Spatio-temporal dynamics of drug-resistant Plasmodium falciparum malaria in Africa: implications for public health

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

Malaria is a parasite which can cause severe illness and death in humans if they do not receive effective treatment. In the 1990s, parasites resistant to malaria drugs spread from Asia throughout the African continent, causing mortality from the disease to double or triple in many areas. New, effective artemisinin therapies are now used across the world. However, recently parasites in South-East Asia have developed resistance to these new treatments and are highly likely to spread to Africa once again.

Dr Okell, a researcher based in the Department of Infectious Disease Epidemiology at Imperial College London, will develop a computer simulation to describe how resistant strains spread across Africa over time, based on extensive analysis of historical data on resistance. Through understanding what factors contributed towards or prevented the spread of drug resistance in the past, the research will identify which control strategies could be the most effective against the new resistant parasites. For example, national control programs could improve the accuracy of diagnosis to reduce the overuse of treatment, or introduce better transmission control. As more than 80% of global malaria cases (200 million) occur in Africa, successful control of drug resistance will have a huge public health impact.

Technical Summary

Background

In the 1990s, the spread of drug-resistant Plasmodium falciparum malaria strains in Africa after importation from South-East Asia led to a substantial increase in malaria mortality. New first-line antimalarial treatments, artemisinin combination therapies (ACTs), are currently efficacious in Africa but artemisinin-resistant strains have recently emerged in South-East Asia. Artemisinin resistance is likely to spread to Africa where more than 80% of global malaria cases currently occur. Given the lack of affordable alternative antimalarials, understanding how resistance spreads in Africa and how it can be contained is a key public health question. An important first step is to characterize the spread of resistance to sulphadoxine-pyrimethamine (SP), the previous first line treatment. Molecular analysis has made it possible to measure the spread of parasite lineages resistant to SP across Africa over time. Mathematical models are powerful tools for analysis of such data. The aim of this project is to use models to identify causal factors behind the pattern of SP resistance spread, indicate likely dispersal routes of artemisinin resistance for monitoring purposes and compare proposed control strategies.



Proposed work

The first objective of this project is to develop a spatially-structured transmission model to describe the spread of SP-resistant genotypes over time across Africa. Factors likely to determine the rate of spread of a resistant strain will be incorporated, including the usage of the antimalarial, the level of transmission intensity, the evolutionary fitness of the resistant strain relative to competing wild-types, and pharmacokinetics of the drug. Available administrative area-level data on antimalarial use and transmission intensity will be used in a metapopulation model framework. Furthermore the role of human travel in transferring resistant strains from Asia to Africa and between areas within Africa will be investigated using gravity models and migration data. The model will be calibrated against geo-referenced data on the prevalence of SP resistance mutations. The next main objective is to adapt the fully-developed model to characterize the potential spatio-temporal spread of artemisinin-resistant parasites under different scenarios and identify key countries at risk where artemisinin resistance should be monitored. Proposed policies to contain this spread will be modelled and contrasted, including vector control, preventing overuse of treatment, introducing multiple first-line therapies and preventing artemisinin monotherapy use. Such models could be key to informing policy given the public health urgency and lack of resources to empirically test the full range of control options across different endemic areas.

Publications

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Gosling RD (2011) The role of antimalarial treatment in the elimination of malaria. in Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

 
Description Citation in Lancet review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
URL http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60310-4/abstract
 
Description Citation in Trends in Parasitology Review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
URL http://www.sciencedirect.com/science/article/pii/S1471492214000336
 
Description Citation in World Health Organization policy document
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Increased use of sensitive malaria diagnostics which increase the number of infections detected and therefore increase treatment rates, reduce transmission, and help to give a better understanding of the true burden of malaria.
URL http://www.who.int/malaria/publications/atoz/policy-brief-diagnosis-low-transmission-settings/en/
 
Description Citation in World Health Organization policy document
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Increased use of sensitive malaria diagnostics which increase the number of infections detected and therefore increase treatment rates, reduce transmission, and help to give a better understanding of the true burden of malaria.
URL http://www.who.int/malaria/publications/atoz/policy-brief-diagnosis-low-transmission-settings/en/
 
Description Citation in World Health Organization policy document
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Increased use of sensitive malaria diagnostics which increase the number of infections detected and therefore increase treatment rates, reduce transmission, and help to give a better understanding of the true burden of malaria.
URL http://www.who.int/malaria/publications/atoz/policy-brief-diagnosis-low-transmission-settings/en/
 
Description Invited talk at Bill &Melinda Gates Foundation, Modeling the Impact of Diagnostics in Global Health Convening Meeting, Seattle: The sensitivity of malaria microscopy
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Invited talk, Modeling to Support Decision Making Meeting, Bill & Melinda Gates Foundation, Seattle: Estimating the impact of dihydroartemisinin-piperaquine on malaria transmission.
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description PATH Technical Advisory Group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
URL http://sites.path.org/dx/malaria/malaria-elimination/
 
Description Presentation at Medicines for Malaria Venture, Geneva
Geographic Reach Africa 
Policy Influence Type Participation in advisory committee
 
Description Report for the World Health Organization Malaria Policy Advisory Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description WHO molecular diagnostics evidence review
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Increased use of sensitive malaria diagnostics which increase the number of infections detected and therefore increase treatment rates, reduce transmission, and help to give a better understanding of the true burden of malaria.
 
Description Challenge Grant
Amount £99,998 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 12/2016 
End 12/2017
 
Description Royal Society Dorothy Hodgkin Fellowship
Amount £483,615 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2020
 
Description Royal Society Fellows Enhancement Award
Amount £105,750 (GBP)
Funding ID RGF\EA\180225 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2022
 
Title Estimating SNP frequency tool 
Description Along with a publication (see below) we published code which estimates SNP frequencies in human Plasmodium falciparum malaria infections, adjusting for multiclonal infections. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2017 
Provided To Others? Yes  
Impact None yet. 
URL https://www.nature.com/articles/s41598-017-06708-9
 
Title Model to estimate malaria prevalence 
Description Based on a systematic review, we provided a spreadsheet tool to estimate malaria prevalence, converting between microscopy and PCR measures. This was provided as a supplement in an Open Access online publication. 
Type Of Material Computer model/algorithm 
Year Produced 2012 
Provided To Others? Yes  
Impact Other research groups are using this model to estimate malaria prevalence. 
URL http://www.nature.com/ncomms/journal/v3/n12/abs/ncomms2241.html#supplementary-information
 
Title PCR & microscopy prevalence systematic review 
Description Database from a systematic review of the prevalence of malaria when measured by different diagnostic techniques: PCR versus microscopy, and other characteristics of studies. The raw data were made available online as part of a publication PMID 23212366 
Type Of Material Database/Collection of data 
Year Produced 2012 
Provided To Others? Yes  
Impact The World Health Organization requested a more detailed version of the raw data. 
URL http://www.nature.com/ncomms/journal/v3/n12/full/ncomms2241.html
 
Title RDT-PCR-microscopy systematic review 
Description This contains the results of a quantitative review of malaria diagnostic methods when used in asymptomatic populations (rapid diagnostic tests, PCR, microscopy). Published as a spreadsheet supplement to the publication detailed below. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact None yet (published Dec 2015) 
URL http://www.nature.com/nature/journal/v528/n7580_supp_custom/full/nature16039.html
 
Description Malawi/Kenya 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Charity/Non Profit 
PI Contribution I recruited a Research Assistant from Malawi, on a UK Royal Society Global Challenges grant, in June 2017 to undertake modelling of the impact of intermittent treatment in pregnancy for malaria on drug resistance development. He worked for a year and a half working with me training in mathematical modelling.
Collaborator Contribution The partner hosted our postdoc for a number of months in Malawi, provided supervision and regular phone calls to discuss the progress of the project. They are also currently undertaking large trials of intermittent preventive treatment in pregnant women, and these trials helped to inform our modelling analysis.
Impact The RA recruited has now gone on to a PhD to LSHTM in the same field, which we hope will contribute to capacity building.
Start Year 2016
 
Description Medicines for Malaria Venture 
Organisation Medicines for Malaria Venture (MMV)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution We are using mathematical modelling to estimate the impact of both existing antimalarial drugs and also products in development on malaria transmission, and their cost-effectiveness.
Collaborator Contribution Funding (research costs and 1 postdoc for 3 years), requests for research and advice on ongoing work.
Impact A data collaboration with the Worldwide Antimalarial Resistance Network and Sanofi Ltd to access clinical trial data. We published three papers: Nature Communications (2017), Malaria Journal (2017) and Trends in Parasitology (2017).
Start Year 2013
 
Description Medicines for Malaria Venture 
Organisation Medicines for Malaria Venture (MMV)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Analysis of data and modelling to estimate impact of post-treatment prophylaxis by the new antimalarial DHA-piperaquine.
Collaborator Contribution Advice on project, funding travel to meetings.
Impact Presentation at MMV meeting in Geneva Symposium at ASTMH 2012, Atlanta, showing initial results. Full report to MMV: Modelling to maximize the benefits of ACTs: Final report to Medicines for Malaria Venture. July 2013 Publication in Nature communications PMID 25425081.
Start Year 2012
 
Description Member of Diagnostics Modelling Consortium 
Organisation Bill and Melinda Gates Foundation
Department Diagnostics Modelling Consortium
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a member of this consortium funded by the Bill & Melinda Gates Foundation, working on identifying target product profiles for a malaria diagnostics with different uses. I am helping to supervise two students on a project to systematically review and compare diagnostic techniques. I attend meetings and give feedback on work done by others in the consortium.
Collaborator Contribution Overview and deciding research questions, as well as giving feedback on research underway by the consortium members.
Impact Publication: Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategies. Wu L, van den Hoogen LL, Slater H, Walker PG, Ghani AC, Drakeley CJ, Okell LC. Nature. 2015 Dec 3;528(7580):S86-93. doi: 10.1038/nature16039.
Start Year 2014
 
Description Member of Malaria Modelling Consortium 
Organisation Bill and Melinda Gates Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution I participated in consortium meetings, and contributed substantially to a Malaria Modelling Consortium report to the World Health Organization Malaria Policy Advisory Group on results from modelling mass drug administration for malaria control.
Collaborator Contribution Other modelling partners contribute modelling results, the Gates Foundation coordinate activities, arrange meetings and fund travel for the meetings.
Impact Malaria Modelling Consortium report to the World Health Organization Malaria Policy Advisory Group on results from modelling mass drug administration for malaria control. This is now published as a paper in Lancet Global Health.
Start Year 2015
 
Description START-IPT study collaborator 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have produced models of Intermittent Preventive Treatment for malaria in school children, to assist the design of a trial and give an estimate of likely effect.
Collaborator Contribution Design and carrying out a cluster-randomized trial of Intermittent Preventive Treatment for malaria in school children in Uganda.
Impact Informed trial design. The collaboration is multi disciplinary, including mathematical modellers, clinicians, epidemiologists.
Start Year 2014
 
Description Sanofi data collaboration 
Organisation Sanofi
Country Global 
Sector Private 
PI Contribution We have carried out secondary analysis of trial data, to estimate the post-treatment prophylactic effect of artesunate amodiaquine.
Collaborator Contribution They contributed data.
Impact Publication draft in progress.
Start Year 2014
 
Description WHO 
Organisation World Health Organization (WHO)
Country Global 
Sector Public 
PI Contribution Supervision of a postdoctoral researcher to work on analysis of the impact of artemisinin resistance in Africa.
Collaborator Contribution Funding and overview, advice on research approach
Impact A report to the World Health Organization: Assessing the impact of artemisinin resistance in Sub-Saharan Africa: Final report to the World Health Organization. December 2013
Start Year 2013
 
Description WWARN 
Organisation Worldwide Antimalarial Resistance Network
Country Global 
Sector Charity/Non Profit 
PI Contribution We set up a study group in 2013 in collaboration with WWARN to conduct an analysis on the prophylactic protection given by the antimalarial amodiaquine. In 2016 we set up a further study group with WWARN to conduct analysis of multiple clinical trials of the antimalarial mefloquine.
Collaborator Contribution WWARN contributed data and guidance.
Impact N/A
Start Year 2013