BRAVO is a Phased Outbreak-response Study in the DRC Evaluating ERVEBO® Vaccination in ~20,000 Frontline Workers During the 2026 BDV Outbreak, Step A Assesses Real-world Effectiveness, Safety, and Impact on Severe Disease and Mortality, While Generating Evidence for Future BDV Vaccination Strategies

The BRAVO study (Bundibugyo: Respondre Avec la Vaccination, "On est ensemble") was developed in response to the 2026 Bundibugyo virus disease (BVD) outbreak in the Democratic Republic of the Congo (DRC). The study focuses on frontline workers (FLWs), who are at increased risk of infection because of their involvement in patient care, outbreak response activities, and contact with affected communities. Protecting this population is critical for maintaining healthcare services and strengthening outbreak control efforts. Currently, there is no licensed vaccine specifically targeting Bundibugyo virus (BDBV) for broad use. However, ERVEBO®, a vaccine licensed against Zaire ebolavirus, is available and has demonstrated a favorable safety profile. Although preclinical and immunological evidence suggests that ERVEBO® may provide some degree of cross-protection against BDBV, the extent of protection remains uncertain. BRAVO therefore aims both to support rapid vaccination of frontline workers during the outbreak and to generate evidence that can inform future vaccine policy and preparedness strategies. BRAVO is designed as a phased study embedded within the public health response. The study population includes adults aged 18 years and older working in Ebola treatment centers, healthcare facilities, or community-based outbreak response activities in affected areas. Both clinical and non-clinical personnel may participate if their duties place them at risk of exposure to infected individuals, infectious materials, or affected communities. The study consists of three steps: Step A: Immediate deployment and evaluation of ERVEBO® during the outbreak. Step B: Potential future evaluation of heterologous prime-boost vaccination strategies if additional vaccines become available and remain relevant. Step C: Potential contribution to evaluation of future Bundibugyo virus-specific vaccines. The primary focus of the current study is Step A, which is a prospective cohort study conducted under real-world outbreak conditions. The main objective is to assess the effectiveness of ERVEBO® vaccination against Bundibugyo virus disease, severe disease outcomes, and death. The primary effectiveness endpoint is whether vaccination reduces case fatality among laboratory-confirmed BVD cases hospitalized in Ebola treatment facilities. Secondary objectives include evaluating whether vaccination reduces: BVD-related mortality in the cohort, Incidence of symptomatic laboratory-confirmed BVD, Indicators of severe disease among confirmed cases. Safety is also an important component of the study. Serious adverse events occurring within one month after vaccination will be documented, and pregnancy outcomes among enrolled pregnant participants will be monitored. Participants may be enrolled regardless of vaccination status, allowing comparisons between vaccinated and unvaccinated frontline workers as vaccine deployment progresses according to operational feasibility and risk prioritization. Written informed consent will be obtained before enrollment and vaccination. The consent process will clearly communicate that protection against Bundibugyo virus has not been established and that additional vaccine options may become available in the future. Participants will generally be followed for six months after enrollment, or until the end of the outbreak if it occurs earlier. Pregnant participants will be followed through pregnancy outcomes. An additional component within Ebola treatment centers will collect information on frontline workers presenting with symptoms compatible with BVD, supporting supplementary analyses of vaccine effectiveness using routinely collected clinical and laboratory data. Step A aims to vaccinate approximately 20,000 frontline workers during the first six months of implementation. Based on projected outbreak assumptions, the study may generate sufficient confirmed BVD cases to provide meaningful estimates of vaccine effectiveness, particularly regarding protection against death. Beyond evaluating the immediate impact of vaccination, BRAVO is expected to strengthen outbreak preparedness by establishing systems for vaccination delivery, pharmacovigilance, data collection, and participant communication. The study is designed to provide decision-relevant evidence during the outbreak rather than after it, helping guide future recommendations for Bundibugyo virus vaccine strategies. Enrollment and vaccination are planned from September through December 2026, with follow-up continuing through June 2027. Final analysis and reporting are expected in September 2027.