INFECTIOUS DISEASE The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model Beth D. Kirkpatrick, 1 * Stephen S. Whitehead, 2 * Kristen K. Pierce, 1 Cecilia M. Tibery, 3 Palmtama L. Grier, 3 Noreen A. Hynes, 4 Catherine J. Larsson, 1 Beulah P. Sabundayo, 3 Kawsar R. Talaat, 3 Anna Janiak, 3 Marya P. Carmolli, 1 Catherine J. Luke, 4 Sean A. Diehl, 1 Anna P. Durbin 3† 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 chal- lenged 6 months later with a DENV-2 strain, rDEN2D30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2D30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2D30 were protected from in- fection with rDEN2D30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2D30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2D30 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. INTRODUCTION Dengue viruses (DENVs) are the most prevalent mosquito-borne vi- ruses in the world, with estimates of 390 million infections in more than 120 countries and more than 2 million cases of dengue hemorrhagic fever annually (1). Dengue infection ranges from an asymptomatic (most common) or mildly symptomatic illness to one that results in bleeding diatheses, plasma leakage, and vascular collapse (dengue hemorrhagic fever/shock syndrome). All four DENVs (DENV-1 to DENV-4) can cause the full spectrum of disease, and, although severe disease can occur after primary infection, epidemiologic studies have determined that preexisting immunity to one DENV serotype is the greatest risk factor for more severe disease upon secondary, heterotypic DENV infection (2–4). The association of a more severe dengue with a second, hetero- typic DENV infection is thought to be mediated by the phenomenon of antibody-dependent enhancement of infection in which cross-reactive, non-neutralizing antibody is able to bind to the virus and allow entry of the virus-antibody complex through the FcgR (Fc-g receptor) on mono- cytes and macrophages (5). Severe or enhanced disease can occur with first infection in infants because of the presence of passively transferred dengue maternal antibody (2, 6). Maternal antibody initially provides protection against dengue, but as the antibody wanes, the once protec- tive antibody enhances dengue infection in the infant. Because the risk of severe disease is greatest in hyperendemic areas, where multiple serotypes of DENV are circulating, and a vaccine that induces only par- tial protection may have long-term safety implications (7), an effective dengue vaccine must protect against all four serotypes (8). There are several candidate dengue vaccines under clinical eval- uation. The vaccine furthest along in development is CYD, a live atten- uated tetravalent (LATV) chimeric three-dose vaccine in which the prM and E proteins of each DENV-1 to DENV-4 replace those of the yellow fever 17D virus (fig. S1). Three efficacy trials of CYD have been completed with varying results (9–11). Efficacy against symptomatic dengue ranged from 30.2% in a phase 2b study in Thailand (9) to 60.8% in a phase 3 study in Latin America (11). In the two trials conducted in Asia, the vac- cine did not afford significant protection against symptomatic DENV-2 infection (9, 10), despite evidence of seroconversion to DENV-2 in >95% of vaccine recipients. In both regions, the vaccine showed strong pro- tection against hospitalization and severe dengue. In both phase 3 trials, the vaccine did not afford significant protection in subjects who were dengue-naïve before vaccination (10, 11). Recent data from the long- term safety assessment demonstrated that in year 3 after vaccination, the risk of hospitalization was higher in CYD recipients compared with placebo recipients in subjects less than 9 years of age and that this risk was highest in subjects 2 to 5 years of age [relative risk (RR), 7.45] (12). The vaccine has recently been licensed in three countries, Mexico, the Philippines, and Brazil. Because of the lower efficacy in dengue-naïve in- dividuals and the safety signal observed in children younger than 9 years, the vaccine was licensed for persons 9 to 45 years of age in the dengue- endemic areas of these countries. Neutralizing antibody appears to cor- relate with protection for other flavivirus vaccines such as YF17D and the live attenuated Japanese encephalitis vaccine SA-14-14-2 (13), and the antibody was previously thought to correlate for protection against dengue, but this was not evident with the antibody induced by CYD (9). 1 Vaccine Testing Center, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05401, USA. 2 National Institutes of Allergy and Infectious Dis- eases, Bethesda, MD 20892, USA. 3 Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. 4 Johns Hopkins Uni- versity School of Medicine, Baltimore, MD 21205, USA. *Co-first authors. †Corresponding author. 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