mRNA vaccines encoding variant forms of Sm-TSP-2 confer protective immunity against Schistosoma mansoni

Despite the global burden of helminth infections, no human vaccines have yet been licensed against these parasites. This study explored the development and evaluation of mRNA vaccine candidates targeting Schistosoma mansoni tetraspanin-2 ( Sm -TSP-2), an antigen currently under evaluation as a protein vaccine. We designed constructs encoding either full-length Sm -TSP-2, or its large extracellular loop (EC2) domain in secretory, membrane-anchored, or cytosolic forms. In a murine challenge model, the secreted and membrane-anchored versions of Sm -TSP-2-EC2 induced the highest of antigen-specific antibody titers. These two construct designs, along with full-length Sm -TSP-2 mRNA, also significantly reduced adult worm and egg burden compared to controls. The membrane-anchored Sm -TSP-2-EC2 mRNA was the most effective, lowering worm and egg burdens by 66.7% and 66.9%, respectively. Protective responses by the mRNA vaccines were comparable to those induced by recombinant Sm -TSP-2-EC2 protein formulated with Alum. Histopathological analysis revealed smaller hepatic granulomas surrounding worm eggs, supporting the immunopathological benefit of vaccination. Using a systematic mRNA-based approach, we optimized the presentation of the Sm -TSP-2-EC2 and demonstrated that extracellular exposure of EC2 is essential for eliciting a protective immune response. These findings lay the groundwork for future development of multivalent mRNA vaccine strategies to achieve broader and more durable protection against schistosomes and other parasitic worms.