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Background: Recombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge. Methods: A randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive one of two formulations of Sm-TSP-2 vaccine (adjuvanted with Alhydrogel only, or with Alhydrogel plus the Toll-like receptor-4 agonist, AP 10–701), and 4 to receive Euvax B hepatitis B vaccine. Successively higher doses of antigen (10 μg, 30 μg, and 100 μg) were administered in a dose-escalation fashion, with progression to the next dose cohort being dependent upon evaluation of 7-day safety data after all participants in the preceding cohort had received their first dose of vaccine. Each participant received 3 intramuscular injections of study product at intervals of 2 months and was followed for 12 months after the third vaccination. IgG and IgG subclass antibody responses to Sm-TSP-2 were measured by qualified indirect ELISAs at pre- and post-vaccination time points through the final study visit. Results: Sm-TSP-2/Alhydrogel administered with or without AP-10-701 was well-tolerated in this population. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. No vaccine-related serious adverse events or adverse events of special interest were observed. Groups administered Sm-TSP-2/Alhydrogel with AP 10–701 had higher post-vaccination levels of antigen-specific IgG antibody. A significant dose-response relationship was seen in those administered Sm-TSP-2/Alhydrogel with AP 10–701. Peak anti-Sm-TSP-2 IgG levels were observed approximately 2 weeks following the third dose, regardless of Sm-TSP-2 formulation. IgG levels fell to low levels by Day 478 in all groups except the 100 μg with AP 10–701 group, in which 50% of subjects (4 of 8) still had IgG levels that were ≥4-fold higher than baseline. IgG subclass levels mirrored those of total IgG, with IgG1 being the predominant subclass response. Conclusions: Vaccination of adults with Sm-TSP-2/Alhydrogel in an area of ongoing S. mansoni transmission was safe, minimally reactogenic, and elicited significant IgG and IgG subclass responses against the vaccine antigen. These promising results have led to initiation of a Phase 2 clinical trial of this vaccine in an endemic region of Uganda. Trial registration: NCT03110757. Author summary: Infection caused by Schistosoma mansoni is a major neglected tropical disease with significant associated morbidity. New tools, such as vaccines, are needed due to the inadequacy of current control strategies. Tetraspanin-2 of S. mansoni (Sm-TSP-2) is one of the lead vaccine candidates for hepatic/intestinal schistosomiasis. Antibodies induced by this vaccine are postulated to interfere with the development of the tegument of adult S. mansoni worms, thereby impairing their development and survival. We conducted a Phase 1 trial of recombinant Sm-TSP-2 adjuvanted with Alhydrogel in 60 healthy adults living in Brazil. Each participant received three vaccinations every 2 months by intramuscular injection of the vaccine administered with or without an aqueous solution of the Toll-like receptor-4 agonist, Glucopyranosyl Lipid A (AP 10–701). Sm-TSP-2/Alhydrogel was well tolerated in schistosomiasis-exposed adults; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion with increasing levels observed after each vaccination. The addition of AP 10–701 to the vaccine resulted in significantly higher antibody responses. Based on these results, the vaccine has been advanced into a Phase 2 clinical trial in an endemic region of Africa. [ABSTRACT FROM AUTHOR]