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

Abstract

Due 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, are discriminatory of spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. Based on 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 compared 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. 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. Funding Statement: This study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5300375400). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The trial received ethical approval from the Namibia MoHSS (17/3/3), and the Institutional Review Boards of the University of Namibia (MRC/259/2017), University of California San Francisco (15– 17422) and London School of Hygiene & Tropical Medicine (10411). Trial Registration: Details of the study are reported on ClinicalTrials.gov: NCT02610400