Invasion,
expansion and
maintenance of
Dengue &
Chikungunya
viruses in the
Americas.
Christine V. F. Carrington
12 June 2014
Dengue
The most rapidly spreading mosquito-borne viral disease
One of the most important emerging diseases of the 21st century
3.5 billion people at risk
Annually:
- 390 million infections (96 million clinically apparent)
- 24,000 deaths
- US$ 2.1 billion (Americas); US$321 million
(Caribbean)
Distribution of Global Dengue Risk
Bhatt et al 2013 Nature, 496(7446), 504-507.
Shepard et al (2011). Am J Trop Med Hyg. 84(2):200-7
Global Strategy for Dengue Prevention and Control, 2012-2020 Fig. 2, Page 2 http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf
Dengue virus (DENV)
‣ Family
‣
Flaviviridae, genus flavivirus
~11kb single stranded positive sense RNA genome
‣ Five
serotypes (DENV1 – 5)
‣ Phylogenetically
distinct genotypes within each serotypes
(Source: ViralZone:www.expasy.org/viralzone, Swiss Institute of Bioinformatics)
Outcomes of DENV infection
Up to an estimated 80% of infections are asymptomatic
DENGUE +/- WARNING SIGNS
SEVERE DENGUE
1. Severe plasma leakage
2. Severe haemorrhage
3. Severe organ impairment
with warning
signs
without
Life long immunity against the infecting serotype
Limited, short lived immunity against other serotypes
Increased risk of severe manifestations with 2o infection
Probable dengue
Warning signs*
Live in / travel to dengue endemic area.
Fever and 2 of the following:
•Nausea, vomiting
•Rash
•Aches and pains
•Tourniquet test positive
•Leukopenia
•Any warning sign
Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation
Mucosal bleeding
Lethargy / restlessness
Liver enlargment >2cm
Laboratory: increase in HCT concurrent with rapid
decrease in platelet count
Laboratory confirmed dengue
* Requiring strict observation and medical intervention
DENGUE: GUIDELINES FOR DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL: WHO, 2009
Chikungunya
Re-emerging mosquito-borne viral disease in the Old world
Recently emerging in the New World
http://www.cdc.gov/chikungunya/pdfs/ChikungunyaMap.pdf
Chikungunya virus (CHIKV)
‣ Family
‣
Togaviridae, genus alphavirus
~12kb single stranded positive sense RNA genome
‣ Three
genotypes: Western African (WAf),
Eastern/Central/South African (ECSA) and Asian
(Source: ViralZone:www.expasy.org/viralzone, Swiss Institute of Bioinformatics)
Chikungunya Fever
Typical symptoms
• High fever (40°C/ 104°F)
• Joint pain (lower back, ankle, knees, wrists or phalanges)
• Joint swelling
• Rash
Rarely fatal.
• Headache
Acute symptoms typically resolve
within 7 – 10 days but some patients
• Muscle pain
report persistent joint pains for
• Nausea
months to years.
• Fatigue
Transmission cycles
Dengue virus and Chikungunya virus
Ae. aegypti
Ae. albopictus
“
”
DENV and CHIKV also exist in sylvatic cycles
DENV sylvatic cycle exists in SE Asia and West Africa.
Currently circulating epidemic DENV1-4 arose as a result
of successful spillover events 100s of years ago.
Ae. aegypti
Ae. albopictus
spillover
•
B
“
Forest dwelling
Aedes spp.
In Africa, during inter-epidemic periods, CHIKV is
maintained in enzootic, sylvatic cycles.
”
DENV made successful cross
species jumps into human
populations at least four
times to give rise to the four
serotypes that are associated
with epidemic disease
globally.
DENV-5 reported by
Vasilakis et al. at 3rd
International Conference on
Dengue and Dengue
Haemorrhagic Fever,
Bangkok 2013
Wang, E. et al. J. Virol. 74, 3227–3234 (2000).
.
Global emergence of Dengue
Average annual no. of Dengue cases reported /
countries reporting dengue, 1955–2007
1970
2004
WHO 2009. Dengue: Guidelines for diagnosis, treatment,
prevention & control
Guzman, M. G. et al. Dengue: A continuing global threat. Nature R
eviews Microbiology 8, S7–S16 (2010).
Dengue emergence and changing disease pattern in the Americas
A history of repeated introductions of viruses from Asia.
Several DF outbreaks
and epidemics;
sporadic severe cases
Reports of Dengue-like illness
since late 1700s.
Geographically restricted, self
limiting outbreaks of DF
Larger, more frequent epidemics with increasing
numbers of severe cases
Figure adapted from Allicock et al (2012) Mol. Biol. Evol. 29(6):1533–1543.
Global expansion of CHIKV
• Pre 1950s: Africa and Asia
• 1953: virus isolated (Tanzania)
• 1950s & 60s: Large outbreaks on Indian subcontinent; disappeared
1970.
• 2005: Urban epidemic in Indian Ocean; spread to subcontinent.
• 2006 onwards: imported cases in Europe, USA and Caribbean; outbreak
in Italy,
• Dec 2013: St. Martin outbreak; spread to other countries in region.
The strain responsible for the Indian Ocean outbreak arose from ECSA strain
Maximum clade credibility (MCC) tree of 80 CHIKV strains.
Volk S M et al. J. Virol. 2010;84:6497-6504
June 2014
Confirmed/Suspected Cases of Chikungunya
6000
5083
5252
5000
4218
4000
3000
2635
2000
1068
1000
487
0
January
February
March
April
May
June
Phylogeny of Chikungunya viruses associated with
outbreak in Saint-Martin
Leparc-Goffart I, Nougairede A, Cassadou S, Prat C, de Lamballerie X.
Chikungunya in the Americas. Lancet 2014; 383: 514.
Factors underlying viral emergence
• Emergence is a result of:
– Evolutionary changes affecting host range,
virulence, transmissibility / infectivity, drug
resistance.
– Changes in host population susceptibility e.g. HIVassociated immunodeficiency, malnutrition, reduced
vaccine coverage.
– Ecological changes that increase the probability of
exposure of susceptible individuals/populations to
infected reservoir hosts or vectors.
Majority of disease emergence is driven
ecological factors associated with human
activity
rapid global transport networks
deforestation
habitat destruction
high-density human populations
unplanned urbanisation
modern agricultural
practices
Factors underlying the global emergence of DENV
rapid global transport
WWII related troop
movements and
population
displacement
global population growth
High density human populations
Inadequate infrastructure
unplanned urbanisation
mosquito breeding sites
Inadequate water supply
Improper waste disposal
water storage
water collection
Inadequate vector control + weak implementation of public health policies
Factors underlying the recent global
emergence of CHIKV
Increased tourism
Rapid global transport
Evolutionary changes
(adaptive E gene mutation favours replication in Ae.
albopictus)
Immune landscape
(Introduction in naïve populations)
After invasion…
What factors underlie epidemic behaviour following
introduction?
What determines rates and directions of viral spread ?
What are the peculiarities of viral gene flow in an island mainland setting?
Identification of the factors underlying the pathogen
spatiotemporal dynamics and their relative contributions
would allows us to better model disease spread and thus
facilitate better surveillance and control.
Factors that may influence changes in mosquitoborne virus population size and patterns of spread
‣
Rate and direction of human movement
- Geographic distance
- Connectivity (Extent of road network / Air traffic / Shipping traffic)
- Historical and socioeconomic links
‣
Rate and direction of mosquito movement
- Geographic distance [Short (unassisted); Long (assisted)]
- Mosquito population density
- Opportunities for assisted movement
‣
Availability of susceptible human hosts
- Immune landscape
- Human population density
‣
Availability of appropriate mosquito vector
‣ Presence of Ae. Aegypti or Ae. Albopictus
‣ Mosquito population density
Traditional epidemiological approach
Understanding factors underlying viral spatiotemporal dynamics
‣
Requires extensive surveillance
-
Labour intensive
-
Costly
-
Time consuming
‣ Deficiencies in public health
infrastructure frustrate collection
of accurate and timely data
-
basic information often delayed,
unavailable or unreliable
-
Type and quality of data varies
between countries / institutions
Map used to link cholera deaths in London to
contaminated water from the Broad Street pump in
1854
Data accompanying samples sent to TPHL for dengue
testing during the 2011 dengue season
Samples with clinical data (n=82).
Only 82 of 710 samples (11.5%) were
accompanied by clinical data.
Samples with demographic data (n =525).
Of 710 samples, 525 (73.9%) were accompanied by
demographic data.
Sahadeo NSD, Brown A, Carrington L, Carrington CVF. Challenges to
dengue reporting & surveillance in Trinidad & Tobago. Presented at the
ASTMH 61st Annual Meeting. Nov 11-15, 2012. Atlanta, Georgia USA.
A Phylogenetic Approach
Sample viruses
from population
Sequence genes / genomes
from sampled individuals
Field trapped vectors. host
reservoirs or patient serum
PCR amplification and
sequencing of specific genes
Create data sets of
aligned sequences
Newly
derived +
Genbank
(Screening by PCR, cell culture)
• Estimate rates of evolution
Infer evolutionary
relationships among
sequences
Numerous computational
approaches
(Maximum likelihood,
Neighbour joining, Bayesian
MCMC)
• Estimate dates of origin for individual viruses or
lineages
• Reconstruct past population dynamics
• Reconstruct spatial dynamics
• Create and compare models describing different
patterns of geographic spread and determine which, if
any, best describe the inferred pattern
BEAST software package
(Bayesian coalescent approach)
‣
DENV 1, 2 and 4
-
Strong spatial structure
-
Clear pattern of lineage extinction
and replacement
‣
DENV2
Phylogenies inferred for
DENV circulating in the
Americas
-
Greater gene flow among
countries
-
Less evidence of lineage turnover
-
Exponential growth
DENV3
DENV 3
Allicock et al. unpublished data;
Allicock et al (2012) Mol. Biol. Evol. 29(6):1533–1543.
Inferred dates and location for most recent
common ancestors (MRCA) & evolutionary rates
‣ Each strain of the serotypes investigated arose from a single introduction
‣ Introductions occurred a mean of 2 - 4 years before 1st epidemiological reports
‣ Locations of MRCA
-
DENV-3, DENV-4: country of 1st report
DENV 2: neighbouring country (Jamaica and Cuba)
DENV 1: Grenada 5 yrs before 1st reported in Jamaica
-
Detection threshold may be quite high due to poor surveillance in many countries.
Allicock et al. unpublished data;
Allicock et al (2012) Mol. Biol. Evol. 29(6):1533–1543.
Spread of DENV 1 inferred from sequence data.
Rapid dispersal followed by more localized maintenance
Allicock et al (unpublished data)
Correlations between predictors & rates of
DENV geographic spread within the Americas
Allicock et al (unpublished data)
More intense virus movement
• between nearby regions (DENV 1 and 3)
• between countries with more air traffic between them (DENV 1-3)
• from smaller to larger populations (DENV 1 and 3)
Less intense virus movement
• out of countries with high % urban populations (DENV 1 – 3)
• out of countries with higher human development indices (DENV 3)
DENV spread in the Americas is best
described by a Gravity Model
Dengue virus in a given location is more likely to move
to a nearby and larger human population than to a
smaller or more distant population.
C
Urban centres attract virus.
A
DEN
V
B
Allicock et al (unpublished data)
Air traffic is a good
predictor of spatial
diffusion patterns for
DENV 1 - 3
DENV
More intense gene flow
C
Limitations
A
‣
Used total air traffic over 30
years; cannot currently
incorporate predictors that
change over time.
‣
Indirect movement not
captured (some countries
have no direct airline links)
B
DENV
Less intense gene flow
Allicock et al (unpublished data)
Acknowledgements / Contributors
Spatiotemporal dynamics of Dengue viruses
Orchid M. Allicock, Philippe Lemey, Andrew J. Tatem,,Oliver G. Pybus, Shannon N.
Bennett,Brandi A. Mueller, Marc A. Suchard,Jerome E. Foster Andrew Rambaut,
Christine V. F. Carrington
Challenges to dengue reporting & surveillance in Trinidad & Tobago. Nikita
Sahadeo, Arianne Brown A, Leslie Carrington, Christine V.F. Carrington.
Provision of DENV isolates and sera. CARPHA (CAREC), Trinidad Public Health
Laboratories
Funding: UWI-RDI Fund, Commonwealth Scholarship Commission, Caribbean Health
Research Council, UWI Campus Research & Publications Fund, International Society
for Infectious Disease