Abstract
This is a selective review of recent publications on dengue clinical features, epidemiology, pathogenesis, and vaccine development placed in a context of observations made over the past half century. Four dengue viruses (DENVs) are transmitted by urban cycle mosquitoes causing diseases whose nature and severity are influenced by interacting factors such as virus, age, immune status of the host, and human genetic variability. A phenomenon that controls the kinetics of DENV infection, antibody-dependent enhancement, best explains the correlation of the vascular permeability syndrome with second heterotypic DENV infections and infection in the presence of passively acquired antibodies. Based on growing evidence in vivo and in vitro, the tissue-damaging DENV non-structural protein 1 (NS1) is responsible for most of the pathophysiological features of severe dengue. This review considers the contribution of hemophagocytic histiocytosis syndrome to cases of severe dengue, the role of movement of humans in dengue epidemiology, and modeling and planning control programs and describes a country-wide survey for dengue infections in Bangladesh and efforts to learn what controls the clinical outcome of dengue infections. Progress and problems with three tetravalent live-attenuated vaccines are reviewed. Several research mysteries remain: why is the risk of severe disease during second heterotypic DENV infection so low, why is the onset of vascular permeability correlated with defervescence, and what are the crucial components of protective immunity?
Highlights
Dengue viruses (DENVs) are relatively new pathogens
Establishing an urban cycle required three separate emergence events: (a) evolution of a West African tree hole-breeding ancestor into Aedes aegypti, an anthropophilic domestic-breeding sub-species, and transportation of this mosquito (b) to tropical America via the slave trade and (c) in reverse direction to Europe and Asia where each of the four DENVs were introduced into the urban transmission cycle[3,4]
These viruses cause a global pandemic, a consequence of jet airplane distribution of viremic humans throughout a tropical world comprehensively infested by Aedes aegypti[7,8]
Summary
Dengue viruses (DENVs) are relatively new pathogens. Transmission of virus from human to human by the bite of the mosquito Aedes aegypti began around three centuries ago[1,2]. When this test was applied to sera from a 10% randomized cohort of phase 3 children, dengue seronegativity rather than age controlled risk to severe hospitalized dengue disease (platelet count of less than 100,000 mm[3] evidence of vascular permeability) over the period 5 to 6 years after first dose in children given vaccine[105] With this evidence of declining efficacy, the World Health Organization (WHO) Scientific Advisory Group of Experts, the Global Advisory Committee on Vaccine Safety, and the WHO Dengue Vaccine Working Group in 2016 recommended that vaccine be given to individuals with known past dengue infection or to populations with 80% DENV seroprevalence[106]. Grant information The author(s) declared that no grants were involved in supporting this work
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