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Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. Trial registration ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35)., Author Summary Typhoid fever is a common cause of febrile illness in tropical countries. Although currently available typhoid vaccines are moderately effective, they are not suitable for use in young children. Development of new vaccines is complicated as Salmonella Typhi, the causative bacteria, only infect humans. In this study, we used a recently developed human typhoid challenge model to directly assess the efficacy of a new oral vaccine candidate, M01ZH09, compared to placebo. A parallel group of participants were given 3-doses of licensed oral Ty21a vaccine as a positive comparator. We found that a single dose of M01ZH09 was not effective in preventing typhoid infection in our model, although significant effects were seen in delaying onset of infection and reducing bacterial numbers. Ty21a also failed to significantly protect against infection suggesting our model was particularly stringent. We discovered that anti-Vi antibodies, present in some individuals prior to vaccination, contributed significantly to preventing infection in some individuals, and when this effect was taken into account, M01ZH09 halved the risk of developing typhoid after being challenged. These results demonstrate the utility of human challenge models in assessing the efficacy of new typhoid vaccine candidates, and suggest that further development of M01ZH09 dosing or delivery strategies may produce better results. These results also support further development of Vi-based vaccines as a potentially preventive intervention.