Sm-p80-based schistosomiasis vaccine: double-blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission-blocking efficacy

Abstract

Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis.

Keywords: Schistosoma mansoni; Sm-p80 vaccine; baboons; efficacy; schistosomiasis; systems biology.

Fig. 1.

Prophylactic efficacy of Sm-p80–based vaccine. (A) Adult Schistosoma mansoni worm recovered per individual baboon in all four trials. (B) Egg burden per gram of tissue. (C) Weekly fecal egg per gram of feces. (D) Egg viability and hatching rate (n is the total number of eggs examined). Panels B, C and D depict cumulative data from all four trials.

Fig. 2.

Maximum anti-Sm-p80 antibody titers in baboons following vaccination. (A) Maximum total IgG titers achieved by each baboon in trials 1–4, (B) Maximum IgM titers, (C) Maximum IgG1 titers and (D) maximum IgA titers for each baboon in Trials 1, 2, 3, and 4. “C” represents the control group (GLA-SE), while “E” represents the experimental group (rSm-p80 + GLA-SE). Serum samples were obtained from each baboon prior to immunizations, parasite challenge and at necropsy.

Fig. 3.

Kinetics of total Sm-p80–specific antibody in immunized baboons. Panels A–D show the production of Sm-p80–specific total IgG antibodies in control animals (panel C, GLA-SE) and experimental animals (panel E, rSm-p80 + GLA-SE) in trials 1, 2, 3 and 4, respectively. Endpoint titers were determined for week 0, week 4, week 8, week 12, week 16, and week 24.

Fig. 4.

Localization of Sm-p80 in S. mansoni adult worms. Representative stitched images of adult worms are shown in panels A (control) and B (vaccinated). The distribution of Sm-p80 in adult worm recovered from three different baboons from control group is shown in A1a–3a respectively while images B1a–3a represent worms from three different vaccinated baboons (magenta). A1b–3b and B1b–3b show a merged of transmitted detector (TD) light and fluorescent Sm-p80. The images were taken using a Nikon T1-E confocal microscopy with a 10× objective and analyzed with NIS software. The stitched images represent a maximum projection intensity derived from a Z-stack. All images acquired with the same laser power and same gain. The arrows indicate the male (♂) and the female (♀) worms respectively.

Fig. 5.

Identification of molecular signatures of Sm-p80–based vaccine-mediated immunogenicity and immunity in baboon PBMCs following vaccination and challenge infection. (A) Venn diagram depicting numbers and percentages of significant differentially expressed genes (DEGs) (p<0.05; 1.5-fold change cutoff) in Sm-p80–immunized baboons at vaccination and necropsy. (B) Distribution of DEGs (y-axis) in Sm-p80–immunized baboon PBMCs at vaccination and necropsy, as well as DEGs common to both time points according to ontology classification. (C) Heat map depicting IPA-identified common canonical pathways with activation z-scores for which z-score was available and not zero. (D) Heat map depicting IPA-identified common upstream regulators with activation z-scores for which scores were available and not zero. (E) Gene network derived from immune-related DEGs in baboon PBMCs following Sm-p80 vaccination. (F) Gene network derived from immune-related DEGs in baboon PBMCs at necropsy.

Fig. 6.

Systems biology approach to identify molecular signatures in PBMCs, lymph nodes, and spleen. (A) Venn diagram depicting numbers and percentages of significant differentially expressed genes (DEGs) (p<0.05; 1.5-fold change cutoff) in Sm-p80–immunized baboon PBMCs, lymph nodes, and spleen at necropsy. (B) Distribution of DEGs (y-axis) in Sm-p80–immunized baboon PBMCs and secondary lymphoid tissues, as well as DEGs common to all tissues at necropsy according to ontology classification. (C) Heat map depicting IPA-identified common canonical pathways with activation z-score for which scores were available and not zero. (D) Heat map depicting IPA-identified common upstream regulators with activation z-scores for which scores were available and not zero. (E) Gene network derived from immune-related DEGs in baboon lymph nodes at necropsy. (F) Gene network derived from immune-related DEGs in baboon spleen at necropsy.