A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics

• Published in: Nature medicine Vol. 26; no. 3; pp. 326 - 332
• Main Authors: Langenberg, Marijke C. C., Hoogerwerf, Marie-Astrid, Koopman, Jan Pieter R., Janse, Jacqueline J., Kos-van Oosterhoud, Janneke, Feijt, Carola, Jochems, Simon P., de Dood, Claudia J., van Schuijlenburg, Roos, Ozir-Fazalalikhan, Arifa, Manurung, Mikhael D., Sartono, Erliyani, van der Beek, Martha T., Winkel, Béatrice M. F., Verbeek-Menken, Petra H., Stam, Koen A., van Leeuwen, Fijs W. B., Meij, Pauline, van Diepen, Angela, van Lieshout, Lisette, van Dam, Govert J., Corstjens, Paul L. A. M., Hokke, Cornelis H., Yazdanbakhsh, Maria, Visser, Leo G., Roestenberg, Meta
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2020; Nature Publishing Group
• Subjects: 631/326/417/2546; 692/1807; 692/308/1426; 692/699/255/1715; Adolescent; Adult; Adverse events; Animals; Antigens; Antigens, Helminth - blood; Antigens, Helminth - immunology; Antiparasitic Agents - pharmacology; Antiparasitic Agents - therapeutic use; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD4 antigen; Cercaria; Cytokines; Cytokines - blood; Drug development; Eggs; Female; Health care facilities; Health services; Human experimentation in medicine; Human performance; Humans; Immunity, Humoral - drug effects; Immunoglobulin G; Immunoglobulin M; Immunoglobulin M - blood; Infections; Infectious Diseases; Infectivity; Letter; Lymphocytes; Lymphocytes T; Male; Medical research; Medicine, Experimental; Metabolic Diseases; Middle Aged; Models, Biological; Molecular Medicine; Neurosciences; Praziquantel; Praziquantel - pharmacology; Praziquantel - therapeutic use; Product development; Product safety; Schistosoma mansoni; Schistosoma mansoni - drug effects; Schistosoma mansoni - physiology; Schistosomiasis; Schistosomiasis mansoni - blood; Schistosomiasis mansoni - drug therapy; Schistosomiasis mansoni - immunology; Schistosomiasis mansoni - microbiology; Self-experimentation in medicine; Seroconversion; Tropical diseases; Vaccines; Vaccines - immunology; Young Adult; Netherlands
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-020-0759-x

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas 1 . Novel medicines and vaccines are urgently needed 2 , 3 . An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324 ), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3–10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4 + T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis. A new human challenge model of schistosomiasis, which affects more than 290 million people globally, will aid development of novel therapies and vaccines for this neglected tropical disease.