Dengue fever is common throughout the tropics and subtropics. Four related viruses can cause dengue fever: DENV-1, DENV-2, DENV-3, and DENV-4. All are spread by Aedes mosquitoes, which also spread Zika virus. Most of the estimated 390 million people infected with dengue virus each year develop mild symptoms or none at all. However, some people develop serious or life-threatening illness. Large outbreaks can cause millions to seek care, severely straining health care infrastructure in affected countries.
An experimental dengue vaccine called TV003 was developed by a research team led by Dr. Stephen Whitehead of NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The vaccine was made from a mixture of 4 live, weakened (attenuated) viruses targeted to each of the 4 dengue virus serotypes. In previous work, the team showed that the vaccine safely produced an immune response against all 4 virus serotypes.
To directly test whether the vaccine could protect against infection, the researchers enrolled 48 healthy adult volunteers at the University of Vermont College of Medicine and the Johns Hopkins Bloomberg School of Public Health. The participants had never been infected by dengue or any related viruses. They were randomly assigned to receive either a single dose of the candidate vaccine or a placebo injection. The trial was double blind—neither the participants nor the researchers knew who received which injection.
Six months after vaccination, 41 of the participants returned for a live virus challenge. They were given a genetically modified version of a DENV-2 strain isolated during an outbreak in the Kingdom of Tonga in 1974 that caused only mild illness. The researchers had carefully established a virus dose that would cause recipients to develop viremia—the presence of virus in the blood—and most to develop a mild rash. Results were published on March 16, 2016, in Science Translational Medicine.
After the challenge, all 20 placebo recipients developed viremia, 16 (80%) developed mild rash, and 4 (20%) had a temporary drop in white blood cell count. In contrast, none of the 21 TV003 vaccine recipients developed viremia or any other sign of infection after the challenge.
“We were pleasantly surprised to see that this candidate vaccine provided complete protection in everyone who received it,” says Dr. Anna Durbin, who led the trial at Johns Hopkins.
“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,” Whitehead says. “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.”
Whitehead’s team is currently developing a similar human challenge model using a modified DENV-3 strain. The team is also using their dengue vaccine experience to develop a vaccine against Zika, which is in the same virus family.