Dengue

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Dengue
Gabriela Paz-Bailey, Laura E Adams, Jacqueline Deen, Kathryn B Anderson, Leah C Katzelnick
Dengue, caused by four closely related viruses, is a growing global public health concern, with outbreaks capable of Lancet 2024; 403: 667–82
overwhelming health-care systems and disrupting economies. Dengue is endemic in more than 100 countries across Published Online
tropical and subtropical regions worldwide, and the expanding range of the mosquito vector, affected in part by January 24, 2024
https://doi.org/10.1016/
climate change, increases risk in new areas such as Spain, Portugal, and the southern USA, while emerging evidence S0140-6736(23)02576-X
points to silent epidemics in Africa. Substantial advances in our understanding of the virus, immune responses, and Centers for Disease Control and
disease progression have been made within the past decade. Novel interventions have emerged, including partially Prevention, San Juan, Puerto
effective vaccines and innovative mosquito control strategies, although a reliable immune correlate of protection Rico (G Paz-Bailey MD,
remains a challenge for the assessment of vaccines. These developments mark the beginning of a new era in dengue L E Adams DVM); Institute of
Child Health and Human
prevention and control, offering promise in addressing this pressing global health issue. Development, National
Institutes of Health, University
Introduction ticks, such as Zika, West Nile, Japanese encephalitis, and of the Philippines, Manila,
Dengue is a systemic viral infection of increasing global tick-borne encephalitis viruses. The four dengue viruses Philippines (J Deen MD);
Department of Microbiology
importance. Epidemics of an illness compatible with are called serotypes because each has different and Immunology, SUNY
dengue were first reported1 in 1779 and the virus was first interactions with the antibodies in human blood.2 They Upstate Medical University,
isolated in 1943.2 Currently, dengue is endemic in more share approximately two-thirds of their genomes,2 with Syracuse, NY, USA
than 100 countries in tropical and subtropical regions of different genotypes existing within each serotype, which (K B Anderson MD); Viral
Epidemiology and Immunity
southeast Asia, Africa, the west Pacific, and the Americas.3 can vary in disease severity. DENV is primarily Unit, Laboratory of Infectious
Dengue is also seen in some regions of Europe, including transmitted through the bite of an infected mosquito Diseases, National Institute of
France, Croatia, Portugal, and Germany, and some parts of vector, with Aedes aegypti as the most common vector, Allergy and Infectious Diseases,
the USA. Climate change, population growth, human although other species (eg, Aedes albopictus) can also National Institutes of Health,
Bethesda, MD, USA
mobility, and urbanisation are anticipated to exacerbate the sustain transmission. Other rare transmission routes (L C Katzelnick PhD)
dengue burden, primarily by increasing risk in endemic include perinatal transmission, blood transfusion, and Correspondence to:
areas, as well as secondarily by expanding the range of the organ transplantation; two cases of sexual transmission Gabriela Paz-Bailey, Centers for
primary vector, Aedes aegypti mosquitoes, into new areas.4 have also been documented.11–15 The incubation period Disease Control and Prevention,
Studies predict that the global population at risk will from exposure to symptom development is typically San Juan 00920, Puerto Rico
[email protected]
increase from 53% in 2015, to 63% in 2080, with high 4–10 days.16
environmental suitability for dengue in tropical and
subtropical areas worldwide (figure 1).5 Epidemiology
Dengue has an important economic impact, The global burden of dengue illness has continued to
resulting in estimated global health-care costs of more rise throughout the past decade, with large outbreaks in
than US$8·9 billion (95% CI 3·7 billion–19·7 billion) endemic areas and more cases of dengue in travellers.
annually.6,7 High costs are associated with loss of During 2007–17, deaths from dengue increased by
productivity, and direct medical costs are incurred from 65·5% to more than 40 500 (95% CI 17 600–49 800)
hospitalisation.8,9 Dengue outbreaks can overwhelm annually.17 Expansion of Aedes mosquito vectors and
health-care systems, disrupt economies, and reduce increasing dengue incidence in non-endemic areas is
public confidence in government responses. Many also a growing concern. New detections of local dengue
commonly used vector control strategies, such as transmission in areas without previous transmission
insecticide spraying, have failed to curb disease and increased cases in areas with sporadic transmission
incidence but continue to be employed in the absence of have been documented in southern Europe and the
robust evidence for their effectiveness or optimal USA, as well as unprecedented outbreaks at high
implementation.10 However, increased understanding of altitudes as seen in Nepal.18–20 Additionally, more DENV
dengue epidemiology and immune mediators of serotypes are cocirculating in endemic areas, producing
symptomatic and severe disease, as well as the availability
of effective clinical management, partially effective
vaccines, candidate vaccines in the pipeline, and novel Search strategy and selection criteria
approaches to mosquito control, have the potential to We searched PubMed for papers published between
inform and substantially improve the effectiveness of Sept 30, 2012, and Oct 10, 2022. We used the search terms
dengue control programmes. “dengue” or “dengue virus”. We also included references cited
in these publications and relevant older references from our
Dengue viruses personal ﬁles. We consulted international dengue control,
DENV-1, 2, 3, and 4 are single-stranded RNA viruses in prevention, and treatment guidelines and WHO policy
the genus Flavivirus, family Flaviviridae. Flavivirus documents.
includes other viruses transmitted by mosquitoes and
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100 person-years among children aged 2–16 years.23 The

A
estimated force of infection (FOI), which is the per
capita rate at which susceptible individuals become
infected, similarly varies by region, with the highest FOI
observed in areas near the tropics (figure 1). However,
FOI estimates are restricted by surveillance data
FOI
0·06 availability and temporal and interannual variability in
0·04 dengue incidence.3
0·02 Risk of infection is driven by susceptibility to the four
0 DENV serotypes; therefore, DENV incidence in
hyperendemic locales is concentrated in children and
B young adults.24 The average age of infection in these
areas has been increasing in the past 3·5 decades, for
reasons such as a decrease in the FOI due to changes in
the population age structure,25 effective vector control,26
or possibly increased awareness and diagnosis of dengue
SD
0·02 in adults. In areas hyperendemic for DENV transmission,
the risk for enhanced disease has been suggested to be
0·01
concentrated within two age-related peaks: the first in
0 infants, with possible contributions from waning
maternal antibodies27–29 and the second in individuals
C experiencing a second DENV infection. Dengue
haemorrhagic fever has not yet been described in an
infant born to a dengue-naive mother, strongly
suggesting that maternal anti-DENV antibodies
contribute to dengue haemorrhagic fever pathogenesis
in infants. However, further studies of infants with
severe dengue are needed to unequivocally show that
maternally derived anti-DENV antibodies are an
Environmental suitability
for dengue (2080)
important risk factor for severe disease in infants.30
1 Delayed diagnosis or detection of shock can lead to an
increased risk of severe disease and death; this risk has
also been shown to be higher for people with
0 comorbidities, such as diabetes or pulmonary, heart, or
Figure 1: Predicted global dengue risk renal disease, than for healthy individuals. A meta-
Means (A) and standard deviations (B) of FOI estimates in dengue-endemic countries across 200 geographically analysis suggests that the relative risks of severe dengue
stratified bootstrap samples. Average FOI was estimated from age-stratified seroprevalence or case notification associated with underlying chronic diseases and
date by use of environmental explanatory variables. Modified from Cattarino et al,3 by permission of the
comorbidities could be much higher than that of
American Association for the Advancement of Science. (C) Environmental suitability for dengue occurrence in
2080. Adapted from Messina et al.5 FOI=force of infection. secondary infection alone.31
Disparities in dengue risk have been identified, with
increased risk occurring in areas with high population
increased case numbers and greater probability of density and poor housing conditions.32,33 Increasing
severe disease from serotype re-introduction or population mobility and tourism have also been linked to
replacement.21 increased dengue transmission, and imported DENV
DENV seroprevalence estimates vary widely across cases have led to outbreaks in non-endemic areas.34 DENV
countries and regions, shaped by differences in transmission occurs commonly within and around
underlying DENV transmission intensity and differences households, with a potential increased risk among people
in methods and assays applied. High IgG antibody in endemic areas who stayed near the home compared
seroprevalence (>60%) has been reported in highly with people with greater mobility.35,36 However, COVID-19-
endemic areas in southeast Asia and the Americas; mid- related disruptions and lockdowns in 2020 were found to
range (10–60%) seroprevalence in areas with frequent or result in a decrease in dengue incidence across endemic
sporadic transmission, such as many countries in Africa regions, with the strongest associations related to school
and the Middle East; and low seroprevalence in non- closures and reduced time in non-residential areas,
endemic areas, such as the USA and Europe.22 Vaccine although changes in health-care access could have also
trials have revealed high variability in DENV incidence contributed to the reduced case numbers reported.37
across study sites in Latin America and Asia, ranging Dengue is the most frequent arboviral disease
from 1·5 to 6·6 episodes of symptomatic dengue per encountered among travellers, with an increasing global
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pattern during 1995–2020.38 Among travellers to southeast

Asia in this period, incidence ranged from 50 dengue Panel 1: The 1997 versus the 2009 WHO dengue classification and case definitions
cases per 1000 ill travellers who sought care in the • The 1997 WHO classification and case definitions of dengue, dengue haemorrhagic
Geosentinel network of travel medicine providers during fever (DHF), and dengue shock syndrome (DSS)43 originated from a clinical study in
non-epidemic years, to 159 cases per 1000 ill travellers in the 1960s of 123 children in Thailand.44 A case definition of DHF is met when all four
epidemic years.38 Although severe dengue often occurs criteria of fever, haemorrhagic manifestations, thrombocytopenia, and evidence of
during second infections in dengue-endemic regions, plasma leakage are present. DHF has four increasing grades of severity towards DSS
primary dengue infections can also be severe and result (grades III and IV). A definition of DHF is required to classify cases as DSS (ie, DHF
in fatal outcomes, which has been documented among plus circulatory failure). The 1997 WHO classifications offer distinct advantages for
travellers without previous dengue infection.39 research studies, as the clinical phenomena described relate to underlying mechanisms
Additionally, asymptomatic infections have been reported of immunopathogenesis (ie, antibody-dependent enhancement) and could guide
to occur among travellers to dengue-endemic areas in a treatment pathways (eg, the timing and degree of fluid replacement with plasma
ratio of approximately 4:1, creating risks for the leakage). Disadvantages of the 1997 criteria include failure to capture severe disease
introduction of dengue viruses or novel serotypes from beyond DHF (eg, cardiac or hepatic end-organ damage) and poor capacity to facilitate
asymptomatic people into areas with competent mosquito the triage of patients with dengue. The WHO regional office for southeast Asia
vectors.40 proposed the term expanded dengue syndrome to describe cases with atypical yet
serious manifestations.45
Classification and clinical course • The 2009 WHO classification system evolved to facilitate triage and management of
Dengue is a self-limiting acute febrile illness with non-
patients with dengue,46 and to capture a broader spectrum of dengue-related disease.
specific manifestations. Among people infected with
Individuals are classified as having dengue, dengue with warning signs, and severe
DENV, approximately 60–80% are asymptomatic or have
dengue.16
subclinical infections, with increased risk of disease in
• The 2009 WHO criteria have been widely implemented to guide dengue clinical
secondary infection particularly among those with longer
management decisions, but they have also been criticised due to the broad
intervals since the previous DENV infection.41,42
recommendations for hospitalisation of patients with dengue warning signs. Multiple
WHO guidelines previously classified symptomatic
studies indicate the general approach of hospitalising for dengue with warning signs,
dengue virus infections as dengue fever, dengue
as per the 2009 WHO criteria, could increase the identification of individuals who will
haemorrhagic fever (DHF), or dengue shock syndrome
progress to severe disease (ie, through improved sensitivity of the criteria), at the
(DSS). However, revised WHO guidelines in 2009
expense of increasing hospitalisation of individuals who will not progress to severe
(panel 1) classified symptomatic dengue as dengue
disease.47,48 The positive predictive value of individual warning signs for severe dengue
without warning signs, dengue with warning signs, or
has been reported to range from 12% to 58%, with some warning signs (eg, clinical
severe dengue (figure 2).16,41,42
fluid accumulation) having better values than others.49 The availability and increasing
Symptomatic dengue generally follows the clinical
use of dengue rapid diagnostic tests could facilitate the use of the 2009 simpler
course of febrile, critical, and recovery phases (figure 3).16,61
dengue classification scheme. However, rapid diagnostic tests are not available in
During the febrile phase, which lasts from 2 days to
most endemic countries. More precise definitions of the 2009 warning signs and
7 days, an acute onset of high-grade fever (≥38·5°C) will
severe dengue are needed, as are improved risk prediction tools for clinical and
typically occur; this fever can be accompanied by nausea,
research use.50–53
vomiting, a transient macular rash, aches, pains, and
• The 2009 classification of dengue without warning signs, dengue with warning signs,
other constitutional symptoms.16 The mucocutaneous
and severe dengue16 has been adapted in several countries and international
manifestations of dengue are varied and can include
guidelines,54–57 while the 1997 dengue, DHF, and DSS classification43 continues to be
transient facial erythema, petechial rash, conjunctival
used in others.58–60
and scleral injection, and a maculopapular or
morbilliform eruption 3–6 days after the onset of fever
that can coalesce but with areas of sparing.65 The
tourniquet test66 can be positive and minor bleeding, uncomplicated dengue than previously recognised.71
such as skin petechiae or bruises, can occur.67 Most Plasma leakage becomes clinically apparent near the time
commonly, fever resolves and is followed by the recovery of defervescence and spontaneously improves after about
phase; in these cases, the illness would be categorised as 48–72 h.72 Warning signs of possible clinical deterioration
uncomplicated dengue. can precede the critical phase of dengue and can be used
Some patients with dengue experience the critical to detect disease progression, including abdominal pain
phase, which generally occurs around days 4–6 of illness or tenderness, persistent vomiting, clinically detectable
and often coincides with defervescence.16,68 The hallmark extravasal fluid accumulation, mucosal bleed, lethargy or
of severe dengue is plasma leakage, when the blood’s restlessness, liver enlargement, and an increase in
protein-rich fluid component flows from blood vessels haematocrit usually concurrent with a rapid decrease in
into surrounding tissue, which can lead to shock and is platelet count (figure 3).16,46 If the patient improves and
sometimes associated with haemorrhage.69,70 Some recovers, the illness is classified as dengue with warning
evidence shows that less severe capillary leakage signs. However, the disease could continue to advance
might be more common in clinically diagnosed towards severe dengue, which occurs in approximately

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Dengue case management

The median case fatality rate for patients with dengue is
Assessment 5% (range 0·01–39%).74 The criteria for severe dengue
include: severe plasma leakage leading to shock or to fluid
Presumptive diagnosis Warning signs accumulation with respiratory distress, severe bleeding as
For individuals who live in or • Severe abdominal pain or evaluated by a clinician, and severe organ involvement
travel to endemic areas, and tenderness including the CNS, heart, or liver (indicated by an aspartate
have fever and two of the • Persistent vomiting
following symptoms: • Mucosal bleed aminotransferase or alanine aminotransferase con
• Nausea and vomiting • Liver enlargement >2 cm centration of 1000 international units per litre or more).16
• Rash • Clinical fluid accumulation
• Aches and pains (eg, • Lethargy or restlessness
Shock is signalled by a rising haemoconcentration
headache, eye pain, muscle • Increase in haematocrit followed by an increase in diastolic pressure with
ache, or joint pain) (haemoconcentration) narrowing pulse pressure, rapid pulse, restlessness,
• Warning signs
• Tourniquet test positive hypotension, signs of poor peripheral perfusion (eg, cold
• Leukopenia extremities and slow capillary refill time), and reduced
urinary output. Repeat shock episodes might occur during
the critical phase.75 Circulatory compromise is generally
For patients with For patients with For patients with worse in the extremes of age; in children (age ≤18 years),
no warning signs warning signs of severe any of the following: this is probably due to increased vascular permeability and
dengue with co-existing • Severe plasma leakage
conditions: leading to shock or fluid a reduced capacity to maintain cardiovascular
• Pregnancy accumulation with homoeostasis, while factors in older people (age ≥60 years)
• Infancy respiratory distress
• Diabetes, asthma, or • Severe bleeding
include comorbidities and vascular ageing.76 Epistaxis,
hypertension • Severe organ impairment gum bleeding, hypermenorrhoea, haemoglobinuria, and
• Social risk (eg, lives far from other haemorrhagic manifestations are most often seen
hospital or is in extreme
poverty) during the critical phase.67 The risk for severe bleeding (eg,
• Old age from the gastrointestinal or vaginal tract) increases in
• Renal failure
profound or prolonged shock, in association with
GROUP A GROUP B GROUP C coagulation abnormalities combined with tissue hypoxia
Outpatient management Inpatient management Inpatient management and acidosis.77
If no warning signs or Coexisting conditions or Severe dengue
warning signs Patient requires in-hospital Involvement of other organ systems can also occur
coexisting conditions, patient
can be sent home with advice Patients with coexisting emergency treatment for close during the various phases of dengue. Hepatitis and
monitoring and intravenous
on controlling fever (eg, by conditions should be referred
fluid resuscitation. Patients
elevated liver enzymes are common among patients
taking paracetamol), drinking to hospital for close
plenty of fluids, resting, and monitoring and fluid should be assessed and treated with symptomatic dengue, but acute liver failure,
watching out for dengue management during the for shock, haemorrhage, and encephalitis, myocarditis, and acute kidney injury are
warning signs. Patient requires critical phase. Patients with any other complications; prompt
dengue diagnostic test, daily warning signs or inadequate infusion of 5–20 mL per kg infrequent.78–81 Sight-damaging ophthalmic inflam
complete blood count, and fluid intake should receive crystalloid solution for those mation during dengue has also been described.82 Dengue
daily clinic review. intravenous crystalloid with shock. The bolus is
repeated, or the rate reduced during pregnancy has implications for the mother. A
solutions (normal 0·9% saline
or Ringer’s lactate) at 5–7 mL according to clinical parameters. greater risk of DHF and DSS has been reported among
per kg per h for 1–2 h, then Blood transfusion should be pregnant women compared with non-pregnant women,83
reduced to 3–5 mL per kg per h given for severe bleeding and
for 2–4 h, and then reduced to colloid solutions are as well as an increased risk of maternal death.84,85 Dengue
2–3 mL per kg per h or less recommended for hypotensive also poses a risk to the fetus, with an increased risk of
according to clinical response. shock. Conduct baseline and
serial haematocrit and other miscarriage,86 stillbirth, and neonatal death.85
In addition to a baseline and
serial haematocrit (every tests as described for group B. During the recovery phase of dengue, extravasated
6–12 h during critical phase),
When can the patient be
fluids are resorbed and wellbeing improves. The patient
complete blood count, liver
function tests, blood glucose, discharged? could develop an erythematous—sometimes pruritic—
albumin, serum electrolytes, Patients can be discharged Herman’s rash with white islands of normal skin.87 In
serum urea and creatinine, when: vital signs are normal,
haemodynamically stable, with adults, postviral fatigue and depression for several weeks
arterial blood gases, cardiac
enzymes, urinalysis, and return of appetite, good urine to months have been described.88
output, no respiratory distress,
urine-specific gravity tests
increasing platelet count, and
Most patients with dengue recover without difficulty,
might be useful to guide
management. stable haematocrit without but promptly recognising people who will require medical
intravenous fluids. intervention is essential. A systematic review showed that
warning signs were associated with progression to severe
Figure 2: Dengue clinical course, classification, laboratory abnormalities, and management dengue but identified potential additional markers,
Adapted from WHO’s Handbook for Clinical Management of Dengue.61
including low serum albumin and elevated aspartate
aminotransferase and alanine aminotransferase
2–5% of patients.46,73 Rates of progression to severe disease concentrations.31 Thrombocytopenia is also commonly
are highly variable by age, underlying comorbidities, seen in patients with dengue, and reduced platelet counts
clinical resources, expertise in managing dengue, and have been associated with progression to severe disease.31
possibly the infecting DENV serotype and genotype.46 Ultrasonography can be used to detect plasma leakage in

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dengue.89 Ascites, pleural effusion, and gallbladder wall Fever and laboratory findings
thickening are the most common findings, but standard
protocols for sonographic procedures and improved Temperature
information about the positive predictive value of early Haematocrit

and low-volume plasma leakage for development of severe
dengue are needed.90,91 Investigations are ongoing to
establish whether inflammatory and vascular markers in
the febrile phase of dengue could be useful to predict Platelets
White blood cells
severe outcomes.92,93
Dengue management Virus and antibody response levels

Currently, no effective prophylactic or therapeutic agent Non-structural protein 1 IgM
IgG secondary
against dengue exists.94 Chloroquine, balapiravir,
celgosivir, lovastatin, corticosteroids, ivermectin, Viral RNA
plasma infusion, recombinant activated factor VII,

anti-D globulin, immunoglobulin, and IL-11 have not
been shown to be beneficial.95–97 However, clinical trials
are restricted by small sample sizes, heterogeneous IgG primary
populations, and difficulties in assessing outcomes, and
additional work is needed to thoroughly assess potential
benefits of these agents. A randomised controlled trial of Critical phase
Febrile phase (1–2 days)
montelukast, a leukotriene receptor antagonist used to Recovery phase (3–5 days)
(0–7 days) Risk of shock and
reduce asthma exacerbation, is ongoing among adult haemorrhage
patients with dengue to evaluate its efficacy in preventing 1 2 3 4 5 6 7 8 9 10
dengue with warning signs (NCT04673422). The small Day of illness
molecule, JNJ-A07, which blocks the intracellular
replication of DENV, has shown promise in preclinical Figure 3: Dengue laboratory findings, virus detection, and immune response
Data from WHO’s dengue guidelines for diagnosis, treatment, prevention, and control,16 Hunsperger et al,62
studies.98 Preclinical studies of therapeutic monoclonal Chaloemwong et al,63 and Dussart et al.64
antibodies against dengue are also ongoing.99
In the absence of specific therapy, the management of Dengue diagnosis
dengue remains supportive. The 2012 WHO handbook,61 The differential diagnosis of dengue is broad. During the
since adapted to other guidelines,54,100 focuses on a febrile phase, it includes other viral infections (eg,
stepwise approach of assessment and treatment measles, rubella, enterovirus, adenovirus, influenza, and
according to groups A, B, and C (figure 2). Group A other arboviruses), and bacterial (leptospirosis and
patients (ie, people with no warning signs, comorbidities, typhoid fever) and parasitic (malaria) illnesses that might
or difficult social circumstances) are sent home with be present in dengue-endemic areas.108 A diagnosis of
daily in-person monitoring. Groups B (patients dengue infection during the acute phase can be made
with comorbidities or warning signs) and C (patients with whole blood, plasma, or serum collected up to 7 days
with severe dengue) require hospital management and after symptom onset by detection of viral RNA through
intravenous fluids (figure 2).55 Fluid replacement is nucleic acid amplification tests (NAAT),109 detection of
lifesaving in severe dengue but must be administered viral antigens such as dengue non-structural protein 1
cautiously and discontinued when plasma leakage (NS1), enzyme-linked immunosorbent assay (ELISA),
subsides to avoid iatrogenic fluid overload.101 Among rapid diagnostic tests, and detection of IgM antibodies
patients with thrombocytopenia, prophylactic platelet from day 4 to approximately 12 weeks post-onset through
transfusion does not prevent bleeding and could serological testing (figure 3).110 NAAT assays are the
contribute to fluid overload.102,103 Although these preferred method of dengue diagnosis;109 in addition to
guidelines are based mainly on expert opinion and small their diagnostic specificity, molecular methods can be
randomised controlled trials,104–107 case fatality rates have used to identify the virus serotype.
been considerably reduced with judicious fluid NS1 can be detected in other bodily fluids such as urine,
replacement. Some areas of uncertainty remain, such as saliva, and cerebrospinal fluid.111 NS1 tests can be as
in the choice of colloid solution and blood products, the sensitive as molecular tests during the first 7 days of
use of ﬂuid boluses, and the optimal treatment of symptoms in primary infections, although sensitivity is
recurrent shock episodes. Steroid use is not lower in secondary infections; after seven days, although
recommended as it has not shown clinical benefit.76,95 sensitivity is reduced, NS1 has been detected in serum up
Training in clinical manage ment, including early to 12 days post symptom onset.111,112 Dengue IgM
recognition of plasma leakage, remains an essential antibodies are detectable for a longer period, from day 4
strategy to reduce morbidity and mortality. to approximately 12 weeks post symptom onset.113 Dengue

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IgG is detectable around day 7 in primary infections; the when differentiating between Zika virus (ZIKV) and
antibody concentration increases slowly thereafter and is dengue could have important clinical implications.110 NS1
thought to persist for life. In patients with secondary antibody ELISA tests for ZIKV have high specificity due
infections, anti-dengue IgG titres rise rapidly within the to the substantial amino acid differences between DENV
first week of illness (figure 3). Although serological assays and ZIKV NS1, and can be useful for differential
provide less certainty than NAAT or NS1 due to cross- diagnosis.111
reactivity with other flaviviruses and longer antibody
duration, a positive anti-DENV IgM suggests recent Dengue immunology
infection (within the past 12 weeks). Additionally, DENV infection is initiated in the skin when an infected
seroconversion or a four-fold rise in titres on anti-DENV mosquito takes a bloodmeal, injecting the virus along
IgM or IgG assays in paired samples is strongly suggestive with salivary proteins that increase recruitment of
of recent infection.113 Many rapid tests are available and susceptible immune cells to the site of infection.116
are an important tool for the early diagnosis of dengue. Myeloid cells are a key target of DENV infection, including
Meta-analyses suggest that immunochromatographic monocytes, macrophages, and dendritic cells. A first
tests that combine IgM, IgG, and NS1 detection have the DENV infection results in an early innate response
best performance compared with tests detecting characterised by stimulation of interferon gamma (IFNγ).
individual analytes, with pooled sensitivity of 90–91% and By contrast, in subsequent DENV infections, binding (but
specificities of 89–96%.114,115 Unfortunately, these tests are not neutralising) antibodies induced by previous exposure
not widely available in dengue-endemic areas. In patients to DENV (or a related flavivirus) facilitate infection of
from areas in which transmission of other flaviviruses is myeloid cells via the fragment crystallisable gamma
common, plaque reduction neutralisation tests (PRNT) receptor (FcγR), producing a larger population of viruses
can help distinguish DENV from other flaviviruses. and further exacerbating disease severity in a process
PRNTs, however, are rarely available in clinical called extrinsic antibody-dependent enhancement
laboratories and typically do not provide results within a (ADE).117–121 Entry via the FcγR also mediates intrinsic
meaningful timeframe for clinical management. PRNTs ADE, which suppresses IFNγ stimulation and innate
might be valuable in circumstances such as pregnancy, immunity and shifts towards a T-helper-2 response
dominated by secretion of IL-10, minimising induction of
other proinflammatory cytokines and hindering the early
Pathogenic Protective
cellular and humoral immune response (figure 4).117 ADE
M
Mature Partially immature is thought to increase replication of the virus at this key
virion virion
early stage and elevate the risk of progression to severe
dengue, DHF, and DSS.132,133 However, although pre-
infection binding antibody concentrations are associated
with increased viremia and risk of DHF and DSS, the
Interleukin-10 causal link from ADE to elevated viremia to DHF or DSS
has not been shown.120
Antibody-dependent enhancement of myeloid cells Broadly neutralising antibodies targeting quaternary
epitopes and with strong effector functions
Mediators of severe disease
CD14+CD16+ monocytes increase in early DENV
infection122,134 and help to trigger a strong plasmablast
response characterised by secretion of high concentrations
of anti-DENV antibodies.122,134 The role that excess antibody
production has in acute dengue is not clear, but could
Strong plasmablast response drives antibody-dependent Protective tissue-resident cytotoxic CD8+ T cells
enhancement and immunopathology contribute to disease pathogenesis by furthering ADE,
Perforin
increasing autoantibodies, and potentially changing
Granzyme
yme B glycosylation of antibodies, which is strongly associated
with DHF and DSS.123,124 DENV can also directly infect B
cells, and although B-cell infection does not substantially
contribute to viremia, it does drive proliferation of B cells
Low-affinity cross-reactive T cells and Effective cytotoxic CD4+ T cells
and stimulation of cytokines.135 Elevated viral load might
original antigenic sin also mediate severe disease by increasing secretion of NS1.
In in-vitro and animal models, NS1 concentrations directly
Figure 4: Correlates of dengue pathogenesis and protection and indirectly trigger vascular leakage, disrupting the
Types of immunological responses associated with increased dengue disease (a pathogenic response, generally glycocalyx and tight junctures between endothelial cells
during a secondary infection, is associated with antibody-dependent enhancement of myeloid
cells,117–119 strong plasmablast response,122–124 and weak T-cell response125) or reduced disease (a protective response is
lining blood vessels and further facilitating plasma leakage
associated with broadly neutralising antibodies126,127 and effective, cytotoxic CD8+ and CD4+ T cells128–131). and dissemination of virus into tissue.136 However, the
Figure created with BioRender.com. association between NS1 concentrations and severe disease

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has not been clearly shown in clinical studies.69 Severe maturation and target quaternary epitopes conserved
dengue is also associated with liver and spleen pathology, across serotypes, therefore providing broad protection.
with autopsies revealing DENV tropism for liver High concentrations of cross-reactive binding antibodies
macrophages (ie, Kupffer cells) and splenic macrophages, and multiple previous DENV infections are associated
which secrete high amounts of cytokines and mediate with reduced risk of symptomatic disease.132,143,151
damage due to deposition of complement, resulting in Consistent with this observation, the Dengvaxia and
necrosis in liver and splenic endothelial cells.137 Qdenga dengue vaccines have high efficacy against
symptomatic and severe disease in DENV-immune
T-cell responses individuals but not naive individuals, further suggesting
The role of DENV-specific T cells has been debated, as they that sequential exposure to distinct DENV strains is
have been implicated in both pathogenic and protective important for inducing broad protection.152,153 A few post-
immunity (figure 4). With regard to a pathogenic role, CD8+ secondary broadly neutralising antibodies have been
T cells induced by previous DENV infection have been identified, such as envelope-dimer-dependent epitope
shown to have low affinity for the new infecting serotype, (EDE) antibodies. These antibodies target conserved
proliferating but with little cytotoxic function, which quaternary epitopes and neutralise by disrupting the
results in delayed viral clearance and stimulation of conformational changes required for viral entry.126,127 EDE-
proinflammatory cytokines that mediate leakage and like broadly neutralising antibodies might be useful
disease.125 However, other studies suggest a protective role, correlates of protection for the evaluation of new dengue
with increased magnitude and more multifunctional, vaccines.
cytokine-producing DENV-specific CD8+ T-cell responses
and specific human leukocyte antigen (HLA) alleles Dengue vaccines
associated with reduced viremia, and lowering the The need for a tetravalent formulation that induces
probability of progression to symptomatic disease and simultaneous and balanced protection against all four
severe dengue.128–130 serotypes has slowed the development of a dengue
DENV-specific CD4+ cells promote CD8+ T cells and vaccine. Among people with a previous DENV infection,
stimulate B cells. Individuals with multiple previous DENV even a vaccine dominated by one serotype is likely to
exposures have populations of clonally expanded cytotoxic induce cross-protective immunity by activating memory
CD4+ cells that could be protective.131 By contrast, although B and T cells. However, in DENV-naive individuals with
T follicular helper (Tfh) cells are crucial for facilitating no immune memory, the protective immune response
maturation of the B-cell response, Tfh expansion in acute will strongly depend on the immunogenicity of each
dengue has been associated with secondary and severe serotype-specific vaccine component.154
dengue and a strong plasmablast response, suggesting a There are currently three leading dengue vaccines.
possible role in immunopathology.138,139 Dengvaxia (CYD-TDV), developed by Sanofi Pasteur
(Lyon, France), was the first licensed dengue vaccine.155
DENV serotypes and post-secondary DENV antibodies Qdenga (TAK-003), developed by Takeda (Osaka, Japan),
Although all DENV serotypes can result in symptomatic was approved by the European Commission in
or severe disease, differences have been identified in risk December, 2020, and is licensed in several countries,
by serotype and infection number (ie, primary or including Indonesia, Brazil, Argentina, the UK, and
secondary). DENV-2-associated and DENV-4-associated Germany.156–158 The third, TV003, was developed by the
dengue illnesses are more frequently identified as National Institutes of Health (Bethesda, MD, USA) and is
secondary DENV infections, whereas DENV-1 and in phase 3 trials.159 All three are live vaccines and contain
DENV-3 can cause frequent primary disease.140–142 DENV-4 four different attenuated vaccine viruses (ie, are
has been associated with a reduced risk of disease tetravalent) targeting each of the DENV serotypes.
compared with the other serotypes, as shown by However, they differ in the number of doses required (one
observations of silent DENV-4 epidemics in Thailand.143 to three) and time to complete the series (up to 1 year),
All sequences of infecting serotypes can cause severe which could affect feasibility and preferences for use in
disease and no defined order in the sequence of DENV different settings. Additionally, the need for a dengue test
infections for worse outcomes exists, although different to establish eligibility (ie, a prevaccination screening)
patterns have been described.144.145 Antigenic differences poses a logistical barrier for vaccines recommended only
between serotypes could be important in explaining the for use among people with a previous DENV infection.
magnitude of dengue epidemics,146–148 and viral sequence, Several other dengue vaccine candidates are undergoing
genotype, and changes in non-structural proteins could clinical trials or preclinical evaluation, including other
also help establish epidemic severity.149,150 live-attenuated vaccines, inactivated vaccines, recombinant
Sequential infection with distinct DENV serotypes vaccines, and DNA vaccines.160 The successful mRNA
induces antibodies capable of neutralising DENV-1–4 vaccine technology used for SARS-CoV-2 is also being
without triggering ADE, probably by activating cross- evaluated for dengue and could provide dengue vaccine
reactive memory B cells to undergo further affinity candidates in the future.161

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Dengvaxia (three cases in the placebo group and 11 cases in the

Dengvaxia uses a three-dose schedule, with doses vaccine group) and were mainly observed at one site.153 In
administered 6 months apart. The vaccine was first December, 2022, the European Commission approved
recommended by WHO in 2016 for people aged 9 years the use of Qdenga regardless of serostatus following a
and older living in highly endemic areas.162 Long-term positive opinion from the European Medicines Agency.156
follow-up data over 5 years from phase 3 trials and further The next step for its use in Europe is official
analyses of the efficacy results163 showed that seropositive recommendations from each EU country.171 Qdenga has
children (with evidence of previous DENV infection) were been approved in several countries and Germany has
protected from severe dengue if they were vaccinated started vaccination among travellers.158 In September, 2023,
with Dengvaxia. However, risk of hospitalisation for the vaccine received a recommendation from the Strategic
dengue and severe dengue was increased among children Advisory Group of Experts (SAGE) on immunisation that
aged 2–16 years without previous DENV infection who encouraged the introduction of Qdenga in settings with
were vaccinated with Dengvaxia and had a subsequent high transmission intensity to maximise its effect on
infection over a 5-year follow-up period in the public health and minimise any potential risk in
trial (hazard ratio for hospitalisation 1·75, seronegative people. SAGE recommended that the
95% CI 1·14–2·70; severe dengue 2·87; 95% CI vaccine be introduced to children aged 6–16 years, and
1·09 –7·61). After these findings, WHO revised the that post-authorisation studies should be conducted to
recommendations for the vaccine to only be given to further study the vaccine’s effectiveness and safety against
children with laboratory-confirmed evidence of a past serotypes 3 and 4.172 Takeda also plans to submit filings to
DENV infection.164 other regulatory agencies.173
For children aged 9–16 years with evidence of previous
DENV infection, Dengvaxia had an efficacy of about 80% TV003
against the outcomes of symptomatic virologically TV003 was developed by the National Institutes of Health
confirmed dengue (VCD), hospitalisation for dengue, and was formulated by selecting serotype-specific
and severe dengue.163,165 Among seropositive children the components to provide a balanced safety and
efficacy by serotype varied,166 with highest protection immunogenicity profile on the basis of an evaluation of
against DENV-4 (89%), followed by DENV-3 (80%), and multiple monovalent and tetravalent candidates
lowest against DENV-1 (67%) and DENV-2 (67%; table).163 (table).174,175 TV003 consists of a single dose and has been
The requirement for a laboratory test before vaccine licensed to several manufacturers globally, including
administration creates a unique challenge for Dengvaxia Merck & Co in the USA and the Instituto Butantan in
implementation. Qualifying laboratory tests include a Brazil. Phase 3 trials in Brazil are underway.176,177
positive NAAT or NS1 test done during an episode of Preliminary results from 2-year follow-up of the phase 3
acute dengue, or a positive result on prevaccination trial were released in December, 2022. Through 2 years
screening tests for serological evidence of previous of follow-up, the efficacy against VCD was 89% among
infection (ie, the presence of IgG antibodies) that meet seropositive people and 74% among seronegative people.
specific performance characteristics. To reduce the risk of Results by serotype are available for DENV-1 and DENV-2,
vaccinating someone without previous DENV infection, with higher efficacy among seropositive participants
high specificity in a prevaccination screening test is a (DENV-1 97% efficacy and DENV-2 84% efficacy)
priority. International working groups and the US Centers compared with seronegative participants (DENV-1 86%
for Disease Control and Prevention recommend using efficacy and DENV-2 58% efficacy).168 Efficacy for other
tests with a minimum sensitivity of 75–85% and serotypes is not available but is expected as part of the
minimum specificity of 95–98%.155,169 Few commercially phase 3 trial.178
available tests currently meet these requirements.170
Vector control
Qdenga People who live in or travel to dengue-endemic areas can
Qdenga, developed by Takeda, consists of two doses given prevent mosquito bites by using approved insect
3 months apart. Among children aged 4–16 years, efficacy repellents and wearing clothing that covers their arms
against VCD was 64% among seropositive children and and legs. The use of screened windows and doors and air
54% among seronegative children at 3 years after conditioning have also been shown to be protective.179–181
vaccination. Efficacy against hospitalisation for dengue Bednets can reduce mosquito populations and can have
was higher than for VCD, at 86% among seropositive an effect on dengue transmission.182 Chemical control of
children and 79% among seronegative children.167 Aedes species mosquitoes is restricted by widespread
Differences in efficacy were observed by serotype. Among insecticide resistance in endemic areas.183 Novel vector
seronegative children, there was no efficacy against control methods have been developed, including the use
DENV-3 and DENV-4 (table). Notably, estimates indicated of genetically modified mosquitoes.184 Genetically modi
a potential increased risk for hospitalisation after fied mosquitoes carry a gene that is passed to their
infection with DENV-3, although numbers were small offspring and kills females in the larval stage. Male

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Dengvaxia (CYD-TDV)163 Qdenga (TAK-003)167 TV003168

Manufacturer Sanofi Pasteur Takeda US National Institutes of Health,
Instituto Butantan, and Merck & Co
Status Recommended by WHO for two Recommended by WHO to be Ongoing phase 3 trial
patient groups: seropositive people considered for introduction in
aged 9–45 years, or all people children aged 6–16 years in settings
regardless of serostatus in high with high transmission intensity.
seroprevalence areas (>80% Licensed in several countries,
seropositivity). Licensed in including Indonesia, Brazil,
20 countries. Recommended for Argentina, the UK, and Germany
seropositive children aged 9–16 years
living in endemic areas in the USA155
Platform Four chimeric viruses for each DENV Attenuated DENV-2 and three Attenuated DENV-1, DENV-3, and
serotype on a yellow fever virus chimeric viruses for each of the four DENV-4, and a chimeric virus for
backbone DENV serotypes DENV-2 on a DENV-4 backbone
Ages of trial participants 9–16 years 6–16 years 2–59 years
Doses Three doses 6 months apart Two doses 3 months apart One dose
Prevaccination antibody screening Yes No Unknown
recommended?
Timeframe for efficacy endpoint 25 months for VCD and 60 months 54 months for VCD and 24 months for VCD
for hospitalisation hospitalisation
Efficacy among seropositive people
VCD: overall 76% (64% to 84%) 64% (58% to 69%) 89% (78% to 96%)
VCD: by serotype
DENV-1 67% (46% to 80%) 56% (45% to 65%) 97% (81% to 100%)
DENV-2 67% (47 to 80%) 80% (73% to 86%) 84% (63% to 94%)
DENV-3 80% (67% to 88%) 52% (37% to 64%) NR
DENV-4 89% (80% to 94%) 71% (40% to 86%) NR
Hospitalisation: overall 79% (46% to 80%) 86% (79% to 91%) NR
Hospitalisation: by serotype
DENV-1 78% (55% to 90%) 67% (37% to 82%) NR
DENV-2 82% (66% to 90%) 96% (90% to 98%) NR
DENV-3 63% (18% to 83%) 74% (39% to 89%) NR
DENV-4 89% (62% to 99%) 100% (NE) NR
Efficacy among seronegative people
VCD: overall 39% (–1% to 63%) 54% (42% to 63%) 74% (58% to 84%)
VCD: by serotype
DENV-1 41% (–7% to 67%) 45% (26% to 60%) 86% (69% to 94%)
DENV-2 –21% (–136% to 38%) 88% (79% to 93%) 58% (21% to 78%)
DENV-3 52% (–6% to 78%) –16% (−108% to 36%) NR
DENV-4 65% (24% to 84%) −106% (−629% to 42%) NR
Hospitalisation overall –41% (–168% to 93%) 79% (64% to 88%) NR
Hospitalisation by serotype
DENV-1 –37% (–219% to 41%) 78% (44% to 92%) NR
DENV-2 –141% (–795% to 35%) 100% (NE) NR
DENV-3 15% (–225% to 78%) –88% (−573% to 48%) NR
DENV-4 7% (–712% to 89%) 100% (NE) NR
Ranges in parentheses are 95% CIs. The Dengvaxia trial included participants aged 2–16 years but the vaccine is licensed for seropositive individuals aged 9 years or older.
Estimates of efficacy against hospitalisation by serotype in seronegative participants aged 2–8 years are: DENV-1:–42 (95% CI 34 to –205); DENV-2: –436 (–58 to –1723);
DENV-3: –141 (9 to –540); and DENV-4: –16 (70 to –344). DENV=dengue virus. NE=not possible to estimate due to a zero cell in one of the groups. NR=not reported.
VCD=virologically confirmed dengue.
Table: Comparison of vaccine efficacy for the target use population for live attenuated tetravalent dengue vaccines that are licensed or in phase 3 trials
offspring, however, survive and pass this gene to future found in wild Aedes mosquitoes,187 have also been used for
generations. As a result, mosquito populations decrease vector control. Wolbachia-mediated suppression refers to
over time.184,185 a reduction in wild populations of Aedes mosquitoes and
Strategies using Wolbachia, an intracellular bacterium is achieved by releasing Wolbachia-infected males into the
found in about 60% of all insects186 but not commonly environment to mate with uninfected wild females, as the

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resulting eggs do not hatch.188 In Wolbachia replacement, theorised that a first DENV infection induced antibodies
both Wolbachia-infected males and female mosquitoes that waned over 2 years to titres that could subsequently
are released, which pass the bacteria to their offspring enhance severe dengue disease, and that secondary
and gradually replace the wild population.189,190 In DENV infection with a different serotype induced stable,
mosquitoes, Wolbachia infection reduces transmission of cross-serotype protective antibodies.193 However, instead
arboviruses, including dengue, chikungunya, and Zika of waning over 2 years, cross-reactive binding antibodies
viruses, when infected female mosquitoes take a associated with protection or enhancement are stable by
bloodmeal. This method has shown reductions of nearly around 8 months after primary infection and are
80% in dengue cases and related hospitalisations in areas maintained at that set point for many years after.143,194 By
of implementation191 and is currently being deployed in contrast, anti-DENV antibodies induced after secondary
Brazil and Indonesia.192 DENV are less stable, wane rapidly for 8 months, and
then gradually decay over longer periods. One study
Dengue controversies, gaps, and opportunities showed vaccine efficacy waned much faster than
Many of the key questions in dengue research revolve geometric mean antibody titres to DENV-1–4, suggesting
around the role and behaviour of antibodies in protective a component of immunity other than waning antibodies
immunity and ADE, and how these change at different that could explain the loss of protection.195
timepoints after infection (panel 2). Previous work Although serotype-specific immunity (ie, homotypic
immunity) has been thought to impart lifelong
Panel 2: Priorities for future dengue virus (DENV) research protection, some evidence suggests that reinfections
with a given DENV serotype could occur.196 This evidence
DENV prevention and control bears further evaluation; if proven, the absence of lifelong
• Effectiveness of combined vaccine and vector control homotypic immunity would have important implications
programmes in decreasing or eliminating DENV infection for dengue vaccines and our understanding of DENV
and illness epidemiology.
• Long-term data on the effectiveness of interventions, Additionally, factors shaping the variability observed in
such as vaccines and Wolbachia-based vector control the severity of dengue epidemics remain poorly understood.
Immune correlates of protection Investigators in Taiwan have reported increasing severity
• Immune signatures durably associated with throughout the time course of a given epidemic, associated
immunopathogenesis and immunoprotection for DENV with increased viral diversity, which they hypothesise to be
• Clinical and immunological interactions between DENV driven by cross-protective immunity.197,198 Whether these
and non-DENV flaviviruses same phenomena are replicated in other regions, with
• Establishing whether the durability of homotypic different levels of population immunity and transmission
protection is lifelong patterns, is unclear.
• Importance of immune boosting in maintaining Identification of a satisfactory immune correlate of
protective immunity for DENV protection—a biomarker measuring immune response to
• Gaps in vaccine efficacy for specific subgroups (eg, in vaccination that is associated with vaccine efficacy—
young children and DENV-naive children, and incomplete remains an important challenge for DENV epidemiological
serotype-specific protection) that could lead to studies and assessments of vaccine immunogenicity
enhancement of severe disease (panel 2). This challenge is mainly due to the dominance
of immunity to cross-reactive epitopes that do not provide
DENV epidemiology effective protection. In the Dengvaxia paediatric vaccine
• Identifying the conditions under which homotypic DENV trial, the discordance between vaccine efficacy and
reinfection might be possible, including frequency of neutralisation response rates indicated that PRNT
occurrence and associated risk factors neutralisation response is not a completely valid correlate
• Identifying and understanding the features of settings of protection. However, increased PRNT titres after three
where DENV severity increases during the course of an doses of Dengvaxia were associated with a reduced rate of
epidemic VCD and hospitalisation overall and for each infecting
• Harmonisation of surveillance and laboratory methods serotype.199 After vaccination, geometric neutralising
across regions experiencing DENV transmission; increased antibodies by PRNT to DENV-1–4 of a ratio of at least 1:100
data sharing, and establishing a coordinated genomic were associated with around 50% protection against
surveillance strategy symptomatic dengue, while titres of at least 1:500 were
Management and diagnosis associated with 80% vaccine efficacy; high titres were also
• Improved point-of-care diagnostics associated with protection against dengue disease
• Clinical evaluation of the effect of antivirals requiring hospitalisation.199,200 In the Qdenga vaccine trials,
• Improved triage and risk assessment tools (eg, biomarkers neutralising antibody titres were lower in participants
and ultrasound) with VCD compared with healthy controls; these
differences were most evident among seropositive

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participants.153 Techniques such as antibody depletion of contributes substantially to transmission but complicates
cross-reactive antibodies provide improved information detection, and the non-specific presentation of acute febrile
about serotype-specific immunity and have shown illness can easily be mistaken for other causes. The non-
associations with serotype-specific vaccine efficacy.153,199–201 specific dengue symptoms are a particular challenge in
Depletion assays have shown that Dengvaxia is dominated malaria-endemic regions in which cases have similar
by DENV-4 type-specific antibodies and the Takeda dengue presentations, in areas with restricted diagnostic test
vaccine by DENV-2 type-specific antibodies, with mostly availability, and regions with infrequent or sporadic dengue
cross-reactive antibodies against other serotypes.154,202 transmission. National dengue surveillance systems also
Many of these serotype-specific antibodies bind quaternary vary widely in surveillance and laboratory capacity, and in
epitopes (ie, two adjacent E proteins simultaneously). The case definitions used; future efforts should work towards
role of neutralising antibodies binding quaternary strengthening country-level surveillance and laboratory
epitopes is an area of research into correlates of protection. capacity, har monising case definitions, establishing
The role of immunological boosting, defined here as regional strategies (eg, for genomic surveillance), and
qualitative or quantitative changes in immunity encouraging public data sharing to better inform dengue
associated with re-exposure to DENV in an individual preparedness and response efforts.
already exposed to that serotype, remains poorly Contributors
understood. The effects of boosting are proposed to be GP-B coordinated the writing of the manuscript and wrote the first and
evident in dynamic antibody patterns among individuals final drafts. LEA was responsible for the section on epidemiology,
LCK for the virus and the immune response, JD for dengue clinical
residing in hyperendemic locales over time.203 If boosting presentation and management, and KBA for controversies, gaps,
were an important contributor to maintenance of DENV and opportunities. All authors contributed to and approved the final
immunity and durability of protection, interventions that manuscript.
decrease the force of infection (eg, incompletely Declaration of interests
protective vaccination programmes or partially effective No funding was used for this publication. GP-B and LEA are employees
mosquito control programmes) could yield paradoxical of the Centers for Disease Control and Prevention. LCK is supported by
the Intramural Research Program of the US National Institute of Allergy
effects by lowering levels of boosting and increasing the and Infectious Diseases. The findings and conclusions in this Seminar
susceptible population. However, partially effective are those of the authors and do not necessarily represent the official
vaccines and mosquito control interventions complement position of the US Centers for Disease Control and Prevention. All other
each other, contributing effectiveness when the other is authors declare no competing interests.
lacking. Mathematical modelling suggests that Acknowledgments

combining interventions could yield consistent high We thank Jorge Muñoz-Jordán and Liliana Sánchez-González for their
expertise and advice on the preparation of figures 2 and 3, and Mike
effectiveness.204 Designing and implementing a dengue Johansson and Lyle Petersen for their review of the manuscript.
control programme that uses a combination of available Editorial note: The Lancet Group takes a neutral position with respect to
interventions is a public health priority. territorial claims in published maps and institutional affiliations.
The immunological and clinical interactions between References
DENV and non-DENV flaviviruses remain poorly 1 Rigau-Pérez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ,
understood, but data suggest that the relationship could Vorndam AV. Dengue and dengue haemorrhagic fever. Lancet 1998;
352: 971–77.
be highly context-dependent and not bidirectional. ZIKV 2 Nature Education. Dengue viruses. https://www.nature.com/
infection has been suggested to predispose people to scitable/topicpage/dengue-viruses-22400925/ (accessed
DHF with a subsequent infection with some, but not Nov 1, 2023).
3 Cattarino L, Rodriguez-Barraquer I, Imai N, Cummings DAT,
necessarily all, serotypes.121 By contrast, increased levels Ferguson NM. Mapping global variation in dengue transmission
of DENV immunity are associated with protection intensity. Sci Transl Med 2020; 12: eaax4144.
against Zika in adults and children,205 while reduced 4 Xu Z, Bambrick H, Frentiu FD, et al. Projecting the future of
levels could increase the risk of Zika microcephaly.206,207 dengue under climate change scenarios: progress, uncertainties
and research needs. PLoS Negl Trop Dis 2020; 14: e0008118.
Japanese encephalitis virus immunity has been variably 5 Messina JP, Brady OJ, Golding N, et al. The current and future
associated with risk of dengue illness208 but also with global distribution and population at risk of dengue. Nat Microbiol
possible protection.209 Given the substantial immuno 2019; 4: 1508–15.
6 Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global
logical cross-reactivity observed between DENV and non- economic burden of dengue: a systematic analysis. Lancet Infect Dis
DENV flaviviruses, these interactions could have 2016; 16: 935–41.
consequences for both the clinical outcomes of DENV 7 Oliveira LNDS, Itria A, Lima EC. Cost of illness and program of
dengue: a systematic review. PLoS One 2019; 14: e0211401.
infection and the immunological outcomes of DENV
8 Hung TM, Shepard DS, Bettis AA, et al. Productivity costs from a
vaccination. Further research on these interactions is dengue episode in Asia: a systematic literature review.
needed, across a range of flavivirus-endemic regions of BMC Infect Dis 2020; 20: 393.
the world, to inform DENV vaccine development and 9 Laserna A, Barahona-Correa J, Baquero L, Castañeda-Cardona C,
Rosselli D. Economic impact of dengue fever in Latin America and
evaluation efforts, as well as diagnostics. the Caribbean: a systematic review. Rev Panam Salud Publica 2018;
Dengue surveillance remains a key challenge in assessing 42: e111.
global dengue burden and temporal and geospatial trends. 10 Achee NL, Gould F, Perkins TA, et al. A critical assessment of vector
control for dengue prevention. PLoS Negl Trop Dis 2015; 9: e0003655.
The large proportion of asymptomatic and subclinical cases

Seminar
11 Lee C, Lee H. Probable female to male sexual transmission of 35 Berry IM, Melendrez MC, Pollett S, et al. Precision tracing of
dengue virus infection. Infect Dis (Lond) 2019; 51: 150–52. household dengue spread using inter- and intra-host viral variation
12 Cedano JA, Mora BL, Parra-Lara LG, Manzano-Nuñez R, Rosso F. data, Kamphaeng Phet, Thailand. Emerg Infect Dis 2021;
A scoping review of transmission of dengue virus from donors to 27: 1637–44.
recipients after solid organ transplantation. 36 Salje H, Wesolowski A, Brown TS, et al. Reconstructing unseen
Trans R Soc Trop Med Hyg 2019; 113: 431–36. transmission events to infer dengue dynamics from viral
13 Sabino EC, Loureiro P, Lopes ME, et al. Transfusion-transmitted sequences. Nat Commun 2021; 12: 1810.
dengue and associated clinical symptoms during the 2012 epidemic 37 Chen Y, Li N, Lourenço J, et al. Measuring the effects of
in Brazil. J Infect Dis 2016; 213: 694–702. COVID-19-related disruption on dengue transmission in southeast
14 Basurko C, Matheus S, Hildéral H, et al. Estimating the risk of Asia and Latin America: a statistical modelling study.
vertical transmission of dengue: a prospective study. Lancet Infect Dis 2022; 22: 657–67.
Am J Trop Med Hyg 2018; 98: 1826–32. 38 Osman S, Preet R. Dengue, chikungunya and Zika in GeoSentinel
15 Phongsamart W, Yoksan S, Vanaprapa N, Chokephaibulkit K. surveillance of international travellers: a literature review from
Dengue virus infection in late pregnancy and transmission to the 1995 to 2020. J Travel Med 2020; 27: taaa222.
infants. Pediatr Infect Dis J 2008; 27: 500–04. 39 Huits R, Schwartz E. Fatal outcomes of imported dengue fever in
16 WHO. Dengue: guidelines for diagnosis, treatment, prevention and adult travelers from non-endemic areas are associated with primary
control: new edition. Geneva: World Health Organization, 2009. infections. J Travel Med 2021; 28: taab020.
17 Zeng Z, Zhan J, Chen L, Chen H, Cheng S. Global, regional, and 40 Olivero RM, Hamer DH, MacLeod WB, et al. Dengue virus
national dengue burden from 1990 to 2017: a systematic analysis seroconversion in travelers to dengue-endemic areas.
based on the global burden of disease study 2017. EClinicalMedicine Am J Trop Med Hyg 2016; 95: 1130–36.
2021; 32: 100712. 41 Montoya M, Gresh L, Mercado JC, et al. Symptomatic versus
18 Cochet A, Calba C, Jourdain F, et al. Autochthonous dengue in inapparent outcome in repeat dengue virus infections is influenced
mainland France, 2022: geographical extension and incidence by the time interval between infections and study year.
increase. Euro Surveill 2022; 27: 2200818. PLoS Negl Trop Dis 2013; 7: e2357.
19 Kretschmer M, Collins J, Dale AP, et al. Notes From the field: first 42 Anderson KB, Gibbons RV, Cummings DA, et al. A shorter time
evidence of locally acquired dengue virus infection—Maricopa interval between first and second dengue infections is associated
County, Arizona, November 2022. MMWR Morb Mortal Wkly Rep with protection from clinical illness in a school-based cohort in
2023; 72: 290–91. Thailand. J Infect Dis 2014; 209: 360–68.
20 Pandey BD, Costello A. The dengue epidemic and climate change 43 WHO. Dengue haemorrhagic fever: diagnosis, treatment,
in Nepal. Lancet 2019; 394: 2150–51. prevention and control, 2nd edn. Geneva: World Health
21 Harapan H, Michie A, Yohan B, et al. Dengue viruses circulating in Organization, 1997.
Indonesia: a systematic review and phylogenetic analysis of data 44 Halstead SB. Dengue—the case definition dilemma: a commentary.
from five decades. Rev Med Virol 2019; 29: e2037. Pediatr Infect Dis J 2007; 26: 291–92.
22 Li Z, Wang J, Cheng X, et al. The worldwide seroprevalence of 45 WHO. Comprehensive guidelines for prevention and control of
DENV, CHIKV and ZIKV infection: a systematic review and meta- dengue and dengue haemorrhagic fever: revised and expanded
analysis. PLoS Negl Trop Dis 2021; 15: e0009337. edition. New Delhi: World Health Organization, 2011.
23 L’Azou M, Moureau A, Sarti E, et al. Symptomatic dengue in 46 Alexander N, Balmaseda A, Coelho IC, et al. Multicentre
children in 10 Asian and Latin American countries. N Engl J Med prospective study on dengue classification in four South-east Asian
2016; 374: 1155–66. and three Latin American countries. Trop Med Int Health 2011;
24 Rodriguez-Barraquer I, Salje H, Cummings DA. Opportunities for 16: 936–48.
improved surveillance and control of dengue from age-specific case 47 Arora SK, Nandan D, Sharma A, Benerjee P, Singh DP. Predictors
data. eLife 2019; 8: 8. of severe dengue amongst children as per the revised WHO
25 Cummings DA, Iamsirithaworn S, Lessler JT, et al. The impact of classification. J Vector Borne Dis 2021; 58: 329–34.
the demographic transition on dengue in Thailand: insights from a 48 Bodinayake CK, Tillekeratne LG, Nagahawatte A, et al. Evaluation of
statistical analysis and mathematical modeling. PLoS Med 2009; the WHO 2009 classification for diagnosis of acute dengue in a
6: e1000139. large cohort of adults and children in Sri Lanka during a dengue-1
26 Ooi EE, Goh KT, Gubler DJ. Dengue prevention and 35 years of epidemic. PLoS Negl Trop Dis 2018; 12: e0006258.
vector control in Singapore. Emerg Infect Dis 2006; 12: 887–93. 49 Ahmad MH, Ibrahim MI, Mohamed Z, et al. The sensitivity,
27 Halstead SB, Lan NT, Myint TT, et al. Dengue hemorrhagic fever in specificity and accuracy of warning signs in predicting severe
infants: research opportunities ignored. Emerg Infect Dis 2002; dengue, the severe dengue prevalence and its associated factors.
8: 1474–79. Int J Environ Res Public Health 2018; 15: 2018.
28 Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence that 50 Hadinegoro SR. The revised WHO dengue case classification: does
maternal dengue antibodies are important in the development of the system need to be modified? Paediatr Int Child Health 2012;
dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988; 32 (suppl 1): 33–38.
38: 411–19. 51 Tomashek KM, Wills B, See Lum LC, et al. Development of
29 O’Driscoll M, Buddhari D, Huang AT, et al. Maternally derived standard clinical endpoints for use in dengue interventional trials.
antibody titer dynamics and risk of hospitalized infant dengue PLoS Negl Trop Dis 2018; 12: e0006497.
disease. Proc Natl Acad Sci USA 2023; 120: e2308221120. 52 Morra ME, Altibi AMA, Iqtadar S, et al. Definitions for warning
30 Halstead SB, Yamarat C. Recent epidemics of hemorrhagic fever in signs and signs of severe dengue according to the WHO 2009
Thailand: observations related to pathogenesis of a “new” dengue classification: systematic review of literature. Rev Med Virol 2018;
disease. Am J Public Health Nations Health 1965; 55: 1386–95. 28: e1979.
31 Sangkaew S, Ming D, Boonyasiri A, et al. Risk predictors of 53 Srikiatkhachorn A, Rothman AL, Gibbons RV, et al. Dengue—how
progression to severe disease during the febrile phase of dengue: best to classify it. Clin Infect Dis 2011; 53: 563–67.
a systematic review and meta-analysis. Lancet Infect Dis 2021; 54 Médecins Sans Frontières. Dengue. https://medicalguidelines.msf.
21: 1014–26. org/en/viewport/CG/english/dengue-16690007.html (accessed
32 Olson MF, Juarez JG, Kraemer MUG, Messina JP, Hamer GL. Oct 25, 2022).
Global patterns of aegyptism without arbovirus. PLoS Negl Trop Dis 55 PAHO. Guidelines for the clinical diagnosis and treatment of
2021; 15: e0009397. Dengue, Chikungunya, and Zika. Washington, DC: Pan American
33 Louis VR, Phalkey R, Horstick O, et al. Modeling tools for dengue Health Organization, 2022.
risk mapping—a systematic review. Int J Health Geogr 2014; 13: 50. 56 WHO. Dengue clinical management: facilitator’s training manual.
34 Eder M, Cortes F, Teixeira de Siqueira Filha N, et al. Scoping Manila: World Health Organization, 2013.
review on vector-borne diseases in urban areas: transmission 57 Zhang FC, He JF, Peng J, et al. Guidelines for diagnosis and
dynamics, vectorial capacity and co-infection. Infect Dis Poverty treatment of dengue in China. Zhonghua Nei Ke Za Zhi 2018;
2018; 7: 90. 57: 642–48.

Seminar
58 WHO. Comprehensive guideline for prevention and control of 81 Diptyanusa A, Phumratanaprapin W. Predictors and outcomes of
dengue and dengue haemorrhagic fever. revised and expanded dengue-associated acute kidney injury. Am J Trop Med Hyg 2021;
edition. https://apps.who.int/iris/handle/10665/204894 (acessed 105: 24–30.
Oct 25, 2022). 82 Vijitha VS, Dave TV, Murthy SI, et al. Severe ocular and adnexal
59 Sri Lanka Ministry of Health. Guidelines on management of complications in dengue hemorrhagic fever: a report of 29 eyes.
dengue fever & dengue haemorrhagic fever in adults. https://www. Indian J Ophthalmol 2021; 69: 617–22.
dengue.health.gov.lk/web/images/Guidelines_on_management_ 83 Machado CR, Machado ES, Rohloff RD, et al. Is pregnancy associated
of_dengue_fever_and_dengue_haemorrhagic_fever_in_adults_1. with severe dengue? A review of data from the Rio de Janeiro
pdf (accessed Oct 25, 2022). surveillance information system. PLoS Negl Trop Dis 2013; 7: e2217.
60 Country Office for India, WHO. National guidelines for clinical 84 Paixao ES, Harron K, Campbell O, et al. Dengue in pregnancy and
management of dengue fever. https://apps.who.int/iris/ maternal mortality: a cohort analysis using routine data. Sci Rep
handle/10665/208893 (accessed Oct 25, 2022). 2018; 8: 9938.
61 WHO. Handbook for clinical management of dengue. Geneva: 85 Rathore SS, Oberoi S, Hilliard J, et al. Maternal and foetal–neonatal
World Health Organization, 2012. outcomes of dengue virus infection during pregnancy.
62 Hunsperger EA, Muñoz-Jordán J, Beltran M, et al. Performance of Trop Med Int Health 2022; 27: 619–29.
dengue diagnostic tests in a single-specimen diagnostic algorithm. 86 Paixão ES, Teixeira MG, Costa MDCN, Rodrigues LC. Dengue
J Infect Dis 2016; 214: 836–44. during pregnancy and adverse fetal outcomes: a systematic review
63 Chaloemwong J, Tantiworawit A, Rattanathammethee T, et al. and meta-analysis. Lancet Infect Dis 2016; 16: 857–65.
Useful clinical features and hematological parameters for the 87 Bothra A, Maheswari A, Singh M, Pawar M, Jodhani K. Cutaneous
diagnosis of dengue infection in patients with acute febrile illness: manifestations of viral outbreaks. Australas J Dermatol 2021;
a retrospective study. BMC Hematol 2018; 18: 20. 62: 27–36.
64 Dussart P, Duong V, Bleakley K, et al. Comparison of dengue case 88 Sigera PC, Rajapakse S, Weeratunga P, et al. Dengue and post-
classification schemes and evaluation of biological changes in infection fatigue: findings from a prospective cohort-the Colombo
different dengue clinical patterns in a longitudinal follow-up of Dengue Study. Trans R Soc Trop Med Hyg 2021; 115: 669–76.
hospitalized children in Cambodia. PLoS Negl Trop Dis 2020; 89 Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, et al. Natural
14: e0008603. history of plasma leakage in dengue hemorrhagic fever: a serial
65 Thomas EA, John M, Kanish B. Mucocutaneous manifestations of ultrasonographic study. Pediatr Infect Dis J 2007; 26: 283–90,
dengue fever. Indian J Dermatol 2010; 55: 79–85. discussion 291–92.
66 Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical 90 Dewan N, Zuluaga D, Osorio L, Krienke ME, Bakker C, Kirsch J.
and laboratory indicators of acute dengue illness. J Infect Dis 1997; Ultrasound in dengue: a scoping review. Am J Trop Med Hyg 2021;
176: 313–21. 104: 826–35.
67 Simmons CP, Farrar JJ, Nguyen V, Wills B. Dengue. N Engl J Med 91 Halstead SB, Tissera H, Kumarasinghe M, Fernando L. Comments
2012; 366: 1423–32. on “dengue management in triage using ultrasound in children
68 Lam PK, Tam DT, Diet TV, et al. Clinical characteristics of dengue from Cambodia: a prospective cohort study”.
shock syndrome in Vietnamese children: a 10-year prospective study Lancet Reg Health West Pac 2022; 25: 100527.
in a single hospital. Clin Infect Dis 2013; 57: 1577–86. 92 Vuong NL, Lam PK, Ming DKY, et al. Combination of inflammatory
69 Malavige GN, Ogg GS. Pathogenesis of vascular leak in dengue and vascular markers in the febrile phase of dengue is associated
virus infection. Immunology 2017; 151: 261–69. with more severe outcomes. eLife 2021; 10: 10.
70 Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 93 Yuan K, Chen Y, Zhong M, Lin Y, Liu L. Risk and predictive factors
Microvascular and endothelial function for risk prediction in for severe dengue infection: a systematic review and meta-analysis.
dengue: an observational study. Lancet 2015; 385 (suppl 1): S102. PLoS One 2022; 17: e0267186.
71 Meltzer E, Heyman Z, Bin H, Schwartz E. Capillary leakage in 94 Obi JO, Gutiérrez-Barbosa H, Chua JV, Deredge DJ. Current trends
travelers with dengue infection: implications for pathogenesis. and limitations in dengue antiviral research. Trop Med Infect Dis
Am J Trop Med Hyg 2012; 86: 536–39. 2021; 6: 180.
72 Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 95 Wilder-Smith A, Ooi EE, Horstick O, Wills B. Dengue. Lancet 2019;
Cardiovascular manifestations of the emerging dengue pandemic. 393: 350–63.
Nat Rev Cardiol 2014; 11: 335–45. 96 Suputtamongkol Y, Avirutnan P, Mairiang D, et al. Ivermectin
73 Jayarajah U, Dissanayake U, Abeysuriya V, et al. Comparing the accelerates circulating nonstructural protein 1 (NS1) clearance in
2009 and 1997 World Health Organization dengue case adult dengue patients: a combined phase 2/3 randomized double-
classifications in a large cohort of South Asian patients. blinded placebo controlled trial. Clin Infect Dis 2021; 72: e586–93.
J Infect Dev Ctries 2020; 14: 781–87. 97 Rajapakse S, de Silva NL, Weeratunga P, Rodrigo C, Fernando SD.
74 Chagas GCL, Rangel AR, Noronha LM, et al. Risk factors for Prophylactic and therapeutic interventions for bleeding in dengue:
mortality in patients with dengue: a systematic review and meta- a systematic review. Trans R Soc Trop Med Hyg 2017; 111: 433–39.
analysis. Trop Med Int Health 2022; 27: 656–68. 98 Kaptein SJF, Goethals O, Kiemel D, et al. A pan-serotype dengue
75 Trieu HT, Khanh LP, Ming DKY, et al. The compensatory reserve virus inhibitor targeting the NS3–NS4B interaction. Nature 2021;
index predicts recurrent shock in patients with severe dengue. 598: 504–09.
BMC Med 2022; 20: 109. 99 Tien SM, Chang PC, Lai YC, et al. Therapeutic efficacy of humanized
76 Trung DT, Trieu HT, Wills BA. Microvascular fluid exchange: monoclonal antibodies targeting dengue virus nonstructural protein
implications of the revised starling model for resuscitation of 1 in the mouse model. PLoS Pathog 2022; 18: e1010469.
dengue shock syndrome. Front Med (Lausanne) 2020; 7: 601520. 100 PAHO. Dengue: guidelines for patient care in the Region of the
77 Wills BA, Oragui EE, Stephens AC, et al. Coagulation abnormalities Americas, 2nd edition. Washington, DC: Pan American Health
in dengue hemorrhagic fever: serial investigations in 167 Organization, 2016.
Vietnamese children with dengue shock syndrome. Clin Infect Dis 101 Rosenberger KD, Lum L, Alexander N, Junghanss T, Wills B,
2002; 35: 277–85. Jaenisch T. Vascular leakage in dengue—clinical spectrum and
78 Chia PY, Thein TL, Ong SWX, Lye DC, Leo YS. Severe dengue and influence of parenteral fluid therapy. Trop Med Int Health 2016;
liver involvement: an overview and review of the literature. 21: 445–53.
Expert Rev Anti Infect Ther 2020; 18: 181–89. 102 Lum LC, Abdel-Latif M-A, Goh AY, Chan PW, Lam SK. Preventive
79 Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological transfusion in dengue shock syndrome—is it necessary? J Pediatr
complications of dengue virus infection. Lancet Neurol 2013; 2003; 143: 682–84.
12: 906–19. 103 Lye DC, Archuleta S, Syed-Omar SF, et al. Prophylactic platelet
80 Nicacio JM, Gomes OV, Carmo RFD, et al. Heart disease and transfusion plus supportive care versus supportive care alone in
arboviruses: a systematic review and meta-analysis. Viruses 2022; adults with dengue and thrombocytopenia: a multicentre, open-
14: 1988. label, randomised, superiority trial. Lancet 2017; 389: 1611–18.

Seminar
104 Dung NM, Day NP, Tam DT, et al. Fluid replacement in dengue 127 Sharma A, Zhang X, Dejnirattisai W, et al. The epitope arrangement
shock syndrome: a randomized, double-blind comparison of four on flavivirus particles contributes to Mab C10’s extraordinary
intravenous-fluid regimens. Clin Infect Dis 1999; 29: 787–94. neutralization breadth across Zika and dengue viruses. Cell 2021;
105 Kalayanarooj S. Choice of colloidal solutions in dengue 184: 6052–6066.
hemorrhagic fever patients. J Med Assoc Thai 2008; 128 Hatch S, Endy TP, Thomas S, et al. Intracellular cytokine
91 (suppl 3): S97–103. production by dengue virus-specific T cells correlates with
106 Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue subclinical secondary infection. J Infect Dis 2011; 203: 1282–91.
shock syndrome: a randomized double-blind comparison of 129 Weiskopf D, Angelo MA, de Azeredo EL, et al. Comprehensive
4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001; analysis of dengue virus-specific responses supports an HLA-linked
32: 204–13. protective role for CD8+ T cells. Proc Natl Acad Sci USA 2013;
107 Wills BA, Nguyen MD, Ha TL, et al. Comparison of three fluid 110: E2046–53.
solutions for resuscitation in dengue shock syndrome. N Engl J Med 130 Wijeratne DT, Fernando S, Gomes L, et al. Quantification of dengue
2005; 353: 877–89. virus specific T cell responses and correlation with viral load and
108 Sharp TM, Anderson KB, Katzelnick LC, et al. Knowledge gaps in clinical disease severity in acute dengue infection.
the epidemiology of severe dengue impede vaccine evaluation. PLoS Negl Trop Dis 2018; 12: e0006540.
Lancet Infect Dis 2022; 22: e42–51. 131 Weiskopf D, Bangs DJ, Sidney J, et al. Dengue virus infection
109 Centers for Disease Control and Prevention. Molecular tests for elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated
dengue virus. https://www.cdc.gov/dengue/healthcare-providers/ with protective immunity. Proc Natl Acad Sci USA 2015;
testing/molecular-tests/index.html (accessed Nov 1, 2023). 112: e4256–63.
110 Sharp TM, Fischer M, Muñoz-Jordán JL, et al. Dengue and zika 132 Katzelnick LC, Gresh L, Halloran ME, et al. Antibody-dependent
virus diagnostic testing for patients with a clinically compatible enhancement of severe dengue disease in humans. Science 2017;
illness and risk for infection with both viruses. 358: 929–32.
MMWR Recomm Rep 2019; 68: 1–10. 133 Mizumoto K, Ejima K, Yamamoto T, Nishiura H. On the risk of
111 Fisher R, Lustig Y, Sklan EH, Schwartz E. The role of NS1 Protein severe dengue during secondary infection: a systematic review
in the diagnosis of flavivirus infections. Viruses 2023; 15: 572. coupled with mathematical modeling. J Vector Borne Dis 2014;
112 Centers for Disease Control and Prevention. Dengue virus antigen 51: 153–64.
detection. https://www.cdc.gov/dengue/healthcare-providers/ 134 Michlmayr D, Andrade P, Gonzalez K, Balmaseda A, Harris E.
testing/antigen-detection.html (accessed Nov 1, 2023). CD14+CD16+ monocytes are the main target of Zika virus infection
113 Centers for Disease Control and Prevention. Serologic tests for in peripheral blood mononuclear cells in a paediatric study in
dengue virus. https://www.cdc.gov/dengue/healthcare-providers/ Nicaragua. Nat Microbiol 2017; 2: 1462–70.
testing/serologic-tests.html (accessed Nov 1, 2023). 135 Upasani V, Vo HTM, Auerswald H, et al. Direct infection of B cells
114 Macêdo JVL, Frias IAM, Oliveira MDL, Zanghelini F, Andrade CAS. by dengue virus modulates b cell responses in a Cambodian
A systematic review and meta-analysis on the accuracy of rapid pediatric cohort. Front Immunol 2021; 11: 594813.
immunochromatographic tests for dengue diagnosis. 136 Glasner DR, Puerta-Guardo H, Beatty PR, Harris E. The good, the
Eur J Clin Microbiol Infect Dis 2022; 41: 1191–201. bad, and the shocking: the multiple roles of dengue virus
115 Mata VE, Andrade CAF, Passos SRL, Hökerberg YHM, nonstructural protein 1 in protection and pathogenesis.
Fukuoka LVB, Silva SAD. Rapid immunochromatographic tests for Annu Rev Virol 2018; 5: 227–53.
the diagnosis of dengue: a systematic review and meta-analysis. 137 Aye KS, Charngkaew K, Win N, et al. Pathologic highlights of
Cad Saude Publica 2020; 36: e00225618. dengue hemorrhagic fever in 13 autopsy cases from Myanmar.
116 King CA, Wegman AD, Endy TP. Mobilization and activation of the Hum Pathol 2014; 45: 1221–33.
innate immune response to dengue virus. Front Cell Infect Microbiol 138 Haltaufderhyde K, Srikiatkhachorn A, Green S, et al. Activation of
2020; 10: 574417. peripheral t follicular helper cells during acute dengue virus
117 Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. infection. J Infect Dis 2018; 218: 1675–85.
Intrinsic antibody-dependent enhancement of microbial infection 139 Rouers A, Chng MHY, Lee B, et al. Immune cell phenotypes
in macrophages: disease regulation by immune complexes. associated with disease severity and long-term neutralizing antibody
Lancet Infect Dis 2010; 10: 712–22. titers after natural dengue virus infection. Cell Rep Med 2021;
118 Halstead SB. In vivo enhancement of dengue virus infection in 2: 100278.
rhesus monkeys by passively transferred antibody. J Infect Dis 1979; 140 Clapham HE, Cummings DAT, Johansson MA. Immune status
140: 527–33. alters the probability of apparent illness due to dengue virus
119 Halstead SB, O’Rourke EJ. Antibody-enhanced dengue virus infection: Evidence from a pooled analysis across multiple cohort
infection in primate leukocytes. Nature 1977; 265: 739–41. and cluster studies. PLoS Negl Trop Dis 2017; 11: e0005926.
120 Waggoner JJ, Katzelnick LC, Burger-Calderon R, et al. Antibody- 141 Nisalak A, Clapham HE, Kalayanarooj S, et al. Forty years of dengue
dependent enhancement of severe disease is mediated by serum surveillance at a tertiary pediatric hospital in Bangkok, Thailand,
viral load in pediatric dengue virus infections. J Infect Dis 2020; 1973–2012. Am J Trop Med Hyg 2016; 94: 1342–47.
221: 1846–54. 142 Soo KM, Khalid B, Ching SM, Chee HY. Meta-analysis of dengue
121 Katzelnick LC, Narvaez C, Arguello S, et al. Zika virus infection severity during infection by different dengue virus serotypes in
enhances future risk of severe dengue disease. Science 2020; primary and secondary infections. PLoS One 2016; 11: e0154760.
369: 1123–28. 143 Salje H, Cummings DAT, Rodriguez-Barraquer I, et al.
122 Kwissa M, Nakaya HI, Onlamoon N, et al. Dengue virus infection Reconstruction of antibody dynamics and infection histories to
induces expansion of a CD14(+)CD16(+) monocyte population that evaluate dengue risk. Nature 2018; 557: 719–23.
stimulates plasmablast differentiation. Cell Host Microbe 2014; 144 Aguas R, Dorigatti I, Coudeville L, Luxemburger C, Ferguson NM.
16: 115–27. Cross-serotype interactions and disease outcome prediction of
123 Wang TT, Sewatanon J, Memoli MJ, et al. IgG antibodies to dengue dengue infections in Vietnam. Sci Rep 2019; 9: 9395.
enhanced for FcγRIIIA binding determine disease severity. Science 145 Halstead SB. Neutralization and antibody-dependent enhancement
2017; 355: 395–98. of dengue viruses. Adv Virus Res 2003; 60: 421–67.
124 Bournazos S, Vo HTM, Duong V, et al. Antibody fucosylation 146 Katzelnick LC, Coello Escoto A, Huang AT, et al. Antigenic
predicts disease severity in secondary dengue infection. Science evolution of dengue viruses over 20 years. Science 2021;
2021; 372: 1102–05. 374: 999–1004.
125 Mongkolsapaya J, Dejnirattisai W, Xu XN, et al. Original antigenic 147 Forshey BM, Reiner RC, Olkowski S, et al. Incomplete protection
sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. against dengue virus type 2 re-infection in Peru. PLoS Negl Trop Dis
Nat Med 2003; 9: 921–27. 2016; 10: e0004398.
126 Barba-Spaeth G, Dejnirattisai W, Rouvinski A, et al. Structural basis 148 Kochel TJ, Watts DM, Halstead SB, et al. Effect of dengue-1
of potent Zika–dengue virus antibody cross-neutralization. Nature antibodies on American dengue-2 viral infection and dengue
2016; 536: 48–53. haemorrhagic fever. Lancet 2002; 360: 310–12.

Seminar
149 OhAinle M, Balmaseda A, Macalalad AR, et al. Dynamics of 170 Centers for Disease Control and Prevention. Laboratory testing
dengue disease severity determined by the interplay between viral requirements for vaccination with Dengvaxia dengue vaccine.
genetics and serotype-specific immunity. Sci Transl Med 2011; https://www.cdc.gov/dengue/vaccine/hcp/testing.html (accessed
3: 114ra128. Nov 1, 2023).
150 Rodriguez-Roche R, Sanchez L, Burgher Y, et al. Virus role during 171 Dal-Ré R, Launay O. Public trust on regulatory decisions: the
intraepidemic increase in dengue disease severity. European Medicines Agency and the AstraZeneca COVID-19
Vector Borne Zoonotic Dis 2011; 11: 675–81. vaccine label. Vaccine 2021; 39: 4029–31.
151 Olkowski S, Forshey BM, Morrison AC, et al. Reduced risk of 172 SAGE. Highlights from the meeting of the Strategic Advisory
disease during postsecondary dengue virus infections. J Infect Dis Group of Experts (SAGE) on immunization, 25–29 September 2023.
2013; 208: 1026–33. https://cdn.who.int/media/docs/default-source/2021-dha-docs/
152 Hadinegoro SR, Arredondo-García JL, Capeding MR, et al. Efficacy highlights-3.pdf?sfvrsn=9237c77d_1 ((accessed Nov 1, 2023).
and long-term safety of a dengue vaccine in regions of endemic 173 Takeda. Takeda’s Biologics License Application (BLA) for dengue
disease. N Engl J Med 2015; 373: 1195–206. vaccine candidate (TAK-003) granted priority review by US Food
153 Rivera L, Biswal S, Sáez-Llorens X, et al. Three-year efficacy and and Drug Administration. https://www.takeda.com/newsroom/
safety of Takeda’s dengue vaccine candidate (TAK-003). newsreleases/2022/takedas-biologics-license-application-bla-for-
Clin Infect Dis 2022; 75: 107–17. dengue-vaccine-candidate-tak-003-granted-priority-review-by-us-
154 White LJ, Young EF, Stoops MJ, et al. Defining levels of dengue food-and-drug-administration/ (accessed Nov 1, 2023).
virus serotype-specific neutralizing antibodies induced by a live 174 Durbin AP, Kirkpatrick BD, Pierce KK, Schmidt AC, Whitehead SS.
attenuated tetravalent dengue vaccine (TAK-003). PLoS Negl Trop Dis Development and clinical evaluation of multiple investigational
2021; 15: e0009258. monovalent DENV vaccines to identify components for inclusion in
155 Paz-Bailey G, Adams L, Wong JM, et al. Dengue vaccine: a live attenuated tetravalent DENV vaccine. Vaccine 2011;
recommendations of the Advisory Committee on Immunization 29: 7242–50.
Practices, United States, 2021. MMWR Recomm Rep 2021; 175 Durbin AP, Kirkpatrick BD, Pierce KK, et al. A single dose of any of
70: 1–16. four different live attenuated tetravalent dengue vaccines is safe and
156 European Medicines Agency. Dengue tetravalent vaccine (live, immunogenic in flavivirus-naive adults: a randomized, double-
attenuated) Takeda: opinion on medicine for use outside EU. blind clinical trial. J Infect Dis 2013; 207: 957–65.
https://www.ema.europa.eu/en/opinion-medicine-use-outside-EU/ 176 Butantan Institute. Phase III trial to evaluate efficacy and safety of a
human/dengue-tetravalent-vaccine-live-attenuated-takeda (accessed tetravalent dengue vaccine. https://clinicaltrials.gov/ct2/show/
Nov 1, 2023). NCT02406729 (accessed Nov 1, 2023).
157 Takeda. Takeda receives positive CHMP opinion recommending 177 Merck. Merck and Instituto Butantan announce collaboration
approval of dengue vaccine candidate in EU and dengue-endemic agreement to develop vaccines to protect against dengue infections.
countries. https://www.takeda.com/newsroom/newsreleases/2022/ https://www.merck.com/news/merck-and-instituto-butantan-
Positive-CHMP-Opinion-Recommending-Approval-of-Dengue- announce-collaboration-agreement-to-develop-vaccines-to-protect-
vaccine/ (accessed Nov 1, 2023). against-dengue-infections/ (accessed Nov 1, 2023).
158 Huang G, Matsuyama K. Japanese pharmaceutical firm Takeda 178 Butantan Institute. Butantan’s dengue vaccine has 79·6% efficacy,
lowers price of dengue shot in Brazil and Indonesia. The Japan partial results from 2-year follow-up show. https://butantan.gov.br/
Times, March 4, 2023. https://www.japantimes.co.jp/ noticias/butantan’s-dengue-vaccine-has-79.6-efficacy-partial-results-
news/2023/03/04/business/dengue-fever-vaccine-takeda/ (accessed from-2-year-follow-up-show (accessed Nov 1, 2023).
Nov 1, 2023). 179 Lindsay SW, Davies M, Alabaster G, et al. Recommendations for
159 Whitehead SS. Development of TV003/TV005, a single dose, highly building out mosquito-transmitted diseases in sub-Saharan Africa:
immunogenic live attenuated dengue vaccine; what makes this the DELIVER mnemonic. Philos Trans R Soc Lond B Biol Sci 2021;
vaccine different from the Sanofi–Pasteur CYD vaccine? 376: 20190814.
Expert Rev Vaccines 2016; 15: 509–17. 180 Centers for Disease Control and Prevention. Dengue: prevent
160 Huang CH, Tsai YT, Wang SF, Wang WH, Chen YH. Dengue mosquito bites. https://www.cdc.gov/dengue/prevention/prevent-
vaccine: an update. Expert Rev Anti Infect Ther 2021; 19: 1495–502. mosquito-bites.html (accessed Oct 10, 2021).
161 Park J, Kim J, Jang YS. Current status and perspectives on vaccine 181 Manrique-Saide P, Che-Mendoza A, Barrera-Perez M, et al. Use of
development against dengue virus infection. J Microbiol 2022; insecticide-treated house screens to reduce infestations of dengue
60: 247–54. virus vectors, Mexico. Emerg Infect Dis 2015; 21: 308–11.
162 WHO. Dengue vaccine: WHO position paper, July 2016— 182 Lenhart A, Orelus N, Maskill R, Alexander N, Streit T, McCall PJ.
recommendations. Vaccine 2017; 35: 1200–01. Insecticide-treated bednets to control dengue vectors: preliminary
163 Sridhar S, Luedtke A, Langevin E, et al. Effect of dengue serostatus evidence from a controlled trial in Haiti. Trop Med Int Health 2008;
on dengue vaccine safety and efficacy. N Engl J Med 2018; 13: 56–67.
379: 327–40. 183 Moyes CL, Vontas J, Martins AJ, et al. Contemporary status of
164 WHO. Dengue vaccine: WHO position paper, September 2018— insecticide resistance in the major Aedes vectors of arboviruses
recommendations. Vaccine 2019; 37: 4848–49. infecting humans. PLoS Negl Trop Dis 2017; 11: e0005625.
165 Hadinegoro SR, Arredondo-García JL, Capeding MR, et al. Efficacy 184 Wang G-H, Gamez S, Raban RR, et al. Combating mosquito-borne
and long-term safety of a dengue vaccine in regions of endemic diseases using genetic control technologies. Nat Commun 2021;
disease. N Engl J Med 2015; 373: 1195–206. 12: 4388.
166 Henein S, Swanstrom J, Byers AM, et al. Dissecting antibodies 185 Dobson SL. When more is less: mosquito population suppression
induced by a chimeric yellow fever–dengue, live-attenuated, using sterile, incompatible and genetically modified male
tetravalent dengue vaccine (CYD–TDV) in naive and dengue- mosquitoes. J Med Entomol 2021; 58: 1980–86.
exposed individuals. J Infect Dis 2017; 215: 351–58. 186 Hilgenboecker K, Hammerstein P, Schlattmann P, Telschow A,
167 Lorenzato F, Tricou V, Folschweiller N, et al. Efficacy and safety of Werren JH. How many species are infected with Wolbachia?
Takeda’s tetravalent dengue vaccine candidate (TAK-003) after A statistical analysis of current data. FEMS Microbiol Lett 2008;
4·5 years of follow-up. 7th Panamerican Dengue Research Network 281: 215–20.
Meeting; Nov 13–Nov 16, 2023 (abstr 53). 187 McGraw EA, O’Neill SL. Beyond insecticides: new thinking on an
168 Nogueira ML, Cintra AT, Moreira JA, et al. Efficacy and safety of ancient problem. Nat Rev Microbiol 2013; 11: 181–93.
Butantan–DV live-attenuated tetravalent dengue vaccine from a 188 O’Connor L, Plichart C, Sang AC, Brelsfoard CL, Bossin HC,
phase 3 clinical trial in children, adolescent and adults. American Dobson SL. Open release of male mosquitoes infected with a
Society of Tropical Medicine and Hygiene Meeting; Oct 18–22, 2023 Wolbachia biopesticide: field performance and infection
(abstr 5778). containment. PLoS Negl Trop Dis 2012; 6: e1797.
169 Fongwen N, Wilder-Smith A, Gubler DJ, et al. Target product profile 189 Hoffmann AA, Montgomery BL, Popovici J, et al. Successful
for a dengue pre-vaccination screening test. PLoS Negl Trop Dis establishment of Wolbachia in Aedes populations to suppress
2021; 15: e0009557. dengue transmission. Nature 2011; 476: 454–57.

Seminar
190 O’Neill SL, Ryan PA, Turley AP, et al. Scaled deployment of 200 Huang Y, Moodie Z, Juraska M, et al. Immunobridging efficacy of a
Wolbachia to protect the community from dengue and other Aedes tetravalent dengue vaccine against dengue and against hospitalized
transmitted arboviruses. Gates Open Res 2019; 2: 36. dengue from children/adolescents to adults in highly endemic
191 Utarini A, Indriani C, Ahmad RA, et al. Efficacy of Wolbachia- countries. Trans R Soc Trop Med Hyg 2021; 115: 750–63.
infected mosquito deployments for the control of dengue. 201 Juraska M, Magaret CA, Shao J, et al. Viral genetic diversity and
N Engl J Med 2021; 384: 2177–86. protective efficacy of a tetravalent dengue vaccine in two phase 3
192 World Mosquito Program. Brazil: Fiocruz and the World Mosquito trials. Proc Natl Acad Sci USA 2018; 115: E8378–87.
Program launch new partnership to provide Brazilian cities with 202 Henein S, Adams C, Bonaparte M, et al. Dengue vaccine
access to safe, effective and affordable protection against Dengue, breakthrough infections reveal properties of neutralizing
Chikungunya, and Zika. https://www.worldmosquitoprogram.org/ antibodies linked to protection. J Clin Invest 2021; 131: e147066.
en/news-stories/media-releases/brazil-fiocruz-and-world-mosquito- 203 Clapham HE, Rodriguez-Barraquer I, Azman AS, et al. Dengue
program-launch-new-partnership#:~:text=30%20March%20 virus (DENV) neutralizing antibody kinetics in children after
2023%2C%20Bras%C3%ADlia%20%E2%80%93%20 symptomatic primary and postprimary DENV infection. J Infect Dis
Fiocruz,in%20Rio%20de%20Janeiro%20and (accessed 2016; 213: 1428–35.
Nov 1, 2023). 204 Hladish TJ, Pearson CAB, Toh KB, et al. Designing effective control
193 Reich NG, Shrestha S, King AA, et al. Interactions between of dengue with combined interventions. Proc Natl Acad Sci USA
serotypes of dengue highlight epidemiological impact of cross- 2020; 117: 3319–25.
immunity. J R Soc Interface 2013; 10: 20130414. 205 Rodriguez-Barraquer I, Costa F, Nascimento EJM, et al. Impact of
194 Katzelnick LC, Zambrana JV, Elizondo D, et al. Dengue and Zika preexisting dengue immunity on Zika virus emergence in a
virus infections in children elicit cross-reactive protective and dengue endemic region. Science 2019; 363: 607–10.
enhancing antibodies that persist long term. Sci Transl Med 2021; 206 Carvalho MS, Freitas LP, Cruz OG, Brasil P, Bastos LS. Association
13: eabg9478. of past dengue fever epidemics with the risk of Zika microcephaly
195 Salje H, Alera MT, Chua MN, et al. Evaluation of the extended at the population level in Brazil. Sci Rep 2020; 10: 1752.
efficacy of the Dengvaxia vaccine against symptomatic and 207 Pedroso C, Fischer C, Feldmann M, et al. Cross-Protection of
subclinical dengue infection. Nat Med 2021; 27: 1395–400. dengue virus infection against congenital zika syndrome,
196 Waggoner JJ, Balmaseda A, Gresh L, et al. Homotypic dengue virus northeastern Brazil. Emerg Infect Dis 2019; 25: 1485–93.
reinfections in Nicaraguan children. J Infect Dis 2016; 214: 986–93. 208 Anderson KB, Gibbons RV, Thomas SJ, et al. Preexisting Japanese
197 Chen HL, Lin SR, Liu HF, King CC, Hsieh SC, Wang WK. encephalitis virus neutralizing antibodies and increased
Evolution of dengue virus type 2 during two consecutive outbreaks symptomatic dengue illness in a school-based cohort in Thailand.
with an increase in severity in southern Taiwan in 2001–2002. PLoS Negl Trop Dis 2011; 5: e1311.
Am J Trop Med Hyg 2008; 79: 495–505. 209 Hoke CH, Nisalak A, Sangawhipa N, et al. Protection against
198 Ko HY, Li YT, Chao DY, et al. Inter- and intra-host sequence Japanese encephalitis by inactivated vaccines. N Engl J Med 1988;
diversity reveal the emergence of viral variants during an 319: 608–14.
overwintering epidemic caused by dengue virus serotype 2 in
southern Taiwan. PLoS Negl Trop Dis 2018; 12: e0006827. Copyright © 2024 Elsevier Ltd. All rights reserved.
199 Moodie Z, Juraska M, Huang Y, et al. Neutralizing antibody
correlates analysis of tetravalent dengue vaccine efficacy trials in
Asia and Latin America. J Infect Dis 2018; 217: 742–53.

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100 person-years among children aged 2–16 years.23 The

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pattern during 1995–2020.38 Among travellers to southeast

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Dengue case management

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information about the positive predictive value of early Haematocrit

Dengue management Virus and antibody response levels

plasma infusion, recombinant activated factor VII,

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Dengvaxia (three cases in the placebo group and 11 cases in the

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Dengvaxia (CYD-TDV)163 Qdenga (TAK-003)167 TV003168

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lacking. Mathematical modelling suggests that Acknowledgments

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