From malaria control to sustainable elimination: Cluster randomised trial comparing targeted versus generalised vector control in South Africa

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Countries that have reduced malaria incidence to low levels face major challenges when trying to eliminate the disease altogether. In trying to reduce transmission further, considerable resources are required for disease prevention through mosquito vector control, for example by indoor residual spraying (IRS) of all houses. Such mass prevention efforts can lead to reduced compliance in communities and control programs who no longer perceive a risk of malaria, and waning political and donor commitment when the disease burden is low, thereby endangering the sustainability of the elimination effort. Evidence based methods of scaling back blanket IRS have to be developed which ensure that populations are not put at risk when IRS is no longer routinely applied.
In this study, targeted focal IRS in response to new cases being reported will be compared with generalised annual IRS of all houses, to determine whether it is as effective, less costly, more acceptable, results in higher coverage and compliance and increased malaria prevention seeking behaviour. A pre-condition for this approach, is a reliable rapid malaria case surveillance system, based on definitive diagnosis of suspected cases. This trial will be carried out in South Africa, which has practised blanket IRS for many decades, where case incidence in many districts is now low enough to be considered pre-elimination, and where a high quality case reporting system is well established. Spray localities will be grouped into clusters of 5,000 to 10,000 persons which will be randomly allocated to either targeted IRS, or to blanket routine IRS. Targeted neighbourhood IRS will be triggered in response to two or more local cases occurring within 4 weeks of each other and residing within 0.5km from one another. Spraying and community awareness activities will be carried out in a radius of 0.5km from each case house. It is postulated that focal spraying will lead to higher quality of IRS application because it can be better supervised and will be seen as protection against real risk of infection due to the occurrence of recent local cases; that it will be more acceptable to householders and hence lead to better co-operation with access to premises and hence higher spray coverage; and that householders will exercise better compliance with not repainting, washing or re-plastering of walls after spraying. As a result we expect that incidence of cases will be no higher in targeted IRS areas than in those receiving mass IRS and that targeted spraying will be more economical and hence more sustainable. The study will measure malaria case incidence, householder acceptability and compliance, spray coverage, and economic costs of the interventions as outcome indicators.
There is some evidence from other countries that in very low transmission settings, incident malaria cases occur in hotspots that are stable over time. If such hotspots can be accurately located, they can be singled out for focal interventions such as targeted IRS at the beginning of each season. To investigate whether such hotspots of local transmission exist in South Africa, it is proposed that filter paper blood spots are collected in communities where targeted IRS is carried out, to be tested for the presence of antibody sero-positivity to malarial antigens. The sero-prevalence of 'outbreak' communities will be compared with sero-prevalence of randomly selected communities in which no recent cases have occurred. This comparison will determine whether neighbourhoods with recent cases have historically been exposed to malaria parasites, and are therefore likely to be hotspots of transmission. The existence of such hotspots would strengthen the case for targeted control efforts.
For countries that have set elimination of malaria as a policy objective this study will provide evidence upon which sustainable policy decisions about mass vector control can be based during the pre-elimination period.

Technical Summary

To achieve malaria elimination, interventions have to be sustainable in low transmission settings. Annual mass treatment of houses with indoor residual spraying (IRS) is costly per case averted when the malaria burden is low and can lead to poor compliance when the perceived risk of malaria is small. An open label two arm cluster randomised non-inferiority trial will compare effectiveness, cost, IRS coverage and householder acceptability between targeted focal IRS, initiated in response to two or more new local cases being reported in an area, no more than 4 weeks apart and within no more than 0.5 km from one another, with generalised annual IRS of all structures. Aggregations of spray localities will be used to form study clusters of between 5,000 and 10,000 inhabitants. Assuming an average of 3 cases/1000 person-years, and a coefficient of variation of 0.4 the trial will require at least 21 clusters per arm (42 in total) for 80% power and 5% significance if cluster populations consist of 6000 persons on average, incidence is measured over a 2 years period and if 1 case/1000 is regarded as the largest difference in the two methods that can be regarded as unimportant. The existence of hotspots of transmission from which cases arise will strengthen the case for focal vector control. Hotspots will be investigated through sero-prevalence surveys in the neighbourhoods of incident cases, compared to control neighbourhoods. Study endpoints will be malaria incidence, IRS coverage, intervention costs, compliance and antibody sero-prevalence. If targeted IRS is shown to be as effective, results in higher coverage, is more acceptable and more economical than mass IRS it will enable countries that have set elimination as a policy objective to make evidence based decisions about mass vector control in the pre-elimination phase.

Planned Impact

The following will benefit from this research:
1. The general public, policy makers and national and provincial malaria control programs (NMCP and PMCP) in countries that have set malaria elimination as a policy objective and who are currently using similar interventions;
2. Communities who are being protected from malaria;
3. National and international donor and development agencies who support malaria control and elimination;

If the trial is successful, the general public in the elimination countries will benefit economically from the ultimate elimination of malaria from their countries, provided the elimination effort is achievable by sustainable means.

Policy makers will benefit because it will help them make policy decisions about possible scaling back of blanket IRS and replacing it with rapid response targeted IRS. This will make elimination efforts more sustainable.

NMCPs and PMCPs have asked for this trial since they want to have evidence upon which to base decisions about withdrawing generalised IRS from areas that have seen very few local cases.

More sustainable malaria elimination will benefit the communities at risk of malaria by protecting them against clinical malaria morbidity, reducing household costs associated with malaria episodes, and enhancing quality of life through less disruption resulting from having their houses sprayed.

National and international donor and development agencies will benefit from the results of this trial since it will enable them to make rational decisions about programme support, and provide exit strategies from supporting IRS programs indefinitely, once a pre-elimination level of transmission has been attained.
 
Description Membership of South African Malaria Elimination Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description South African Malaria Elimination Committee
Geographic Reach Africa 
Policy Influence Type Participation in a advisory committee
 
Description Engagement with the Elimination 8 Initiative 
Organisation Elimination Eight
Country Namibia 
Sector Private 
PI Contribution Information and awareness about evidence based targeted vector control in malaria pre-elimination settings, to promote sustainable malaria elimination
Collaborator Contribution Awareness and information about the needs and challenges of national malaria control programs striving and planning to eliminate malaria in eight countries in Southern Africa. (South Africa, Swaziland, Botswana, Namibia, Angola, Zimbabwe, Zambia and Mozambique).
Impact None yet
Start Year 2016
 
Description Targeted parasite elimination 
Organisation University of California, San Francisco
Department Malaria Elimination Initiative
Country United States 
Sector Academic/University 
PI Contribution Contribution and experience gained has been beneficial in the design of a trial targeted reactive malaria interventions in Namibia
Collaborator Contribution Mutual exchange of ideas and approaches towards effective, safe and practical approaches to the delivery of targeted reactive interventions in low transmission malaria endemic regions.
Impact 1. Medzihradsky OF, Kleinschmidt I, Mumbengegwi D, Roberts KW, McCreesh P, Dufour MK, Uusiku P, Katokele S, Bennett A, Smith J, Sturrock H, Prach LM, Ntuku H, Tambo M, Didier B, Greenhouse B, Gani Z, Aerts A, Gosling R, Hsiang MS. Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia. BMJ Open. 2018 Jan 27;8(1):e019294. doi: 10.1136/bmjopen-2017-019294.
Start Year 2012
 
Title Application to capture data on tablet device during malaria case investigation 
Description An "app" has been developed to capture case, household, neighbourhood and vector control data during malaria case investigation, including capture geo-loaction for subsequent mapping. This has previously been done using paper records. This software will be refined and improved during the course of the study. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2015 
Impact The impact of this app is to speed up case investigation, reduce errors and improve malaria case surveillance. The app and devices will be available for the provincial malaria control programmes after the end of the study. 
 
Description Attendance of the South African Malaria Elimination Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The purpose and relevance of the Targeted Indoor Residual Spraying Trial in South Africa was explained to the South African Malaria Elimination Committee. The committee noted the importance of this trial for the goal of achieving and maintaining malaria elimination in South Africa.
Year(s) Of Engagement Activity 2015
 
Description Briefing to Policy Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Update of study to members of the South African Malaria Elimination Committee (SAMEC). Members include experts in malaria and government officials responsible for malaria control in South Africa.
Discussion of translating results into policy once trial concludes, and results warrant policy change.
Year(s) Of Engagement Activity 2016
 
Description Final results presented to South African Malaria Elimination Committee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation of final results of the economic analysis of the trial. Many were surprised by the strong economic case for targeted approaches to vector control.
Year(s) Of Engagement Activity 2018
 
Description Meeting with ward councillors (community representatives) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact At a meeting of community representatives in the district of Bushbuckridge the purpose of the targeted vector control trial for the reduction in malaria transmission was explained.
Year(s) Of Engagement Activity 2015
 
Description Presentation to Roll Back Malaria Vector Control Working Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Is targeted reactive vector control a non-inferior substitute for generalised indoor residual spraying in areas of very low malaria transmission - results from a cluster randomised trial. Poster presentation to Roll Back Malaria Technical Working Group. This was intended to persuade members of the malaria vector control community that targeted IRS is safe and feasible in malaria elimination settings.
Year(s) Of Engagement Activity 2018
 
Description Presentation to South African Malaria Elimination Committee (SAMEC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact National and provincial malaria control staff from all malaria endemic provinces, and South African malaria researchers were briefed about initial findings of the trial
Year(s) Of Engagement Activity 2017
 
Description Scientific seminar at Multilateral Initiative against Malaria (MIM) conference, Dakar, Senegal 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A scientific seminar on reactive focal malaria control interventions was organised in which two presentations were given presenting the results of the trial. In particular, the results of the cost effectiveness of the intervention drew significant interest from the audience. The MIM conference takes place every 3 to 4 years with very wide international participation from malaria researchers, national malaria control programme officials and national and international policymakers.
Year(s) Of Engagement Activity 2018
 
Description Talk at South African malaria conference, Johannesburg 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Conference presentation sparked interest from practitioners from the region where targeted approaches to malaria control will need to be adopted for more sustainable funding in future.
Year(s) Of Engagement Activity 2018