Dengue Vaccine Development: A 75% Solution

5824 Edson Lane, Bethesda, MD 20852, USA. Electronic address: .
The Lancet (Impact Factor: 45.22). 09/2012; 380(9853). DOI: 10.1016/S0140-6736(12)61510-4
Source: PubMed
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    • "Dengue vaccine development is an area of active research: significant advances have occurred in recent years and several vaccine candidates are showing promise in clinical studies [5]. The most advanced vaccine candidate showed efficacy of 30% and protection against 3 of the 4 serotypes of dengue [6]. With several dengue vaccine candidates progressing through clinical trials, a licensed dengue vaccine is expected to be available in less than 10 years [3]. "
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    ABSTRACT: SUMMARY A dengue vaccine is expected to be available within a few years. Once vaccine is available, policy-makers will need to develop suitable policies to allocate the vaccine. Mathematical models of dengue transmission predict complex temporal patterns in prevalence, driven by seasonal oscillations in mosquito abundance. In particular, vaccine introduction may induce a transient period immediately after vaccine introduction where prevalence can spike higher than in the pre-vaccination period. These spikes in prevalence could lead to doubts about the vaccination programme among the public and even among decision-makers, possibly impeding the vaccination programme. Using simple dengue transmission models, we found that large transient spikes in prevalence are robust phenomena that occur when vaccine coverage and vaccine efficacy are not either both very high or both very low. Despite the presence of transient spikes in prevalence, the models predict that vaccination does always reduce the total number of infections in the 15 years after vaccine introduction. We conclude that policy-makers should prepare for spikes in prevalence after vaccine introduction to mitigate the burden of these spikes and to accurately measure the effectiveness of the vaccine programme.
    Epidemiology and Infection 08/2014; 143(06):1-11. DOI:10.1017/S0950268814001939 · 2.54 Impact Factor
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    • "The ways in which DENV evades STING signalling is of particular interest because the dysregulated production of cytokines and chemokines during DENV infection is known to contribute to symptoms associated with severe dengue disease [29] [34]. Furthermore , developing a DENV vaccine has so far proven challenging [35] [36], and understanding how DENV modulates the immune response may lead to improved vaccine strategies. "
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    ABSTRACT: STING has emerged in recent years as an important signalling adaptor in the activation of type I interferon responses during infection with DNA viruses and bacteria. An increasing body of evidence suggests that STING also modulates responses to RNA viruses, though the mechanisms remain less clear. In this review, we give a brief overview of the ways in which STING facilitates sensing of RNA viruses. These include modulation of RIG-I-dependent responses through STING's interaction with MAVS, and more speculative mechanisms involving the DNA sensor cGAS, and sensing of membrane remodelling events. We then provide an in-depth literature review to summarise the known mechanisms by which RNA viruses of the families Flaviviridae and Coronaviridae evade sensing through STING. Our own work has shown that the NS2B/3 protease complex of the flavivirus Dengue virus binds and cleaves STING, and that an inability to degrade murine STING may contribute to host restriction in this virus. We contrast this to the mechanism employed by the distantly related hepacivirus Hepatitis C virus, in which STING is bound and inactivated by the NS4B protein. Finally, we discuss STING antagonism in the coronaviruses SARS coronavirus and Human coronavirus NL63, which disrupt K63-linked polyubiquitination and dimerisation of STING (both of which are required for STING-mediated activation of IRF-3) via their papain-like proteases. We draw parallels with less-well characterised mechanisms of STING antagonism in related viruses, and place our current knowledge in the context of species tropism restrictions that potentially affect the emergence of new human pathogens.
    Cytokine & Growth Factor Reviews 08/2014; 25(6). DOI:10.1016/j.cytogfr.2014.08.004 · 5.36 Impact Factor
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    • "A vaccine would be the most effective prophylactic public health intervention for control of dengue, but the development of an efficacious tetravalent dengue vaccine is proving to be a challenge [20, 21]. An alternative or adjunctive approach is the use of drug chemoprophylaxis in the community. "
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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. DOI:10.1093/infdis/jiu062 · 6.00 Impact Factor
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