Navigating the immuno-epidemiology of malaria: Potential metrics for surveillance and cluster randomised trials

As malaria endemic countries progress towards elimination, accurately measuring community-level transmission is critical for monitoring control strategies and the design of efficacy trials. However, measuring malaria transmission often faces challenges in pre-elimination settings due to the complexity of human immunity and its interaction with vector and parasite dynamics. This study evaluates current and emerging epidemiological measures of malaria transmission, and explores the use of novel serological markers of malaria infection as metrics in surveillance and cluster-randomised trials (CRTs). The relative sensitivity of commonly used surveillance diagnostics - polymerase chain reaction (PCR), rapid diagnostic tests (RDTs), and microscopy – are cross-compared with respect to their accuracy in quantifying cluster-level prevalence of malaria infection. These are further evaluated against immunological measures of transmission based on antibody responses to two malaria parasite antigens - PfMSP119 and PfAMA1 - used extensively in serological surveillance for the last decade. To investigate novel serological markers of malaria infection, a multiplexed immunoassay was used to characterise post-infection antibody dynamics to 20 Plasmodium falciparum antigens. This was based on a subset of 192 individuals from an all-age longitudinal cohort study in The Gambia. Antibody responses against several antigens showed accuracy in detecting infection in the preceding six months. These may have potential utility in measuring time since infection or short-term changes in transmission. However, variations in immune response by age and transmission intensity were observed and should be taken into consideration for future optimisation of serological assays. Antigens identified as the most promising biomarkers of recent infection were used to estimate cluster-level transmission in four villages in The Gambia. Serological responses are compared between dry and wet season and geographical regions of low and high transmission intensity. Their application was also extended to compare study arms of a cluster-randomised trial in the Zambezi Region, Namibia, comparing the effectiveness of reactive focal case detection, reactive focal mass drug administration, and reactive vector control. These findings may help to inform the development of new serological diagnostic assays for malaria, their use in future malaria surveillance and elimination strategies, and the design of cluster-randomised trials in low transmission settings.