The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model

Abstract

A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.

Recent advances in human flavivirus vaccines

“…The lowest serotype-specific response was obtained against DENV2 [53]. To assess the protective efficacy of TV003 towards DENV2, a human challenge model was performed using a DENV2 strain, rDEN2Δ30 [54]. TV003 All four DENV serotypes were produced in insect cells and inactivated with formalin.…”

Vector Control Interventions to Prevent Dengue: Current Situation and Strategies for Future Improvements to Management of Aedes in India

“…Significant progress in vaccine development during the last decade has led to the regulatory authority approval of the first product in 2016 [27]. However, its cost may prevent widespread use in developing countries, [28,29] where control of the mosquito vector will remain the most effective measure to combat dengue [30].…”

Use of a Recombinant Gamma-2 Herpesvirus Vaccine Vector against Dengue Virus in Rhesus Monkeys

“…The DENV1, DENV3, and DENV4 strains used in this vaccine harbor deletions in the 3= untranslated region, and the attenuated strain of DENV4 was employed as a backbone for the remaining dengue virus serotype 2 (15). One formulation (TV003) elicited full protection against DENV infection in small-scale testing using a human challenge model (16). Results of human clinical trials have yet to be reported.…”