Invasion expansion and maintenance of dengue chikungunya viruses in the americas
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Invasion, expansion and maintenance of Dengue & Chikungunya viruses in the Americas. . Christine V. F. Carrington 12 June 2014. 3.5 billion people at risk Annually: 390 million infections ( 96 million clinically apparent ) 24,000 deaths

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Invasion, expansion and maintenance of Dengue & Chikungunya viruses in the Americas.

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Invasion expansion and maintenance of dengue chikungunya viruses in the americas

Invasion, expansion and maintenance of Dengue & Chikungunya viruses in the Americas.

Christine V. F. Carrington

12 June 2014


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

  • 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)

DengueThe most rapidly spreading mosquito-borne viral disease One of the most important emerging diseases of the 21st century

  • 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

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

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

  • 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

  • Laboratory confirmed dengue

Warning signs*

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

* Requiring strict observation and medical intervention

DENGUE: GUIDELINES FOR DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL: WHO, 2009


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

ChikungunyaRe-emerging mosquito-borne viral disease in the Old worldRecently emerging in the New World

  • http://www.cdc.gov/chikungunya/pdfs/ChikungunyaMap.pdf


Chikungunya virus chikv

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

Chikungunya Fever

Typical symptoms

  • High fever (40°C/ 104°F)

  • Joint pain (lower back, ankle, knees, wrists or phalanges)

  • Joint swelling

  • Rash

  • Headache

  • Muscle pain

  • Nausea

  • Fatigue

Rarely fatal.

Acute symptoms typically resolve within 7 – 10 days but some patients report persistent joint pains for months to years.


Transmission cycles dengue virus and chikungunya virus

Transmission cyclesDengue virus and Chikungunya virus

  • Ae. aegypti

  • Ae. albopictus

“ ”


Denv and chikv also exist in sylvatic cycles

DENV and CHIKV also exist in sylvatic cycles

  • B

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

“ ”

  • Forest dwelling

  • Aedes spp.

In Africa, during inter-epidemic periods, CHIKV is maintained in enzootic, sylvatic cycles.


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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).


Average annual no of dengue cases reported countries reporting dengue 1955 2007

Average annual no. of Dengue cases reported / countries reporting dengue, 1955–2007

Global emergence of Dengue

1970

2004

WHO 2009. Dengue: Guidelines for diagnosis, treatment, prevention & control

Guzman, M. G. et al. Dengue: A continuing global threat. Nature Reviews Microbiology 8, S7–S16 (2010).


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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

Larger, more frequent epidemics with increasing numbers of severe cases

Reports of Dengue-like illness since late 1700s.

Geographically restricted, self limiting outbreaks of DF

Figure adapted from Allicock et al (2012) Mol. Biol. Evol. 29(6):1533–1543.


Global expansion of chikv

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.


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

June 2014


Phylogeny of chikungunya viruses associated with outbreak in saint martin

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

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. HIV-associated 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

Majority of disease emergence is driven ecological factors associated with human activity

  • deforestation

  • habitat destruction

rapid global transport networks

modern agricultural practices

high-density human populations

unplanned urbanisation


Factors underlying the global emergence of denv

Factors underlying the global emergence of DENV

rapid global transport

global population growth

High density human populations

Inadequate infrastructure

unplanned urbanisation

Inadequate water supply

Improper waste disposal

WWII related troop movements and population displacement

water storage

water collection

  • mosquito breeding sites

Inadequate vector control + weak implementation of public health policies


Factors underlying the recent global emergence of chikv

Factors underlying the recent global emergence of CHIKV

Evolutionary changes

(adaptive E gene mutation favours replication in Ae. albopictus)

Increased tourism

Rapid global transport

Immune landscape

(Introduction in naïve populations)


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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 mosquito borne virus population size and patterns of spread

Factors that may influence changes in mosquito-borne 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

Traditional epidemiological approachUnderstanding 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

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.


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

A Phylogenetic Approach

Sample viruses

from population

Sequence genes / genomes from sampled individuals

Create data sets of aligned sequences

Newly derived + Genbank

Field trapped vectors. host reservoirs or patient serum

(Screening by PCR, cell culture)

PCR amplification and sequencing of specific genes

  • Estimate rates of evolution

  • Estimate dates of origin for individual viruses or lineages

Infer evolutionary relationshipsamong sequences

  • Reconstruct past population dynamics

  • Reconstruct spatial dynamics

Numerous computational approaches

(Maximum likelihood, Neighbour joining, Bayesian MCMC)

  • 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)


Phylogenies inferred for denv circulating in the americas

Phylogenies inferred for DENV circulating in the Americas

  • DENV 1, 2 and 4

    • Strong spatial structure

    • Clear pattern of lineage extinction and replacement

  • DENV 3

    • Greater gene flow among countries

    • Less evidence of lineage turnover

    • Exponential growth

DENV2

DENV3

Allicock et al. unpublished data;

Allicocket al (2012) Mol. Biol. Evol. 29(6):1533–1543.


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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;

Allicocket al (2012) Mol. Biol. Evol. 29(6):1533–1543.


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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

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)


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

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.

Urban centres attract virus.

C

DENV

DENV

A

B

Allicock et al (unpublished data)


Invasion expansion and maintenance of dengue chikungunya viruses in the americas

Air traffic is a good predictor of spatial diffusion patterns for DENV 1 - 3

DENV

More intense gene flow

Limitations

  • 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)

C

A

B

DENV

Less intense gene flow

Allicock et al (unpublished data)


Acknowledgements contributors

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


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