Clinical tolerance but no protective efficacy in a placebo-controlled trial of repeated controlled schistosome infection

Abstract

BACKGROUNDPartial protective immunity to schistosomiasis develops over time, following repeated praziquantel (PZQ) treatment. Moreover, animals develop protective immunity after repeated immunization with irradiated cercariae. Here, we evaluated the development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni in healthy, Schistosoma-naive participants using single-sex, controlled human S. mansoni infection.METHODSTwenty-four participants were randomized in a double-blinded (1:1) manner to either the reinfection group, which received 3 exposures (weeks 0, 9, and 18) to 20 male cercariae, or to the infection control group, which received 2 mock exposures with water (weeks 0 and 9) prior to cercariae exposure (week 18). Participants were treated with PZQ (or placebo) at weeks 8, 17, and 30. Attack rates (ARs) after the final exposure (weeks 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events (AEs) were collected for safety.RESULTSTwenty-three participants completed the follow-up. No protective efficacy was observed, given an 82% (9 of 11) AR after the final exposure in the reinfection group and 92% (11 of 12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; P = 0.5). Related AEs were higher after the first infection (45%) compared with the second (27%) and third (28%) infections. Severe acute schistosomiasis was observed after the first infections only (2 of 12 in the reinfection group and 2 of 12 in the infection control group).CONCLUSIONRepeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported following subsequent infections, but did not result in protection against reinfection.TRIAL REGISTRATIONClinicalTrials.gov NCT05085470.FUNDINGEuropean Research Council (ERC) Starting Grant (no. 101075876).

Keywords: Infectious disease; Parasitology.

Figure 1. Consort flow for study participants.

Figure 2. Eosinophil counts and CAA levels after (re)exposure to S. mansoni cercariae.

Plots show the changes over time in eosinophils (A) and CAA (B) in infection control (pink, n = 12) and reinfection (blue, n = 12) participants. Eosinophils (C) and CAA (D) in the reinfection group were then plotted by stratification on the basis of whether single-sex (M-M-M) exposure (purple, n = 7) or accidental mixed-sex (M-F-M) exposure occurred. Individual participant data are plotted, with thicker lines showing the group means. The horizontal black line shows the cutoff for abnormal counts (≥0.5 × 10⁹/mL for eosinophils; ≥1.0 pg/mL for CAA). The solid, gray vertical line shows S. mansoni exposure weeks, while the gray, black vertical line shows when PZQ treatment was given.

Figure 3. Antibody, chemokine, and cytokine responses after (re)exposure to S. mansoni cercariae.

Plots show the individual changes in antibody levels in worm-specific IgM (A), AWA-specific IgG (B), AWA-specific IgG1 (C), and SEA IgG (D). For CCL23 (E), CCL4 (F), CXCL10 (G), IL-10 (H), IL18 (I), and TNF (J), individual participant data and group means (thicker lines) are plotted. Data were stratified for infection controls (pink, n = 12), reinfection single-sex (M-M-M) exposure (purple, n = 7), and reinfection accidental mixed-sex (M-F-M) exposure (green, n = 5). The solid gray vertical line shows S. mansoni exposure weeks (0, 9, and 18), and the dotted gray vertical line shows when PZQ treatment was given (weeks 8, 17, and 30).