The clinical trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.
Dengue fever, prevalent in many tropical and subtropical regions of the world, is caused by any of four related viruses-DENV-1, DENV-2, DENV-3 and DENV-4 -that are transmitted to humans by Aedes mosquitoes. The World Health Organization estimates that every year, 50 million to 100 million cases of dengue occur worldwide, resulting in 500,000 hospitalizations of patients with severe disease, many of them in children.
Infection with one dengue virus results in immunity to that specific virus but not to the other three. Research shows that the likelihood of severe disease increases when a person is subsequently infected with a different dengue virus. This observation suggests that the ideal dengue vaccine would be tetravalent-that is, protective against all four dengue viruses.
"The global burden of dengue is enormous-and it is growing. We are cautiously optimistic about these recent clinical trial results with this candidate tetravalent vaccine developed at NIAID; however, much more work still needs to be done," said NIAID director Anthony S. Fauci, M.D.
The Phase I clinical trial, launched in July 2010 and led by principal investigator Anna Durbin, M.D., at Johns Hopkins Bloomberg School of Public Health in Baltimore, tested a single dose of each of four versions of the investigational dengue vaccine TetraVax-DV. The vaccine was developed by scientists in NIAID's Laboratory of Infectious Diseases. It is a live, attenuated vaccine, which means that the viruses it contains are weakened enough such that they do not cause illness but still can induce an immune response. Each of the four vaccines tested included different mixtures of components designed to protect against all four dengue viruses.
The Phase I study was conducted in Baltimore; Burlington, Vt.; and Washington, D.C. The final study analysis included 112 healthy men and women ages 18 to 50 years who had not previously been exposed to dengue or related viruses such as West Nile virus and yellow fever virus.
The researchers found that all four candidate vaccine combinations induced antibody responses against each of the dengue viruses. However, one vaccine combination, TV003, appeared to induce the most balanced antibody response against the dengue viruses.
A single dose of TV003 resulted in an antibody response to all four dengue viruses in 45 percent of participants and against three of the four viruses in an additional 45 percent. Overall, an immune response to at least three viruses was seen in 90 percent of vaccinees given TV003.
"What is promising about TV003 is that it elicited solid antibody responses after just one dose. Other vaccines in development require two or three injections at higher doses to achieve similar results," explained Stephen Whitehead, Ph.D., of NIAID's Laboratory of Infectious Diseases, who led the development of the vaccine candidates.
All four candidate tetravalent vaccines were found to be safe, and no participants experienced fever or dengue-like illness after vaccination. The most common side effect was a faint rash (in 64 percent of vaccinees and none of the placebo recipients) consisting of small, non-painful bumps on the arms and torso that resolved within five to seven days.
The presence of the rash appeared to correlate with being white and having a stronger immune response to vaccination, according to the researchers.
The researchers are conducting studies to further evaluate the vaccine's safety and ability to stimulate an immune response in healthy volunteers and in people who have been infected previously by dengue or related viruses.
The trial results were published online in the Journal of Infectious Diseases.