The use of antimalarial antibodies to measure malaria transmission in low transmission and pre-elimination settings

Global declines in malaria transmission in recent years have refocused efforts towards elimination. An essential part of this effort is adequate detection of transmission patterns. However, meta-analyses have shown that microscopy detects about half of all polymerase chain reaction (PCR)-confirmed infections. To date, the performance of rapid diagnostic tests (RDTs) relative to microscopy and PCR has not been evaluated in a comprehensive meta-analysis. Therefore, the relationship between PCR, RDT and microscopy prevalence estimates in asymptomatic populations was determined using data from cross-sectional surveys in endemic settings (Chapter 3). Overall, RDTs detected 41% of all PCR-confirmed infections, and RDT-undetected (i.e. low-density) infections increased with age and decreasing transmission intensity. Another approach to estimate transmission is to use malaria-specific immune responses of resident populations as a measure of exposure to infection. Antimalarial antibodies, in combination with age, reflect both historical and recent exposure. Until recently, the majority of sero-surveillance data were based on a few well-characterised antigens using enzyme-linked immunosorbent assays (ELISA). However, which antibodies most accurately reflect exposure to recent low-density infections remains largely unknown. To address this, Chapter 4 examined antibody responses in previously naïve, controlled human malaria infections (CHMI) participants using protein microarray. Nearly all participants showed measurable antibody responses to a subset of four antigens one month post-CHMI. In addition to protein microarray, multiplex bead assays (MBAs) enable multiplex detection of antibodies. However, MBA protocols may require further adaptation in scenarios where results must be readily available to inform control and elimination policies. The precision of an adapted MBA protocol with improved throughput and ease-of-use was determined in Chapter 5 using data collected in three large-scale transmission surveys. For some antigens, inter-plate variability seemed to increase during the third survey, possibly due to long-term storage of reagents. Commercially available ELISAs are standardised in their production and have been used to test blood products prior to donation to reduce the risk of transfusion-transmitted malaria. However, their performance in an epidemiological context has not been investigated. In Chapter 6, one of five commercially available ELISAs evaluated, accurately described transmission in a low transmission and pre-elimination setting. A low-cost, high-throughput assay for which results are readily interpretable may help to directly inform control activities targeting areas with remaining transmission