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

Nature Medicine volume 26, pages 326–332 (2020)Cite this article

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Abstract

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas1. Novel medicines and vaccines are urgently needed2,3. 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.

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Fig. 1: Study flow diagram.
Fig. 2: Adverse events.
Fig. 3: Pre-patent period and serum CAA levels.
Fig. 4: Humoral immune response.
Fig. 5: Cytokine responses.
Fig. 6: Immunological and microbiological data integration.

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Data availability

The data that support this publication are available at ImmPort (https://www.immport.org) under study accession SDY1609. All data will be made available for further research, provided that reference is made to the LUMC source.

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Acknowledgements

We thank P. van Genderen for reviewing the safety data and providing his advice as safety monitor of our study. We thank M. Casacuberta Partal, M.A.A. Erkens, J.L. Fehrmann-Naumann, M.S. Ganesh, H. Gerritsma, G.C. Hardeman, P.T. Hoekstra-Mevius, Y.C.M. Kruize, Y.D. Mouwenda, H.H. Smits, K. Suijk-Benschop, J.J.C. de Vries and C.J.G. van Zeijl-van der Ham for their laboratory, clinical and data-analyzing support during the study. Most of all we thank all volunteers participating in the study, without whom the study could not have been performed. Dr. Roestenberg was supported by a Veni grant (no. 016.156.076) from the Netherlands Organization for Health Research and Development and a Gisela Thier Fellowship (no. 14-0645) from LUMC. Dr. Langenberg and Dr. Hoogerwerf were supported by a grant from Dioraphte Foundation (no. 16020405). The funding sources had no role in collecting, analyzing, interpreting or reporting the data. Dr. Jochems has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie grant agreement no. 707404. The opinions expressed in this document reflect only the author’s view. The European Commission is not responsible for any use that may be made of the information that it contains.

Author information

Author notes

  1. These authors contributed equally: Marie-Astrid Hoogerwerf, Jan Pieter R. Koopman.

  2. These authors jointly supervised this work: Cornelis H. Hokke, Maria Yazdanbakhsh, Leo G. Visser.

Authors and Affiliations

  1. Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands

    Marijke C. C. Langenberg, Marie-Astrid Hoogerwerf, Jan Pieter R. Koopman, Jacqueline J. Janse, Janneke Kos-van Oosterhoud, Carola Feijt, Simon P. Jochems, Roos van Schuijlenburg, Arifa Ozir-Fazalalikhan, Mikhael D. Manurung, Erliyani Sartono, Béatrice M. F. Winkel, Koen A. Stam, Angela van Diepen, Lisette van Lieshout, Govert J. van Dam, Cornelis H. Hokke, Maria Yazdanbakhsh & Meta Roestenberg

  2. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands

    Claudia J. de Dood & Paul L. A. M. Corstjens

  3. Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands

    Martha T. van der Beek

  4. Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands

    Petra H. Verbeek-Menken, Leo G. Visser & Meta Roestenberg

  5. Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

    Fijs W. B. van Leeuwen

  6. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands

    Pauline Meij

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  1. Marijke C. C. Langenberg
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Contributions

M.C.C.L., M.-A.H., J.P.R.K., L.G.V. and M.R. were the clinical investigators. J.J.J. performed the trial data management. P.H.V.-M. was the trial nurse and responsible for clinical quality assurance. J.J.J., J.K.-v.O., C.F., A.O.-F., M.T.v.d.B., F.W.B.v.L., P.M., A.v.D. and C.H.H. were responsible for the production, quality assurance and quality control of infectious cercariae. C.J.d.D., R.v.S., M.D.M., E.S., B.M.F.W., L.v.L., G.J.v.D. and P.L.A.M.C. were responsible for parasitological testing, antibody and cellular assays. M.C.C.L., G.J.v.D., C.H.H., M.Y., L.G.V. and M.R. prepared the research protocol and were involved in the study design. M.C.C.L., S.P.J., K.A.S. and M.R. performed the data analysis and statistical analysis. M.C.C.L. and M.R. wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Meta Roestenberg.

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Extended data

Extended Data Fig. 1 Eosinophil counts.

a-c. Eosinophil counts (x109/L) per volunteer and the median per group. The thin green, red, and blue lines represent data of individual volunteers infected with 10 (n = 3), 20 (n = 11) or 30 (n = 3) cercariae respectively, while thick lines represent the median of each group.

Extended Data Fig. 2 Relation between symptoms of an acute schistosomiasis syndrome and immunological readouts.

The relation between the presence of symptoms of an acute schistosomiasis infection and a. the highest eosinophil count (n = 17), b. the median serum CAA level from week 7 to 12 (n = 17), or c. the AWA specific IgG1 response at week 16 (n = 16). All using the two-sided Mann-Whitney U test. Individual data is presented as dots, the line represents the median, while the error bars represent the interquartile range of the groups.

Extended Data Fig. 3 Urine CAA levels.

a. Urine CAA levels after exposure and b. after first and second praziquantel treatment (week 0) and at week 52 after exposure. The thin green, red, and blue lines represent of individual volunteers infected with 10 (n = 3), 20 (n = 11) or 30 (n = 3) cercariae respectively, while thick lines represent the median of each group before treatment.

Extended Data Fig. 4 Serum CAA levels after treatment.

a-c. Serum CAA levels in pg/ml after the first treatment, second treatment, and at week 52. All values below the detection threshold of 0.5 pg/mL, are plotted at 0.25 pg/mL. The gray, yellow and blue lines represent data of individual volunteers infected with 10 (n = 3), 20 (n = 11) or 30 (n = 3) cercariae respectively.

Extended Data Fig. 5 IFNg and TH2 cytokine producing CD4 + T-cells over time.

The percentage of a. IFNγ and b. Th2-cytokine producing CD4+ T-cells over time in weeks after exposure in the 10 cercariae (gray, n = 3), 20 cercariae (yellow, n = 10) and 30 cercariae (blue, n = 3) groups. Dotted lines are linear regression lines, gray areas are confidence intervals, light dots are individual data, and horizontal lines with dots are the average values.

Extended Data Fig. 6 Effect of eosinophil data and model performance.

a. Individual predictions across folds for the full model per dataset including majority vote. Each symbol represents one prediction, with volunteers in columns and datasets in rows. Filled circles indicate a correct prediction and open circles a false prediction. Symptomatic and asymptomatic volunteers are indicated in red and the number of correct predictions per dataset is indicated. b. Mean Pearson correlation score between datasets using the first component of the projection onto the latent space across all folds from the model including all datasets. Size and color of circles reflect the mean rho value. c. Permutations analysis (n = 1000) with leave-one-out cross-validation on the full model using all subjects and including the four datasets without eosinophils. Blue and red dashed lines indicate the 99th percentile and the accuracy when comparing symptomatic and asymptomatic individuals (99.6%), respectively. d. Spearman correlation matrix of the seven consensus features selected in > 75% of folds in the leave-one-out cross-validation. Features were clustered using hierarchical clustering with complete linkage on Euclidean distance. All graphs are based on n = 16.

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Langenberg, M.C.C., Hoogerwerf, MA., Koopman, J.P.R. et al. A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics. Nat Med 26, 326–332 (2020). https://doi.org/10.1038/s41591-020-0759-x

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