigators established the virus dose that would cause all recipients to develop viremia–the presence of virus in the blood–and most to develop a mild rash.

“This modified dengue virus is very attractive for use as a challenge virus because we can use it to reliably induce dengue infection in a very high percentage of inoculated volunteers without causing serious illness,” said Dr. Whitehead. By inducing only rash (without fever) in the majority of recipients, the challenge virus mimics natural dengue virus infection, which often features such a rash, he noted.

A human challenge model of dengue infection–rather than illness–is an important characteristic, explained Anna Durbin, M.D., who led the clinical trial at Johns Hopkins.

“Because there are no specific therapies for dengue fever, it is desirable to have a challenge virus that causes infection, but does not result in significant symptoms of disease,” she said. The reliably high percentage of those who develop viremia following exposure to this challenge virus is another advantage–when most or all volunteers develop viremia or other signs of infection, clinical trials can enroll relatively small numbers of people but still achieve answers to such questions as whether a candidate vaccine protects against infection, she noted.

In this study, all 20 placebo recipients developed viremia, 16 (80 percent) developed mild rash and 4 (20 percent) had a temporary drop in white blood cell count following challenge with the virus. None of the 21 TV003 vaccine recipients developed viremia or any other sign of infection after challenge.

“We were pleasantly surprised to see that this candidate vaccine provided complete protection in everyone who received it,” said Dr. Durbin. “The dengue-2 serotype is considered the relatively weaker component in this, and other, candidate dengue vaccines, so its ability to confer protection from a challenge with dengue-2 virus was encouraging.”

Dr. Whitehead is currently developing a human challenge model using a modified dengue serotype-3 virus. This challenge virus could be used in future clinical trials to test the efficacy of candidate dengue vaccines or therapies.

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