Salmonella Typhimurium expressing chromosomally integrated Schistosoma mansoni Cathepsin B protects against schistosomiasis in mice

Abstract

Schistosomiasis threatens hundreds of millions of people worldwide. The larval stage of Schistosoma mansoni migrates through the lung and adult worms reside adjacent to the colonic mucosa. Several candidate vaccines are in preclinical development, but none is designed to elicit both systemic and mucosal responses. We have repurposed an attenuated Salmonella enterica Typhimurium strain (YS1646) to express Cathepsin B (CatB), a digestive enzyme important for the juvenile and adult stages of the S. mansoni life cycle. Previous studies have demonstrated the prophylactic and therapeutic efficacy of our plasmid-based vaccine. Here, we have generated chromosomally integrated (CI) YS1646 strains that express CatB to produce a viable candidate vaccine for eventual human use (stability, no antibiotic resistance). 6–8-week-old C57BL/6 mice were vaccinated in a multimodal oral (PO) and intramuscular (IM) regimen, and then sacrificed 3 weeks later. The PO + IM group had significantly higher anti-CatB IgG titers with greater avidity and mounted significant intestinal anti-CatB IgA responses compared to PBS control mice (all P < 0.0001). Multimodal vaccination generated balanced TH1/TH2 humoral and cellular immune responses. Production of IFNγ by both CD4+ and CD8+ T cells was confirmed by flow cytometry (P < 0.0001 & P < 0.01). Multimodal vaccination reduced worm burden by 80.4%, hepatic egg counts by 75.2%, and intestinal egg burden by 78.4% (all P < 0.0001). A stable and safe vaccine that has both prophylactic and therapeutic activity would be ideal for use in conjunction with praziquantel mass treatment campaigns.

Schistosoma mansoni vaccine candidates identified by unbiased phage display screening in self-cured rhesus macaques

“…Encouragingly, immunization with selected antigens expressed in phage has generated antibodies against SmCatB and SmAE in mice, causing a significant reduction in total worm burden by 22% and in females worm burden by 25%. Reduction in worm burden aligns with previous research with S. mansoni, where immunization of mice with full length rSmCatB and rSmCatL alone or combined have elicited a 54-65% worm burden reduction [50][51][52] , immunization with multi-antigenic-peptide constructs comprising two epitopes from CatB and CatL elicited significant 39% reduction in challenge worm burden with an opposite effect of 64% increase in liver eggs 53 , while immunization with full length rSmCatB led to an impressive >80% reduction in worm burden in mice 54,55 ; of note, immunization of mice with rSmAE resulted in a 37% decrease in egg-laying 56 . Generating an effective vaccine against S. mansoni has been challenging.…”