jats:pSchistosomiasis remains a neglected tropical disease of major public health concern with high levels of morbidity in various parts of the world. Although considerable efforts in implementing mass drug administration programs utilizing praziquantel have been deployed, schistosomiasis is still not contained. A vaccine may therefore be an essential part of multifaceted prevention control efforts. In the 1990s, a joint United Nations committee promoting parasite vaccines shortlisted promising candidates including for schistosomiasis discussed below. After examining the complexity of immune responses in human hosts infected with schistosomes, we review and discuss the antigen design and preclinical and clinical development of the four leading vaccine candidates: Sm-TSP-2 in Phase 1b/2b, Sm14 in Phase 2a/2b, Sm-p80 in Phase 1 preparation, and Sh28GST in Phase 3. Our assessment of currently leading vaccine candidates revealed some methodological issues that preclude a fair comparison between candidates and the rationale to advance in clinical development. These include (1) variability in animal models - in particular non-human primate studies - and predictive values of each for protection in humans; (2) lack of consensus on the assessment of parasitological and immunological parameters; (3) absence of reliable surrogate markers of protection; (4) lack of well-designed parasitological and immunological natural history studies in the context of mass drug administration with praziquantel. The controlled human infection model - while promising and unique - requires validation against efficacy outcomes in endemic settings. Further research is also needed on the impact of advanced adjuvants targeting specific parts of the innate immune system that may induce potent, protective and durable immune responses with the ultimate goal of achieving meaningful worm reduction.</jats:p>