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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. 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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  1. Invasion, expansion and maintenance of Dengue & Chikungunya viruses in the Americas. Christine V. F. Carrington 12 June 2014

  2. 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

  3. 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)

  4. 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

  5. ChikungunyaRe-emerging mosquito-borne viral disease in the Old worldRecently emerging in the New World • http://www.cdc.gov/chikungunya/pdfs/ChikungunyaMap.pdf

  6. 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)

  7. 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.

  8. Transmission cyclesDengue virus and Chikungunya virus • Ae. aegypti • Ae. albopictus “ ”

  9. 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.

  10. 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).

  11. 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).

  12. 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.

  13. 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.

  14. 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

  15. June 2014

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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)

  21. 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.

  22. 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

  23. 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

  24. 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.

  25. 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)

  26. 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.

  27. 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.

  28. Spread of DENV 1 inferred from sequence data. Rapid dispersal followed by more localized maintenance Allicock et al (unpublished data)

  29. 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)

  30. 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)

  31. 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)

  32. 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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