Modeling Driving-Y Gene Drive - PowerPoint Presentation

1. Modeling Driving-Y Gene DrivetoEliminate Malariain the Democratic Republic of Congo (DRC)Nawaphan Metchanun Center for Development Research (ZEF)16.04.2019

2. DRC is facing challenges in malaria control2The second highest malaria burden countryNearly all of the DRC population lives in high malaria transmission zones The difficulty in access to malaria control methods has been prominent in this complex operating environment

3. Ongoing challenges in the management of malaria3Current methods for malaria control focus on Drug therapyVector controlKey challengesResistance to anti-malarial drugsInsecticide resistanceResidual and outdoor transmission

4. Difficult to implement core vector control methods4Core vector control methodsLong-lasting insecticidal nets (LLINs)Indoor residual spraying (IRS) There are limitations to LLINs/IRS, and that we need to look beyond these tools to find novel vector control interventionsOne proposed set of tools relies on the release of genetically modified mosquitoes

5. Gene drive allows some genes to spread rapidly through populations 5Mendelian inheritance versus Gene drive inheritance

6. Three approaches are considered and developed for using gene drive in the context of malaria6Mosquito population replacementMoving an anti-parasite transgene through the mosquito population, rendering it refractory to Plasmodium infection or ineffective at transmissionMosquito population suppressionTargeting fertility genes in mosquitoes leads to population suppression or collapseDriving-Y system: Y chromosome in the modified male mosquito damages the X chromosomes in the germline, resulting in gametes that predominantly carry a Y chromosome and a distorted sex ratio in viable offspring

7. Driving-Y gene drive as a new intervention?7Modified males have predominantly male offspringUnder certain parameters for X-shredding and fecundity reduction, this could lead to local population collapseDriving-Y gene drive

8. Driving-Y parameters8X-shredding rate: The shredding rate of the X chromosome in which favors the unaffected Y-bearing sperm and results in the production of a male-biased progeny.Fecundity reduction: The reduction of the potential to reproduce offspring

9. WHO targets malaria elimination by 20309Elimination: Reduction to zero (or a very low defined target rate) of new cases of an infectious disease in a defined geographical areaRequires continued measures to prevent re-establishment of disease transmissionEradication: The complete and permanent worldwide reduction to zero new cases of an infectious disease No further control measures are required

10. Applying Driving-Y model: could gene drives help the DRC achieve malaria elimination by 2030?10Simulation frameworkPlanning gene-drive mosquito release strategy in non-spatial setup:Assessed X-shredding rate and fecundity reduction Determined potential mosquito release patterns (frequency and number)Evaluating interventions in spatial setup:Built 8 models of 8 DRC provinces capturing transmission intensities, transmission seasonality, and demographicsIdentified current core malaria control methods that could help eliminate malaria for each provinceAdded driving-Y gene drive in packages that failed to achieve elimination to see if it could help achieve elimination

11. Modeling Driving-Y gene drives11Simulations were carried out using Epidemiological MODeling software (EMOD) version 2.18The mechanisms to implement gene drive were added to the basic EMOD model applying genetic variable:All females were wildtype while modified males carried a driving Y-chromosome  mating produced offspringFor each female that mated with a modified male, the total egg batch size was reduced by the parameter fecundity reduction Only females that mated with a driving-Y male had their fertility reduced

12. Effective gene drives required high X-shredding rate and low fecundity reduction12Driving-Y parameters of 200 gene-drive mosquitoes in Kinshasa provinceDriving-Y parameters that would later applied:Fecundity reduction: 0.05, 0.1, 0.15X-shredding rate: 0.9, 0.95, 1.0

13. Single release of sufficient amount worked faster13Kinshasa province

14. Target locations are representatives of what could happen everywhere in DRC14Provincial stratification based on reported malaria parasite prevalence* (%)The selected provinces span the range of transmission intensities across the whole countriesLarval habitat was calibrated to the reported parasite prevalence data*From prevalence data presented in DRC-Demographic and Health Survey (DHS) II 2013-2014

15. Applying interventions15ITN: Insecticide-Treated NetIRS: Indoor Residual SprayingACT: treatment of symptomatic cases with Artemisinin-based Combination TherapySchematic of scenario description for EMOD simulations conductedInterventions evaluated:• ITNs• IRS• ACT: Artemether + Lumefantrine• Driving-Y gene drive mosquitoesCoverage: 50%, 80%, and 95%Simulated 25 nodes (observation points) per province 5km between nodes  25km*25km gridVector migration300 gene drive mosquitoes were single released at central node of each location in scenarios that failed to reach elimination Other interventions were implemented in all nodes

16. Gene drives could help eliminate malaria in target locations within 15 years16NA = Not Applicable** = both single and 2-combination (50% ITN+ACT) failed to eliminate malaria

17. The present simulations focused on a single species Can be generalized in setting with multiple local Anopheles vectors (highest vectorial capacity  insufficient summed vectorial capacity to sustain malaria)Models Assumed no resistance Assumed no human migrationUsed mean transmission seasonality of year 2000-2015 for every node within the same provinceUsed mean parasite prevalence of estimated parasite rate in children between the ages of two and ten (PfPR2-10) year 2000-2015 for each nodeThe spatial simulations were performed within 25km*25km gridLimitations and future work17

18. Acknowledgement18Center for Development Research (ZEF), University of Bonn Christian Borgemeister Joachim von BraunThe German Academic Exchange Service (DAAD) The Institute for Disease Modeling (IDM) Jaline Gerardin Benoit Raybaud

19. Supplement 1: intervention coverage (DRC’s current national status) 19Source: WHO Malaria report 2018.

20. Supplement 2: intervention parameters applied 20InterventionParameterValueITNAdherence65%Probability of success when not fully compliant0%IRSAdherence100%Probability of success when not fully compliant0%ACT(Artemether + Lumefrantrine) Parameters and values used in the model followed (source)

21. Supplement 2: intervention parameters applied (2) 21ITNsinitial strength of the blocking effect for indoor mosquito fed on an individual with an ITN was 0.9 blocking decayed at an exponential rate in 730 daysinitial strength of the killing effect that the mosquitoes were killed, conditionally on a successfully blocked feed was 0.6. killing effect decayed at an exponential rate in 1,460 daysThe model assumed an individual who received a bednet used it and the bednet was replaced every 3 years.Since the ITN coverage was varied, the fraction of individuals in the target demographics received ITNs variedIRSThe model assumed no blocking effect though IRS also has a repellency effect which decayed over the period of 730 days The initial killing effect was 0.7 The initial killing efficacy is held 30 days, then the efficacy decays at an exponential rate over 120 days.