Abstract
SummaryBackgroundDue to challenges in measuring changes in malaria at low transmission, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal studies have shown that serological markers, such as Etramp5.Ag1, can reflect spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials.MethodsBased on data from 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), this study conducted a secondary analysis comparing antibody responses between intervention arms as trial endpoints. Antibody responses were measured on a multiplex immunoassay, using a panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2.FindingsReductions 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 prevalence ratio (aPR) for Etramp5.Ag1 was 0.78 (95%CI 0.65 – 0.91, p = 0.0007) in the rfMDA arms and 0.79 (95%CI 0.67 – 0.92, p = 0.001) in the RAVC arms. For the combined rfMDA plus RAVC intervention, aPR was 0.59 (95%CI 0.46 – 0.76, p < 0.0001). 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).InterpretationWhile the observed relative reduction in qPCR prevalence in the study was greater than serology, the use of serological endpoints to evaluate trial outcomes measured effect size with improved precision and study power. 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.FundingThis study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5,300,375,400).
Highlights
In elimination settings, cluster randomised trials measuring changes in malaria transmission face a number of challenges, when estimating clinical incidence and parasite prevalence as endpoints
This study aims to (1) assess whether reduced antibody responses for the candidate markers evaluated would be observed in intervention arms due to relative reductions in malaria transmission, and (2) estimate a number of trial design parameters based on serology as a trial endpoint, including inter-cluster coefficient of variation and trial sample sizes, to assess whether improved study power and trial efficiencies can be achieved
Age and gender distribution were balanced across study arms, with the proportion of individuals aged 15 years and older ranging from 52.9% (396 out of 749 in reactive focal mass drug administration (rfMDA) plus reactive vector control (RAVC) arm) to 55.5% (508 out of 915 in the rfMDA only arm) and proportion of females ranging from 53.4% (400 out of 749 in the rfMDA plus RAVC arm) to 56.1% (555 out of 990 in the RACD only arm) (Supplementary Table S2)
Summary
Cluster randomised trials measuring changes in malaria transmission face a number of challenges, when estimating clinical incidence and parasite prevalence as endpoints. Passive surveillance based on routine health systems often do not capture asymptomatic individuals or may under-estimate clinical incidence in areas where care-seeking is low.[2−5] While active surveillance measuring parasite prevalence can improve the detection of infections in the wider community, fluctuations in parasite density throughout a season can result in a sizeable number of infections becoming undetectable at any given time.[6,7]. For these reasons, measuring clinical incidence and parasite prevalence as trial endpoints can be imprecise, making it difficult to design studies with adequate sample sizes or study power.[8] Passive surveillance based on routine health systems often do not capture asymptomatic individuals or may under-estimate clinical incidence in areas where care-seeking is low.[2−5] While active surveillance measuring parasite prevalence can improve the detection of infections in the wider community, fluctuations in parasite density throughout a season can result in a sizeable number of infections becoming undetectable at any given time.[6,7] For these reasons, measuring clinical incidence and parasite prevalence as trial endpoints can be imprecise, making it difficult to design studies with adequate sample sizes or study power.[8]
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