BACKGROUND. Disease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all four serotypes in phase 3 efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help down select vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus. METHODS. Two randomized controlled clinical trials were performed. In study 1, 42 subjects received TV005 or placebo (n = 21 each) and six months later all were challenged with dengue 2 virus (DEN2Δ30) at a dose of 103 PFU. In study 2, 23 subjects received TV005, 20 subjects received placebo and six months later all were challenged with 104 PFU dengue 3 virus (DEN3Δ30). Subjects were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia and by occurrence of rash and neutropenia, were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent DENV2 or DENV3 challenge strains. RESULTS. TV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or 3 (none infected in either group). Placebo recipients had viremia post-challenge (100% in study 1, 85% in study 2) and all experienced rash following challenge with either serotype. CONCLUSIONS. TV005 is a leading tetravalent dengue vaccine candidate which fully protects against infection with DENV2 and DENV3 in an established controlled human infection model. CLINICAL TRIALS REGISTRATION NUMBERS. NCT02317900 and NCT02873260.
Kristen K. Pierce, Anna P. Durbin, Mary-Claire Walsh, Marya Carmolli, Beulah P. Sabundayo, Dorothy M. Dickson, Sean A. Diehl, Stephen S. Whitehead, Beth D. Kirkpatrick