Review
Dengue infection and advances in dengue vaccines for children

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Summary

Dengue viruses are endemic in most tropical and subtropical countries where they produce disease ranging from a mild fever to a severe, potentially fatal vascular permeability syndrome. We reviewed the status of development and testing in children of three vaccines designed to protect against the four dengue viruses. The first dengue virus vaccine, Dengvaxia, now licensed in 20 endemic countries, the EU and the USA, provides protection against severe dengue in seropositive individuals but increases the risk for naive recipients to develop severe dengue and to be hospitalised. We discuss mechanisms and implications of shortcomings of the licensed vaccine and describe the structure and attributes of two other dengue virus vaccines. Based upon human dengue challenge studies, one of these vaccines promises to deliver solid, long-lasting immunity after a single dose. Because dengue virus infections are ubiquitous in residents and visitors to tropical countries, in the absence of a protective vaccine paediatricians should recognise the early signs and clinical presentation of severe dengue, understand its pathophysiology and appropriate management.

Introduction

There are four closely related dengue viruses (designated DENV-1, 2, 3, and 4). All dengue viruses cause an acute febrile disease and are transmitted by the bite of Aedes aegypti, an anthropophilic mosquito that infests virtually all tropical and subtropical countries.1 Hundreds of millions of people are infected every year with outcomes that are variable and unique (figure).3, 4 From the perspective of human health, the most important feature of dengue is the ability of a first infection, or passively acquired dengue antibodies, to increase the severity of the next dengue virus infection.5 This immunopathological phenomenon, termed antibody dependent enhancement (ADE), is coupled with a late-in-illness vascular permeability.6 Vascular permeability during dengue infections, identified as the dengue vascular permeability syndrome, allows fluid and small macromolecules to escape circulation and is accompanied by thrombocytopenia, altered haemostasis, elevated liver enzymes, elevated concentrations of cytokines or chemokines and activation of complement.6, 7, 8 Compelling evidence exists to suggest that much of this damage is produced by circulation during the febrile phase of a toxic viral non-structural protein 1 (NS1).9, 10 For reasons not fully understood, not all humans are equally at risk to this immunopathological outcome. Attack rates are substantially lower among dengue virus-infected sub-Saharan Africans than among European or Asian populations.11 Moreover, the syndrome is most severe in young children, the elderly, and those with pre-existing conditions.12, 13

Despite the fact that A. aegypti was largely eradicated from the Americas during the successful effort to conquer urban yellow fever in the early 20th century, sustained control of this mosquito has proved impossible.14 Dengue is a major human infectious disease in endemic countries and a substantial cause of febrile disease in tourists to tropical destinations.15 As a result there is a major effort to develop protective vaccines. However, the success of vaccines has been impacted by the dengue immunopathology phenomenon. This Viewpoint looks at the status of vaccine development, testing, and introduction in the context of what is known about disease causation and innate clinical responses to dengue infection.

Section snippets

Dengue immunopathology

Until the 1950s, dengue was known as a disease that produced epidemics of self-limited febrile exanthemata with little mortality. This pattern changed when shock and gastrointestinal haemorrhage started being reported in association with dengue infection.16 That severe dengue might be an immunological phenomenon was suggested when it was discovered that dengue haemorrhagic fever and dengue shock syndrome accompanied a second heterotypic dengue virus infection.17 Investigating this phenomenon in

Dengue disease causation

Late in the febrile period of dengue vascular permeability syndrome there might be a sudden and profound capillary leak. At first it was thought that when an increased number of dengue virus-infected target cells (monocytes, macrophages and dendritic cells) was attacked by the immune elimination response, a marked release of pro-inflammatory and anti-inflammatory factors resulted.28 These factors were thought to damage capillary integrity resulting in hypovolemic shock (also called a cytokine

Infection in the absence of dengue virus antibodies

In infants and children aged 1–5 years, a first dengue virus infection is commonly inapparent.39 During mid-childhood, an initial dengue virus infection usually results in a short febrile disease, the dengue fever syndrome, with potential headache, flushed face, inappetence, upper respiratory symptoms, nausea, vomiting, myalgia, leukopenia, and prostration.39 First dengue virus infections in adolescents are generally more reactogenic leading to school absenteeism in 10–20% of such individuals

Disease management

Because of the high volume of travel to tropical destinations, patients with acute dengue might present to any clinical practice at any time of the year, so paediatricians should always be prepared.41, 48 Successful management of dengue vascular permeability syndrome relies on meticulous regulation of parenteral fluids and colloids during the period of increased vascular leakage, together with proactive management of major bleeding.41 The physician should remember that all fluid administered

Dengvaxia

Dengvaxia, developed by Sanofi Pasteur, is the only licensed dengue vaccine. It is live-attenuated tetravalent chimeric vaccine that incorporates the structural genes of the four dengue viruses into the genome of the yellow fever vaccine. It has been tested for vaccine efficacy and safety in placebo-controlled clinical trials enrolling approximately 35 000 children, aged 2–16 years in ten dengue-endemic countries.46 Efficacy results, published in 2015, were mixed. At year 3 after the first

Conclusion

There is reason for optimism about obtaining a successful dengue vaccine. Protection against live dengue virus challenge of vaccinated volunteers suggests that the NIH dengue vaccine soon to complete phase 3 testing will satisfy safety and efficacy requirements. Meanwhile, an intense effort is being mounted to understand the requirements for stable immune protection against homotypic and heterotypic dengue infections of humans. An important component of this research will be to understand why

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