ReviewDengue infection and advances in dengue vaccines for children
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
References (84)
- et al.
Figure 2 in: The global burden of dengue: an analysis from the Global Burden of Disease Study 2013
Lancet Infect Dis
(2016) - et al.
Effect of age on outcome of secondary dengue 2 infections
Int J Infect Dis
(2002) - et al.
Dengue
Lancet
(2019) - et al.
Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes
Lancet Infect Dis
(2010) Immunological parameters of togavirus disease syndromes
- et al.
Microvascular and endothelial function for risk prediction in dengue: an observational study
Lancet
(2015) - et al.
Studies of dengue hemorrhagic fever. V. Hemodynamic studies of clinical shock associated with dengue hemorrhagic fever
J Pediatr
(1973) - et al.
Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial
Lancet
(2017) - et al.
Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine
Lancet Infect Dis
(2019) - et al.
Development of an anti-dengue NS1 IgG ELISA to evaluate exposure to dengue virus
J Virol Methods
(2018)
Development of DENVax: a chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever
Vaccine
Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study
Lancet Infect Dis
Live attenuated tetravalent dengue vaccine
Vaccine
Innate and adaptive cellular immunity in flavivirus-naive human recipients of a live-attenuated dengue serotype 3 vaccine produced in Vero cells (VDV3)
Vaccine
Testing of a dengue 2 live-attenuated vaccine (strain 16681 PDK 53) in ten American volunteers
Vaccine
Construction of infectious cDNA clones for dengue 2 virus: strain 16681 and its attenuated vaccine derivative, strain PDK-53
Virology
Protective role of cross-reactive CD8 T cells against dengue virus infection
EBioMedicine
Modelling adult Aedes aegypti and Aedes albopictus survival at different temperatures in laboratory and field settings
Parasit Vectors
Refining the global spatial limits of dengue virus transmission by evidence-based consensus
PLoS Negl Trop Dis
The global distribution and burden of dengue
Nature
Pathogenesis of dengue: challenges to molecular biology
Science
Dengue and chikungunya virus infection in man in Thailand, 1962-1964. I. Observations on hospitalised patients with hemorrhagic fever
Am J Trop Med Hyg
The potential pathogenic role of complement in dengue hemorrhagic shock syndrome
N Engl J Med
Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection
Arch Virol
Flavivirus NS1 triggers tissue-specific vascular endothelial dysfunction reflecting disease tropism
Cell Reports
The good, the bad, and the shocking: the multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis
Annu Rev Virol
OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans
PLoS Pathog
The emergence of epidemic dengue fever and dengue hemorrhagic fever in the Americas: a case of failed public health policy
Rev Panam Salud Publica
Risk of dengue in travelers: implications for dengue vaccination
Curr Infect Dis Rep
Viruses associated with epidemic hemorrhagic fevers of the Philippines and Thailand
Science
Hemorrhagic fever in Thailand; recent knowledge regarding etiology
Jpn J Med Sci Biol
Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection
J Infect Dis
Immunologic enhancement of dengue virus replication
Nat New Biol
Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody
J Exp Med
How innate immune mechanisms contribute to antibody-enhanced viral infections
Clin Vaccine Immunol
Cell type specificity and host genetic polymorphisms influence antibody dependent enhancement of dengue virus infection
J Virol
Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants
Am J Trop Med Hyg
A prospective nested case-control study of dengue in infants: rethinking and refining the antibody-dependent enhancement dengue hemorrhagic fever model
PLoS Med
Clinical and virological features of dengue in Vietnamese infants
PLoS Negl Trop Dis
Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms
Nat Rev Immunol
An antigen capture enzyme-linked immunosorbent assay reveals high levels of the dengue virus protein NS1 in the sera of infected patients
J Clin Microbiol
Protection of mice against dengue 2 virus encephalitis by immunization with the dengue 2 virus non-structural glycoprotein NS1
J Gen Virol
Cited by (31)
Harnessing the power of goat milk-derived extracellular vesicles for medical breakthroughs: A review
2024, International Journal of Biological MacromoleculesHigh viral load positively correlates with thrombocytopenia and elevated haematocrit in dengue infected paediatric patients
2021, Journal of Infection and Public HealthCitation Excerpt :Clinical manifestations range from mild febrile illness, to haemorrhagic condition to fatal shock syndrome. Of the fatal cases, majority occur in children under 15 years of age [2,3]. Dengue virus (DENV) belonging to Flaviviridae family consists of single stranded positive sense RNA genome of around 10.9 kb.
Detection of anti-premembrane antibody as a specific marker of four flavivirus serocomplexes and its application to serosurveillance in endemic regions
2024, Emerging Microbes and InfectionsIntegrative bulk and single-cell transcriptome profiling analysis reveals IFI27 as a novel interferon-stimulated gene in dengue
2023, Journal of Medical Virology