Dengue viruses (DENV) currently infect approximately 400 million people each year causing millions to seek care and overwhelming the health care infrastructure in endemic areas.
Vaccines to prevent
dengue and
therapeutics to treat
dengue are not currently available. The efficacy of the most advanced candidate
vaccine against symptomatic
dengue in general and DENV-2 in particular was much lower than expected, despite the ability of the
vaccine to induce
neutralizing antibody against all four DENV serotypes. Because seroconversion to the DENV serotypes following vaccination was thought to be indicative of induced protection, these results have made it more difficult to assess which candidate
vaccines should or should not be evaluated in large studies in endemic areas. A
dengue human
infection model (DHIM) could be extremely valuable to down-select candidate
vaccines or
therapeutics prior to engaging in efficacy trials in endemic areas. Two DHIM have been developed to assess the efficacy of live attenuated tetravalent (LATV)
dengue vaccines. The first model, developed by the Laboratory of
Infectious Diseases at the U. S. National Institutes of Health, utilizes a modified DENV-2 strain DEN2Δ30. This virus was derived from the DENV-2 Tonga/74 that caused only very mild clinical
infection during the outbreak from which it was recovered. DEN2Δ30 induced
viremia in 100%,
rash in 80%, and
neutropenia in 27% of the 30 subjects to whom it was given. The Walter Reed Army Institute of Research (WRAIR) is developing a DHIM the goal of which is to identify DENV that cause symptomatic
dengue fever. WRAIR has evaluated seven viruses and has identified two that meet
dengue fever criteria. Both of these models may be very useful in the evaluation and down-selection of candidate
dengue vaccines and
therapeutics.