J Vector Borne Dis 53, December 2016, pp.

293–304

Review Articles

The epidemiology of dengue infection: Harnessing past experience and

current knowledge to support implementation of future control strategies

Narayan Gyawali, Richard S. Bradbury & Andrew W. Taylor-Robinson

Central Queensland University, Rockhampton, Australia

ABSTRACT

Dengue is the most important mosquito-borne viral infection of humans. Although outbreaks of disease which are
now recognized as clinically consistent with dengue have been reported for centuries, it was not until half a
century ago that laboratory identification of dengue viruses as the etiological agent of febrile illness was achieved.
This debilitating and sometimes fatal disease is widely distributed in >125 countries in tropical and subtropical
zones of the world. Asia, South America and the Pacific Islands are hyper-epidemic regions while currently there
is less prevalence in Europe, North America and Australia. The estimated global incidence ranges between 200
and 400 million clinical cases per year. While some areas of past epidemics are now considered to be under
control, recent decades have witnessed an epidemic rise in dengue worldwide. Major factors facilitating expansion
include climate change and increase in urbanization and international travel. Concurrently, the non-availability of
an efficacious antiviral drug or vaccine and a lack of effective vector control strategies collectively make dengue
a serious public health concern. Thus, it is of paramount importance to analyze the history of the spread of
infection and to gain a deeper understanding of patterns of transmission in order to anticipate epidemiological
trends more accurately, thereby enabling better preparedness for future outbreaks.
Key words Aedes; control; dengue; epidemiology; transmission

INTRODUCTION vere plasma leakage, severe bleeding, or organ failure)4.

Prior to this revision, infection was widely classified as
Dengue is a mosquito-transmitted viral disease. More dengue fever (DF), dengue haemorrhagic fever (DHF) or
than 2.5 billion people in the tropics and subtropics are at dengue shock syndrome (DSS)5. The unavailability of ef-
risk of infection1 and an estimated 390 million dengue fective antiviral drugs and licensed vaccines until now,
infections occur annually in around 125 countries world-
wide2 (Fig. 1). In the last 50 yr the incidence of dengue has
increased almost 30 fold (Fig. 2). The etiological agent of
disease is dengue virus (DENV), a member of the family
Flaviviridae. Although, a large number of potential vec-
tors have been identified, Aedes aegypti and Ae. albopictus
are responsible for the majority of dengue transmission.
These mosquito species are distributed throughout tropi-
cal regions of Asia, Africa, Australia, South Pacific, the
Americas and some parts of the Middle East3. The World
Health Organization (WHO) and Special Programme for
Research and Training in Tropical Diseases (TDR) have
recently revised the guidelines for dengue case classifica-
tion. It categorizes clinical infection as either: Mild self-
limiting illness; dengue with a wide range of warning signs
(abdominal pain, persistent vomiting, fluid accumulation,
mucosal bleeding, lethargy and increasing haematocrit with Fig. 1: Global distribution of dengue (World Health Organization
decreasing platelets); or severe dengue (dengue with se- 2014).
294 J Vector Borne Dis 53, December 2016
Fig. 2: Number of dengue cases reported to the World Health
Organization [With minor modification; Source: Disease
Surveillance and Epidemiology, WHO Southeast Asia Regional
Office (SEARO)].
despite decades of intensive research, makes dengue a
major global public health priority. This review provides a
detailed history of dengue, highlights the current epide-
miological situation, and predicts future trends in trans-
mission of infection and measures for its control.
Dengue viruses
Dengue is one of the major human pathogens of the
family Flaviviridae, which also includes viruses that cause
yellow fever, Japanese encephalitis and West Nile en-
cephalitis. Four serotypes (DENV-1 to 4) have been
known for years. Recently, a mooted fifth serotype has
been reported6, although its recognition remains to be rati-
fied. This was discovered during screening of virus
samples which were collected during an outbreak that
occurred in Malaysia in 20076. The established four den-
gue viruses are similar, showing around 65% genome
homology7, while the ostensible fifth serotype appears
phylogenetically distinct6.
DENV is single-stranded positive sense RNA virus
of approximately 50 nm in diam8. Structurally, its ge-
nome is surrounded by a capsid (C) and again by an outer
glycoprotein shell and inner lipid bilayer. The similar na-
ture of the lipid layer to the host cell membrane suggests
that it is derived from the later. Surface projections in the
lipid membrane consist of envelope (E) and membrane
(prM/M) glycoproteins. The genome is about 11 kb in
size and encodes three structural genes (C, prM and E)
and seven non-structural (NS) genes (NS1, NS2A, NS2B,
NS3, NS4A, NS4B and NS5). The proteins coded by the
NS genes play roles in viral replication and assembly8.
Dengue history: Past and present
Dengue is a historically important disease which has
been known for centuries. Symptoms recorded in a Chi-
nese medical encyclopaedia in 992 AD are compatible
with recognised clinical manifestations of dengue9. This
may be the first documented information relating to den-
gue. Several archived manuscripts reported Africa to be
the origin of DENV, which as late as the 18th century
was distributed to many parts of the world, due in large
part to the transatlantic and African-Middle East-Asian
slave trade10-12. The principal vector, Ae. aegypti, is also
thought to have arisen in Africa13. However, its origin
has been debated to be from either Africa or Asia14–15. A
strong rationale to suggest the evolution of the virus in
Asia from a progenitor of African origin is the mainte-
nance of all the serotypes in enzootic forest cycles in Af-
rica16. Moreover, it is believed that the DENV may have
originated from a forest cycle involving lower primates
and canopy-dwelling mosquitoes in the Malay Penin-
sula17. Later, humans and/or monkeys exposed to viruses
in the forest acted as carriers for its introduction to vil-
lage settings where further propagation took place through
transmission by peri-domestic Anopheles mosquitoes.
Finally, villagers introduced the infection to urban areas18.
There are still multiple opinions relating to the origin of
DENV in humans, discussion of all of which is beyond
the scope of this review.
It is possible that different DENV serotypes evolved
in taxonomically related mosquito species in different
geographical regions. The first four recognised DENV
serotypes have been documented to exist in a forest cycle
in Asia, while only one (DENV-2) has been reported in
Africa19, suggesting that DENV probably had an Asian
origin. Moreover, serological surveys conducted in rural
communities of Malaysia in the early 1950s also support
the concept of Asian origin12. Regardless, by the start of
the 19th century, dengue was globally widespread in tropi-
cal coastal zones as a consequence of the inadvertent trans-
portation of both infectious mosquitoes and humans in
shipping vessels to ports around the world15, 20. Later, the
incidence of dengue flared during World War II when
troops deployed within and between countries were con-
voyed by sea 14. Although, dengue emerged as a
major public health concern only in the second half
of the 20th century in many tropical and sub-tropical
regions of the world, its evolutionary history shows
that the time to the most recent common ancestor of all of
the dengue serotypes and the time of the split of
the DENV-4 lineage were during or prior to the 4th
century AD21.
 Gyawali et al: Epidemiology of dengue infection
Global distribution
Dengue in Asia: Disruption of ecosystems, in-
creased troop movement and rapid urbanization after
World War II facilitated the spread of DENV in Asia.
Discarded water storage containers for domestic purposes,
surplus war equipment and other mechanised debris all
served as ideal breeding habitats for Ae. aegypti. By 1945,
Cambodia, Philippines, Thailand and Vietnam; countries
that were already endemic for dengue, became hyperen-
demic22. Isolation of all serotypes in the 1940s and 1950s
in these areas led to an assumption of their earlier exist-
ence16, 23. DHF emerged in Manila, Philippines, in 195424,
then in Thailand in 1958 and in Malaysia, Cambodia,
Singapore and Vietnam in the 1960s20. In India, the first
virologically proven epidemic occurred in Kolkata and
the East Coast in 1963–64. By 1988, DHF was starting to
simmer in various parts of India25–26. Cases of DHF were
also reported in Karachi, Pakistan, in 199427. It has been
estimated that Asia bears 70% of the global dengue bur-
den, a figure to which India alone is calculated to con-
tribute 34%2. As India is the largest trading hub in South
Asia, it is likely to be the major disseminating source of
infection for neighbouring countries like Bangladesh,
Bhutan, Maldives, Nepal, and Pakistan. In Bangladesh,
DF was documented from the mid-1960s to the mid-
1990s, but an outbreak of DHF was reported in 200028.
Bhutan29 and Nepal30 reported epidemics only as recently
as 2004.
Approximately, two thirds of the global population
that is exposed to dengue resides in the Asia-Pacific re-
gion31. Of these, around 1.3 billion people live in ten den-
gue-endemic countries of Southeast Asia where dengue
is one of the most common causes of hospitalisation and
fatalities in children32. The rate of severe dengue in the
region is 18 times higher than that in the Americas1, 33. A
total of 1,87,333 dengue cases from the region were re-
ported to WHO in 201034. According to WHO, dengue-
risk territories are Bangladesh, Bhutan, Brunei, Cambo-
dia, Hong Kong, India, Indonesia, Laos, Macau, Malaysia,
Myanmar, Nepal, Pakistan, Philippines, Singapore, Sri
Lanka, Taiwan, Thailand, and Vietnam1. It is apparent
that 11 countries in the WHO Southeast Asia region
(Bangladesh, Bhutan, India, Indonesia, Maldives,
Myanmar, Nepal, North Korea, Sri Lanka, Thailand and
East Timor) have become hyper-endemic, with regular
reporting of dengue cases since 2000 with the exception
of North Korea. The highest ever combined totals of clini-
cal cases (3,55,525) and deaths (1982) were recorded in
201032.
Several countries in Southeast Asia have recently re-
ported large increase in dengue fever cases for October
295
2015, when compared to the same time in 201435. Nota-
bly, increases in cases were seen in Malaysia (19.4% in-
crease), the Philippines (31.9%) and Vietnam (21.1%)
when compared to the same time in 2014. A decreasing
number of cases were reported for China and Cambo-
dia35. Using mathematical modelling, Cummings et al36.
predicted that DENV in Thailand spreads at an average
speed of 148 km per month, and suggested that similar
rates of range increase may be expected elsewhere. De-
spite a major outbreak in western Japan between 1942
and 1945, it was thought that Japan was subsequently a
dengue risk-free country. However, according to the na-
tional case-based surveillance system of Japan, the re-
ported DENV incidence was 200 in 2010, four times
greater than that in 2006. While these cases were, in fact,
associated with travelers, the combined effect of the per-
sistence of Ae. albopictus and globalization has always
posed a threat of possible outbreaks in Japan37.
Dengue in Australia: Dengue appeared in Australia
in 1873 with the importation of eight cases from Mauritius.
Subsequent outbreaks occurred in what is now
Queensland, in Townsville (1879) and Rockhampton
(1885). The first death caused by dengue was recorded in
Charters Towers in 1885. Since then there have been at
least 13 major dengue outbreaks in Queensland38. Den-
gue reached Brisbane in 1905. Cases were also reported
in northern New South Wales (1898) and Western
Australia (1909–10). In 1925-26, the epidemic extended
as far south as Newcastle, New South Wales. No cases
have been reported in Western Australia since the 1940s.
The last epidemic in the Northern Territory (Darwin)
occurred in 195539–41.
The widely distributed vector of dengue in Australia
is Ae. aegypti, which may have been introduced inadvert-
ently in the early or mid-19th century with the settlement
of the tropics and subtropics39. By the end of the 19th
century, this mosquito dispersed extensively in northeast
coastal areas. Later, due to the successful implementa-
tion of vector control interventions, the Ae. aegypti popu-
lation as well as the disease it transmits declined from
northern New South Wales and Western Australia. In con-
trast, Darwin in the Northern Territory and Cairns and
Townsville in the tropical north of Queensland have al-
ways remained at risk of dengue outbreak39. A multi-
sectoral approach has led to the progressive decline of
Ae. aegypti from Australia. This strategy includes the
conversion of urban water supplies from household rain-
water tanks to a reticulated supply, the change from steam
to diesel locomotives, the use of domestic insecticides,
the advent of the motor mower, and greater awareness by
local environmental health officers promoting improved
296 J Vector Borne Dis 53, December 2016
education of the general public 39, 42. Although Ae.
albopictus is not the principal vector of dengue in Aus-
tralia, it is widespread in the northern Torres Strait Is-
lands. This mosquito is thought to have been
introduced into the Australasian region by widespread il-
legal fishing activity originating from Indonesia43.
Following a quarter of a century without incidence,
dengue re-emerged in northern Queensland in 1981–82.
Unlike a previous epidemic in the same region and in
neighbouring Northern Territory in 1955, which
was caused by DENV-344, this outbreak was due to
DENV-145–46. Cairns, Townsville and Thursday Island
were affected by this epidemic. Further to this, DENV-1
and -2 cases were reported sporadically during 1990–9339.
In the most recent Queensland epidemic of 1993, 238 se-
rologically positive cases of DF and one case of DHF
were identified while outbreaks of DENV-2 centred on
Townsville and in Charters Towers with 1,850 clinically
suspected and laboratory confirmed cases were reported
among around 2,00,000 inhabitants of these regional
towns47–49.
Dengue is a major cause of illness for overseas trav-
ellers returning to Australia. The majority of cases iden-
tified in Australia were related to a travel history to Indo-
nesia (Bali), Thailand, East Timor and Papua New
Guinea50. The main concern arising from such imported
cases is the infected person potentially providing a focus
for local transmission. The number of overseas-acquired
cases of dengue, almost 10 times higher than
locally acquired, continues to increase each year: 350 in
2007–08; 593 in 2009–10; 1133 in 2010–11; 1390 in
2011–1250–51.
A 14-yr retrospective study (1999–2012) showed that
over half of all cases with a known country of acquisition
originated in Indonesia52. For Western Australia, in 2010–
11, >80% of cases from Indonesia were acquired in the
popular holiday destination of Bali, a trend which contin-
ued in 201253. During 2000–11 the relative risk of travel-
lers returning to Australia with dengue from Indonesia
compared to all other destinations was 8.352.
Dengue in the Pacific Islands: Dengue epidemics
were first reported in the Pacific Islands during the sec-
ond half of the 19th century54. There has been a recent
increase in dengue cases in many Pacific Islands includ-
ing the Cook Islands, French Polynesia, Fiji, New
Caledonia, Samoa, Tonga and Vanuatu54. With reference
to current data (April 2015), there is an ongoing DENV-
2 outbreak in Macuata Province, Fiji. In French Polynesia
and Tonga, incidences of DENV-1 and DENV-3 have
been notified, respectively55.
There were frequent outbreaks reported from French
Polynesia and Tahiti in 1996–756, and from French
Polynesia and the Solomon Islands in 201357. Unlike for
inhabitants of Southeast Asian countries, it is rare for more
than one serotype to circulate in Pacific Islanders. How-
ever, to date, all four established serotypes have been iden-
tified within the population. The pattern of single sero-
type circulation was DENV-3 (1989–96), DENV-2
(1996–2000), DENV-1 (2001–09), and DENV-4
(2008–09)56. The main reason for outbreaks of dengue in
these geographically isolated islands is international and
inter-island travel56. Post World War II was the most
prevalent period for occurrence of dengue in countries of
this region.
Dengue in Africa: As far back as the 19th and early
20th centuries, dengue was recorded in a number of geo-
graphically widespread African countries: Zanzibar (1823,
1870); Egypt (1887, 1927); Burkina Faso (1925); South
Africa (1926–27); and Senegal (1927–28). These dengue
cases were confirmed by neutralizing antibody tests per-
formed in the mid 1950s58–59. Since 1960, 20 laboratory-
confirmed outbreaks of dengue have been reported in 15
African nations, with most occurring in East Africa.
Nearly 300,000 cases were reported in the five largest
epidemics in the Seychelles (1977–7900), Réunion Is-
land (1977–78), Djibouti (1992–93), Comoros (1992–93)
and Cape Verde (2009)59–60. Five countries in North Af-
rica (Algeria, Libya, Morocco, Tunisia and Western Sa-
hara), from which the vectors have yet to be clearly iden-
tified, are considered to be at low risk for dengue61.
The first laboratory isolated dengue virus in Africa
was from Nigeria in 196462. All four established DENV
serotypes have been isolated, with DENV-2 reported to
cause most epidemics61. These serotypes are maintained
in enzootic cycles, most likely between non-human pri-
mates and arboreal mosquitoes8, 63. Outbreaks in Pemba,
Mozambique during 1984–85 were due to DENV-3. This
was also detected in Somalia and the area around the Per-
sian Gulf in 1993. Although occurring infrequently,
DENV-4 was isolated from Senegal in the 1980s. Other
than Ae. aegypti and Ae. albopictus, common vectors in
Africa are Ae. africanus and Ae. luteocephalus61. There
are 34 countries across all regions of Africa that are en-
demic for dengue. The remaining 12 nations have identi-
fied dengue cases among travelers returned from endemic
zones64. In the last few years, infection with DENV-3
has been reported in travellers returning to Europe from
several West African countries (Benin, Burkina Faso,
Ivory Coast, Mali, and Senegal)65.
Although, the enzootic forms of DENV may be be-
coming less infective in Africa, there is still a potential
for endemic forms of the virus to emerge from sylvatic
 Gyawali et al: Epidemiology of dengue infection
cycles between mosquitoes and non-human primates63.
It is acknowledged that poor diagnostic facilities may have
prevented the exact prevalence of dengue in African coun-
tries from being revealed.
Dengue in Europe: Europe is a continent with rela-
tively less or no prevalence for dengue infection. In gen-
eral, cases reported in Europe are usually associated with
return travel from another region. According to
the European Centre for Disease Prevention and Control
(ECDC), Europe has not experienced sustained transmis-
sion of DF since outbreaks in Athens in the late 1920s66,
with the exception of a large outbreak of DENV-1 infec-
tion in 2012 which occurred on the Portuguese autono-
mous region of the Madeira Islands in the Atlantic Ocean,
to the east of Morocco, from October 2012 to March 2013,
resulting in over 2100 cases67. This outbreak resulted in
78 active dengue fever cases being introduced into 13
other European countries via travelers departing Ma-
deira67. A total of 42 cases imported from this Madeira
outbreak were reported in the UK and Germany alone68.
Due to recent changes in climate and temperatures, the
environment across Europe has become increasingly
favourable for mosquito breeding; hence, the distribution
of Ae. aegypti has increased. This provides the potential
for future dengue outbreaks in Europe. Although, Ae.
aegypti is the predominant vector, Ae. albopictus has also
become established in Europe. Several domestic inci-
dences of dengue due to Ae. albopictus transmission have
been noted in France and Croatia69–70. The occurrence of
this mosquito was reported initially in Albania in 1979,
then in Italy in 199071. At present, this mosquito is estab-
lished in southeastern France (including Corsica), the
eastern coast of Spain, most of Italy (including Sardinia
and Sicily), southern Switzerland, Slovenia, Malta, San
Marino, Vatican City, Croatia, Bosnia and Herzegovina,
Montenegro and Albania. Serbia, the western coast of
Greece, southeastern Bulgaria and western Turkey71–72.
It has also been detected, in imported used tyres in
Belgium and the Netherlands and in green houses in the
Netherlands71, 72.
Dengue in North America: Dengue is an emerging
infection in North America. Travel-associated dengue
infections have been reported in each of the 48 contigu-
ous states of USA73. Since, the vector Ae. aegypti is abun-
dant all year around in Puerto Rico, the US Virgin Is-
lands, American Samoa and Guam, these territories are
endemic for DENV. This has presented a particular chal-
lenge in Puerto Rico, where outbreaks have been recorded
for one hundred years74, and for which since the late 1960s
large island-wide epidemics have been documented75. The
virus, DENV-3 serotype, was first isolated from Puerto
297
Rico during a large outbreak in 1963–6475. The first case
of DHF was documented in 1975, with notifications more
frequent after 198676. Prior to this time, dengue trans-
mission had been significantly interrupted during the
1960s and early 1970s following an Ae. aegypti eradica-
tion campaign in the Americas. However, re-infestation
of mosquitoes and periodic outbreaks of dengue occurred
in the Caribbean, Mexico and Central America because
of poor vector surveillance and control measures77. By
2005, locally acquired outbreaks had been described in
Hawaii, US Virgin Islands, along the Texas-Mexico bor-
der78, and in the western part of Florida 79.
Dengue in South and Central America: Reports of
dengue have come from most countries in South and Cen-
tral America. Argentina, Brazil, Colombia, Dominican
Republic, El Salvador, Guatemala, French Guyana,
Mexico, Peru, Puerto Rico and Venezuela are nations in
which infections of all four established DENV serotypes
have been recorded80–81. Chile and Uruguay are the only
countries in Latin America without indigenous transmis-
sion of any serotype80, 82. There was partial interruption
of dengue during the 1960s and early 1970s as a conse-
quence of the Ae. aegypti mosquito eradication campaign
designed to prevent yellow fever83. However, poor vec-
tor surveillance and control measures enabled mosquito
re-infestations and hence reintroduction of dengue, nota-
bly DENV-2, in these regions. In the late-70s and early-
80s, DENV-1 and DENV-4 were introduced into some
Latin American and Caribbean countries, causing devas-
tating epidemics84. Since then, the region has reported
the highest incidence of cases globally (68% of all notifi-
cations worldwide during 2000-06), with periodic out-
breaks every 3–5 yr. The first large epidemic of DHF in
the region occurred in Cuba in 1981, with 24,000 cases
of DHF, 10,000 cases of DSS and 158 deaths reported
during a three month period80, 83–84. In 1986–87, massive
dengue outbreaks were reported in Brazil85. In 1990,
nearly a quarter of the 3,00,000 inhabitants of Iquitos,
Peru, acquired DF, and in the same year, 3108 cases of
DHF with 78 deaths were reported in Venezuela. To date,
the largest epidemic occurred in 2002, with <1 million
reported cases80, 86–87. From 2000-07 the average annual
number of case reports was 71.5 per 100,000 people, an
increase on the period from 1990–99. The average inci-
dence rate of DHF was 1.7 per 1,00,000 during 2000–07,
with a total of 1391 dengue-related deaths80. Over the
last decade the Southern Cone countries (Argentina, Bra-
zil, Chile, Paraguay and Uruguay) have reported the ma-
jority of dengue incidence. During 2001–07, 64.6%
(2,798,601) of all dengue cases (DEN-1, -2 and -3) in the
Americas were reported from this region, of which 6733
298 J Vector Borne Dis 53, December 2016
were DHF with a total of 500 deaths86. Brazil accounted
for the vast majority (98.5%) of these fatalities.
Future perspectives
There is considerable evidence to support the pro-
posal that public health problems relating to dengue are
set to become increasingly severe15, 88–89. Vaccination and
vector control treatment are the major strategies for com-
bating dengue although at present there are no effective
strategies. Vaccines are still in clinical trial, and to date
there are no effective antiviral drugs. Therefore, a magni-
fied focus should be directed towards disease prevention
and mosquito control. Despite the launch of many aware-
ness programmes, various challenges remain to be handled
effectively. Rapid urbanization, lack of basic sanitation,
and increased intra- and inter-migratory activities have
compounded the problem in most regions. In this con-
text, it is also worth considering potential factors that drive
dengue activity, such as virus evolutionary changes (vi-
ral genotype switching), climate diversity, industrializa-
tion, urbanization and the trade cycle, and the potential
for spread from urban to rural foci.
Viral genotype switching
On the basis of the nature of transmission and sever-
ity of clinical infection in humans, DENV serotypes have
been categorized as making a low, medium or high epi-
demiological impact90. Viruses that are maintained within
sylvatic cycles and among non-human primate popula-
tions are rarely transmitted to humans, while other geno-
types cause mild to severe disease in humans. For DENV-
2 and DENV-3, genotypes found more commonly in the
Americas are comparatively less virulent than Asian geno-
types. By analysis of modifications to the virus envelope
protein postulated to correlate with endemic and/or epi-
demic emergence, it was shown that domain III of the E
protein may play a role in viral adaptation to hosts, whether
mosquito or human91. Moreover, phylogenetic and epi-
demiological analyses suggest that genotypes with greater
virulence are driving out virus strains of lesser epidemio-
logical impact88, 91.
Climate diversity
As a result of increased global warming, mean air
temperatures are predicted to rise. In 2000, it was esti-
mated that average global temperatures would rise by 1–
3.5°C by 201192. This has a direct impact on the survival
and migration of mosquitoes. Any adverse climate con-
ditions influences the vector to choose a more favourable
environment for settlement. This will ultimately make
suitable habitats of previously non-endemic geographi-
cal regions93. Proliferation of Aedes mosquitoes is cli-
mate-dependent; hence, meteorological factors can po-
tentially provide useful information on predictive mod-
els of dengue incidence94–96. This presents a challenge to
tropical and subtropical regions that are currently non-
endemic for dengue but which share similar climatic con-
ditions to endemic areas. Evidence suggests that both Ae.
aegypti and Ae. albopictus could become established or
re-established in the near future in presently un-colonised
areas15. A rise in global temperatures observed over the
last four decades may correlate with increased risk of
dengue outbreaks97. Climate changes – elevated average
global temperature and humidity – increase the epidemic
potential of dengue15, 40. It has been estimated that half of
the world’s population may be living in areas at risk of
dengue transmission by the year 208593. In contrast, only
35% of people would be at risk if anticipated changes in
climate did not eventuate.
Urbanization, trade and travel
As a consequence of the predilection of Aedes for
citified settings, dengue is unusual for a mosquito-borne
disease in having a greater prevalence in urban areas than
in rural villages98. Urban and suburban development may
also provide plentiful ready-made breeding sites, for in-
stance artificial containers often used for urban water
collection99. The increased density of both mosquito and
human populations in the same location as a result of ur-
banization promotes man-vector contact and thus trans-
mission of dengue15, 99.
An effect of globalization is increased travel and trade,
which are major factors for heightened dengue transmis-
sion. Growth of commerce such as exportation and im-
portation of goods, and movement of students both within
and between countries for educational purposes are prob-
able reasons for the expanded epidemiology of dengue99.
Developed nations such as Australia, Canada, Germany,
Denmark, Norway, Sweden, UK and USA are the focus
of migration for residency, work and education. Hence,
there is always a risk of introducing travel-associated
dengue into these countries.
Travel and tourism are key issues in the context of
dengue transmission as the movement of dengue-infected
persons is thought to be a main driver for global expan-
sion of the disease40, 99. Fast track transportation has fa-
cilitated rapid expansion of dengue from endemic areas
into geographically distant non-endemic areas100. Routes
by which importation of dengue is an increased risk have
been established through passenger air travels15, 100. In
particular, routes between Latin America and the USA,
and between Asia and Europe, were identified as risky
 Gyawali et al: Epidemiology of dengue infection
for dengue dissemination100.
International transportation of cargo and freight, es-
pecially via commercial sea shipment, also facilitates the
export and import of dengue vectors101. Used motor ve-
hicle tyres may carry both adult and larval mosquitoes.
The capacity of Aedes to hatch, breed and survive sea
travel has contributed to a major public health threat in
recent decades102. The inevitable escalation of private car
ownership in future will lead to a vast number of tyres to
be discarded; if they collect rain water, each will serve as
an ideal breeding site for mosquitoes.
Rural areas: A potential future locus of dengue infection
Previous underestimation of the importance of rural
locations for dengue transmission may have contributed
to providing vector-suitable breeding sites similar to those
in urban areas. With increasing ease of transportation,
interconnectivity between rural and urban areas has grown
commensurately. People from the countryside now travel
daily to towns and cities for the purposes of employment,
education, health and for trading livestock, crops, fruits
and vegetables. In contrast, many people visit rural re-
gions for recreation and to enjoy the peaceful environ-
ment. The extended construction of trunk roads, espe-
cially in developing countries, has effectively narrowed
the travel time, if not actual distance, between rural and
urban areas, and has thereby acted as a silent conduit of
dengue transmission103. In addition to environmental and
climatic factors, human practices have performed a sig-
nificant part in creating a situation that is conducive to
the global spread of dengue40.
Discovery of a new dengue serotype: DENV-5
The recently claimed discovery of a new serotype,
DENV-5, provides a further challenge to dengue control6.
As this has yet to be confirmed by publication in the peer-
reviewed scientific literature an unequivocal demonstra-
tion of this serotype awaits the attaining of an isolate,
which should be characterized definitively to confirm, or
conversely to refute, its novelty. It appears that the four
previously discovered serotypes originated from monkeys
and transferred to humans either in Africa or Asia a few
hundred years ago104. However, the first recorded isola-
tion of DENV-1 to DENV-4, respectively, were in 1943
in Japan, 1944 in Papua New Guinea, and 1953 in Philip-
pines and Thailand105. Interestingly, these four serotypes
have human cycles, while the fifth one belongs to a
sylvatic cycle6–7. Although much further research is
needed to determine the extent of its current existence,
its past epidemiology and its future potential epidemic
strength, it should be assumed that DENV-5 poses a threat
299
to human beings. Following this finding it may be said
that dengue is not limited to only five serotypes; it is quite
possible that there are others, as yet undetected, which
also circulate in sylvatic cycles. In itself, the discovery of
DENV-5 complicates both dengue diagnosis and vaccine
development.
Public knowledge, attitude and practice
The existing level of knowledge of the general pub-
lic, their attitude and behaviour all play major roles in
determining the outcome of programmes that are imple-
mented to limit dengue. Although, many people might
have heard of dengue, most of them are unaware of the
symptoms of disease and possess inadequate knowledge
of preventive methods or vector control. While this may
be anticipated for poorer nations, ignorance regarding
dengue also applies to the residents of countries like
Australia 106, which is economically developed and
has a literacy rate of almost 99%. Hence, not prioritizing
the fitting of domestic door and window screens,
careless discarding of domestic waste, inattentive main-
tenance of external household containers (e.g. disposed
tyres, broken bowls and cups, flower pots) in which
water may collect and thereby provide breeding sites
for mosquitoes, all contribute to vector proliferation and
dispersal.
Future options for dengue control
Integrated vector management: WHO is advocating
integrated vector management (IVM) as a further method
of combating Aedes transmission of dengue107. IVM is
defined as “a rational decision-making process for the
optimal use of resources for vector control”. The premise
behind IVM is an integrated collaborative initiative among
different contributing sectors for support, social mobili-
zation and legislation108. The fundamentals of dengue con-
trol under this multidisciplinary strategy are to implement
evidence-based selection and delivery of different inter-
ventions (or combinations of interventions) that are in-
formed by, and thereby tailored to, local settings.
Biological control: A new vector control tool for Ae.
aegypti population suppression and replacement is cur-
rently under investigation. This is the ‘release of
insects carrying a dominant lethal’ (RIDL) system for
mass rearing of male mosquitoes with the introduction of
a lethal genetic mutation109. The principle of this tech-
nique is to micro-inject a lethal gene into the eggs of Ae.
aegypti. Subsequently, the gene integrates into the ge-
nome of the mosquito and regulates the production of
toxic metabolites in the larval stage, killing the newly
300 J Vector Borne Dis 53, December 2016
hatched larva. Antibiotics such as tetracycline, which in-
hibit expression of the lethal gene, are used in the labora-
tory to enable the larva to develop into an adult mos-
quito110. It is intended that under controlled environmental
conditions, RIDL males will be released to mate with wild
type females. Fertilized females should produce RIDL
gene-containing eggs that hatch into larvae. All those car-
rying the gene will die at late larval or early pupal stage.
This project is being conducted by the Malaysia Institute
for Medical Research in three phases: (1) establishment
of the transgenic Malaysian strain of Ae. aegypti; (2) simu-
lated release trial inside a field house; and (3) field re-
lease in a suitable experimental field site111. Currently,
phase three is underway.
Another development for biological control of the
vector is to introduce strains of a naturally occurring in-
tracellular endosymbiotic bacterium called Wolbachia into
Ae. aegypti. In trials, the effects observed in mosquitoes
depend on the strain of Wolbachia that is used112–113. The
introduced bacterial strains should be effective for vector
control by both direct blocking of virus transmission and,
indirectly, by reducing the expected lifespan of the mos-
quitoes. Only older mosquitoes transmit DENV, so this
is predicted to reduce transmission. An additional benefit
of using Wolbachia is that while it can spread actively in
insect populations it is non-infectious to humans. It is
transmitted between generations inside the eggs of the
mosquito. It also inhibits reproduction of females that do
not themselves carry Wolbachia, when mated with in-
fected males, by a phenomenon known as cytoplasmic
incompatibility114.
Vaccines: For several years, despite major challenges
dengue vaccine development has been an area of active
research. Although, clinical testing of attenuated vaccine
candidates began in the 1980s, a vaccine licensed for com-
mercial use is not yet available115. With the increased in-
cidence and continued geographical spread of dengue,
there is a pressing need for a new and highly effective
vaccine that is safe and affordable. Several vaccine can-
didates are showing promise in current clinical trials116.
The preparation of a tetravalent formulation, which aims
to be active against all of the four established serotypes,
DENV 1–4, is a technically challenging task. However,
recombinant DNA approaches have provided significant
advances and a number of products are in different clini-
cal phases115–116. Sanofi Pasteur has completed the ac-
tive phase of two pivotal IIb/III efficacy studies for
ChimeriVax, a DENV 1–4 vaccine, which were carried
out in Asia and Latin America117. The ChimeriVax tech-
nology is based on four recombinant viruses containing
the prM and E genes from each of DENV 1–4 inserted
into the Yellow Fever virus 17D vaccine strain back-
bone118–119. Following completion of these clinical trials
a number of questions have been raised that pertain to
either serotype-specific efficacy, anti-dengue baseline pre-
immunity or surrogate markers of prior exposure. How-
ever, these aspects should be on the manufacturer’s list
of priorities to be addressed. A more detailed description
of current approaches and future directions for dengue
vaccine strategies is provided elsewhere116, 120.
CONCLUSION
Although, dengue was considered initially as a ne-
glected tropical disease, it has recently been prioritized
via the multi-sectoral approaches of the WHO’s Global
Strategy for Dengue Prevention and Control31. This strat-
egy aims to reduce the burden of dengue through applied
research, field-based training and capacity building be-
tween relevant public health stakeholders at regional and
national levels. The strengthening of capacity develop-
ment is recognized to require advocacy, partnership, co-
ordination and collaboration. Sustainable vector control
is one technical element of the Global Strategy for Den-
gue Prevention and Control, 2012–20. In light of limited
therapeutic strategies and the current lack of a vaccine,
effective mosquito control methods are an essential com-
ponent of the drive to reduce dengue mortality and mor-
bidity by 2020. The IVM is the strategic approach pro-
moted to dengue-endemic countries by the WHO as a
rational, cost-effective and optimal decision-making pro-
cess for vector control programmes31.
In spite of many and varied efforts to target both the
dengue virus and its mosquito vector, with strategies ini-
tiated and programs practiced in many endemic regions,
to date the outcome has been disappointing. Over the past
fifty years, the global incidence of dengue has risen by a
factor of 30 (Fig. 2)31, which is a matter of serious global
public health concern. With a regular pattern of dengue
epidemics every 3–5 yr, an increase in clinical cases has
been reported for all countries of South East Asia during
the last decade. Nearly 75% of the worldwide incidence
of dengue occurs in the Asia-Pacific region31. The situa-
tion is almost as alarming in the Americas, where in the
last 30 yr the number of dengue cases has increased more
than eight-fold80. While the trend for expansion is not
repeated in Africa, it is possible that there is under-re-
porting in this continent due to inadequate provision of
diagnostic resources. Australia has implemented success-
ful vector control interventions that eradicated the Ae.
aegypti population and eliminated cases of dengue from
New South Wales and Western Australia, states which
 Gyawali et al: Epidemiology of dengue infection
experienced outbreaks of dengue a couple of decades ear-
lier. However, the number of overseas-acquired cases re-
ported in Australia continues to increase each year52,
which poses an ongoing threat for local transmission of
dengue in north and central queensland, where Ae. aegypti,
still persists106. For all countries in which there is local
transmission of dengue, it is an imperative to effectuate a
range of technical factors that promote anti-dengue ac-
tivity, as well as to promulgate the strategic direction that
is required in order to achieve the WHO goal of IVM on
a global scale.
Conflict of interest
The authors declare no conflicts of interest.
Disclaimer
Richard Bradbury is co-authoring this manuscript in
his personal capacity and as an adjunct academic at Cen-
tral Queensland University.
REFERENCES
1. Dengue and severe dengue. Fact sheet. Geneva: World Health
Organization (updated July 2016).
2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes
CL, et al. The global distribution and burden of dengue. Nature
2013; 496(7446): 504–7.
3. Higa Y. Dengue vectors and their spatial distribution. Trop Med
Health 2011; 39 (Suppl 4): 17–27.
4. Dengue: Guidelines for diagnosis, treatment, prevention and
control. New edn. Geneva: World Health Organization and the
Special Programme for Research and Training in Tropical Dis-
eases (TDR) 2009; p. 1–147.
5. Deen JL, Harris E, Wills B, Balmaseda A, Hammond SN, Rocha
C, et al. The WHO dengue classification and case definitions:
Time for a reassessment. Lancet 2006; 368(9530): 170–3.
6. Mustafa MS, Rasotgi V, Jain S, Gupta V. Discovery of fifth se-
rotype of dengue virus (DENV-5): A new public health dilemma
in dengue control. Med J Armed Forces India 2015; 71(1): 67–
70.
7. Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler
DJ, et al. Dengue: A continuing global threat. Nat Rev Microbiol
2010; 8( Suppl 12): S7–16.
8. Henchal EA, Putnak JR. The dengue viruses. Clin Microbiol Rev
1990; 3(4): 376–96.
9. Gubler DJ. Dengue/dengue haemorrhagic fever: History and cur-
rent status. Novartis Found Symp 2006; 277: 3–16.
10. Hirsch A. Dengue, a comparatively new disease: Its symptoms.
Handbook of Georaphical and Historical Pathology. London:
Sydenham Society 1883; p. 55–81.
11. Gordon SC. A localized outbreak of dengue fever in Kuala
Lumpur: Epidemiological and clinical aspects. Med J Malaya
1956; 10(4): 289–303.
12. Brown JE, Evans BR, Zheng W, Obas V, Barrera Martinez L,
Egizi A, et al. Human impacts have shaped historical and recent
evolution in Aedes aegypti, the dengue and yellow fever mos-
quito. Evolution 2014; 68(2): 514–25.
301
13. The Arboviruses: Ecology and epidemiology. Monath TP,
editor. Boca Raton, FL: CRC Press 1988.
14. Wilder-Smith A, Gubler DJ. Geographic expansion of dengue:
The impact of international travel. Med Clin North Am 2008;
92(6): 1377–90.
15. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of den-
gue: Past, present and future prospects. Clin Epidemiol 2013;
5(1): 299–309.
16. Gubler DJ. Dengue and dengue hemorrhagic fever: Its history
and resurgence as a global public health problem. In: Gubler DJ,
Kuno G, editors. Dengue and Dengue Hemorrhagic Fever. Lon-
don: CAB International 1997; p. 1–22.
17. Sirisena PD, Noordeen F. Evolution of dengue in Sri Lanka—
Changes in the virus, vector, and climate. Int J Infect Dis 2014;
19: 6–12.
18. Gubler DJ. The changing epidemiology of yellow fever and den-
gue, 1900 to 2003: full circle? Comp Immunol Microbiol Infect
Dis 2004; 27(5): 319–30.
19. Rudnick A, Lim TW, Ireland J, Perubatan IP. Dengue Fever Stud-
ies in Malaysia. Kuala Lumpur: Institut Penyelidikan Perubatan
1986.
20. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a
public health, social and economic problem in the 21st century.
Trends Microbiol 2002; 10(2): 100–3.
21. Costa RL, Voloch CM, Schrago CG. Comparative evolutionary
epidemiology of dengue virus serotypes. Infect Genet Evol 2012;
12(2): 309–14.
22. Halstead SB. Dengue in the Americas and Southeast Asia: Do
they differ? Rev Panam Salud Publica 2006; 20(6): 407–15.
23. Sabin AB. Research on dengue during World War II. Am J Trop
Med Hyg 1952; 1(1): 30–50.
24. Hammon WM, Rundnick A, Sather G. Viruses associated with
epidemic hemorrhagic fevers of the Philippines and Thailand.
Science 1960; 131(3407): 1102–3.
25. Gupta N, Srivastava S, Jain A, Chaturvedi UC. Dengue in India.
Indian J Med Res 2012; 136(3): 373–90.
26. Sarkar J, Chatterjee S, Chakravarty SK. Haemorrhagic fever in
Calcutta: Some epidemiological observations. Indian J Med Res
1964; 52: 651–9.
27. Chan YC, Salahuddin NI, Khan J, Tan HC, Seah CL, Li J, et al.
Dengue haemorrhagic fever outbreak in Karachi, Pakistan, 1994.
Trans R Soc Trop Med Hyg 1995; 89(6): 619–20.
28. Rahman M, Rahman K, Siddque AK, Shoma S, Kamal AH, Ali
KS, et al. First outbreak of dengue hemorrhagic fever,
Bangladesh. Emerg Infect Dis 2002; 8(7): 738–40.
29. Dorji T, Yoon IK, Holmes EC, Wangchuk S, Tobgay T, Nisalak
A, et al. Diversity and origin of dengue virus serotypes 1, 2, and
3, Bhutan. Emerg Infect Dis 2009; 15(10): 1630–2.
30. Pandey BD, Rai SK, Morita K, Kurane I. First case of dengue
virus infection in Nepal. Nepal Med Col J 2004; 6(2): 157–9.
31. Global Strategy for Dengue Prevention and Control, 2012–2020.
Geneva: World Health Organization 2012; p. 1–35.
32. Dash AP, Bhatia R, Kalra NL. Dengue in Southeast Asia: An
appraisal of case management and vector control. Dengue Bull
2012; 36: 1–13.
33. Shepard DS, Undurraga EA, Halasa YA. Economic and disease
burden of dengue in Southeast Asia. PLoS Negl Trop Dis 2013;
7(2): e2055.
34. Ferreira GL. Global dengue epidemiology trends. Rev Inst Med
Trop São Paulo 2012; 54 (Suppl 18): S5–6.
35. Dengue situation update 477: Update on the dengue situation in
the Western Pacific Region. World Health Organization, West-
302 J Vector Borne Dis 53, December 2016
ern Pacific Region 2015. Available from: http://www.wpro.who.
int/emerging_diseases/dengue_biweekly_ 20151103.pdf?ua=1
(Accessed on March 4, 2016).
36. Cummings DAT, Iamsirithaworn S, Lessler JT, McDermott A,
Prasanthong R, Nisalak A, et al. The impact of the demographic
transition on dengue in Thailand: Insights from a statistical analy-
sis and mathematical modeling. PLoS Med 2009; 6(9): e100013.
37. Nakamura N, Arima Y, Shimada T, Matsui T, Tada Y, Okabe N.
Incidence of dengue virus infection among Japanese travellers,
2006 to 2010. Western Pac Surveill Response J 2012; 3(2): 39–
45.
38. Lumley GF, Taylor FH. Dengue: Medical, Part I. Australia:
Australasian Medical Publishing Company Limited 1943; p. 1–
171.
39. Mackenzie JS, la Brooy JT, Hueston L, Cunningham AL. Den-
gue in Australia. J Med Microbiol 1996; 45(3): 159–61.
40. Russell RC, Currie BJ, Lindsay MD, Mackenzie JS, Ritchie SA,
Whelan PI. Dengue and climate change in Australia: Predictions
for the future should incorporate knowledge from the past. Med
J Aust 2009; 190(5): 265–8.
41. McLean DM, Magrath WJ. Dengue in the Northern Territory.
Med J Aust 1959; 46: 719–21.
42. Ritchie SA, Pyke AT, Hall-Mendelin S, Day A, Mores CN,
Christofferson RC, et al. An explosive epidemic of DENV-3 in
Cairns, Australia. PloS One 2013; 8(7): e68137.
43. Beebe NW, Ambrose L, Hill LA, Davis JB, Hapgood G, Cooper
RD, et al. Tracing the tiger: Population genetics provides valu-
able insights into the Aedes (Stegomyia) albopictus invasion of
the Australasian region. PLoS Negl Trop Dis 2013; 7(8): e2361.
44. Doherty RL, Westaway EG, Whitehead RH. Further studies of
the aetiology of an epidemic of dengue in Queensland, 1954–
1955. Med J Aust 1967; 2(24): 1078–80.
45. Guard RW, Stallman ND, Wiemers MA. Dengue in the northern
region of Queensland, 1981–1982. Med J Aust 1984; 140(13):
765–9.
46. Kay BH, Barker-Hudson P, Stallman ND, Wiemers M, Marks
EN, Holt P, et al. Dengue fever. Reappearance in northern
Queensland after 26 years. Med J Aust 1984; 140(5): 264–8.
47. Phillips D, Pearce M, Weimers M, Blumke G. Dengue-2 infec-
tion in northern Queensland. Comn Dis Intell 1992; 16: 192–3.
48. Row D, Pearce M, Hapgood G, Sheridan J. Dengue and dengue
haemorrhagic fever in Charters Towers, Queensland. Comn Dis
Intell 1993; 17: 182–3.
49. McBride WJ, Mullner H, LaBrooy JT, Wronski I. The 1993 den-
gue 2 epidemic in Charters Towers, North Queensland: Clinical
features and public health impact. Epidemiol Infect 1998; 121(1):
151–6.
50. Knope KE, Doggett SL, Kurucz N, Johansen CA, Nicholson J,
Feldman R, et al. Arboviral diseases and malaria in Australia,
2011–12: Annual report of the National Arbovirus and Malaria
Advisory Committee. Comm Dis Intell Q Rep 2014; 38(2): E122–
42.
51. Knope K, Whelan P, Smith D, Nicholson J, Moran R, Doggett S,
et al. Arboviral diseases and malaria in Australia, 2010–11: An-
nual report of the National Arbovirus and Malaria Advisory Com-
mittee. Comm Dis Intell Q Rep 2013; 37(1): E1–20.
52. Knope K, Giele C. Increasing notifications of dengue in Austra-
lia related to overseas travel, 1991 to 2012. Comm Dis Intell Q
Rep 2013; 37: E55–99.
53. Government of Western Australia: Department of Health. Bali
travel behind spike in dengue fever. Dis Watch [Serial on the
internet] 2012 ; 16(5). Available from: http://www.health.wa.gov.
au/diseasewatch/vol16_issue5/bali_ travel.cfm (Accessed on
March 4, 2016).
54. Aubry M, Roche C, Dupont-Rouzeyrol M, Aaskov J, Viallon J,
Marfel M, et al. Use of serum and blood samples on filter paper
to improve the surveillance of dengue in Pacific Island Coun-
tries. J Clin Virol 2012; 55(1): 23–9.
55. European Centre for Disease Prevention and Control. Dengue-
Multistate (world) — Monitoring seasonal epidemics. Comm Dis
Threats Rep [serial on the internet] 2015; CDTR week 14, 29
March–4 April 2015. Available from: http://ecdc.europa.eu/en/
publications/Publications/communicable-disease-threats-report-
04-April-2015. pdf (Accessed on March 4, 2016).
56. Cao-Lormeau V-M, Roche C, Musso D, Mallet HP, Dalipanda
T, Dofai A, et al. Dengue virus type 3, South Pacific Islands,
2013. Emerg Infect Dis 2014; 20(6): 1034–6.
57. Nogareda F, Joshua C, Sio A, Shortus M, Dalipanda T, Durski
K, et al. Ongoing outbreak of dengue serotype-3 in Solomon
Islands, January to May 2013. Western Pac Surveill Response J
2013; 4(3): 28–33.
58. Gubler DJ, Clark GG. Dengue/dengue hemorrhagic fever: The
emergence of a global health problem. Emerg Infect Dis 1995;
1(2): 55–7.
59. Amarasinghe A, Kuritsk JN, Letson GW, Margolis HS. Dengue
virus infection in Africa. Emerg Infect Dis 2011; 17(8): 1349–
54.
60. Cornet M. Dengue in Africa. Epidemiology of dengue and den-
gue hemorrhagic fever. Monograph on dengue/dengue hemor-
rhagic fever. Geneva: World Health Organization 1993; p. 39–
47.
61. Were F. The dengue situation in Africa. Paediatr Int Child Health
2012; 32(Suppl 1): 18–21.
62. Carey DE, Causey OR, Reddy S, Cooke AR. Dengue viruses
from febrile patients in Nigeria, 1964–68. Lancet 1971; 1(7690):
105–6.
63. Vasilakis N, Holmes EC, Fokam EB, Faye O, Diallo M, Sall
AA, et al. Evolutionary processes among sylvatic dengue type 2
viruses. J Virol 2007; 81(17): 9591–5.
64. Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von
Sonnenburg F, et al. Spectrum of disease and relation to place of
exposure among ill returned travelers. N Engl J Med 2006; 354(2):
119–30.
65. Franco L, Di Caro A, Carletti F, Vapalahti O, Renaudat C, Zeller
H, et al. Recent expansion of dengue virus serotype 3 in West
Africa Euro Surveill 2010; 15(7): 19490.
66. Louis, Christos. Daily newspaper view of dengue fever epidemic,
Athens, Greece, 1927–1931. Emer Infect Dis 2012, 18(1): 78–
82.
67. Alves M, Fernandes P, Amaro F, Osório H, Luz T, Parreira P, et
al. Clinical presentation and laboratory findings for the first au-
tochthonous cases of dengue fever in Madeira Island, Portugal,
October 2012. Euro Surveill 2013;18 (6): 20398.
68. Frank C, Höhle M, Stark K, Lawrence J. More reasons to dread
rain on vacation? Dengue fever in 42 German and United King-
dom Madeira tourists during autumn 2012. Euro Surveill 2013;
18(14): 20446.
69. La Ruche G, Souares Y, Armengaud A, Peloux-Petiot F,
Delaunay P, Despres P, et al. First two autochthonous dengue
virus infections in metropolitan France, September 2010. Euro
Surveill 2010; 15(39): 19676.
70. Gjenero-Margan I, Aleraj B, Krajcar D, Lesnikar V, Klobucar
A, Pem-Novosel I, et al. Autochthonous dengue fever in Croatia,
August–September 2010. Euro Surveill 2011; 16(9): 19805.
 Gyawali et al: Epidemiology of dengue infection
71. Medlock JM, Hansford KM, Schaffner F, Versteirt V, Hendrickx
G, Zeller H, et al. A review of the invasive mosquitoes in Eu-
rope: Ecology, public health risks, and control options. Vector
Borne Zoonotic Dis 2012; 12(6): 435–47.
72. Caminade C, Medlock JM, Ducheyne E, McIntyre KM, Leach
S, Baylis M, et al. Suitability of European climate for the Asian
tiger mosquito Aedes albopictus: Recent trends and future sce-
narios. J R Soc Interface 2012; 9(75): 2708–17.
73. Beatty M, Boni MF, Brown S, Buathong R, Burke D, Coudeville
L, et al. Assessing the potential of a candidate dengue vaccine
with mathematical modeling. PLoS Negl Trop Dis 2012; 6(3):
e1450.
74. King WW. The epidemic of dengue in Puerto Rico: 1915. New
Orleans Med Surg 1917; 69: 564–71.
75. Tomashek KM, Rivera A, Muñoz-Jordan JL, Hunsperger E,
Santiago L, Padro O, et al. Description of a large island-wide
outbreak of dengue in Puerto Rico, 2007. Am J Trop Med Hyg
2009; 81(3): 467–74.
76. Neff JM, Morris L, Gonzalez-Alcover R, Coleman PH, Lyss SB,
Negron H. Dengue fever in a Puerto Rican community. Am J
Epidemiol 1967; 86(1): 162–84.
77. Natham MB, Dayal-Drager R, Guzman M. Epidemiology, bur-
den of disease and transmission. Dengue — Guidelines for diag-
nosis, treatment, prevention and control. New edn. Geneva: World
Health Organization 2009; p. 1–21.
78. Mohammed HP, Ramos MM, Rivera A, Johansson M, Muñoz
Jordan JL, Sun W, et al. Travel associated dengue infections in
the United States, 1996 to 2005. J Travel Med 2010; 17(1): 8–
14.
79. Centers for Disease Control and Prevention (CDC). Locally ac-
quired dengue – Key West, Florida, 2009–2010. MMWR Morb
Mortal Wkly Rep 2010; 59(19): 577–81.
80. San Martín JL, Brathwaite O, Zambrano B, Solórzano JO,
Bouckenooghe A, Dayan GH, et al. The epidemiology of den-
gue in the Americas over the last three decades: A worrisome
reality. Am J Trop Med Hyg 2010; 82(1): 128–35.
81. Torres JR, Castro J. The health and economic impact of dengue
in Latin America. Cad Saude Pública 2007; 23(Suppl 1): S23–
31.
82. Wilson ME, Chen LH. Dengue in the Americas. Dengue Bull
2002; 26: 44–61.
83. Gubler DJ. Aedes aegypti and Aedes aegypti-borne disease con-
trol in the 1990s: Top down or bottom up. Am J Trop Med Hyg
1989; 40(6): 571–8.
84. Istúriz RE, Gubler DJ, Castillo JB. Dengue and dengue hemor-
rhagic fever in Latin America and the Caribbean. Infect Dis Clin
North Am 2000; 14(1): 121–40.
85. Figueiredo LT, Cavalcante SM, Simões MC. Dengue serologic
survey of schoolchildren in Rio de Janeiro, Brazil, in 1986 and
1987. Bull Pan Am Health Organ 1990; 24(2): 217–25.
86. Shepard DS, Coudeville L, Halasa YA, Zambrano B, Dayan GH.
Economic impact of dengue illness in the Americas. Am J Trop
Med Hyg 2011; 84(2): 200–7.
87. Cafferata ML, Bardach A, Rey-Ares L, Alcaraz A, Cormick G,
Gibbons L, et al. Dengue epidemiology and burden of disease in
Latin America and the Caribbean: A systematic review of the
literature and meta-analysis. Value Health Reg Issues 2013; 2:
347–56.
88. Messina JP, Brady OJ, Pigott DM, Golding N, Kraemer MU,
Scott TW, et al. The many projected futures of dengue. Nature
Rev Microbiol 2015; 13(4): 230–9.
89. Wilder-Smith A, Ooi EE, Vasudevan SG, Gubler DJ. Update on
303
dengue: Epidemiology, virus evolution, antiviral drugs, and vac-
cine development. Curr Infect Dis Rep 2010; 12(3): 157–64.
90. Åström C, Rocklöv J, Hales S, Béguin A, Louis V, Sauerborn R.
Potential distribution of dengue fever under scenarios of climate
change and economic development. Eco Health 2012; 9(4): 448–
54.
91. Rico-Hesse R. Microevolution and virulence of dengue viruses.
Adv Virus Res 2003; 59: 315–41.
92. Wang E, Ni H, Xu R, Barrett AD, Watowich SJ, Gubler DJ, et
al. Evolutionary relationships of endemic/epidemic and sylvatic
dengue viruses. J Virol 2000; 74(7): 3227–34.
93. Githeko AK, Lindsay SW, Confalonieri UE, Patz JA. Climate
change and vector-borne diseases: a regional analysis. Bull World
Health Organ 2000; 78(9): 1136–47.
94. Hales S, De Wet N, Maindonald J, Woodward A. Potential ef-
fect of population and climate changes on global distribution of
dengue fever: An empirical model. Lancet 2002; 360(9336):
830–4.
95. Earnest A, Tan SB, Wilder-Smith A. Meteorological factors and
El Niño Southern Oscillation are independently associated with
dengue infections. Epidemiol Infect 2012; 140(7): 1244–51.
96. Wu P-C, Guo H-R, Lung S-C, Lin C-Y, Su H-J. Weather as an
effective predictor for occurrence of dengue fever in Taiwan.
Acta Trop 2007; 103(1): 50–7.
97. Hii YL, Rocklöv J, Ng N, Tang CS, Pang FY, Sauerborn R. Cli-
mate variability and increase in intensity and magnitude of den-
gue incidence in Singapore. Glob Health Action 2009; 2: 2036
98. Banu S, Hu W, Hurst C, Tong S. Dengue transmission in the
Asia Pacific region: Impact of climate change and socio envi-
ronmental factors. Trop Med Int Health 2011; 16(5): 598–607.
99. Nepal H, Ansari S, Gyawali N, Gautam R, Paudel R, et al. De-
tection of IgM against dengue virus in clinically suspected pa-
tients presenting at a tertiary care centre, Narayani zone, Nepal.
J Trop Dis 2014; 2: 2.
100. Gubler DJ. Dengue, urbanization and globalization: The unholy
trinity of the 21st century. Trop Med Health 2011; 39 (Suppl 4):
3–11.
101. Gardner LM, Fajardo D, Waller ST, Wang O, Sarkar S. A pre-
dictive spatial model to quantify the risk of air-travel-associated
dengue importation into the United States and Europe. J Trop
Med 2012; 2012: 103679.
102. Islam R, Salahuddin M, Ayubi MS, Hossain T, Majumder
A, Taylor-Robinson AW, et al. Dengue epidemiology and patho-
genesis: images of the future viewed through a mirror of the past.
Virol Sin 2015; 30(5): 326–43.
103. Reiter P. Aedes albopictus and the world trade in used tires, 1988–
1995: the shape of things to come? J Am Mosq Control Assoc
1998; 14(1): 83–94.
104. Vong S, Khieu V, Glass O, Ly S, Duong V, Huy R, et al. Dengue
incidence in urban and rural Cambodia: Results from popula-
tion-based active fever surveillance, 2006–2008. PLoS Negl Trop
Dis 2010; 4(11): e903.
105. Holmes EC, Twiddy SS. The origin, emergence and evolution-
ary genetics of dengue virus. Infect Genet Evol 2003; 3(1):
19–28.
106. Gyawali N, Bradbury RS, Taylor-Robinson AW. Knowledge,
attitude and recommendations for practice regarding dengue
among the resident population of Queensland, Australia. Asian
Pac J Trop Biomed 2016; 6(4): 360–6.
107. Messina JP, Brady OJ, Scott TW, Zou C, Pigott DM, Duda KA,
et al. Global spread of dengue virus types: Mapping the 70 year
history. Trends Microbiol 2014; 22(3): 138–46.
304 J Vector Borne Dis 53, December 2016

108. Mammen MP Jr, Pimgate C, Koenraadt CJ, Rothman AL,
Aldstadt J, Nisalak A, et al. Spatial and temporal clustering of
dengue virus transmission in Thai villages. PLoS Med 2008;
5(11): e205.
109. Franz AW, Clem RJ, Passarelli AL. Novel genetic and molecu-
lar tools for the investigation and control of dengue virus
transmission by mosquitoes. Curr Trop Med Rep 2014; 1(1):
21–31.
110. Massonnet-Bruneel B, Corre-Catelin N, Lacroix R, Lees RS,
Hoang KP, Nimmo D, et al. Fitness of transgenic mosquito Aedes
aegypti males carrying a dominant lethal genetic system. PLoS
One 2013; 8(5): e62711.
111. Lee HL, Vasan S, Ahmad NW, Idris I, Hanum N, Selvi S, et al.
Mating compatibility and competitiveness of transgenic and wild
type Aedes aegypti (L) under contained semi-field conditions.
Transgenic Res 2013; 22(1): 47–57.
112. Dengue/Dengue haemorrhagic fever: History and current sta-
tus. Gubler DJ, editor. Novartis Foundation Symposium.
Chichester: John Wiley 2006.
113. McMeniman CJ, O’Neill SL. A virulent Wolbachia infection
decreases the viability of the dengue vector Aedes aegypti dur-
ing periods of embryonic quiescence. PLoS Negl Trop Dis 2010;
4(7): e748.
114. Ritchie SA, Townsend M, Paton CJ, Callahan AG, Hoffmann
AA. Application of wMelPop Wolbachia strain to crash local
populations of Aedes aegypti. PLoS Negl Trop Dis 2015; 9(7):
e0003930.
115. Ishikawa T, Yamanaka A, Konishi E. A review of successful
flavivirus vaccines and the problems with those flaviviruses for
which vaccines are not yet available. Vaccine 2014; 32(2): 1326–
37.
116. Ansari S, Taylor-Robinson AW. Strategic approaches to multi-
valent vaccine development against dengue virus infection. Ann
Vaccine Immuniz 2014; 1(2): 1005.
117. Guy B, Lang J, Saville M, Jackson N. Vaccination against den-
gue: Challenges and current developments. Annu Rev Med 2016;
67: 387–404.
118. Guy B, Saville M, Lang J. Development of Sanofi Pasteur tet-
ravalent dengue vaccine. Hum Vaccine 2010; 6(9): 696–705.
119. Guy B, Barrere B, Malinowski C, Saville M, Teyssou R, Lang J.
From research to phase III: Preclinical, industrial and clinical
development of the Sanofi Pasteur tetravalent dengue vaccine.
Vaccine 2011; 29(42): 7229–41.
120. Gyawali N, Taylor-Robinson AW. Vaccine development against
dengue, a viral disease of increasing significance to global pub-
lic health. Immun Dis 2014; 2 (A10): 1–4.

Correspondence to: Prof. Andrew W. Taylor-Robinson, School of Medical and Applied Sciences, Central Queensland University, Rockhampton,
QLD 4702, Australia.
E-mail: a.taylor-robinson@cqu.edu.au

Received: 2 December 2015 Accepted in revised form: 31 March 2016