The study appears in the April 1, 2013 issue of the Journal of Infectious Diseases.
Transmitted to humans by Aedes mosquitoes and prevalent in many tropical and subtropical regions of the world, dengue infection is caused by any of four related viruses: Dengue viruses (DENV) 1 through 4. Classically described dengue fever includes fever, headache, severe joint and muscle pain, and rash. Severe dengue infections, dengue hemorrhagic fever, and dengue shock syndrome include a higher risk of complications and death and are more commonly seen after a second infection with dengue viruses. The World Health Organization estimates that 500,000 patients, many of them children, are hospitalized every year with severe dengue-related disease.
Launched in July 2010 and led by principle investigators Beth Kirkpatrick, M.D., UVM associate professor of medicine, and Anna Durbin, M.D., of Johns Hopkins Bloomberg School of Public Health in Baltimore, Md., the Phase I clinical trial tested a single dose of each of four versions of the investigational dengue vaccine TetraVax-DV. The vaccine was developed by scientists in the National Institute of Allergy and Infectious Diseases’ 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, Md., 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.
Participants were randomized into four groups. In each group, 20 volunteers received a single 0.5-milliliter subcutaneous (under the skin) injection of one of the tetravalent candidate vaccine combinations, and eight others received placebo. All were monitored for immediate adverse reactions for at least 30 minutes after vaccination, and subsequently took their body temperatures three times daily for 16 days to check for possible adverse reactions. Participants also received a physical exam every other day up to Study Day 16, and then again on study days 21, 28, 42 and 180, when blood tests were also performed.
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.
Kristen Pierce, M.D., assistant professor of medicine and investigator at UVM, says that she and her collaborators found that a single dose of the NIH vaccine induced an immune response comparable to three doses of the leading candidate vaccine, which was developed by Sanofi Pasteur. Pierce adds that the trial had another plus – low production cost, and thereby, greater potential for better accessibility.
“The safety of the vaccine has now been clearly demonstrated after many vaccine trials at both UVM and Johns Hopkins,” says Pierce. “Over the last year, the focus has really been to determine which of the formulations, or combinations, of the four vaccines will provide vaccine recipients with the best antibody response to all four serotypes of dengue.”
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.
“What is promising about TV003 is that it elicited solid antibody responses after just one dose,” explained Stephen Whitehead, Ph.D., of NIAID’s Laboratory of Infectious Diseases, who led the development of the vaccine candidates. “Other vaccines in development require two or three injections at higher doses to achieve similar results.”
All four candidate tetravalent vaccines were found to be safe, and no participants experienced fever or dengue-like illness after vaccination.
“The results of this Phase I dengue vaccine study look very promising, and the NIAID is pursuing further development of TV003,” says Kirkpatrick., director of UVM’s Vaccine Testing Center. The NIAID, in conjunction with the site investigators, 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.
TV003’s inexpensive production cost – less than $1 per dose – is critical to its potential use in developing countries, Kirkpatrick says. Manufacturers in Brazil, India and Vietnam – countries where dengue is prevalent – have licensed the vaccine technology for production and further evaluation. Phase II trials to evaluate the safety of TV003 and its capacity to create an immune response will begin soon in Brazil and Thailand.
To date, UVM Vaccine Testing Center researchers have tested the experimental vaccine on approximately 200 healthy volunteers.
“The next phase is to ensure that this antibody response will be adequate to provide protection against natural dengue infection, and whether a booster of the vaccine would provide better protection,” explains Pierce.
UVM’s Vaccine Testing Center has made significant contributions to the development and testing of a variety of vaccines of global importance since 2002. For the NIH dengue vaccine, UVM’s role in the future will focus on defining a precise dose and timing, as well as benefit of a second dose. In addition, says Pierce, the UVM researchers may also engage in vaccine trials on West Nile infection.
(This article was adapted from a news release produced by the National Institutes of Health.)