S

M
T
384

REVIEW

Dengue Fever and International Travel

Irani Ratnam, FRACP,∗† Karin Leder, FRACP,∗‡ Jim Black, FAFPHM,† and
Joseph Torresi, FRACP§||
∗
The Royal Melbourne Hospital, Victorian Infectious Disease Service, Melbourne, Victoria, Australia; † The Nossal Institute of
Global Health, The University of Melbourne, Melbourne, Victoria, Australia; ‡ Department of Epidemiology and Preventive

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Medicine, Monash University, Melbourne, Victoria, Australia; § Department of Infectious Diseases, Austin Hospital, Melbourne,
Victoria, Australia; || Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia

DOI: 10.1111/jtm.12052

See the Editorial by Annelies Wilder-Smith, pp. 341–343 of this issue.

Background. Dengue is a leading public health problem with an expanding global burden. Dengue virus is also a significant
cause of illness in international travelers with an increasing number of cases of dengue fever identified in travelers returning from
dengue-endemic countries.
Methods. This review focuses on the clinical illness of dengue infection in international travelers and provides a summary of the
risk of infection for travelers, clinical features of infection, and an overview of dengue vaccines and their potential applicability to
travelers.
Results. Four prospective studies of travelers to dengue-endemic destinations have shown that the dengue infection incidence
ranges from 10.2 to 30 per 1,000 person-months. This varies according to travel destination and duration and season of travel.
Dengue is also a common cause of fever in returned travelers, accounting for up to 16% of all febrile illnesses in returned travelers.
Although the majority of infections are asymptomatic, a small proportion of travelers develop dengue hemorrhagic fever. The
diagnosis of dengue in travelers requires a combination of serological testing for IgG and IgM together with either nucleic acid
or NS1 antigen testing. Several vaccine candidates have now entered into clinical trials including ChimeriVax Dengue, which is
currently in phase 3 trials, live-attenuated chimeric vaccines (DENV-DENV Chimera, Inviragen), live-attenuated viral vaccines,
recombinant protein subunit vaccines, and DNA vaccines.
Conclusions. Dengue infection in international travelers is not infrequent and may be associated with substantial morbidity.
Furthermore, an accurate diagnosis of dengue in travelers requires the use of a combination of diagnostic tests. Although a vaccine
is not yet available a number of promising candidates are under clinical evaluation. For now travelers should be provided with
accurate advice regarding preventive measures when visiting dengue-endemic areas.

D engue is the most common arthropod-borne viral

infection in the world and is endemic in over
100 countries throughout Africa, the Americas, Asia,
both of which are widely spread throughout Asia, the
Pacific, and the Americas.
There has been a dramatic increase in the number
Eastern Mediterranean, and Western Pacific. Dengue of dengue cases worldwide with an estimated 30-fold
fever (DF) is transmitted by mosquitoes that remain increase of documented dengue infections in the last
in close proximity to humans and can be caused by 50 years. Regional surveillance data of dengue infections
any of the four dengue virus serotypes (DENV-1, by the Pan American Health Organization (PAHO)
DENV-2, DENV-3, and DENV-4) belonging to the reflects this upward trend in global dengue disease
genus Flavivirus, family Flaviridae. The main vectors burden (Figure 1). The World Health Organization
for dengue viruses are Aedes aegypti and Aedes albopictus, (WHO) estimates that each year over 100 million cases
of DF and 500,000 cases of dengue hemorrhagic fever
(DHF) are reported resulting in 25,000 deaths, although
Corresponding Author: A/Prof Joseph Torresi, FRACP, it is likely that significant underreporting occurs.1,2
Department of Infectious Diseases, Austin Hospital, 145 However, Bhatt and colleagues have recently shown
Studley Road, Heidelberg, Melbourne, Victoria 3084, that each year there are approximately 390 million
Australia. E-mail: [email protected] dengue infections, of which 96 million are clinically

© 2013 International Society of Travel Medicine, 1195-1982

Journal of Travel Medicine 2013; Volume 20 (Issue 6): 384–393
Dengue Fever and International Travel 385

A rates ranging from <1% to 5%.6 The greatest burden

of severe illness occurs in children and infants in
endemic countries.7
In 2009, the WHO revised the case definitions for
DHF and DSS because severe dengue cases that did
not fulfill the criteria were poorly categorized and also
because of reported difficulties with the applicability
of the existing criteria. The new model distinguishes
between dengue and severe dengue and proposes
warning signs for disease progression. Its performance
is currently being tested in over 18 countries (Table 1).8

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Incidence of Dengue in Travelers
Four published prospective studies of travelers to
dengue-endemic destinations have been performed over
B the last decade (Table 2).9 – 12 Among 447 short-term
(mean travel duration of 1 month) Dutch travelers
visiting tropical and sub-tropical destinations, the
incidence rate (number of dengue infections per person-
months of exposure) of DF was 30 per 1,000 person-
months [95% confidence interval (CI) 17.4–51.6]. This
translates to an attack rate (number of dengue infections
divided by the number of travelers that were exposed)
of 2.8%.9 Season of travel, travel duration, and specific
destination were not identified as predictors of infection,
possibly because of an insufficient sample size. Only 3
of 13 travelers reported symptoms suggestive of DF,
translating into a clinical-to-subclinical rate of 1 : 3.3.
A second prospective study examined dengue
incidence among Israelis who had traveled to Asia,
South America, and Africa for 3 to 6 months. Of
104 travelers, 7 (6.7%) had serological evidence of
dengue infection, 4 of whom were symptomatic. The
Figure 1 (A, B) Cases of dengue fever (DF) and dengue dengue incidence in long-term travelers was estimated
hemorrhagic fever (DHF) in the Americas between 2003 at 11 infections per 1,000 person-months. The attack
and 2011. Source: The data depicted in this figure have been rates by region of travel were 1.1% (5/451) for
adapted from the Pan American Health Organization website Southeast Asia, 0.6% for South America (1/159),
(http://new.paho.org/hq/index.php?option=com_content& and 4% (1/25) for Africa. Many travelers had been
view=article&id=264&Itemid=363). vaccinated for Japanese encephalitis or yellow fever
virus, but cross-reactivity with other flaviviruses was
apparent.3 The increased mobility of humans across not explored, so the actual incidence may have been
international borders has contributed to sharp increases overestimated.10
in dengue spread. Additionally, the ease by which A third recent incidence-estimate study was
viremic travelers can introduce dengue into different performed among a cohort of 387 Australian tourists to
regions poses significant challenges for public health Asia. Over two-thirds of participants were short-term
interventions aimed at reducing the global burden of travelers (<30 days of travel). The dengue incidence
dengue. was found to be 10.2 infections per 1,000 person-months
Infection with dengue virus is often asymptomatic (95% CI 2.7–26.1).12 The four travelers with serological
or presents as an acute self-limiting febrile illness.4 evidence of dengue infection were asymptomatic. The
Acute dengue may be associated with additional baseline dengue seroprevalence was 4.4%, possibly
symptoms including rash, headache, retro-orbital pain, related to previous travel to Asia by over 70% of
myalgia, arthralgia, nausea or vomiting, diarrhea, and participants.
hemorrhagic manifestations including petechiae or The final study was performed prospectively among
ecchymoses.5 Most clinical dengue infections are mild short-term Dutch travelers to dengue-endemic areas
to moderate in severity although a small proportion in Asia, Africa, South and Central America, and the
(1%–3%) of patients develop DHF or dengue shock Caribbean. The incidence density of recent dengue
syndrome (DSS) which are associated with case-fatality infection was 14.6 per 1,000 person-months (95% CI

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386 Ratnam et al.

Table 1 WHO criteria for the classification of dengue fever and severe dengue infection

Criteria for dengue ± warning signs Criteria for severe dengue

Probable dengue Warning signs Severe plasma leakage

Live in/travel to dengue-endemic area •Abdominal pain or tenderness Leading to:
Fever and two of the following criteria: •Persistent vomiting •Shock (DSS)
•Nausea, vomiting •Clinical fluid accumulation •Fluid accumulation with respiratory distress
•Rash •Mucosal bleeding Severe bleeding
•Aches and pains •Lethargy, restlessness As evaluated by clinician
•Tourniquet test positive •Liver enlargement >2 cm Severe organ involvement
•Leukopenia •Laboratory: increase in HCT •Liver: AST or ALT ≥ 1,000
•Any warning sign concurrent with rapid decrease in •CNS: Impaired consciousness

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platelet count •Heart and other organs
Adapted from http://www.who.int/tdr/publications/training-guideline-publications/dengue-diagnosis-treatment/en/index.html
DSS = dengue shock syndrome; WHO = World Health Organization; ALT = alanine transaminase; AST = aspartate transaminase; HCT = hematocrit; CNS = central
nervous system.

8.3–23.9), with most infections occurring in travelers in 2% of cases. Febrile travelers who had visited Asia
to Southeast and Southern Asia, especially during the were again significantly more likely to have dengue
rainy season.11 The majority (64%) of infections were infection compared with travelers from other regions.17
asymptomatic. Previous dengue infection was identified In a study of febrile Swedish travelers who visited
in 6.5% and positively correlated with increasing age, malaria-endemic countries between 2005 and 2008, 4%
previous trips to dengue-endemic countries, being were diagnosed with dengue infection.16 A more recent
born in a dengue-endemic country, and traveling for study from Italy (conducted in 2009–2010) identified
the purpose of visiting friends and relatives.11 The dengue as the cause of fever in 16% of febrile returned
incidence estimates of dengue in travelers by region of travelers,15 the higher proportion perhaps indicative
travel as determined by the two most recent studies are of the cyclical increase in dengue activity, development
illustrated in Figure 2. of better diagnostic assays, and/or an increasing
These four studies demonstrate that a significant burden of dengue as a cause of illness in travelers.
risk of dengue infection exists in international travelers Increasing case numbers of travel-associated dengue
to dengue-endemic regions and that the incidence were reported between 2005 and 2010.21,22 However,
ranges from 10.2 to 30 per 1,000 person-months, as the overall number of international travelers visiting
varying according to travel destination and duration. dengue-endemic countries has also increased, this
This risk estimate is notably higher than the incidence increase in dengue cases cannot definitely be ascribed
of other travel-related infections such as hepatitis A and to increasing absolute risk of dengue infection.
typhoid.13

Clinical Severity in Travelers

Dengue Infection as a Cause of Fever in Returned Asymptomatic Infections
Travelers
The determinants of clinical versus subclinical infection
Most cases of dengue infections in febrile travelers are are not clearly defined, but infecting viral strains,
diagnosed in travelers returning from Asia, followed cross-reactive immunity from infection with different
by the Americas then Africa. In a recent large viral serotypes, and preexisting host immunity may
retrospective study of infections in returned travelers, all contribute. The ratio of clinical to subclinical
dengue was either as frequent as or more frequent infection identified in studies of local endemic
than malaria as a cause of febrile illness in travelers populations has ranged from 1 : 0.2 to 1 : 7.23 – 25
returning from all parts of the world except for Seroprevalence studies of travelers who have spent
sub-Saharan Africa.14 variable time periods in dengue-endemic countries have
Retrospective studies have identified dengue demonstrated dengue antibody presence in 8.7% to
infection as the cause of fever in 2% to 16.5% of 19.5% of individuals, many of whom have reported
febrile returned travelers.15 – 19 An Australian study of no consistent clinical illness.26,27 This finding was
fever in returned travelers found that 5% of febrile also observed in the prospective studies of dengue
travelers who visited dengue-endemic regions between infections in travelers where 43% to 100% of dengue
1998 and 2004 had dengue infection, with the odds infections were asymptomatic.9 – 12 Traveler surveillance
of travel to Asia being five times greater among data likely underestimates dengue infections as only
those with dengue.20 A study of French travelers clinical infections are reported.9,11,12 This has major
hospitalized after returning from tropical destinations implications for dengue naive countries with vectors
(1999–2003) identified dengue as the cause of illness able to transmit the disease.

J Travel Med 2013; 20: 384–393

 Table 2 Available prospective studies quantifying incidence estimates of dengue in travelers
Dengue Fever and International Travel

Birth in Median travel

or childhood duration
Study (author/ Study Travelers Median Gender in endemic (days or months, Regions Traveler Symptomatic: Incidence
county) period (n)* age, range (% male) country range) Traveler type visited days Asymptomatic rates

Potasman et al., Published in 104 22.4 ±2.2 years† N/A N/A 6.1 months‡ N/A Asia, the 19,358 4:3 11 per 1,000
Israel 1999 (3–13 months) Americas person-months
Cobelens et al., 1991–1992 447 36 (20–79) 213 (47.6%) 50 (11.2%) 28 (7–84) Tourism: 418 Asia 6,071.8 1 : 3.3 30 per 1,000
The (93.5%). Work: person-months
Netherlands 14 ( 3.1). VFR: (95%CI
15 (3.4%) 17.4–51.6)
Ratnam et al., 2006–2008 387 37 (17–78) 157 (40.6%) 19 (4.6%) 21 (7–326) Tourism: 285 Asia 11,840 0:4 10.2 per 1,000
Australia (73.6%). Work: person-months
68 (17.6%). (95% CI
VFR: 19 (4.9%) 2.7–26.1)
Baaten et al., 2009–2010 1,207 38 (29–51) 521 (43%) 89 (7%) 21 (IQR 16–28) Tourism: 1,032 Asia, Americas, 28,776 1 : 1.8 14.6 per 1,000
The (86%). Work: and Africa person-months
Netherlands 99 (8.2%). VFR: (95% CI
76 (6.2%) 8.3–23.9)
IQR = interquartile range; VFR = visiting friends and relatives; N/A = not available.
*Participants with complete serological/epidemiological data.
†Mean age.
‡Average length of stay.

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387

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388 Ratnam et al.

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Figure 2 Incidence estimates of dengue infections in travelers by region of travel (distribution of countries or areas at risk of
dengue transmission, worldwide, 2008).

Symptomatic Dengue Infection in Travelers In endemic countries, DHF previously occurred

Of the travelers who experience a clinical illness, fever mainly in children. However, an increasing average age
(86%–100%) is the most commonly reported symptom. of DHF among children and more frequent diagnosis
Other common symptoms are myalgia (42.2%–79%), of DHF among adults are now being reported.35 Also a
headache (59.2%–68%), nausea (34%–37%), vomiting relationship between subsequent infection with a differ-
(8%–19%), diarrhea (20.4%–37%), abdominal pain ent serotype and the development of antibody-mediated
(15%), and the development of a rash (29.2%–74%) immune enhancement has been suggested to be associ-
The laboratory features that are typically seen ated with an increased risk of DHF and DSS.36,37 This
are thrombocytopenia (<100,000 μL, 52.6%–72%), may contribute to more severe dengue infection in
leukopenia (80%–89.5%), and elevated liver transami- preexposed travelers.33 Several cases of DHF occurring
nases (ALT, 47%–70%).28 – 30 with both primary and secondary dengue infection
have been reported in travelers.33,38 However, the
development of capillary leakage which has been
Hospitalization of Dengue Infected Travelers
considered to be the hallmark of DHF/DSS has not
The number of dengue-infected travelers requiring been shown to be associated with secondary infection
hospitalization is increasing, with a recent US study or with dengue severity in travelers with dengue.39,40
reporting a tripling of hospitalized cases between 2000 Retrospective and surveillance studies of febrile
and 2007. The increase in both the number of cases returned travelers have described a 0.9% to 3%
in dengue-endemic regions and the number of US prevalence of DHF,30,41 – 44 which mirrors the DHF
travelers to dengue-endemic regions are likely to be prevalence in endemic populations. However, the
contributing factors.31 Several single center studies proportion of DHF in travelers may be overestimated
have reported that dengue infection is among the four as individuals experiencing more severe symptoms are
commonest reasons for hospitalization of ill travelers more likely to seek medical attention.35
returning from Asia, following malaria and undifferen-
tiated febrile illness, accounting for 13% of all post- Mortality in Travelers
travel hospitalizations.18,32 In contrast, travelers from Whilst dengue infection rarely leads to a fatal outcome
Africa were most commonly hospitalized with malaria.32 in travelers, several have been reported in the literature.
Overall, up to 25% of returned travelers require hos- Primary dengue infections have been identified in
pitalization and of these average length of the hospital some of these fatal cases and causes of death have
stay was up to 5 days, with a range of 1 to 11 days.30,33 been attributed to intra-cranial hemorrhages, other
hemorrhagic events, and fulminant hepatic failure.45 – 48
Dengue Hemorrhagic Fever in Travelers
DHF has been described infrequently in travelers and Autochthonous Transmission of Dengue
no prospective studies have reported its travel-associated
incidence.28,34,35 Heterogeneous risk factors for DHF Recent reports of autochthonous transmission of
have been reported but overall a lack of a consensus per- dengue infection in Madeira (Portugal), metropolitan
sists about what places travelers at risk of DHF or DSS.2 and coastal France, Florida, and Croatia highlight

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Dengue Fever and International Travel 389

the propensity for its establishment in disease-naive diagnosis. NS1 antigen testing is more sensitive when
countries that house A albopictus.49 – 52 Immediate steps used in the first 3 days after fever onset, in patients
that were taken to reduce the spread of the virus with primary infection, high-level viremia, DENV-1
and the risk of an epidemic in metropolitan France infection, and in patients with DF compared with DHF
included targeted vector control measures, active case and DSS.62,64,66 The kinetics of the clearance of viremia
finding, and enhanced dengue virus education of health and NS1 antigenemia from serum is different in primary
professionals. In response to these cases and the versus secondary infection, across dengue serotypes, and
likelihood that concomitant increases in vector density with disease severity.67 Both in endemic populations
favors secondary transmission of imported dengue and in travelers, combining NS1 antigen or PCR with
viruses, a surveillance program for dengue infections IgM/IgG testing can increase the diagnostic yield in
in travelers from dengue-endemic areas was initiated in acute dengue infection (85%–99%).61,66,68 In one study
2010 in France.50,51 looking at the performance of NS1 antigen in travelers,

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Other measures such as airport screening of febrile the sensitivity of NS1 antigen detection was highest
travelers in Taiwan did not demonstrate any preventive on days 6–7 after the onset of the illness which is
benefit.53 Avoidance of mosquito bites whilst in the different to NS1 antigen detection studies of endemic
febrile period, which occurs inadvertently as cases are populations where the sensitivity is reported as highest
often hospitalized in the febrile period, is another around day 3 after fever onset.68,69
measure to reduce transmission in areas where the Distinguishing between primary and secondary
vectors are present. In Northern Queensland, Australia, dengue infection via serology is difficult, but may be
dengue is not endemic but this region experiences possible by determining the ratio of IgM to IgG. An
annual epidemics originating from imported dengue IgM : IgG ratio of ≥1.78 on day 6 of illness is considered
by viremic travelers. In 2009, four separate outbreaks of to be consistent with primary infection while a ratio
DF occurred, with dengue importations from Southeast of <1.2 indicates secondary infection.57,70 IgG avidity
Asia (57% of cases) from the South Pacific islands of tests in nonvaccinated (flavivirus) individuals can also
Samoa, Vanuatu, Fiji, Cook Islands, and Tonga (32%).54 be used to determine primary versus secondary dengue
infections.71 – 73

Diagnosis of Dengue Dengue Vaccines

Dengue diagnosis relies on serological assays, molecular Development of a dengue vaccine has been hampered by
diagnostics, and antigen detection. Serology using the complex virology of dengue viruses and the essential
hemagglutination-inhibition, immunofluorescence requirement of producing a balanced immunological
antibody assays, and enzyme-linked immunosorbent response against four serotypes. With live-attenuated
assay (ELISA) tests is widely used55 but is limited by viral (LAVs) vaccines, interference between dengue
variable sensitivity and specificity due to cross-reactivity viruses has presented significant problems in developing
to other flavivirus infections and flavivirus vaccines.56 an effective quadrivalent vaccine. Over-attenuation
In acute dengue infection, serum IgM becomes positive of viruses is also problematic and results in poor
within 4 to 5 days and is followed by development of immunogenicity. Balancing adequate viral attenuation
IgG after day 7 of the illness. However, the sensitivity to avoid pathogenicity while ensuring retention of
of commercially available ELISAs for diagnoses of immunogenicity and production of long-term immune
acute dengue varies from 60% to 90% and specificity responses has proven difficult.
from 80% to 99%.55 Several vaccine candidates have now entered into
Dengue specific tests include RNA detection clinical trials,74 – 80 including ChimeriVax Dengue
methods and nonstructural (NS1) antigen assays. (Sanofi Pasteur, Lyon, France),74,81 live-attenuated
Polymerase chain reaction (PCR) assays enable the chimeric vaccines (DENV-DENV Chimera, Inviragen,
early identification of dengue RNA during the viremic Fort Collins, CO, USA), LAV vaccines (US National
phase (usually in the first 5 days after onset of Institutes of Health, NIH, Bethesda, MD, USA),
illness).57 – 60 PCRs have many advantages such as recombinant protein subunit vaccines (Hawaii Biotech,
rapidity, serotype specificity (including detection of Inc., Aiea, HI, USA), and DNA vaccines (US Naval
concurrent infections by different serotypes), ability Medical Research Center, Silver Spring, MD, USA).
for quantitative measurements, and high sensitivity The ChimeriVax TDV vaccine is based on four
(92%–98.5%) and specificity (92.4%–100%).57 – 60 recombinant viruses containing the prM and E genes
More recently, NS1 antigen detection has become from each dengue serotype, which have been introduced
widely available. NS1 antigen detection is highly into the yellow fever virus 17D vaccine backbone.82
specific for acute dengue (95%–100%) but has variable This vaccine is most advanced in clinical development
sensitivity (65%–85%).61 – 65 The high specificity of the and is highly immunogenic,83,84 able to induce broad
NS1 antigen means that a negative result does not neutralizing antibodies against dengue 1 to 4,85 and has
exclude the diagnosis of dengue; however, a positive been found safe and immunogenic in phase 1 and 2
test means a very high likelihood of confirming the clinical trials. Administration of three doses of vaccine

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390 Ratnam et al.

at 0, 6, and 12 months induces production of high titer Vaccine Prospects for International Travelers
neutralizing antibodies against all four dengue serotypes
in 77% to 100% of vaccine recipients.74,81,83,86 The introduction of dengue vaccines into national
The results of a phase 2b efficacy study have immunization programs of dengue-endemic countries
recently been reported. The trial, conducted in northern with high disease burden takes precedence over a travel
Thailand and enrolling 4,002 individuals, demonstrated vaccine.91 However, the high incidence of dengue in
an overall efficacy of 30.2%. The efficacy against travelers visiting endemic countries coupled with the
DENV1, 3, and 4, was 61.2, 81.9, and 90.0%, role that travelers play in the global spread of dengue
respectively, while for DENV2 the efficacy was only argues a place for vaccine availability for travelers in
3.5%, in spite of vaccine recipients developing high titer the future. When this becomes available, it will be
neutralizing antibodies against all serotypes.80 Reasons important to determine which traveler groups are at
for the failure of the DENV2 component are unclear, greatest risk of dengue infection in order to prioritize

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but the hospitalization rate was nevertheless reduced by vaccine recipients. From the studies presented in this
45% in vaccine recipients compared with unvaccinated review it is reasonable to suggest that travelers visiting
controls.80 The vaccine is currently in phase III trials Southeast Asia during the rainy season or those who
in Asia and Brazil to further evaluate the efficacy of travel frequently to dengue-endemic regions could be
ChimeriVax TDV. These trials have recently completed most strongly considered for vaccination.41 Travelers
recruitments and the results will be available in the near visiting destinations with epidemic dengue activity may
future. also be appropriate for targeted vaccination. Individuals
A number of LAV vaccines have also entered with a prior dengue diagnosis may also be vaccine
clinical trials.75,76 The National Institute of Allergy and candidates as this may help reduce the likelihood of a
Infectious Disease (NIAID)/Laboratory of Infectious secondary and possibly more severe dengue infection.
Diseases (LID) has developed a LAV tetravalent vaccine Dengue vaccination of travelers poses some significant
comprised of recombinant dengue viruses containing challenges. The vaccine most likely to first become
deletions in the 3 noncoding region of the virus that commercially available is ChimeriVax DEN (Sanofi
reduces the ability of the virus to replicate.75,87,88 This Pasteur). The three-dose schedule over a 12-month
vaccine has entered into phase 1 clinical trials and has period required for ChimeriVax DEN vaccine means
been shown to be safe and able to induce production of that many travelers will be unable to achieve full
high titers of neutralizing antibodies. In addition, the vaccination prior to departure. The long-term safety of
LAV vaccine may result in balanced immune responses travelers who receive only one or two pre-travel doses
against all four serotypes.88,89 The NIAID/LID vaccine is unknown. Although the possibility of severe dengue
has been licensed to a number of developers including infection exists,92 the recently reported efficacy trial in
Instituto Butantan in Brazil, Biological E and Panacea Thailand failed to demonstrate more severe infection
Biotec in India, and VaBiotech in Vietnam for further in partially immunized vaccine recipients.80 Vaccines
development and for progression to clinical trials to requiring fewer doses or with a shorter dosing schedules
determine vaccine efficacy. Inviragen has also developed would be more suitable for travelers. However, other
a chimeric tetravalent LAV vaccine based on DENV2 vaccine candidates have not yet entered phase 3 safety,
and consisting of viruses containing envelope proteins immunogenicity, or efficacy studies and consequently
of all four serotypes. This vaccine appears immunogenic will not be commercially available for several years.
and has entered into phase II trials. Sustained immunity in travelers and evidence of long-
An alternative approach to chimeric and LAV term efficacy of the vaccine with only one or two doses
vaccines are subunit protein vaccines76,77,90 which would be ideal features of a dengue vaccine. As with
avoid the problems of viral interference and use of all vaccines, the risk of infection versus the potential
replicating virus associated with LAV vaccines. This negative consequences of vaccination will need to be
approach may be safer and result in induction of considered for each individual traveler.
balanced immune responses against all four serotypes.
Merck & Co in conjunction with Hawaii Biotech, Conclusions
Inc. have developed a recombinant subunit protein
vaccine containing recombinant C-terminally truncated In conclusion, dengue infection in international
recombinant envelope glycoproteins (DEN-80E) of travelers occurs frequently and may be associated
the four dengue viruses. This vaccine appeared safe with substantial morbidity. Although there have been
and immunogenic in a phase 1 clinical trial77 and is relatively few prospective studies these have confirmed
undergoing further clinical development. that the incidence rate for dengue infection in
A DNA vaccine (D1ME-VR-P) has also been short-term travelers to dengue-endemic countries is
developed by the US Naval Medical Research substantial. An accurate diagnosis of dengue in travelers
Center76,78,90 and has been tested in a phase 1 clinical is best done using more than one diagnostic test,
study. It appears safe and moderately immunogenic and like any infection in endemic countries requires
with 40% of vaccine recipients developing neutralizing a combination of serological testing for IgG and IgM
antibody and 83% developing T-cell responses.78 together with either nucleic acid testing or NS1 antigen

J Travel Med 2013; 20: 384–393

Dengue Fever and International Travel 391

testing. A safe and effective vaccine providing effective 16. Ansart S, Perez L, Vergely O, et al. Illnesses in travelers
protection against all four serotypes of DENV is not yet returning from the tropics: a prospective study of 622
available, although a number of promising candidates patients. J Travel Med 2005; 12:312–318.
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returning from tropical areas: prospective observational
available, travelers should be provided with accurate
study of 613 cases hospitalised in Marseilles, France,
advice regarding preventive measures when visiting 1999–2003. Travel Med Infect Dis 2006; 4:61–70.
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19. Fenner L, Weber R, Steffen R, Schlagenhauf P. Imported
Declaration of Interests infectious disease and purpose of travel, Switzerland.
Emerg Infect Dis 2007; 13:217–222.

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to declare. travelers and immigrants/refugees: the 6-year experience
of two Australian infectious diseases units. J Travel Med
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