Research ArticleInfectious Disease

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

Science Translational Medicine  16 Mar 2016:
Vol. 8, Issue 330, pp. 330ra36
DOI: 10.1126/scitranslmed.aaf1517

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Dengue model rises to the challenge

Human efficacy testing remains a major hurdle in bringing new vaccine candidates to the clinic. In the absence of accepted correlates of protection, rounds of safety trials must be performed before efficacy can be tested in a large population in an endemic area. Kirkpatrick et al. have developed a controlled dengue human challenge model to assess the protective efficacy of the most clinically advanced dengue vaccine candidate. They found that TV003, a live attenuated dengue vaccine that induces antibodies to all four dengue virus serotypes, protected against infection of an attenuated virus in 21 recipients when compared with 20 nonvaccinated controls. This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials.

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.

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