Cornelis H. Hokke, Donald P. McManus, Alex Loukas, Govert J. van Dam, Takafira Mduluza, Said M. Ali, Thewarach Laha, Al Jasinskas, Maria Elena Bottazzi, Mark S. Pearson, Beatrice Greco, Sujittra Chaiyadet, A.A. Adegnika, Paul L. A. M. Corstjens, Matthew A. Field, Abena S. Amoah, Denise L. Doolan, Gebeyaw G Mekonnen, Javier Sotillo, Fatma Kabole, Claude Oeuvray, Bemnet Amare Tedla, Carla Proietti, Philip L. Felgner, Stefanie Knopp, Rie Nakajima, Luke Becker, David Rollinson, Pengfei Cai, Francisca Mutapi, Australian Trade and Investment Commission, Fundación Merck Salud, Bill & Melinda Gates Foundation, Australian Institute of Tropical Health and Medicine, University of Georgia (Estados Unidos), National Health and Medical Research Council (Australia), James Cook University (Australia), Wellcome Trust, Thrasher Research Fund, and European and Developing Countries Clinical Trials
Background: Sensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field. Methods: We did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format. Findings: From array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]serum=0·98 [95% CI 0·95-1·00]; AUCurine=0·96 [0·93-0·99]), and MS3_01370 (AUCserum=0·93 [0·89-0·97]; AUCurine=0·81 [0·72-0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69-0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%. Interpretation: We identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance. This study received financial support from Merck Global Health Institute and the Australian Trade and Investment Commission (Australian Tropical Medicine Commercialisation grants programme ATMC50322). Research for the Zanzibar Elimination of Schistosomiasis Transmission project was funded by the University of Georgia Research Foundation, which is funded by the Bill & Melinda Gates Foundation for the Schistosomiasis Consortium for Operational Research and Evaluation projects (prime award number 50816, sub-award number RR374-053/4893206). SK received financial support by sub-award number RR374-053/4893196 and via direct grants from the Gates Foundation (investment identification numbers OPP1191423 and OPP1198086). AL was funded by a National Health and Medical Research Council Senior Principal Research Fellowship (number APP1117504). BAT was funded by a James Cook University Postgraduate Scholarship. GGM was funded by an Australian Institute of Tropical Health and Medicine postgraduate scholarship. Funding was granted to AAA by a European and Developing Countries Clinical Trials Partnership senior fellowship training award (number TA_11_40200). FM was funded by the Thrasher Research Fund (number 12440) and the Wellcome Trust (number 108061/Z/15/Z). Sí