Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated with Live-Attenuated Tetravalent Dengue Virus 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 a arboviral infection that represents a major global health burden. There is an unmet need for effective dengue therapeutics to reduce symptoms, duration of illness and incidence of severe complications. Here, we con-sider the merits of a dengue human infection model (DHIM) for drug development. A DHIM could allow exper-imentally controlled studies of candidate therapeutics in preselected susceptible volunteers, potentially using smaller sample sizes than trials that recruited patients with dengue in an endemic country. In addition, the DHIM would assist the conduct of intensive pharmacokinetic and basic research investigations and aid in deter-mining optimal drug dosage. Furthermore, a DHIM could help establish proof of concept that chemoprophylaxis against dengue is feasible. The key challenge in developing the DHIM for drug development is to ensure the model reliably replicates the typical clinical and laboratory features of naturally acquired, symptomatic dengue.The Journal of Infectious Diseases 06/2014; 209(Suppl 2):S66-70. · 5.85 Impact Factor
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ABSTRACT: Dengue is an expanding public health problem in the tropics and subtropical areas. Millions of people, most from resource-constrained countries, seek treatment every year for dengue-related disease. Despite more than 70 years of effort, a safe and efficacious vaccine remains unavailable. Antidengue antiviral drugs also do not exist despite attempts to develop or repurpose drug compounds. Gaps in the knowledge of dengue immunology, absence of a validated animal or human model of disease, and suboptimal assay platforms to measure immune responses following infection or experimental vaccination are obstacles to drug and vaccine development efforts. The limited success of one vaccine candidate in a recent clinical endpoint efficacy trial challenges commonly held beliefs regarding potential correlates of protection. If a dengue vaccine is to become a reality in the near term, vaccine developers should expand development pathway explorations beyond those typically required to demonstrate safety and efficacy.Annals of the New York Academy of Sciences 04/2014; · 4.38 Impact Factor
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ABSTRACT: There is an unmet need for a dengue vaccine to further prevent the spread of this disease and contain the growing pandemic. To this end several vaccine companies and academic groups are actively pursuing the development of a tetravalent vaccine to prevent dengue. In the last few years progress has been made in this area, including the first results of a vaccine efficacy trial and improved understanding of the immune responses to the infection. Despite this progress, development of dengue vaccines faces important challenges including the need for a vaccine that induces balanced immune responses against all dengue strains and an incomplete understanding of the mechanism(s) of protection against infection and disease. This is a summary of a Consultation on dengue vaccines held in June 26-28, 2013 by the National Institute of Allergy and Infectious Diseases (part of the US National Institutes of Health) and the Dengue Vaccine Initiative (part of the International Vaccine Institute). The primary goal of this consultation was to review the progress in dengue vaccine development, evaluate the known mechanism of protection of dengue vaccines and discuss avenues for future research.Vaccine 04/2014; · 3.77 Impact Factor