Flavivirus Infections: Pathogenesis and Prevention

The overall objective of this Program Project is to identify and refine strategies for the prevention and management of dengue. Dengue continues to be an expanding public health problem, disproportionally affecting resource-poor countries in tropical and subtropical regions. Although morbidity from clinically mild infections is still considerable, the principal challenge presented by dengue virus is its ability to cause dengue hemorrhagic fever (DHF), a potentially fatal plasma leakage syndrome. There is no specific therapy or vaccine available against dengue, and development of treatments or vaccines has been problematic because of the evidence that DHF is immunologically mediated.

An experienced interdisciplinary team of university, military, and industry investigators in the US and Thailand is conducting coordinated studies to:

  • advance understanding of DHF epidemiology, pathophysiology, and immunopathogenesis, and
  • use this knowledge to identify and validate approaches to management and prevention of dengue disease.

The program involves two inter-related research projects:

Project 1 (Clinical Studies on the Mechanisms of DF/DHF) involves two prospective clinical studies in Thailand. The first, a prospective study in Bangkok of symptomatic children hospitalized with acute dengue illness, is defining the pathophysiology of severe dengue with the goal of improving the evaluation and triage of cases. The second study, a prospective population-based study of dengue transmission and disease in Kamphaeng Phet province, is defining optimal methods for evaluation of dengue vaccine efficacy and identifying correlates of protective immunity.

Project 2 (Molecular Immunopathogenesis of DHF/DSS) involves detailed laboratory studies of innate and adaptive immune responses to dengue in vitro and in vivo. The goal of this project is to understand the contribution of individual components of the immune response to different clinical disease manifestations. These findings will help to define the immunologic mechanisms underlying protection and disease pathogenesis and identify key immunological correlates of vaccine-induced protection vs. immunopathology.