Conference 2021 Pre-Recorded Video
Cathepsin B delivered by an attenuated Salmonella Typhimurium vector confers therapeutic protection in a murine model of chronic schistosomiasis
Authors and Affiliations
Adam S. Hassan1,2, Dilhan J. Perera2,3, Brian J. Ward1,2,3, Momar Ndao1,2,3
1. Department of Microbiology & Immunology, McGill University, Montreal, Canada
2. Infectious Diseases and Immunity in Global Health program, Research Institute of the McGill University Health Centre, Montreal, Canada
3. Division of Experimental Medicine, McGill University, Montreal, Canada
Schistosomiasis is among the most important neglected tropical diseases and Schistosoma mansoni threatens hundreds of millions of people in over 50 countries worldwide. S. mansoni resides adjacent to mucosal tissues as adult worms. Praziquantel is an oral anthelminthic that paralyzes the adult worms and has an efficacy of 85-90%. However, resistance is a growing concern and treatment does not prevent re-infection. Several prophylactic non-living vaccines are in pre-clinical and clinical development, but only one has been assessed for therapeutic effect in an animal model with modest results. Live attenuated Salmonella have multiple potential advantages as vaccine vectors. We have repurposed an attenuated Salmonella enterica Typhimurium strain (YS1646) to produce such a vaccine. We have initially targeted Cathepsin B (CatB), a digestive enzyme important for both juvenile and adult worms.
Female C57BL/6 mice were infected with 150 S. mansoni cercariae. Once infection was well-established, mice were immunized at either two or four months post-infection. A multi-modality immunization schedule was used that included three oral (PO) doses of CatB-bearing YS1646 on days one, three, and five as well as an intramuscular (IM) dose of recombinant CatB on day one. Serum (IgG) responses to CatB were monitored by ELISA. Mice were sacrificed at intervals post-vaccination to assess adult worm and egg burden (liver and intestinal tissue) that were expressed relative to the saline control group numbers.
Although all animals were infected with S. mansoni, serum anti-CatB IgG levels were significantly increased in immunized animals. Compared to the mock-vaccinated animals, all parasitological outcomes (worm numbers and hepatic/intestinal egg burdens) were 40-50% reduced at 4 weeks post-vaccination with further reductions (approx. 55-70%) at 8 weeks post-vaccination. Both relative and absolute reductions in worm numbers and hepatic/intestinal egg burdens continued to increase over time as mice were sacrificed 12, 16, and 24 weeks post-vaccination, suggesting that the vaccine led to a slow but progressive loss of adult worms and/or female worm fecundity.
We are currently generating chromosomally integrated Salmonella strains to produce a more acceptable vaccine for eventual human use. A vaccine that has both prophylactic and therapeutic activity would be ideal for use in conjunction with mass treatment campaigns with praziquantel.