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Papain, an experimental model protease, was used to decipher the protective mechanism(s) of the cysteine peptidase-based schistosomiasis vaccine. To examine the role of T lymphocytes, athymic nude (nu/nu) and immunocompetent haired (nu/+) mice were subcutaneously (sc) injected with 50 mg active papain two days before percutaneous exposure to 100 cercariae of Schistosoma mansoni. Highly significant (P 80% in dead parasite ova in the small intestine were independent of T cell activity and likely relied on the innate immune axis. To investigate the role of enzymatic activity, immunocompetent mice were sc injected with 50 mg active or E-64-inactivated papain two days before exposure to cercariae. The reductions in worm burden were highly significant (P 65% and 40% in active and inactivated papain-treated mice, respectively. Similar highly significant (P | Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice