Serological Evaluation of a Cluster Randomised Trial on the Use of Reactive Focal Mass Drug Administration and Reactive Vector Control to Reduce Malaria Transmission in Zambezi Region, Namibia

Due to challenges in measuring changes in malaria in low transmission settings, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal cohort studies have shown serological markers, such as Etramp5.Ag1, to be particularly discriminatory of spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. This study is an extended analysis of a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC). A panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2 - was used on a multiplex immunoassay to measure population antibody responses as trial endpoints. Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted Etramp5.Ag1 prevalence ratio (aPR) was 0.77 (95%CI 0.65 - 0.90, p<0.001) for rfMDA and 0.79 (95%CI 0.67 - 0.92, p=0.001) for RACD. For combined rfMDA plus RAVC, aPR was 0.58 (95%CI 0.45 - 0.75, p<0.001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). The use of serological endpoints to evaluate trial outcomes was comparable to qPCR and measured effect size with improved precision. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting.

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The Effectiveness of Reactive Focal Mass Drug Administration (rfMDA) and Reactive Focal Vector Control (RAVC) to Reduce Malaria Transmission: A Cluster-Randomised Controlled Open Label Two-by-Two Factorial Design Trial from the Low-Endemic Setting of Namibia

SSRN Electronic Journal ◽

10.2139/ssrn.3454698 ◽

2019 ◽

Author(s):

Michelle Hsiang ◽

Henry Ntuku ◽

Kathryn W. Roberts ◽

Mi-Suk Kang Dufour ◽

Brooke Whittemore ◽

...

Keyword(s):

Vector Control ◽

Factorial Design ◽

Malaria Transmission ◽

Drug Administration ◽

Mass Drug Administration ◽

Open Label ◽

Endemic Setting ◽

Cluster Randomised ◽

Randomised Controlled

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Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial

The Lancet ◽

10.1016/s0140-6736(20)30470-0 ◽

2020 ◽

Vol 395 (10233) ◽

pp. 1361-1373 ◽

Cited By ~ 5

Author(s):

Michelle S Hsiang ◽

Henry Ntuku ◽

Kathryn W Roberts ◽

Mi-Suk Kang Dufour ◽

Brooke Whittemore ◽

...

Keyword(s):

Vector Control ◽

Factorial Design ◽

Malaria Transmission ◽

Drug Administration ◽

Mass Drug Administration ◽

Open Label ◽

Endemic Setting ◽

Cluster Randomised ◽

Randomised Controlled

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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 ◽

10.1136/bmjopen-2017-019294 ◽

2018 ◽

Vol 8 (1) ◽

pp. e019294 ◽

Cited By ~ 5

Author(s):

Oliver F Medzihradsky ◽

Immo Kleinschmidt ◽

Davis Mumbengegwi ◽

Kathryn W Roberts ◽

Patrick McCreesh ◽

...

Keyword(s):

Vector Control ◽

Factorial Design ◽

Malaria Transmission ◽

Drug Administration ◽

Mass Drug Administration ◽

Indoor Residual Spraying ◽

Health Facilities ◽

Infection Prevalence ◽

Cluster Randomised ◽

Randomised Controlled

IntroductionTo interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia.Methods and analysisThis is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness.Ethics and disseminationFindings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia.Trial registration numberNCT02610400; Pre-results.

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Evaluation of integrated interventions layered on mass drug administration for urogenital schistosomiasis elimination: a cluster-randomised trial

The Lancet Global Health ◽

10.1016/s2214-109x(19)30189-5 ◽

2019 ◽

Vol 7 (8) ◽

pp. e1118-e1129 ◽

Cited By ~ 23

Author(s):

Stefanie Knopp ◽

Bobbie Person ◽

Shaali M Ame ◽

Said M Ali ◽

Jan Hattendorf ◽

...

Keyword(s):

Drug Administration ◽

Mass Drug Administration ◽

Randomised Trial ◽

Cluster Randomised Trial ◽

Urogenital Schistosomiasis ◽

Cluster Randomised

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Mass drug administration for the acceleration of malaria elimination in a region of Myanmar with artemisinin-resistant falciparum malaria: a cluster-randomised trial

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(20)30997-x ◽

2021 ◽

Author(s):

Alistair R D McLean ◽

Chanida Indrasuta ◽

Zay Soe Khant ◽

Aung Kyaw Phyo ◽

Sai Maung Maung ◽

...

Keyword(s):

Falciparum Malaria ◽

Drug Administration ◽

Mass Drug Administration ◽

Malaria Elimination ◽

Randomised Trial ◽

Cluster Randomised Trial ◽

Cluster Randomised

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Optimising systemic insecticide use to improve malaria control

BMJ Global Health ◽

10.1136/bmjgh-2019-001776 ◽

2019 ◽

Vol 4 (6) ◽

pp. e001776 ◽

Cited By ~ 1

Author(s):

Hannah R Meredith ◽

Luis Furuya-Kanamori ◽

Laith Yakob

Keyword(s):

Vector Control ◽

Malaria Transmission ◽

Drug Administration ◽

Mass Drug Administration ◽

Companion Animals ◽

Malaria Vectors ◽

Systemic Insecticide ◽

Blood Concentrations ◽

Systemic Insecticides ◽

The Impact

BackgroundLong-lasting insecticidal nets and indoor residual sprays have significantly reduced the burden of malaria. However, several hurdles remain before elimination can be achieved: mosquito vectors have developed resistance to public health insecticides, including pyrethroids, and have altered their biting behaviour to avoid these indoor control tools. Systemic insecticides, drugs applied directly to blood hosts to kill mosquitoes that take a blood meal, offer a promising vector control option. To date, most studies focus on repurposing ivermectin, a drug used extensively to treat river blindness. There is concern that overdependence on a single drug will inevitably repeat past experiences with the rapid spread of pyrethroid resistance in malaria vectors. Diversifying the arsenal of systemic insecticides used for mass drug administration would improve this strategy’s sustainability.MethodsHere, a review was conducted to identify systemic insecticide candidates and consolidate their pharmacokinetic/pharmacodynamic properties. The impact of alternative integrated vector control options and different dosing regimens on malaria transmission reduction are illustrated through mathematical model simulation.ResultsThe review identified drugs from four classes commonly used in livestock and companion animals: avermectins, milbemycins, isoxazolines and spinosyns. Simulations predicted that isoxazolines and spinosyns are promising candidates for mass drug administration, as they were predicted to need less frequent application than avermectins and milbemycins to maintain mosquitocidal blood concentrations.ConclusionsThese findings will provide a guide for investigating and applying different systemic insecticides to achieve more effective and sustainable control of malaria transmission.

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The effect of mass mosquito trapping on malaria transmission and disease burden (SolarMal): a stepped-wedge cluster-randomised trial

The Lancet ◽

10.1016/s0140-6736(16)30445-7 ◽

2016 ◽

Vol 388 (10050) ◽

pp. 1193-1201 ◽

Cited By ~ 54

Author(s):

Tobias Homan ◽

Alexandra Hiscox ◽

Collins K Mweresa ◽

Daniel Masiga ◽

Wolfgang R Mukabana ◽

...

Keyword(s):

Malaria Transmission ◽

Disease Burden ◽

Randomised Trial ◽

Cluster Randomised Trial ◽

Stepped Wedge ◽

Cluster Randomised

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Investigating the impact of enhanced community case management and monthly screening and treatment on the transmissibility of malaria infections in Burkina Faso: study protocol for a cluster-randomised trial

BMJ Open ◽

10.1136/bmjopen-2019-030598 ◽

2019 ◽

Vol 9 (9) ◽

pp. e030598 ◽

Cited By ~ 1

Author(s):

Katharine A Collins ◽

Alphonse Ouedraogo ◽

Wamdaogo Moussa Guelbeogo ◽

Shehu S Awandu ◽

Will Stone ◽

...

Keyword(s):

Case Management ◽

Burkina Faso ◽

Malaria Transmission ◽

Randomised Trial ◽

Standard Of Care ◽

Recruitment Strategy ◽

Cluster Randomised Trial ◽

Community Case Management ◽

Cluster Randomised ◽

The Impact

IntroductionA large proportion of malaria-infected individuals in endemic areas do not experience symptoms that prompt treatment-seeking. These asymptomatically infected individuals may retain their infections for many months during which sexual-stage parasites (gametocytes) are produced that may be transmissible to mosquitoes. Reductions in malaria transmission could be achieved by detecting and treating these infections early. This study assesses the impact of enhanced community case management (CCM) and monthly screening and treatment (MSAT) on the prevalence and transmissibility of malaria infections.Methods and analysisThis cluster-randomised trial will take place in Sapone, an area of intense, highly seasonal malaria in Burkina Faso. In total, 180 compounds will be randomised to one of three interventions: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced CCM, comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus MSAT using RDTs. The study will be conducted over approximately 18 months covering two high-transmission seasons and the intervening dry season. The recruitment strategy aims to ensure that overall transmission and force of infection is not affected so we are able to continuously evaluate the impact of interventions in the context of ongoing intense malaria transmission. The main objectives of the study are to determine the impact of enhanced CCM and MSAT on the prevalence and density of parasitaemia and gametocytaemia and the transmissibility of infections. This will be achieved by molecular detection of infections in all study participants during start and end season cross-sectional surveys and routine sampling of malaria-positive individuals to assess their infectiousness to mosquitoes.Ethics and disseminationThe study has been reviewed and approved by the London School of Hygiene and Tropical Medicine (LSHTM) (Review number: 14724) and The Centre National de Recherche et de Formation sur le Paludisme institutional review board (IRB) (Deliberation N° 2018/000002/MS/SG/CNRFP/CIB) and Burkina Faso national medical ethics committees (Deliberation N° 2018-01-010).Findings of the study will be shared with the community via local opinion leaders and community meetings. Results may also be shared through conferences, seminars, reports, theses and peer-reviewed publications; disease occurrence data and study outcomes will be shared with the Ministry of Health. Data will be published in an online digital repository.Trial registration numberNCT03705624.

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