Dengue Conference, Mandurai, India, July What role should mathematical models & transgenic mosquitoes play in dengue control programs in India?

Transcription

1 Dengue Conference, Mandurai, India, July 2013 What role should mathematical models & transgenic mosquitoes play in dengue control programs in India? John M. Marshall Department of Infectious Disease Epidemiology, Imperial College London, London, UK R 2 a bce 0 2 gr gn

2 Talk outline 1. Mathematical models: Why model? Malaria model developed at Imperial College Steps to building a dengue model for India Usage in policy development 2. GM mosquitoes: Mother Teresa GM sterile males Wolbachia Population replacement Public attitudes

3 Why model? Provides a framework to: Synthesize information Answer difficult questions Natural history of pathogen Population demography Contact patterns Epidemiology Available interventions Model Conceptual understanding (simple model) Predictions (realistic, validated model) Operational (intervention, delivery, monitoring, etc.)

4 Difficult questions 1. Suppose a 30% efficacious vaccine became available for malaria, what impact would it have on transmission in Africa? 2. Or a dengue vaccine for India? 3. For HIV, how often do people need to be tested for Treatment as Prevention to work? 4. Of all the interventions being proposed to control dengue in India at this meeting, what is the ideal combination in each regional transmission setting?

5 Malaria transmission model Larval Stages (Instars & pupae) Adult mosquitoes Parasite transmission People Ecological constraints on carrying capacity (K) Rainfall-driven seasonality Temperature

6 Environmental data input into model Satellite-derived high resolution data determines larval capacity K: Climate MIR EVI Day & night temperature Rainfall Altitude Population density Land-use

7 Fitting model to epidemiological data Model fitted using MCMC to seasonand age-stratified parasite prevalence data from MARA Excludes data recorded during interventions 3561 locations fitted to. 379 (~10%) retained for validation. 73% correlation between observed and predicted PrP 2-10 in validation data Parameter estimates used in v. large scale simulation of malaria in Africa.

8 Vectors per person EIR PrP 2-10 Pre-intervention malaria map % 100% 40% 30% 20% 10% 0% Year Log(EIR) PrP 2-10

9 Vectors per person EIR PrP 2-10 Scaling up LLINs and IRS (currently available tools) LLINs every 5 years, IRS every 3 years, 80% coverage, staggered timing. 40% 30% 20% 10% 0% Log(EIR) PrP Year

10 Vectors per person EIR PrP 2-10 Transmission blocking vaccine 90% coverage, 95% reduction in transmission, plus LLIN & annual IRS 40% 30% 20% 10% 0% Log(EIR) PrP Year

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14 Modeling dengue transmission in India Some things to consider: Dengue virus: 4 serotypes (+ multiple genotypes) Cross-protective immunity Antibody-dependent enhancement Vector population: Ae. aegypti vs. An. albopictus Dependence on climate/environment Seasonality/monsoon season Human population: Urban/rural distribution Age/gender/socio-economic status Mobility & contact patterns -> Try to reproduce dynamics of dengue epidemics

15 Modeling dengue transmission in India Interventions: Vector control: Fogging, insecticide spraying Removal of breeding containers Vaccine: Sanofi Pasteur (furthest in development, phase 2b trial) Some efficacy against DENV 1, 3 & 4 No efficacy against DENV 2 GM mosquitoes: Sterile males (RIDL) Wolbachia (lifespan shortening, refractory to dengue, spatial spread) Integrate into modeling framework -> Determine combinations of interventions that are likely effective

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19 GM sterile mosquitoes (RIDL) Pros: Species-specific. Genetic sexing methods are available. GM males are more fit than irradiated males. Cons: Requires continued release.

20 Wolbachia-infected mosquitoes Wolbachia: wmelpop strian: Is an inherited intracellular bacterium capable of manipulating its host s reproductive biology to favor its spread through a population. Has several beneficial features for dengue control in Ae. aegypti: Reduced mosquito lifespan. Reduced dengue viral load. Reduced ability to obtain blood meals with age.

21 Genetic population replacement Use of gene drive systems to spread disease-refractory genes into mosquito populations. e.g. Medea: + refractory gene: A dengue refractory gene in Aedes aegypti has been engineered by taking advantage of a natural antiviral pathway in the mosquito and placing it under the control of a blood-meal specific promoter.

22 Public attitude surveys in Mali suggest that people would like to see a successful confined trial before accepting a release: I would have to see an example of modified mosquitoes reducing malaria in another village before I believe this claim 72-year-old man, Tienfala, Mali

23 Conclusion 1. What role should mathematical models play in dengue control programs in India? Biologically-meaningful models fitted to local data can be used to determine: Optimal combinations of interventions Potential of current vector control Impact of a partially effective vaccine Impact of GM mosquitoes & Wolbachia 2. What role should GM mosquitoes play in dengue control programs in India? RIDL is an effective populations suppression strategy, but requires continued releases Wolbachia-infected mosquitoes have shown great promise in Australian trials Population replacement technologies are still in development

24 Malaria group, Imperial College Hay lab, Caltech Neil Ferguson Maria-Gloria Basanez Tom Churcher Deirdre Hollingsworth John Marshall Lucy Okell Jamie Griffin Azra Ghani Wes Hinsley Emilie Pothin Tini Garske Michael White Bhargavi Rao Emmett Elvin Mother Teresa