Identification of a circulating carbohydrate antigen as a highly specific and sensitive target for schistosomiasis serology

The World Health Organization (WHO) 2030 roadmap for schistosomiasis calls for development of highly sensitive and specific diagnostic tools to continue and sustain progress towards elimination. Serological assays are excellent for sensitive detection of primary schistosome infections and for schistosomiasis surveillance in near- and post-elimination settings. To develop accurate assay formats, it is necessary to identify defined antibody targets with low cross-reactivity and potential for standardized production. Here we aim to identify such target(s) with focus on defined schistosome glycan antigens. Target identification was performed by assessing antibody responses in well-characterized cross-sectional and cohort sample sets (n = 366 individuals) on tailor-made antigen microarrays. IgM and IgG binding to candidate diagnostic targets was measured for serum/plasma samples from controlled human schistosome infection models, schistosome-infected travelers, soil-transmitted helminth-infected individuals, and non-infected individuals. We found that antibodies to a schistosome gut-associated glycan, the circulating anodic antigen (CAA), identify schistosome infection with high sensitivity (IgM >= 100%, IgG >= 97%) and specificity (IgM >= 93%, IgG >= 97%) in the test samples. Infection dose affected timing of anti-CAA antibody isotype switch. Furthermore, we demonstrate that other non-specific glycan epitopes in crude schistosome cercarial and egg antigen preparations can contribute to generation of false schistosomiasis positives, which is relevant for current serological assays based on these antigen mixtures. In conclusion, CAA is an excellent single glycan antigen target for development of highly sensitive and specific tools for schistosomiasis serology with use cases for travelers and surveillance in near- and post-elimination settings, as well as emerging transmission zones. IMPORTANCE The WHO 2030 roadmap deems diagnostics developments for schistosomiasis critically needed. Here we present identification of an antibody target with superior performance compared to traditionally used crude antigens in schistosomiasis serology. Access to unique controlled human infection model samples, traveler samples, and negative controls enabled this discovery, which forms the basis for development of new diagnostic tools urgently needed in travel medicine, surveillance in emerging transmission zones driven by climate change, and in pre- and post-elimination scenarios.