Cysteine Peptidases as Schistosomiasis Vaccines with Inbuilt Adjuvanticity

Abstract

Schistosomiasis is caused by several worm species of the genus Schistosoma and afflicts up to 600 million people in 74 tropical and sub-tropical countries in the developing world. Present disease control depends on treatment with the only available drug praziquantel. No vaccine exists despite the intense search for molecular candidates and adjuvant formulations over the last three decades. Cysteine peptidases such as papain and Der p 1 are well known environmental allergens that sensitize the immune system driving potent Th2-responses. Recently, we showed that the administration of active papain to mice induced significant protection (P<0.02, 50%) against an experimental challenge infection with Schistosoma mansoni. Since schistosomes express and secrete papain-like cysteine peptidases we reasoned that these could be employed as vaccines with inbuilt adjuvanticity to protect against these parasites. Here we demonstrate that sub-cutaneous injection of functionally active S. mansoni cathepsin B1 (SmCB1), or a cathepsin L from a related parasite Fasciola hepatica (FhCL1), elicits highly significant (P<0.0001) protection (up to 73%) against an experimental challenge worm infection. Protection and reduction in worm egg burden were further increased (up to 83%) when the cysteine peptidases were combined with other S. mansoni vaccine candidates, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH) and peroxiredoxin (PRX-MAP), without the need to add chemical adjuvants. These studies demonstrate the capacity of helminth cysteine peptidases to behave simultaneously as immunogens and adjuvants, and offer an innovative approach towards developing schistosomiasis vaccines

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

“…Thereafter, levels of IgG1, IgA and IgE, but not IgM or IgG2b, humoral antibodies to the parasite ESP, SG3PDH, significantly rose associated with significant decrease in liver worm burden as compared to untreated infected mice. The data confirm our findings that documented association of resistance against S. mansoni [29,52,53] and S. haematobium [37] 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 immunepathology [54].…”

“…For 2 independent experiments, significant (P < 0.001) decrease of approximately 60% in challenge worm burden was recorded in the mice preimmunized with papain alone, and not the papain-free antigen Mix. These reproducible data point to the critical role of type 2-related immune responses in resistance to S. mansoni infection [28,29,37,52,53], similarly to the intestinal helminths, the resistance to which is characterized almost universally by type 2 response [40,41,45,55,56].…”

“…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 .…”

“…These reproducible data point to the critical role of type 2‐related immune responses in resistance to S . mansoni infection , similarly to the intestinal helminths, the resistance to which is characterized almost universally by type 2 response .…”

“…Inclusion of cathepsin L1, which possesses reproduction‐related functions, in the vaccine formula was necessary to achieve highly significant ( P < 0.0001) decrease of >65% in challenge S . mansoni and S. haematobium worm egg count in host liver and intestine .…”