Dengue Human Infection Model Study

University of Vermont vaccine researchers Sean Diehl, Ph.D., and Beth Kirkpatrick, M.D., of the UVM Vaccine Testing Center (VTC) and UVM colleagues Jon Boyson, Ph.D., and Jason Botten, Ph.D., just received a three-year $2.2 million grant from the Bill and Melinda Gates Foundation to study the immunological basis of protection from dengue fever, a mosquito-borne viral disease that affects as many as 400 million people annually. Lab Tech looking in microscope

Dengue infection is caused by any of four related viruses and can cause fever, headache, intense joint and muscle pain, and rash. A reported 40 percent of the world’s population – 2.5 billion people – are at risk for dengue infection, with a rising number of home-grown cases occurring in the U.S over the past decade. No directed therapeutic options nor licensed vaccines exist, says Diehl, an Assistant Professor of Medicine. Although some infections are asymptomatic, severe infections can cause hemorrhagic fever and dengue shock syndrome, and have a higher risk of complications and death. Like all infections, dengue activates the immune system and that’s the goal for the dengue vaccines as well: to build up the body’s immunity to completely prevent the disease. A major focus of this new study is the antibodies and T-cell responses produced in the blood in response to the dengue.

In addition to UVM VTC investigators, the team includes researchers from the Johns Hopkins Bloomberg School of Public Health, the National Institute of Allergy and Infectious Disease (NIAID), the La Jolla Institute for Allergy and Immunology, the University of North Carolina, and Atreca, Inc. Diehl and Kirkpatrick, UVM Professor of Medicine and VTC Director, and colleagues are conducting and coordinating research that examines how the immune system recognizes dengue virus in an effort to confirm the protective effects of new vaccines in development. To date, the team’s research has shown that the antibodies produced by the vaccines can block infection of cells in a laboratory culture dish. However, other recent clinical trials of a different dengue vaccine candidate have revealed that vaccinated individuals can have a high level of antibodies in their bloodstream without being adequately protected from dengue infection.

“These results have caused a seismic shift in the dengue community, since such antibodies have long been thought to be the basis of protection against dengue disease,” Diehl says. “The consensus is that new blood tests are needed to predict the effectiveness of a dengue vaccine as efforts move towards field trials.”

Field trials – considered the “gold standard” for vaccine utility – help prove a vaccine’s effectiveness in a natural setting, as opposed to a laboratory. However, conducting tests of samples from thousands of study participants is difficult to accomplish in this setting, which requires a sizable infrastructure and creates a bottleneck in the vaccine development process.

Taking voluteer's blood pressureClinical studies to circumvent this problem can be safely performed with highly weakened vaccine strains. Work at UVM and Johns Hopkins – currently underway – aims to better understand the optimal immune response that will reflect protection from natural infection with dengue viruses. In these studies, participants are closely monitored and blood tests are conducted to gain information about clearance of a weakened virus, changes in blood chemistry, and cell counts. The team led by Diehl and Kirkpatrick will also work to isolate new antibodies to dengue. This will be done with a patented technique developed by Diehl to clone individual antibody-producing B cells from vaccine recipients who were protected from challenge versus those who were not. UVM’s effort to understand the dengue immune response will be bolstered by Botten, an assistant professor of medicine, and Boyson, an associate professor of surgery, who will investigate the role of T cells, another type of immune cell with colleagues from the La Jolla Institute for Allergy and Immunology. “This work will help fill important knowledge gaps that will help drive vaccine development and implementation and will advance diagnostics for both dengue disease and to gauge vaccine effectiveness,” Diehl says.