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Introduction Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm) on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents. Methods In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs. Results Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly. Conclusions The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population. Trial registration ClinicalTrials.gov NCT02178748, Author summary There is an urgent global need for an improved TB vaccine strategy. Adolescents are an important target population for a TB vaccine. In field settings where the need for a vaccine is greatest, co-infection with other pathogens including malaria, HIV and helminths, may interfere with the impact of such strategies. In this study, we used a model TB vaccine candidate based on a genetically engineered viral vector, and with an excellent safety profile, to determine whether there was any immunological interference when this vaccine was used in adolescents who were co-infected with S. mansoni. Our data shows comparable immunogenicity in adolescents infected and uninfected with S. mansoni, suggesting that co-infection with this helminth species may not have an adverse impact on candidate TB vaccines of this type. The vaccine was safe and induced robust cellular responses in both the infected and uninfected adolescents following immunisation. These findings are important and encouraging for tuberculosis vaccine development.