BACKGROUND: In response to the 2014-16 Ebola virus disease (EVD) epidemic in West Africa, the EBOVAC1 consortium fast-tracked the clinical development of a two-dose heterologous vaccine regimen comprising the experimental Ad26.ZEBOV and MVA-BN-Filo vaccines against Ebola virus (EBOV). AIMS AND METHODOLOGY: This analytic commentary for a PhD by prior publication aims to synthesise and critically appraise the published results of four studies conducted under the EBOVAC1 project in Sierra Leone, a country severely affected by the West African EVD epidemic. These studies included a cross-sectional seroprevalence study, a randomised controlled trial (VAC52150EBL3001), an open-label trial (VAC52150EBL2011) and a cohort study, and were all conducted in Kambia district in the northwest of the country. The main overarching objectives of these studies were to assess: The seroprevalence of EBOV Glycoprotein (GP) Immunoglobulin G (IgG) antibodies in a population affected by the 2014-16 EVD epidemic. The safety and immunogenicity of an Ad26.ZEBOV, MVA-BN-Filo vaccine regimen with a 56-day interval between doses in participants from a population affected by the EVD epidemic. The safety and immunogenicity of an Ad26.ZEBOV booster in participants who had been previously vaccinated with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. The effect of malaria on the immune response to the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. RESULTS: Approximately 8% of Sierra Leonean adults and children who enrolled in the seroprevalence study and who reported never having had signs or symptoms of EVD had serologic responses to EBOV GP above a seropositivity threshold. The Ad26.ZEBOV, MVA-BN-Filo vaccine regimen, with a 56-day interval between doses, was well tolerated and induced a humoral immune response that persisted for at least two years in adults and three years in children. Booster vaccination with Ad26.ZEBOV in previously vaccinated adults and children was safe and induced a robust anamnestic response within seven days. Malaria infection did not affect the binding antibody response 21 days after the second dose of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. Conclusions and impact of the presented work: The results of the EBOVAC1 seroprevalence study suggest that EBOV can potentially transmit undetected with some infections occurring asymptomatically or with milder symptoms. The results of the clinical trials support the use of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen for EVD prophylaxis in adults and children 1-17 years of age, with the option of providing an additional Ad26.ZEBOV booster to previously vaccinated people at imminent risk of EVD, such as at the start of an EVD outbreak. Some of these findings informed the marketing authorisation under exceptional circumstances granted to the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in the European Union in July 2020. This vaccine regimen is suitable for EVD prophylaxis in areas where malaria is highly endemic and where the vaccine may be most needed in the future.