Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases

Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences—consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies.

[1]  Alexander Grey,et al.  The Mathematical Theory of Infectious Diseases and Its Applications , 1977 .

[2]  T. Scott,et al.  Skeeter Buster: A Stochastic, Spatially Explicit Modeling Tool for Studying Aedes aegypti Population Replacement and Population Suppression Strategies , 2009, PLoS neglected tropical diseases.

[3]  C. M. Gonçalves,et al.  Distinct variation in vector competence among nine field populations of Aedes aegypti from a Brazilian dengue-endemic risk city , 2014, Parasites & Vectors.

[4]  Richard J Maude,et al.  The role of simple mathematical models in malaria elimination strategy design , 2009, Malaria Journal.

[5]  Raymond A Smego Effectiveness of antimalarial drugs. , 2005, The New England journal of medicine.

[6]  R. May,et al.  Directly transmitted infections diseases: control by vaccination. , 1982, Science.

[7]  Karline Soetaert,et al.  Inverse Modelling, Sensitivity and Monte Carlo Analysis in R Using Package FME , 2010 .

[8]  Yanzhao Cao,et al.  Optimal control of vector-borne diseases: Treatment and prevention , 2009 .

[9]  D. Gubler,et al.  The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle? , 2004, Comparative immunology, microbiology and infectious diseases.

[10]  D. McNaughton,et al.  Designing a Community Engagement Framework for a New Dengue Control Method: A Case Study from Central Vietnam , 2014, PLoS neglected tropical diseases.

[11]  David L. Smith,et al.  Mosquito Population Regulation and Larval Source Management in Heterogeneous Environments , 2013, PloS one.

[12]  Frank H. Collins,et al.  A Research Agenda for Malaria Eradication: Vector Control , 2011, PLoS medicine.

[13]  Hervé C Bossin,et al.  Transgenic mosquitoes and the fight against malaria: managing technology push in a turbulent GMO world. , 2007, The American journal of tropical medicine and hygiene.

[14]  Willem Takken,et al.  Ecological aspects for application of genetically modified mosquitoes , 2003 .

[15]  Kenichi W. Okamoto,et al.  A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Stochastic, Spatial Model , 2013, PloS one.

[16]  F. Carrat,et al.  A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics , 2006, BMC medicine.

[17]  J A P Heesterbeek,et al.  The type-reproduction number T in models for infectious disease control. , 2007, Mathematical biosciences.

[18]  F. Agusto,et al.  Impact of mating behaviour on the success of malaria control through a single inundative release of transgenic mosquitoes. , 2014, Journal of theoretical biology.

[19]  Priyanga Amarasekare,et al.  The biological control of disease vectors. , 2012, Journal of theoretical biology.

[20]  Peter S Hill,et al.  Development of a framework for evaluating the sustainability of community-based dengue control projects. , 2009, The American journal of tropical medicine and hygiene.

[21]  Pierre Degond,et al.  From Bloch model to the rate equations , 2004 .

[22]  R. Ross,et al.  Prevention of malaria. , 2012, BMJ.

[23]  Lawrence M. Wein,et al.  Analyzing the control of mosquito-borne diseases by a dominant lethal genetic system , 2007, Proceedings of the National Academy of Sciences.

[24]  N. Halsey,et al.  Measles in developing countries , 2006, BMJ : British Medical Journal.

[25]  Austin Burt,et al.  Requirements for effective malaria control with homing endonuclease genes , 2011, Proceedings of the National Academy of Sciences.

[26]  David N. Fisman,et al.  Estimation of the Health Impact and Cost-Effectiveness of Influenza Vaccination with Enhanced Effectiveness in Canada , 2011, PloS one.

[27]  Bernadette A. Thomas,et al.  Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[28]  Camilla Beech,et al.  Open Field Release of Genetically Engineered Sterile Male Aedes aegypti in Malaysia , 2012, PloS one.

[29]  Lorenz von Seidlein,et al.  Artemisinin resistance: current status and scenarios for containment , 2010, Nature Reviews Microbiology.

[30]  Zhiyong Xi,et al.  The Endosymbiotic Bacterium Wolbachia Induces Resistance to Dengue Virus in Aedes aegypti , 2010, PLoS pathogens.

[31]  M E Halloran,et al.  Optimal vaccine trial design when estimating vaccine efficacy for susceptibility and infectiousness from multiple populations. , 1998, Statistics in medicine.

[32]  W. Takken,et al.  Interindividual variation in the attractiveness of human odours to the malaria mosquito Anopheles gambiae s. s. , 2006, Medical and veterinary entomology.

[33]  Prashant Yadav,et al.  A Research Agenda for Malaria Eradication: Vaccines , 2019 .

[34]  Amanda Ross,et al.  Mathematical modeling of the impact of malaria vaccines on the clinical epidemiology and natural history of Plasmodium falciparum malaria: Overview. , 2006, The American journal of tropical medicine and hygiene.

[35]  R. Anderson,et al.  Measles in developing countries. Part II. The predicted impact of mass vaccination , 1988, Epidemiology and Infection.

[36]  Robert S McCann,et al.  Reemergence of Anopheles funestus as a vector of Plasmodium falciparum in western Kenya after long-term implementation of insecticide-treated bed nets. , 2014, The American journal of tropical medicine and hygiene.

[37]  Christl A Donnelly,et al.  Late-acting dominant lethal genetic systems and mosquito control , 2007, BMC Biology.

[38]  Christopher Dye,et al.  Models for the population dynamics of the yellow fever mosquito, Aedes aegypti , 1984 .

[39]  S. Brailsford,et al.  Impact of combined vector-control and vaccination strategies on transmission dynamics of dengue fever: a model-based analysis , 2015, Health care management science.

[40]  Hiroshi Nishiura,et al.  Mathematical and statistical analyses of the spread of dengue , 2006 .

[41]  Yongyuth Yuthavong,et al.  A Research Agenda for Malaria Eradication: Drugs , 2011, PLoS medicine.

[42]  Christophe Boëte,et al.  A theoretical approach to predicting the success of genetic manipulation of malaria mosquitoes in malaria control , 2002, Malaria Journal.

[43]  Murray E Alexander,et al.  A comparative evaluation of modelling strategies for the effect of treatment and host interactions on the spread of drug resistance , 2009, Journal of Theoretical Biology.

[44]  Thomas Walker,et al.  Limited Dengue Virus Replication in Field-Collected Aedes aegypti Mosquitoes Infected with Wolbachia , 2014, PLoS neglected tropical diseases.

[45]  C. Shiff,et al.  Integrated Approach to Malaria Control , 2002, Clinical Microbiology Reviews.

[46]  R. Bos,et al.  Exploiting the potential of vector control for disease prevention , 2005 .

[47]  Fred Gould,et al.  A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Deterministic Model , 2013, PloS one.

[48]  Christophe Boëte,et al.  Evolutionary ideas about genetically manipulated mosquitoes and malaria control. , 2003, Trends in parasitology.

[49]  S. Halstead,et al.  Controlling Dengue with Vaccines in Thailand , 2012, PLoS neglected tropical diseases.

[50]  H. McCallum,et al.  How should pathogen transmission be modelled? , 2001, Trends in ecology & evolution.

[51]  Modelling,et al.  malERA: An updated research agenda for combination interventions and modelling in malaria elimination and eradication , 2017, PLoS medicine.

[52]  Jason L. Rasgon,et al.  Multi-Locus Assortment (MLA) for Transgene Dispersal and Elimination in Mosquito Populations , 2009, PloS one.

[53]  A. James,et al.  Engineering RNA interference-based resistance to dengue virus type 2 in genetically modified Aedes aegypti. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Peter Winskill,et al.  Genetic control of Aedes aegypti: data-driven modelling to assess the effect of releasing different life stages and the potential for long-term suppression , 2014, Parasites & Vectors.

[55]  Amy C Morrison,et al.  Characteristics of the spatial pattern of the dengue vector, Aedes aegypti, in Iquitos, Peru. , 2003, The American journal of tropical medicine and hygiene.

[56]  S. Ritchie,et al.  The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations , 2011, Nature.

[57]  Sibao Wang,et al.  Genetic approaches to interfere with malaria transmission by vector mosquitoes. , 2013, Trends in biotechnology.

[58]  David M. Hartley,et al.  A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970–2010 , 2013, Journal of The Royal Society Interface.

[59]  Andrew J. Tatem,et al.  Recasting the theory of mosquito-borne pathogen transmission dynamics and control , 2014, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[60]  Pejman Rohani,et al.  Dynamics of infectious diseases and pulse vaccination: Teasing apart the embedded resonance effects , 2006 .

[61]  Geoffrey Louis Chi-Johnston,et al.  Mathematical Modeling of Malaria: Theories of Malaria Elimination , 2012 .

[62]  S W Lindsay,et al.  A malaria control trial using insecticide-treated bed nets and targeted chemoprophylaxis in a rural area of The Gambia, west Africa. 5. Design and implementation of the trial. , 1993, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[63]  Nikos Vasilakis,et al.  Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public health , 2011, Nature Reviews Microbiology.

[64]  Y Dumont,et al.  Mathematical studies on the sterile insect technique for the Chikungunya disease and Aedes albopictus , 2012, Journal of mathematical biology.

[65]  Karline Soetaert,et al.  Solving Differential Equations in R: Package deSolve , 2010 .

[66]  Louise A Kelly-Hope,et al.  Malaria and lymphatic filariasis: the case for integrated vector management. , 2013, The Lancet. Infectious diseases.

[67]  Chonggang Xu,et al.  Modeling the Dynamics of a Non-Limited and a Self-Limited Gene Drive System in Structured Aedes aegypti Populations , 2013, PloS one.

[68]  Alan Brooks,et al.  Modeling the public health impact of malaria vaccines for developers and policymakers , 2013, BMC Infectious Diseases.

[69]  Erin N. Bodine,et al.  The antiretroviral rollout and drug-resistant HIV in Africa: insights from empirical data and theoretical models. , 2005, AIDS.

[70]  Peter A. Ryan,et al.  A Wolbachia Symbiont in Aedes aegypti Limits Infection with Dengue, Chikungunya, and Plasmodium , 2009, Cell.

[71]  E Massad,et al.  Will people change their vector-control practices in the presence of an imperfect dengue vaccine? , 2013, Epidemiology and Infection.

[72]  Jeremy N. Burrows,et al.  The state of the art in anti-malarial drug discovery and development. , 2011 .

[73]  Peter G Szilagyi,et al.  Vaccine epidemiology: efficacy, effectiveness, and the translational research roadmap. , 2010, The Journal of infectious diseases.

[74]  K. Mulholland,et al.  Measles and pertussis in developing countries with good vaccine coverage , 1995, The Lancet.

[75]  C. Donnelly,et al.  Field performance of engineered male mosquitoes , 2011, Nature Biotechnology.

[76]  Karline Soetaert,et al.  A Practical Guide to Ecological Modelling: Using R as a Simulation Platform , 2008 .

[77]  Joshua M. Epstein,et al.  Modelling to contain pandemics , 2009, Nature.

[78]  John J. Grefenstette,et al.  A game dynamic model for vaccine skeptics and vaccine believers: measles as an example. , 2012, Journal of theoretical biology.

[79]  J Hemingway,et al.  A malaria control trial using insecticide-treated bed nets and targeted chemoprophylaxis in a rural area of The Gambia, west Africa. 3. Entomological characteristics of the study area. , 1993, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[80]  C. F. Curtis,et al.  Measuring public-health outcomes of release of transgenic mosquitoes , 2004 .

[81]  M. Malecela,et al.  Neglected Tropical Diseases and the Millennium Development Goals-why the "other diseases" matter: reality versus rhetoric , 2011, Parasites & Vectors.

[82]  Michael B. Bonsall,et al.  A Model Framework to Estimate Impact and Cost of Genetics-Based Sterile Insect Methods for Dengue Vector Control , 2011, PloS one.

[83]  D. Earn,et al.  A simple model for complex dynamical transitions in epidemics. , 2000, Science.

[84]  M. G. Roberts,et al.  A new method for estimating the effort required to control an infectious disease , 2003, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[85]  Solomon Nwaka,et al.  Science & society: Virtual drug discovery and development for neglected diseases through public–private partnerships , 2003, Nature Reviews Drug Discovery.

[86]  S. Blower,et al.  Control Strategies for Tuberculosis Epidemics: New Models for Old Problems , 1996, Science.

[87]  S. Halstead,et al.  Dengue vaccine development: a 75% solution? , 2012, The Lancet.

[88]  Randy Kobes,et al.  Effects of vaccination and population structure on influenza epidemic spread in the presence of two circulating strains , 2011, BMC public health.

[89]  Edward C. Holmes,et al.  Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes , 2013, Proceedings of the National Academy of Sciences.

[90]  Julien Arino,et al.  A model for influenza with vaccination and antiviral treatment. , 2008, Journal of theoretical biology.

[91]  Kenichi W. Okamoto,et al.  Feasible Introgression of an Anti-pathogen Transgene into an Urban Mosquito Population without Using Gene-Drive , 2014, PLoS neglected tropical diseases.

[92]  N. Hens,et al.  Dynamic Epidemiological Models for Dengue Transmission: A Systematic Review of Structural Approaches , 2012, PloS one.

[93]  N. Ling The Mathematical Theory of Infectious Diseases and its applications , 1978 .

[94]  Saravudh Suvannadabba,et al.  Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial , 2012, The Lancet.

[95]  P. Pitisuttithum,et al.  Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial , 2014, The Lancet.

[96]  C. Dye,et al.  Population dynamics of mosquito-borne disease: effects of flies which bite some people more frequently than others. , 1986, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[97]  E. McGraw,et al.  Beyond insecticides: new thinking on an ancient problem , 2013, Nature Reviews Microbiology.

[98]  B. Murphy,et al.  Prospects for a dengue virus vaccine , 2007, Nature Reviews Microbiology.

[99]  Christl A. Donnelly,et al.  Suppression of a Field Population of Aedes aegypti in Brazil by Sustained Release of Transgenic Male Mosquitoes , 2015, PLoS neglected tropical diseases.

[100]  Alun L Lloyd,et al.  Stochasticity and heterogeneity in host–vector models , 2007, Journal of The Royal Society Interface.

[101]  Inacio Mandomando,et al.  Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial , 2004, The Lancet.

[102]  Chonggang Xu,et al.  Assessing the Feasibility of Controlling Aedes aegypti with Transgenic Methods: A Model-Based Evaluation , 2012, PloS one.

[103]  David L. Smith,et al.  Ross, Macdonald, and a Theory for the Dynamics and Control of Mosquito-Transmitted Pathogens , 2012, PLoS pathogens.

[104]  Kelly Chibale,et al.  The state of the art in anti-malarial drug discovery and development. , 2011, Current topics in medicinal chemistry.

[105]  M. Halloran,et al.  Design and interpretation of vaccine field studies. , 1999, Epidemiologic reviews.

[106]  Duane J. Gubler,et al.  A Critical Assessment of Vector Control for Dengue Prevention , 2015, PLoS neglected tropical diseases.

[107]  Christl A. Donnelly,et al.  Considerations in the Design of Clinical Trials to Test Novel Entomological Approaches to Dengue Control , 2012, PLoS neglected tropical diseases.