In a small clinical trial led by the Johns Hopkins Bloomberg School of Public Health, researchers say that a promising single-dose dengue vaccine, developed by scientists at the National Institutes of Health, was 100 percent effective in preventing human volunteers from contracting the virus, the most prevalent mosquito-borne virus in the world.
The findings, published March 16, 2016 in Science Translational Medicine, could be the final puzzle piece in developing a vaccine that is effective against dengue, which infects nearly 400 million people across more than 120 countries each year. While most of those who are infected with dengue survive with few or no symptoms, more than two million people annually develop what can be a dangerous dengue hemorrhagic fever, which kills more than 25,000 people each year.
Preventing dengue has been a particular challenge. A three-dose vaccine called Dengvaxia received limited licensure in 2016 in Mexico, the Philippines, and Brazil. That vaccine produced antibodies against the dengue in a clinical trial and protected against dengue during the first year after vaccination. But two years after vaccination, children who were under the age of nine when they received the vaccine were hospitalized for dengue at a significantly higher rate than those who received the placebo. For this reason, the researchers, led by Anna P. Durbin, MD, an associate professor in International Health at the Bloomberg School, were concerned that measuring antibodies alone may not truly indicate the ability of the vaccine to protect against dengue.
In February, based on the new findings, researchers in Brazil began administering the new single-dose vaccine in a large Phase 3 clinical trial designed to look at vaccine efficacy against naturally occurring dengue.
"Knowing what we know about this new vaccine, we are confident that it is going to work," Durbin says. "And we have to be confident: Dengue is unique and if you don't do it right, you can do more harm than good."
Dengue is marked by a high fever, with other symptoms including severe headaches, severe pain behind the eyes, rash and joint, muscle or bone pain. Dengue hemorrhagic fever occurs when blood leaks from the blood vessels into other parts of the body, which can lead to failure of the circulatory system and shock, and possibly death, without prompt, appropriate treatment.
There are four very different strains of dengue that circulate and a successful vaccine must prevent all four strains. It has long been known that people who are infected once with one dengue virus are likely to get sicker if they are infected a second time with a different strain. For this reason, a good dengue vaccine needs to protect against all four dengue viruses, the researchers say.
The TV003 vaccine, as it is known, was already in pretty good shape in preventing dengue 1, 3 and 4 viruses, but the portion of the vaccine that was designed to prevent dengue 2 did not induce as strong an immune response in people as the other three components. So the researchers decided to see if the vaccine could specifically protect against the dengue 2 virus if people were exposed to that strain six months after being vaccinated. For this study, instead of looking only at antibodies, the researchers looked for the evidence of actual infection: virus in the blood, rash and low white blood cell count.
In the investigation, researchers from the Bloomberg School and the University of Vermont administered the TV003 dengue vaccine to 24 healthy adults, while 24 others received a placebo. Six months later, the remaining 41 study participants were exposed to the dengue 2 virus. None of the 21 people who had received the vaccine had any evidence of infection in their blood, nor did they develop a rash or have low white blood cell counts. In contrast, 100 percent of the 20 placebo recipients who were exposed to the virus had virus in their blood, 80 percent developed a rash and 20 percent had low white blood cell counts. Only a single dose of the vaccine was necessary and while researchers believe the effects will be long lasting, they only tested it after six months.
Often, vaccine trials are looking to see whether a person has developed antibodies to the virus. That didn't appear to be good enough in an earlier study of Dengvaxia in Thailand. While people who were vaccinated there developed antibodies, those antibodies did not protect against dengue 2 infection and could have played a role in causing more serious disease.
One of the small study's strengths is that it was conducted in a controlled environment in the U.S., far from where dengue circulates in the population. This was so researchers could test it on people who would not have been previously exposed to any strain of the virus because ultimately, the vaccine will be used in areas where dengue circulates widely in young children who have not been previously exposed to dengue.
"What we're trying to do is accelerate vaccine development, weeding out poor candidates before testing them in large numbers of people in places where dengue is endemic," says Durbin, who has been working on a vaccine for dengue for more than 15 years.
Durbin says the methods used in this study could be the basis for developing a vaccine against the Zika virus, another mosquito-borne infection that is in the same family of viruses as dengue, in the coming months and years. Zika is racing across parts of Latin America and the Caribbean and could be associated with birth defects in the fetuses of pregnant women who become infected and may also be linked to adult cases of the neurological disorder Guillain-Barre. Ideally, Durbin says, a virus that protects against all four strains of dengue and Zika will be developed.
"The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model" was written by Beth D. Kirkpatrick, Stephen S. Whitehead, Kristen K. Pierce, Cecilia M. Tibery, Palmtama L. Grier, Noreen A. Hynes, Catherine J. Larsson, Beulah P. Sabundayo, Kawsar R. Talaat, Anna Janiak, Marya P. Carmolli, Catherine J. Luke, Sean A. Diehl and Anna P. Durbin.
The study was supported by a contract with the National Institutes of Health's National Institute of Allergy and Infectious Diseases' Intramural Research Program (HHSN272200900010C).