Induction of Protective Immune Responses Against Schistosomiasis haematobium in Hamsters and Mice Using Cysteine Peptidase-Based Vaccine

Abstract

One of the major lessons we learned from the radiation-attenuated cercariae vaccine studies is that protective immunity against schistosomiasis is dependent on the induction of T helper (Th)1-/Th2-related immune responses. Since most schistosome larval and adult-worm-derived molecules used for vaccination uniformly induce a polarized Th1 response, it was essential to include a type 2 immune response-inducing molecule, such as cysteine peptidases, in the vaccine formula. Here, we demonstrate that a single subcutaneous injection of Syrian hamsters with 200 μg active papain, 1 h before percutaneous exposure to 150 cercariae of Schistosoma haematobium, led to highly significant (P < 0.005) reduction of >50% in worm burden and worm egg counts in intestine. Immunization of hamsters with 20 μg recombinant glyceraldehyde 3-phosphate dehydrogenase (rSG3PDH) and 20 μg 2-cys peroxiredoxin-derived peptide in a multiple antigen peptide construct (PRX MAP) together with papain (20 μg/hamster), as adjuvant led to considerable (64%) protection against challenge S. haematobium infection, similar to the levels reported with irradiated cercariae. Cysteine peptidases-based vaccination was also effective in protecting outbred mice against a percutaneous challenge infection with S. haematobium cercariae. In two experiments, a mixture of Schistosoma mansoni cathepsin B1 (SmCB1) and Fasciola hepatica cathepsin L1 (FhCL1) led to highly significant (P < 0.005) reduction of 70% in challenge S. haematobium worm burden and 60% reduction in liver egg counts. Mice vaccinated with SmCB1/FhCL1/rSG3PDH mixture and challenged with S. haematobium cercariae 3 weeks after the second immunization displayed highly significant (P < 0.005) reduction of 72% in challenge worm burden and no eggs in liver of 8–10 mice/group, as compared to unimmunized mice, associated with production of a mixture of type 1- and type 2-related cytokines and antibody responses.

Papain‐Based Vaccination Modulates Schistosoma mansoni Infection‐Induced Cytokine Signals

“…The mechanism by which papain pretreatment or papain‐based vaccination leads to considerable reduction in challenge S . mansoni and S. haematobium is not elucidated as yet. It was repeatedly reported that immunization of BALB/c and C57BL/6 mice with papain alone induced production of IL‐4, IL‐5 and IL‐13 in draining LN and serum IgG1 and IgE, but not IgM or IgG2b, antibodies.…”

“…The data confirm our findings that documented association of resistance against S . mansoni and S. haematobium challenge infection with type 2 biased‐immunity. Accordingly, type 2 responses are fundamental for resistance against schistosome infection, not only for protection against the parasite‐related immune‐pathology .…”

Development of a schistosomiasis vaccine

“…Adjuvanted rSjIR reduced fecal eggs in mice by 56–67% [18] while immunization with a monovalent rSjTPI vaccine in buffaloes resulted in up 52% reduction in worm burden. Additionally, a cysteine peptidase-based vaccine and a cocktail of antigens have been tested in single formulations for both S. mansoni and S. haematobium and have shown very promising levels of protection (>70%) in mice [59;60]. In addition, lead candidates, Sm14 and Sm-TSP-2 have also been tested in combination with an additional antigen with the aim of enhancing protection in the murine model but this combinational antigen approach has yielded less than 50–60% reduction in worm burden [61–63].…”

Excretion/secretion products from Schistosoma mansoni adults, eggs and schistosomula have unique peptidase specificity profiles

“…proteases or proteolytic enzymes) are vital to successful parasitism, and facilitate invasion of the host, digestion of host proteins, reproduction, modulation of the host’s physiology [11–19] and immune response [14, 20]. Interference with these mechanisms by specific vaccines [21, 22] or drugs may provide therapeutic benefits. Indeed, peptidases are excellent druggable targets [23–25] and a large body of literature exists demonstrating the therapeutic benefits of small molecule inhibitors targeting peptidases of schistosomes [26–29] and other infectious organisms [30–36].…”