Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines
ABSTRACT Background. Protection against dengue requires immunity against all 4 serotypes of virus. Experimental challenge may be useful in evaluating vaccine-induced immunity.Methods. Ten subjects previously vaccinated with a live-attenuated tetravalent dengue vaccine (TDV) and 4 dengue naïve control subjects were inoculated subcutaneously (s.c.)with either 10(3) pfu's of Dengue-1 (DENV-1) or 10(5) pfu's of Dengue-3 (DENV-3) challenge viruses. Two additional subjects who did not develop DENV-3 neutralizing antibody (Nab) from TDV were re-vaccinated with 10(4) pfu's of live-attenuated DENV-3 vaccine to evaluate memory response.Results. All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3 2 were protected. All DENV-3 challenge subjects who developed viremia also developed elevated liver enzymes, 2 had values greater than 10 times normal. Of the 2 subjects revaccinated with DENV-3 vaccine 1 showed a secondary response to DENV-2 while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of Nab though one subject was protected despite lack of measurable Nab at the time of DENV-1 challenge.Conclusions. Vaccination with live-attenuated TDV induced variable protection against s.c. challenge. DENV-3 experimental challenge was associated with transient but significant hepatitis.
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ABSTRACT: Dengue is the most common arboviral disease of humans. There is an unmet need for a therapeutic intervention that reduces the duration and severity of dengue symptoms and diminishes the likelihood of severe complications. To this end, there are active discovery efforts in industry and academia to develop interventions, with a focus on small molecule inhibitors of dengue virus replication that are suitable for therapy or chemoprophylaxis. Advancements in animal models of dengue virus infection together with the possibility of a dengue human infection model have further enhanced the platform for dengue drug discovery. Whilst drug discovery efforts gestate, there are ongoing clinical research designed to benefit today's patients, including trials of supportive care interventions, and descriptive studies that should improve the ability of clinicians to make an accurate diagnosis early in the illness course and to identify patients most at risk of progression to severe disease. This review provides a state of the art summary of dengue drug discovery, clinical trials, and supportive allied research and reflects discussions at the 2nd International Dengue Therapeutics Workshop held in Ho Chi Minh City, Vietnam, in December 2013.PLoS Neglected Tropical Diseases 08/2014; 8(8):e3025. DOI:10.1371/journal.pntd.0003025 · 4.49 Impact Factor
Article: Dengue.[Show abstract] [Hide abstract]
ABSTRACT: Dengue viruses have spread rapidly within countries and across regions in the past few decades, resulting in an increased frequency of epidemics and severe dengue disease, hyperendemicity of multiple dengue virus serotypes in many tropical countries, and autochthonous transmission in Europe and the USA. Today, dengue is regarded as the most prevalent and rapidly spreading mosquito-borne viral disease of human beings. Importantly, the past decade has also seen an upsurge in research on dengue virology, pathogenesis, and immunology and in development of antivirals, vaccines, and new vector-control strategies that can positively impact dengue control and prevention.
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ABSTRACT: Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.Frontiers in Immunology 09/2014; 5:452. DOI:10.3389/fimmu.2014.00452