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The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG1 and IgG3 from putatively resistant individuals resident in S. mansoni endemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to the immunogenic 5B region of the hookworm aspartic protease and vaccine antigen, Na-APR-1. Sm-TSP-2 formulated with alum/CpG showed significant reductions in adult worm and liver egg burdens in two separate murine schistosomiasis challenge studies. Sm-TSP-2/5B afforded significantly greater protection than Sm-TSP-2 alone when both antigens were formulated with alum/CpG. The enhanced protection obtained with the chimeric fusion protein was associated with increased production of anti-Sm-TSP-2 antibodies and IL-4, IL-10 and IFN-γ from spleen cells of vaccinated animals. Sera from 666 individuals from Brazil who were infected with S. mansoni were screened for potentially deleterious IgE responses to Sm-TSP-2. Anti-Sm-TSP-2 IgE to this protein was not detected (also shown previously for Na-APR-1), suggesting that the chimeric antigen Sm-TSP-2/5B could be used to safely and effectively vaccinate people in areas where schistosomes and hookworms are endemic., Author Summary There are currently no vaccines available to combat helminth (worm) infections in humans. The most devastating of the diseases caused by human helminths are schistosomiasis (or bilharzia) and hookworm disease. By fusing one of the lead schistosomiasis vaccine antigens, Sm-TSP-2, with a protective fragment from one of the lead hookworm vaccine antigens, Na-APR-1, we have produced a chimeric vaccine, termed Sm-TSP-2/5B that might provide protection against two debilitating and co-endemic neglected tropical diseases. Sm-TSP-2/5B provided increased protection compared to Sm-TSP-2 alone when formulated with human approved adjuvants and tested in a mouse model of schistosomiasis. Moreover, IgE against Sm-TSP-2 or Na-APR-1 has not been detected in the blood of residents from an area in Brazil that is endemic for schistosomes and hookworms, indicating that vaccines based on these molecules would be unlikely to generate allergic reactions in recipients from developing countries.