Melbourne School of Population and Global Health - Theses
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ItemAnopheles salivary antibodies as biomarkers of vector exposure and malaria transmission in the Greater Mekong Subregion( 2023-06)Measurement of human antibodies against Anopheles salivary antigens has been suggested as a sensitive and feasible alternative to measure human biting rates (HBR), improving on logistically challenging gold-standard entomological approaches that provide crude measures of total exposure to vector bites. To understand how this approach could be used to advance the Greater Mekong Subregion’s (GMS) malaria elimination agenda, in this thesis I sought to formally quantify the association between anti-Anopheles salivary antibodies and HBR, and investigate the programmatic application of these antibodies for serosurveillance of malaria transmission and as outcomes in vector control intervention effectiveness trials. Firstly, I performed a systematic review with multilevel modelling and quantified a positive non-linear association between antibodies against gSG6 (from the dominant African vector An. gambiae) and HBR, as well as metrics of malaria transmission. However, I identified that this association was weaker outside Africa where An. gambiae is absent. These findings provide evidence that anti-Anopheles salivary antibodies could serve as biomarkers of Anopheles biting exposure, but novel species-specific antigens may be needed to estimate HBR in the GMS. Secondly, I measured the seroprevalence of antibodies against Anopheles salivary antigen gSG6 in 104 villages in Southeast Myanmar and employed Bayesian geostatistical modelling to quantify the micro-heterogeneity in Anopheles biting exposure, which was found to be high (mean: 66%) yet heterogeneous (range: 9-99%). I combined vector (gSG6) and transmission-stage malaria parasite (CSP) antibody biomarkers with PCR-detectable infections in a novel joint modelling framework to predict malaria transmission across Southeast Myanmar. These maps identify several foci of ongoing transmission and could be used to micro-stratify malaria risk for targeting interventions. Thirdly, I quantified the effect of topical insect repellent on the levels of antibodies against Anopheles salivary antigen gSG6. By estimating a series of lagged effects of repellent distribution (to model gradual antibody decay from prolonged use), I observed reduced antibody levels after 6-months of repellent use, particularly for high-risk participants (migrants and forest-goers). These findings suggest anti-Anopheles salivary antibodies could be an informative trial outcome measure and provide important parameters on antibody decay dynamics to inform the design of future vector control interventions effectiveness trials. Finally, I directly quantified the boosting and decay of IgG and IgM antibodies against a series of Anopheles species-specific salivary antigens in response to controlled biting exposure from dominant vectors of the GMS. I found that antibody levels decayed overall, but were boosted with and following mosquito biting. These associations were similar across Anopheles species-specific salivary antigens and antibody isotypes, and species-specific antibodies levels were all highly correlated (spearman’s rho>0.8). These findings provide evidence that anti-Anopheles species-specific salivary antibodies could be sensitive biomarkers of exposure to Anopheles bites in the GMS. Collectively, the findings of this thesis provide a comprehensive investigation of anti-Anopheles salivary antibodies as biomarkers of exposure to Anopheles bites in the GMS. These findings directly quantify (previously-assumed) associations with entomological and malariometric measures of exposure and transmission, and support the application of these antibodies as endpoints in surveillance programs and vector control intervention effectiveness trials.