SYRACUSE, N.Y. — Upstate Medical University has partnered with the U.S. Army Medical Research and Materiel Command (USAMRMC) in the development of a dengue human infection model (DHIM). USAMRMC will invest up to $12 million over the next 3.5 years to fund five FDA-regulated clinical trials in which healthy adults between the ages of 18 and 45 can volunteer to participate.
Establishment of a safe and well-tolerated DHIM will be instrumental in understanding the immune response to dengue disease and advancing the development of safe and effective vaccines and drugs to protect humans from all four dengue viral strains; criteria that are necessary for complete protection from dengue.
"This effort is re-tooling a century old method of addressing a global health problem for which there is no solution currently available," said COL. Stephen Thomas of the Walter Reed Army Institute of Research (WRAIR).
Dengue is mosquito-borne viral disease that affects about half of the world's population, according to the World Health Organization. There are no licensed dengue vaccines or antiviral therapies currently available. The severity of dengue can range anywhere from mild flu-like symptoms to the life-threatening dengue hemorrhagic fever that most often occurs in children under the age of 10. In the U.S., most dengue cases occur in Puerto Rico, the U.S. Virgin Islands, Samoa and Guam. However, the mosquito responsible for the spread of dengue is present in much of the southern and eastern U.S.
"The development of a safe and effective dengue vaccine is of particular importance to the military in its efforts to protect U.S. Service Members who are deployed to dengue endemic regions," said Lou Jasper, product manager for the Dengue Vaccine Program in the Pharmaceutical Systems Program Management Office of the U.S. Army Medical Materiel Development Activity (USAMMDA).
The DHIM was the topic of a workshop hosted in April 2014 by the National Institute of Allergy and Infectious Diseases and the U.S. Food and Drug Administration. It was concluded at this workshop that studies with a DHIM could be conducted ethically and within the framework of FDA regulations if risks were minimized and informed consent was thoroughly executed.
Upstate was selected as a partner in this development effort, in part, because of Upstate's established clinical trial center with investigators who are experts in dengue disease and experienced with human infection trials. Leading the studies are Timothy Endy, MD, MPH, and Mark Polhemus, MD, of Upstate's Center for Global Health & Translational Science (CGHATS) and Division of Infectious Diseases. Both have collaborated previously with WRAIR and USAMMDA on dengue vaccine studies.
Endy says that human infection models for other viruses, such as influenza, have proved successful in speeding vaccine development and also show promise in the development of a vaccine against the malaria parasite. The USAMRMC and the Upstate research teams continue to focus on minimizing safety risks and are confident that the DHIM will speed the development of safe and effective dengue vaccines and drugs.
Traditional vaccine development involves many stages, from basic research and development to clinical field-testing where the vaccine candidates are tested in thousands of study volunteers. Dengue vaccine development can be particularly challenging because the field currently lacks tools to assess a vaccine candidate's potential to protect against infection without conducting large-scale (thousands of volunteers) field studies. The dengue human infection model will provide the opportunity to test vaccine performance in a smaller group of people (dozens) rather than large-scale field studies in areas where dengue is prevalent.
"Basic science will play an important role in our human infection model," said Endy, chief of Infectious Disease for the Department of Medicine at Upstate and a founding member of Upstate's Center for Global Health & Translational Science. "Dengue is a very complicated and unique virus, having four viralstrains that have each adapted to use the human body as its host. To develop an effective dengue vaccine, it is important to understand the cellular and molecular makeup of each dengue strain and how the immune system reacts to each of these strains. Simply put, we will look for markers in each of the strains that tell us where, why, how and at what point the immune system loses its ability to produce antibodies needed to fight dengue infection."
"Once developed, the dengue human infection model can be used by vaccine developers to improve existing dengue vaccines that are not completely effective, or aid in the development of novel dengue vaccines currently still in early in testing." said Polhemus, director of the Center for Global Health & Translational Science, who also serves as associate professor of medicine and microbiology and immunology at Upstate.
For more information about the study or to participate, contact the clinical research coordinators at the Center for Global Health & Translational Science at 315-459-3031 or email [email protected]
* See accompanying page for details of the studies
Dengue Human Infection Model (DHIM) studies:
• The research team is looking for healthy men and women between the ages of 18 to 45 who want to be part of this dengue study. The volunteers will be screened to ensure that they are medically fit, are dengue free, and have a healthy and uncompromised immune system. Each volunteer will be financially compensated for the time associated with their six-month participation in the study.
• Study volunteers will be injected in the arm with one of four attenuated (mild) dengue live-virus challenge (DLVC) strains that were manufactured by the USAMRMC and approved for use in these studies by the FDA. The overall objective of the clinical studies is to stimulate the human body to produce a dengue immune response for each of the four DLVC strains (dengue-1, dengue-2, dengue-3 and dengue-4).
• The first study will begin by testing the first serotype, dengue-1, to determine the dose needed to create mild, but not harmful, dengue-like symptoms and evaluating the immune response which develops. It is a dose-escalation study which means that one group will receive a low dose of the DLVC strain, with subsequent groups receiving higher doses. The end state is safe, reproducible mild dengue-like symptoms in a group.
• There are risks associated with this study and getting dengue; they range from common and mild to rare and severe. All risks associated with a particular study will be discussed with you by an investigator before you join the study.
• Similar studies will be conducted in other groups of volunteers for each of the
three subsequent DLVC strains until all four serotypes have been evaluated.
• Throughout each study, blood will be collected to study how the immune system reacts to each dose for each of the serotypes. To accomplish this, they will use sophisticated methods, including RNA sequencing, and place particular focus on the body's immune cells and how they respond to the various doses.
• From the information gleaned from the above studies, the researchers can establish a profile of each dengue strain. The four profiles, with the protocols for DLVC production, screening of volunteers, dose for inoculation and evaluation after inoculation become the Dengue Human Infection Model that will give vaccine developers direction in formulating and developing a safe vaccine or drug that is effective in protecting humans from all four dengue strains.
• Dengue is caused any one of four related viruses transmitted to humans through a bite from an Aedes aegypti mosquito, the type of mosquito that serves as a vector (carrier and transmitter) for the dengue virus. These mosquitoes are commonly found in tropical and subtropical regions throughout the world, including the United States. The mosquitoes are necessary for the transmission of the dengue virus as the virus cannot be spread directly from person-to-person. However, a human who is infected with dengue becomes a host for the virus and can infect a non-dengue infected Aedes aegypti mosquito that in turn can infect another person.
• There are more than 100 million dengue infections annually and an estimated
500,000 hospitalizations due to severe dengue disease. Moreover, dengue disease has been spreading; there has been a 30-fold increase in the last 50 years.
• In the United States, locally acquired cases of dengue are experienced in Florida, Texas, and Hawaii as well as the US territories of Puerto Rico, Samoa, Guam, and the Virgin Islands. However, anyone who travels to areas endemic with dengue is at risk.
The U.S. Army Medical Materiel Development Activity is the U.S. Department of Defense's (DOD) advanced medical materiel development activity for products designed to protect and preserve the lives of Service Members. USAMMDA develops new drugs, vaccines, and medical devices that enhance readiness, ensure provision of the highest quality medical care to the DOD and maximize the survival of medical casualties on the battlefield.
About the Walter Reed Army Institute of Research (WRAIR)
Established in 1893, WRAIR is the oldest, largest and most programmatically diverse military research institute of the US Army Medical Research and Materiel Command and Department of Defense. WRAIR has an extensive international research network that includes sites in Africa, Thailand and elsewhere in Southeast Asia, Germany, and Georgia. The Institute is comprised of the Center for Infectious Disease Research and the Center for Military Psychiatry and Neuroscience.
About the Center for Global Health and Translational Science
CGHATS brings together faculty, staff and students at Upstate Medical University to address health divergences. We facilitate interdisciplinary research, education and service in global health. CGHATS addresses global health issues with resources and expertise from the entire university and partners. Upstate's Center for Global Health & Translational Science is targeting dengue at various fronts through vaccine trials and other studies evaluating the climate drivers and social risk factors that contribute to the spread of dengue. Center researchers are currently working on a U.S. Department of Defense study to create a prototype for a new device that will attract and exterminate Aedes aegypti mosquitoes. For more information about research efforts at the Center for Global Health & Translational Science, visit http://www.upstate.edu/cghats.
Caption: U.S. Army Col. Stephen J. Thomas, MD, deputy commander of operations at the Walter Reed Army Institute for Research, speaks at a press conference to announce a partnership with the Upstate Medical University to begin work on testing dengue virus vaccines. A dengue vaccine is of particular importance to the military whose troops deployed to dengue endemic regions.