Dengue Human Infection Model (DHIM) Prototype Development
Dengue viruses (DENVs) are flaviviruses transmitted by infected Aedes mosquitoes that cause a clinical spectrum of human disease ranging from mild viremia to severe intravascular volume depletion and hemorrhage. Efforts are underway worldwide to develop safe, effective anti-viral drugs and vaccines against Dengue but significant technical barriers impede progress including the immunologic complexity of the disease and lack of a correlate of protection or validated animal models of disease. Consequently, medical product developers must rely primarily on the conduct of large clinical studies in endemic regions (typically in pediatric volunteers) at great expense and financial risk.
The U.S. military Dengue Vaccine Program seeks to change this paradigm by co-developing a safe and reproducible Dengue Human Infection Model (DHIM). A successful DHIM will be a future enabling technology for DENV medical product developers and clinical researchers to: (i) test and predict efficacy of candidate vaccines, early chemoprophylaxis and anti-virals against DENV; (ii) identify and validate biomarkers of DENV disease progression for diagnosis, clinical care or epidemiology studies; (iii) compare or otherwise cross-reference the performance of different medical technologies or modalities in a U.S. Food and Drug Administration (FDA) regulated test and evaluation system; and (iv) elucidate the host response at the molecular level during uncomplicated DENV infection with the goals of understanding and controlling disease progression or identifying biological correlates of protection.
The DHIM represents an opportunity for consortium members and other qualified partners to reduce their overall risk during clinical development. For example, product developers may leverage the DHIM to explore pre-infection immune profiles and correlate results with post-experimental infection clinical outcomes across a range of conditions and scenarios. It also may clarify how human humoral- and/or cellular-immune responses are associated with protection against DENV disease progression and, therefore, reduce the size and scope of future clinical trials and facilitate an improved use of existing laboratory animal models. In the long term, the DHIM could become a validated tool, recognized by the US FDA, to fill gaps in efficacy data from field studies and subsequently expedite licensure.
The research project award recipients were selected from the Offerors who responded to MTEC’s Request for Project Proposals (17-01-DHIM).
Title of project: Dengue Human Infection Model (DHIM) Prototype Development – DENV-2 and DENV-4
Project Team: University of Maryland School of Medicine, Subs: Leidos Corporation, University of California, Irvine
Award Amount: $2,013,410
Project Duration: 12 months
Project Objective: The overall objective of this program is to accelerate the ongoing development of the Dengue Human Infection Model (DHIM) to safely and reproducibly create uncomplicated dengue infections in human volunteers using live, attenuated dengue virus (DENV) challenge material (DENV-2, DENV-3, and DENV-4); specifically establishing DHIM-2, DHIM-3 and DHIM-4. The University of Maryland’s Center for Vaccine Development is a collaborator within this program and will be responsible for DHIM-4. The specific tasks of this effort are:
- To establish the Investigational New Drug (IND) application and assume IND for DHIM-4.
- To develop and execute DHIM -4 challenge models to include protocol and document development, IRB approval, trial execution, data management, quality control management, regulatory oversight, and trial reports including a study close-out report.
- Develop a Commercialization Plan to maximize return-on-investment and advance the DHIM towards FDA-regulated DENV countermeasures and pharmacologic development.
Year One Accomplishments:
- The IND modules including the chemistry, manufacturing, and controls (CMC) and the Investigator’s Brochure (IB) have been created for DHIM-4 and are pending IND submission.
- The DHIM-4 protocol and informed consent have been created and Institutional Review Board (IRB) submission to the University of Maryland Office of Research and Development is pending.
- The ADVP 005 project was awarded to the University of Maryland.
The initial ADVP005 protocol has been drafted and discussions are underway to determine the best use of clinical samples for immunologic analysis.
Title of project: Establishment of Sponsorship Capabilities for Dengue Human Infection Model
Project Team: The Research Foundation for State University of New York (SUNY), on behalf of SUNY Upstate Medical University; ICON Government and Public Health Solutions (ICON GPHS)
Award Amount: $1,055,808
Project Duration: 13 months
Project Objective: The objective of this project is to establish sponsorship capabilities at SUNY Upstate Medical University (SUNY-UMU) for future execution of Dengue Human Infection Model (DHIM) studies. The SUNY-UMU team in conjunction with ICON-GPHS will prepare and submit all required documents for IND submission, establish all offices for IND oversight and develop a validated database. The establishment of these capabilities within SUNY-UMU will streamline activities between DOD partners, academia and industry to further the development of DHIM as a valuable tool for dengue countermeasure development efforts.