| Schistosomiasis is a chronic, debilitating parasitic disease affecting 200 million people throughout the world. Studies have focused on controlling this disease through vaccination. To date, there are two paradigms in schistosome vaccinology. The first is that only the larval stages are susceptible to immune killing. The second paradigm is that the adult stage, utilizing several immune evasion mechanisms, is not susceptible to immune killing, and can flourish in the hostile host environment. One defense mechanism used by schistosomes involves antioxidant enzymes that neutralize the effects of reactive oxygen species. We therefore hypothesized that stimulating an immune response to parasite antioxidant enzymes may neutralize their effect, thereby making the adult parasite susceptible to immune elimination. To test this hypothesis, an experimental mouse model vaccinating with the cDNA's of two Schistosoma mansoni antioxidants, cytosolic superoxide dismutase (SmCT-SOD) and glutathione peroxidase (SmGPX) in the expression vector, pcDNAI/AMP (pc) was utilized. The immunized mice were challenged by surgical transfer of adult worms directly into the mesenteric circulation to circumvent all larval stages and immune responses engendered by them. In three independent experiments, vaccination with pcSmCT-SOD gave a significant mean reduction in worm burden (39%) compared to controls. Vaccination with pcGPX did not lead to significant protection. Another group of mice received a 1.7kb fragment of the cDNA for Sm-filamin, a structural protein. Vaccination with pcfilamin conferred significant protection (50%) compared to controls. Furthermore, an increase in specific total IgG responses was noted in both protected groups 4-weeks post challenge. Antibody isotypes as well as secreted cytokine levels were analyzed to define the protective immune mechanism(s) involved in adult worm killing. The data presented here suggest a role for specific IgG2a antibody and IFN-γ. Finally, in an attempt to enhance the response(s) elicited by DNA vaccination, mice received a DNA prime followed by boosting with recombinant vaccinia virus (RVV) vector containing their respective cDNA. This DNA prime/RVV boost regime did not confer significant protection to mice challenged with adult worms. Taken together, these data challenge existing paradigms in schistosome vaccinology by targeting adult worms, and suggest a therapeutic role for an antioxidant enzyme vaccine. |
