Researchers at Upstate Medical University in collaboration with the U.S. Army have advanced the development of an experimental Dengue Human Infection Model (DHIM) that is expected to be used widely by drug makers to advance the development of safe and effective vaccines against the dengue viruses. 

Details of a recent study performed at Upstate describing how dengue virus infects humans and drives immune responses are contained in a paper published Oct. 26 in the high-impact journal Science Translational Medicine.

Dengue is a disease spread by infected Aedes aegypti and Aedes albopictus mosquitos that infects an estimated 400 million people every year, according to the World Health Organization. The severity of dengue can range anywhere from mild flu-like symptoms to life-threatening dengue hemorrhagic fever. Reports show that 20,000 people die from dengue virus infections annually. While dengue virus is not commonly found in the continental United States, the mosquito responsible for the spread of dengue is expanding its range to parts of the South and Southeastern United States. There are no dengue antiviral therapies currently available, and the only currently available dengue vaccine is only recommended for use in individuals previously infected with dengue and living in areas where dengue is common.

“We have demonstrated the ability to safely and consistently infect people with a weakened dengue virus, generate a mild dengue-like illness, and then study how the virus and human immune system interact,” said the study’s lead author, Adam Waickman, PhD, Upstate assistant professor of microbiology and immunology. “This dengue human infection model is actively being used to test vaccines and drugs.”

To develop the model, researchers injected nine individuals with a weakened strain of dengue virus and then monitored their health daily for the first 28 days after inoculation and then in various intervals up to 180 days post-infection.

Within the first month of receiving the injection of the virus, all participants had reported mild to moderate symptoms consistent with dengue including headache, muscle aches, and fatigue. All volunteers had detectable levels of the virus in their bloodstream. Researchers used blood samples taken after infection to intensely characterize how the virus replicated and how the immune system responded to the virus.

Completing this type of characterization allows researchers to be more informed when they design vaccines or drugs to prevent or treat dengue and allows them to put these countermeasures to the test early in their development.

Waickman said the challenges of studying disease in dengue-endemic regions for the development of vaccines can be nearly impossible. For example, is it difficult to capture people in the first few days after infection and before symptoms develop, and many people living in dengue-endemic regions have had a pre-existing dengue infection, resulting in immunity from the getting the virus of a similar strain. And most importantly it is difficult to collect blood samples with a frequency that allows for detailed analyses.

Currently there are only a few vaccines in development, but the single dengue vaccine currently available is limited to people 9 years of age and older and only to those who have previously been infected with dengue.

“While several promising candidates are in early-stage clinical development, there is no dengue antiviral currently available for prophylaxis or as a therapeutic. Therefore, despite more than a century of basic science research, countermeasure development efforts, and attempts at vector control, dengue remains a largely unchecked public health burden,” says the study’s senior author, Stephen Thomas, MD, Upstate Professor and acting chair of the department of microbiology and immunology

The Upstate research team hopes this new Dengue Human Infection Model accelerates vaccine and drug development and starts to lessen the global dengue burden.

The study was supported by Johnson and Johnson.

Paper authors from Upstate Medical University, in addition to Waickman, include Joseph Q. Lu, HengSheng Fang, Mitchell Waldran, Chad Gebo, Lisa Ware, Timothy P. Endy, MD, MPH, and Stephen J. Thomas, MD, representing the Department of Microbiology and Immunity and the Institute for Global Health and Translational Sciences.

Other authors include Jeffrey Currier, of Viral Diseases Branch, Walter Reed Institute;  Liesbeth van Wesenbeeck, Nathalie Verpoorten, Oliver Lenz, Lotke Tambuyzer, Marnix van Loock, of Janssen Pharmaceutica; and Guillermo Herrera-Taracena, of Janssen Global Public Health.

 

Caption:  Stephen Thomas, MD, professor and interim chair of microbiology and immunology, left, and Adam Waickman, PhD, assistant professor of microbiology and immunology, served as senior author and lead author, respectively.