Developing methods to assess the impact of malaria interventions upon transmission and the progress towards elimination

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

Abstract

Malaria, an infectious disease transmitted by mosquitoes, is estimated to cause around 1 million deaths per year, with the majority of these deaths occurring in sub-Saharan Africa, primarily amongst young children. Over the last decade there has been an increase in funding from high-income countries and global agencies with the aim of reducing transmission and hence decreasing the burden of disease. This has resulted in the large-scale distribution of interventions of cheap and effective interventions such as the provision of protective bed nets and antimalarial medication in many parts of the world.

Malaria is, however, a complicated disease. It is spread between humans by mosquitoes and people become more immune to the disease the more they are infected (and less immune when they are not). This makes it difficult to work out the progress that has been made in reducing transmission. For example, a 50% reduction in the number of mosquito bites would not necessarily produce a 50% reduction in the proportion of people with malaria. Moreover, as transmission is imperfect and requires an infected mosquito to survive until it becomes infectious to humans, it is not necessary to kill all mosquitoes or prevent all members of the population from being bitten to achieve elimination.

In Western Kenya, particularly around the shores of Lake Victoria, malaria transmission remains intense, even in areas where bed nets have been used by the majority of the population for over a decade and despite the availability of effective anti-malarial medication for those with the disease. As a result, further intervention measures are currently being considered, including a forthcoming trial looking at the effects of testing all residents within a village for infection and giving highly effective anti-malarial medication to all those who test positive to infection in an attempt to break transmission. In order to better understand the progress towards this goal, and the implication the trial outcome has for malaria elimination more generally, it is important to understand where the trial started and where the trial ended in terms of transmission (i.e. the chances of an infected person passing infection to others via a mosquito), as this is the only reliable measure of the extent to which elimination is likely to be sustainable.

In this project, Dr Patrick Walker, a researcher at the Department of Infectious Disease Epidemiology, Imperial College, will use mathematical models of the spread of malaria to estimate the changes in transmission that occur during this trial to assess the progress being made towards local elimination of the disease. This will first involve developing a statistical technique which is able to estimate changes in transmission intensity during a previous trial of protective nets in the same area This work will also allow him to investigate the extent to which the disease spreads from one village to another and how this is affected by the presence of nets within different areas. This technique will then be adapted and applied to the different arms of the drug trial, taking into account changes in transmission up to the beginning of the trial.

In the event that the mass administration of anti-malarials proves effective as a tool for helping Western Kenya to eliminate malaria, this research will help to further define the criteria by which to judge where else in the world the intervention could be effective. Alternatively, if the intervention does not prove effective the work will provide an indication of the additional level of control required to achieve elimination. Moreover, monitoring whether transmission changes throughout the trial could provide an indication as to whether the effectiveness of anti-malarial drugs remains the same throughout the trial, which is an important consideration in light of concerns about drug resistance.

Technical Summary

Malaria is estimated to cause around 1 million deaths per year, with the majority of these deaths occurring in sub-Saharan Africa, primarily amongst young children. Over the last decade there has been an increase in funding from high-income countries and global agencies and renewed interest in achieving local elimination in various regions and the prospects of global eradication of the disease.
Measuring progress towards elimination requires an estimate of the reduction in transmission that has occurred over time and the proximity to the threshold reproduction number value of one. However, these changes are not linearly related to measures of disease prevalence and burden (the quantities often used to track progress). The first aim of this project is to develop and adapt methods used for reproduction number estimation in epidemic models to estimate the changes in transmission which have occurred in an area of Western Kenya which has served as a key focus for malaria research over the past few decades. This will provide estimates of the additional control necessary to achieve elimination in an area of intense transmission with high LLIN coverage. It will also provide insights into the direct and indirect effects of insecticide treated nets and how this varies during a long-term intervention.
The second objective of this fellowship is to estimate the impact of different control strategies involving the mass administration of artemisinin combination therapy on transmission during a forthcoming trial in the same area. The detailed data likely to be collected during this trial will be used to estimate transmission at a high spatial and temporal resolution. Using the results from the first part of the project of the level of transmission and trajectory of changing transmission prior to the trial, I will then assess the extent to which reductions in prevalence are likely to be sustainable and the prospects for elimination, both within the study area and more generally.

Planned Impact

The proposed research involves developing methods to assess the impact of interventions in terms of changes in transmission and progress towards elimination. This will also involve looking at the specific examples of the implementation and long-term use of ITNs and the impact of MSAT in areas of Western Kenya, a region which itself is the focus of much research interest. As a result, there are a wide range of likely beneficiaries of this work on a number of different levels.

At the local level, modelling the spatial and temporal dynamics of transmission in the area will provide public health officials and authorities with more information about how best to target available interventions, the possible impact of catch-up campaigns upon the likely spread of infection and the identification of key hotspots in transmission. Understanding the main foci of transmission in the area, before and after the IMSAT trial, is likely to be of particular importance when attempting to prevent any resurgence of malaria, if elimination has not been achieved by the end of the trial, or in ensuring elimination is sustained, in the event the trial is successful in completely interrupting transmission.

At a regional level, the work will provide insight into how the baseline epidemiological state of malaria endemicity and trends in intervention scale-up in different areas of Western Kenya, with the resulting impact this has had upon transmission, interact with the incremental prospects of MSAT for reducing the reproduction number below one. This will help inform malaria researchers from CDC/KEMRI, as well as Ministry of Health officials, as to whether these interventions can be applied more widely in the region to help move the level of transmission in Western Kenya and, in turn, the country itself towards achieving WHO-defined pre-elimination status.

The model outputs, in terms of the changes in transmission and the reproduction number achieved during the trial are also likely to be useful for comparing and explaining the effectiveness of MSAT in western Kenya, in terms of progress towards elimination, with those observed during similar trials in other countries. As member of the Imperial College Malaria Group, which is already heavily involved in determining optimal combinations of control packages in different settings, this will then help to inform the feasibility of using strategies involving mass drug administration across Africa as part of a globally integrated malaria control program. The development of tools capable of translating observed changes in readily available malariometric indices, either within the context of a trial or following the implementation of an intervention strategy, into reductions in transmission and the reproduction number are also likely to be of increasing importance as research effort continues to focus upon looking at strategies which aim to reduce transmission and which could feasibly lead to achieving malaria elimination. The beneficiaries of these outputs are likely to include major international agencies concerned with public health such as the World Health Organisation, the Bill and Melinda Gates Foundation and the US Centers for Disease Control.

Finally, in the long-term, an aim of the proposed research is to provide benefits to the wider public. The eradication of malaria would remove one of the greatest burdens upon global development, health and life-expectancy. It is hoped, by better understanding the capacity of the currently available tools, and some of those proposed in the near-future, to reduce transmission towards elimination in one of the historically most intense areas of transmission in the world, that this research will help to improve our knowledge about the feasibility of this aim.
 
Description Elimination Scenario Planning meeting - Ministry of Health, Port Moresby, Papua New Guinea
Geographic Reach Australia 
Policy Influence Type Participation in a national consultation
Impact I participated and presented during the Elimination Scenario Planning Workshop in Port Moresby. My presentation provided the ministry of health and other partners responsible for implementing malaria control with projections for the public health impact of different control strategies. This information is now helping these partners to prepare their concept note to be submitted to the Global Fund for replenishment of malaria control funding.
URL http://www.looppng.com/content/png-working-eliminate-malaria
 
Description Global Fund Elimination Scenario Planning- Senegal and The Gambia
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
 
Description Intermittent Screening and Treatment for malaria in pregnancy policy working group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact As a member of this working group I attended the Evidence Review group into the Intermittent screening and treatment in pregnancy and the safety of ACTs in the first trimester and presented mathematical modelling work which contributed directly to the recommendations made by this group. In particular, our modelling work looking at the potential benefit, in areas with high resistance of the existing drug used for intermittent preventative therapy, of adding a single screen-and-treat using a highly effective artemisinin combination therapy drug has led to WHO recommending this strategy should be trialled. Our work looking at the relationship between transmission and malaria in pregnancy burden also helped to "support[s] the current WHO position that it is not possible, based on current evidence, to establish a threshold level of malaria transmission below which IPTp-SP is no longer cost-effective".
URL http://www.who.int/malaria/mpac/mpac-sept2015-erg-mip-report.pdf
 
Description Published estimates of Impact of President's Malaria Initiative used in 12th annual report to congress
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Our estimates, published in PLoS Medicine, of the impact of the PMI since it's conception were used by PMI in it's report to congress. This report is used to advocate for resources for malaria prevention across 19 focus countries, amid a time when the US' contribution to foreign aid was being questioned.
URL https://www.pmi.gov/docs/default-source/default-document-library/pmi-reports/2018-pmi-twelfth-annual...
 
Description Research on the treatment and prevention of malaria in pregnancy in sub-Saharan Africa: East Africa Regional Meeting
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact This was the first of two regional meetings in Africa I will attend as part of the Implementation of Malaria in Pregnancy Policy Action Consortium (IMPPACT) a body aiming to translate WHO recommendations into country-level policy and implementation. This was a meeting between members of 6 different East African national malaria control programs, researchers such as myself and various other policymakers and implementing partners. My presentation summarised the current state of malaria pregnancy risk and burden and current coverage of interventions in each country. This emphasised that malaria in pregnancy becomes more severe as transmission falls and that many women most are at risk (young, first time mothers) are those least well protected by current strategies (insecticide treated nets and intermittent preventative therapy(IPTp)). This contributed substantially to hours of discussion on malaria in pregnancy policy between those directly responsible for implementing these interventions within country. The conclusions of this meeting, where consensus was reached that malaria in pregnancy remains a public health priority, are likely to have substantial policy, health and efficiency impact. For example, as was recommended in this meeting and by WHO, the strategy of switching to Intermittent Screening and Treatment in pregnancy has not been adopted by any country. The strategy of incorporating a single screen and treat on top of existing IPTp policy (a strategy being considered in part due to my research and presentations at the Evidence Review Group of WHO) has been adopted nationwide in both Kenya and Tanzania. As a result of this meeting I have remained in direct contact with members of the control programmes of both Zambia (Dr Busiku Hamainza) and Tanzania (Dr Frank Chaky) to conduct research into the potential for using data from such a strategy to inform malaria surveillance and operational planning.
URL http://www.mip-consortium.org/ConferenceProgramme.htm
 
Description EDCTP 2 Programme
Amount € 61,008 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 03/2016 
End 02/2017
 
Description Developing statistical tools to estimate the impact of malaria interventions upon transmission 
Organisation Pasteur Institute, Paris
Country France 
Sector Charity/Non Profit 
PI Contribution I am working with Dr Simon Cauchemez, the Director of the Mathematical Modelling of Infectious Diseases Unit to develop new inferential techniques which attempt to infer the impact of interventions such as insecticide treated nets. This involves using spatial and longitudinal data to look at how the effect of these interventions vary over space and time.
Collaborator Contribution Dr Simon Cauchemez is a world leader in these kinds of statistical techniques and provides vital methodological support.
Impact Meetings have taken place which have culminated in an early-stage model estimating spatial patterns of mosquito/human interaction and the subsequent impact of these being developed and fitted to trial data from Western Kenya. This tool will be further developed to provide a framework in which to look at the impact of interventions taking into account local heterogeneity in coverage and transmission intensity.
Start Year 2014
 
Description Diagnostics Modelling Consortium 
Organisation Bill and Melinda Gates Foundation
Department Diagnostics Modelling Consortium
Country United Kingdom 
Sector Academic/University 
PI Contribution I provide academic support to members of the consortium attempting to assess the role of more accurate diagnostics in reducing the transmission of malaria. I am also working to personally to use data on submicroscopic infection during pregnancy to assess the ability of antigen-based diagnostics to assess sequestered parasite biomass and to look at how this might relate to the force of infection in the general population and metrics of elimination.
Collaborator Contribution Members of the consortium are carrying out analysis looking at how detectability and transmissibility correlate which is directly relevant to my research and are also providing technical insight into my work assessing the role of diagnostics in malaria in pregnancy to help reduce burden and to look at the potential to use these to measure changes in transmission.
Impact I have carried out a review of how diagnostic accuracy depends on transmission and timing during pregnancy and presented this analysis to a meeting of the consortium during the 2014 ASTMH meeting in New Orleans.
Start Year 2014
 
Description IMPPACT: Maximising the public health impact of interventions to control malaria in pregnancy 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution To generate modelling and mapping of optimal preventative strategies for the prevention of malaria in pregnancy. These results were presented at Regional meetings of national policymakers in West and East Africa in Togo and Kenya respectively.
Collaborator Contribution Other partners were responsible for organising meetings, developing stakeholder interviews and translating results from recent trials into other policy-relevant recommendations and outputs.
Impact Multi-disciplinary: Modelling, Qualitative and Quantitive research, health economics and policy-making Regional meetings in Togo and Kenya Publication in PLoS Medicine and further publication pending.
Start Year 2015
 
Description IMPPACT: Maximising the public health impact of interventions to control malaria in pregnancy 
Organisation Sixth Framework Programme (FP6)
Department European and Developing Countries Clinical Trials Partnership
Country Netherlands 
Sector Public 
PI Contribution To generate modelling and mapping of optimal preventative strategies for the prevention of malaria in pregnancy. These results were presented at Regional meetings of national policymakers in West and East Africa in Togo and Kenya respectively.
Collaborator Contribution Other partners were responsible for organising meetings, developing stakeholder interviews and translating results from recent trials into other policy-relevant recommendations and outputs.
Impact Multi-disciplinary: Modelling, Qualitative and Quantitive research, health economics and policy-making Regional meetings in Togo and Kenya Publication in PLoS Medicine and further publication pending.
Start Year 2015
 
Description Malaria in Pregnancy 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration involves estimating the burden of malaria in pregnancy, its relationship with transmission and the impact of interventions. I provide mathematical modelling expertise, data analysis to questions relevant to these issues.
Collaborator Contribution Members of the Malaria in Pregnancy Consortium Secretariat provide support for these analyses in terms of providing access to data and academic support and input. As well as providing funding for travel to meetings.
Impact I developed the first model of malaria in pregnancy (Walker et al, Nature Communications 2012) and its link to transmission and using this was able to develop the first map of potential low birth weight burden attributable to malaria (Walker et al, Lancet Global Health 2014). I am also part of a working group looking at the incremental impact of switching to a policy of testing pregnant women for malaria and treating them if infected (Incremental Screening and Treatment) relative to treating them presumptively which will provide scientific support to an Evidence Review Group which will report to the Malaria Policy Advisory Committee of the World Health Organisation about the potential area of application of this strategy. I provided a preliminary version of this analysis during a Malaria in Pregnancy symposium at ASTMH 2014 in New Orleans. Research from this collaboration was also presented at the Evidence Review Group meeting into Intermittent screening and treatment in pregnancy and the safety of ACTs in the first trimester at WHO in Geneva in July 2015 and had direct influence on WHO malaria in pregnancy policy.
Start Year 2014
 
Description Modelling the impact of Mass Administration of antimalarial treatment in Western Kenya 
Organisation Kenyan Institute for Medical Research (KEMRI)
Department KEMRI/CDC Research and Public Health Collaboration
Country Kenya 
Sector Charity/Non Profit 
PI Contribution I am providing mathematical modelling support to guide the implementation of different mass treatment strategies for malaria in Western Kenya (mass screen and treat and mass drug administration) towards an ongoing large-scale trial of these interventions. I have also provided guidance as to the additional value of providing more intensive vector control in the area. I have also visited the institute and given a seminar on insights modelling can provide on these issues.
Collaborator Contribution My partners have made various historical datasets available to me and have committed to providing me with data from these trials in order to furhter this research. They have also hosted me at the Institute and provided me with access to the study site to better understand the logistics of implementing these interventions.
Impact Outputs from this work have been used to help draft a trial protocol for the implementation of mass drug administration (MDA) within the trial. If this protocol is approved by the Kenyan Government this trial will provide substantial evidence as to the value of these kinds of strategies for malaria control in areas of substantial transmission.
Start Year 2014
 
Description Interview with the BBC World Service Business Daily 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed by the BBC World Service about my research into the indirect effects of the Ebola crisis in West Africa upon malaria morbidity and mortality in the affected countries.
Year(s) Of Engagement Activity 2015
 
Description Invited Seminar - Insitute of Medical Research, Madang, Papua New Guinea 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave a seminar on my work on malaria in pregnancy. As this is a research institute heavily involved in this field I got a lot of enthusiastic responses and the audience seemed very receptive to my ideas about the relative merits of different intervention options. We also made plans to use data collected in PNG to help conduct an analysis of the most effective malaria control strategy for PNG.
Year(s) Of Engagement Activity 2015
 
Description Lancet Infectious Disease press release and subsequent mass media coverage - Impact of Ebola upon Malaria 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A press release of my work looking at the indirect effect of Ebola upon malaria was released ahead of World Malaria Day on the 23rd of April by the Lancet Infectious Disease. Information from this release was used to refer to the research in various mass media outlets and on social media, with the work appearing in the print version of major newspaper including the The Guardian and The Times in the UK. The research currently features in the top 99th percentile for research outputs of a similar age.

Following the release I was contacted by Reuters, the BBC World Service and MSF to provide further information about the work.
Year(s) Of Engagement Activity 2015
URL https://elsevier.altmetric.com/details/3937783
 
Description Malaria Modelling Workshop - PATH, Seattle 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Third sector organisations
Results and Impact I developed and led a three day training workshop on Malaria Modelling for the PATH Malaria Centre for Excellence in Seattle, USA. The intended purpose was to introduce the researchers within that centre, whose expertise range from policy guidance, microbiology and market dynamics, to the core concepts of modelling the dynamics of malaria and how this can link with other researcher to improve malaria research and policy. The feedback from the course was very positive and we are currently closely engaged with participants within the course in order to help guide malaria policy using modelling in both Zambia and Senegal.
Year(s) Of Engagement Activity 2016
 
Description Optimal interveniton packages for malaria elimination milestones in Africa - Presentation ASTMH 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The work aims to provide insight into how mathematical models can provide insight into the most cost-effective way to achieve elimination milestones, as well as estimates of these optimal packages of interventions from one existing model of malaria transmission. As such the presentation sparked engaging conversations about how best to apply models to these types of analysis from those involved in doing similar work and from people involved in carrying out interventions in areas of malaria transmission including Kenya and Zambia.

The presentation took place very recently (a week ago) so no firm outputs have occured as of yet.
Year(s) Of Engagement Activity 2014
 
Description Presentation- UCSF Low Dose Primaquine Meeting (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My presentation was part of a meeting looking at the prospects of adding a new drug to malaria treatment as part of an elimination strategy. Afterwards the talk lead to a long and interesting talk and resulted in me being contacted to provide the results in the talk to others including policy-makers involved in deciding whether the drug should be included in national malaria programmes in Africa.

I was contacted by a representative of the Clinton Health Access Initiative - a body which works with national malaria control programmes in Africa who was in the audience who asked if he could use the slides to present to other colleagues in his organisation. Consequently the results shown in this analysis were used by National Malaria Control Programme in Swaziland to decide against providing the drug due to concerns about safety and effect upon transmission. Some of these results were also presented by Nyasatu NTSHALINTSHALI during a high profile debate at the annual meeting of the American Society of Tropical Medicine and Health about whether to provide the drug as standard malaria therapy in areas aiming to achieve malaria elimination.
Year(s) Of Engagement Activity 2014
 
Description Seminar (CDC, Atlanta) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to give a Division of Parasitic Diseases and Malaria Seminar at the US Center for Disease Control in Atlanta, USA into modelling insights into Mass Drug Administration as a tool for Malaria Elimination. Around 50 people attended, primarily members of the CDC but also from other organisations interested in malaria control such as PATH, PMI and WHO. The talk generated a lot of discussion, a lot of which has lead to further collaboration with CDC in Kenya and with PATH.
Year(s) Of Engagement Activity 2016
 
Description Seminar - Modelling insights into transmission reduction strategies, (KEMRI/CDC research Institute, Kisumu, Kenya 2014) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A gave a seminar to the Malaria branch of the Institute. Audience members included researchers and members of the Kenyan Ministry of Health. Afterwards there was a lot of discussion about the implications for the modelling results in terms of plans for intervention strategies in western Kenya.

Results from this work were included in a protocol for the implementation of a trial of Mass Drug Administration and have provided the researchers with insights as to the potential impact of other strategies such as increased vector control in the area.
Year(s) Of Engagement Activity 2014