Periodic Reporting for period 4 - EBOVAC3 (Bringing a prophylactic Ebola vaccine to licensure) Reporting period: 2021-06-01 to 2022-05-31 Summary of the context and overall objectives of the project EBOVAC3 is one of the Innovative Medicines Initiative (IMI)’s Ebola+ Program projects, focused on supporting the development of a two-dose preventive vaccine regimen against Ebola Virus Disease (EVD) from Janssen Vaccines & Prevention B.V. part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and its partner Bavarian Nordic A/S. Other Ebola+ projects include, among others EBOVAC1, EBOVAC2, EBODAC and EBOMAN. Significant progress has been made in the development of this vaccine regimen, in large part due to the contributions made through the above-named IMI-funded projects. On the 1st July 2020, the European Commission granted marketing authorisation to the Janssen Ebola vaccine regime, Zabdeno® (Ad26.ZEBOV) and Mvabea® (MVA-BN-Filo). Data from the EBOVAC 1, 2 and 3 projects were used in the vaccine’s approval process. The authorisation was granted in one month, following a positive opinion adopted by the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) demonstrating the importance of this preventative tool to the Commission and its public health agenda. The Janssen Ebola vaccine regimen, Zabdeno® (Ad26.ZEBOV) and Mvabea® (MVA-BN-Filo), was also granted WHO Prequalification in April 2021. This will facilitate registration of the vaccine in African countries and allow broader access to communities at risk for EVD. The WHO and the government of Sierra Leone have recently begun administering the Janssen Ebola vaccine regimen as part of a WHO early access clinical program aimed at preventing further spread of Ebola in West Africa. In June 2021, the Strategic Advisory Group of Experts (SAGE) on Immunization for the World Health Organization (WHO) granted a recommendation in support of the use of Janssen two-dose Ebola vaccine regimen, Zabdeno® (Ad26.ZEBOV) and Mvabea® (MVA-BN-Filo), both during outbreaks for individuals at some risk of Ebola exposure and preventively, before outbreaks, for national and international first responders.EBOVAC3 aims to further support the vaccine regimen licensure pathway, providing information on long-term safety and antibody persistence following vaccination and, on the safety, and immunogenicity of the vaccine regimen in infants and health care workers. The project is also preparing for future Ebola outbreaks through activities including mathematical modelling and social science research. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the first three years, the EBOVAC3 project was focused on set-up activities and implementation & conduct of the clinical trials. During the fourth year, EBOVAC3 is completing or continuing the implementation of the clinical trials of the two-dose Ebola vaccine regimen:• EBL2005 (Safety and immunogenicity study of the two-dose heterologous vaccine in healthy infants in Guinea & Sierra Leone): participants’ follow-up have been completed.• EBL2007 (Open-label safety and immunogenicity study of the two-dose heterologous vaccine regimen in health care providers in the Democratic Republic of Congo): the study is currently ongoing.• EBL3005 (Long-term safety and immunogenicity study of the two-dose heterologous vaccine regimen in Sierra Leone): the study is currently ongoing.For all three trials, study documents including protocols and informed consent forms were developed and approved by the relevant ethics and regulatory authorities. Study sites in Guinea, Sierra Leone, and the Democratic Republic of Congo were identified and site preparations such as staff recruitment and training were carried out. All three trials started in 2019 and reached target recruitment in the second year of the project. The EBL2005 study has completed participant follow-up. EBOVAC3’s outbreak preparedness activities were set up in the first year of the project. Research protocols were developed for social science research in Guinea and Sierra Leone into community understanding, expectations and acceptance of various Ebola vaccine strategies. Data collection started in 2019. A protocol has been developed in DRC for social research on outbreak preparedness. A research protocol was drafted to study regulatory authorities’ experiences of Ebola vaccine studies during the epidemic which was approved by the ethics committee in Sierra Leone. A study protocol to identify gaps in preparedness for a future Ebola outbreak in Guinea, Sierra Leone & the DRC is under preparation. Staff have been recruited to lead these research activities. The feasibility assessment and pilot of linking vaccine label to biometric profile using barcode has been completed and the deliverable report has been written.The mathematical modelling work progressed with the joint analysis of EBOVAC1 and 2 trial data to study immune responses to the vaccine. Modelling work was conducted to evaluate the effect of different vaccination approaches (mass, ring, and targeted) to inform the design of efficient Ebola vaccination strategies. Work was also conducted to improve the design of studies to evaluate the effect of vaccination. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The second-largest outbreak of Ebola affected the eastern North Kivu and Ituri provinces of the DRC from August 2018 - June 2020, in the first two years of the EBOVAC3 project. In May 2019, WHO’s SAGE on Immunization recommended that the Janssen Ebola vaccine be used to help contain the geographic spread of the outbreak, in a deployment that was coordinated with and complementary to that of Merck’s Ebola vaccine. In June 2020, as the outbreak in the eastern DRC ended with the help of these vaccines, a new outbreak was declared in Équateur Province in western DRC. On 14th February 2021, an outbreak was declared in Guinea after a cluster of cases were reported in the Nzérékoré Region, the first time that the disease was reported in Guinea since the previous outbreak ended in 2016. These events underscore the ongoing need for preventive immunization in vulnerable communities.The work of the EBOVAC family of projects is therefore as important as ever to the global fight against Ebola and supported the licensure in July 2020 of the two-dose Ebola vaccine regimen for prophylactic use in adults and children ≥1-year-old in the European Union. This also enabled WHO prequalification, which was granted in April 2021.The data gathered from the clinical trials implemented by the EBOVAC3 project could contribute further to the licensure pathway of the two-dose vaccine regimen, providing additional data on the long-term safety and persistence of immune response associated with the vaccine, as well as the safety and immunogenicity of the vaccine in infants and healthcare workers specifically. This will inform the clinical use of the vaccine regimen and facilitate real-world vaccination efforts to combat or prevent future outbreaks of Ebola.The preparedness activities will inform an understanding of how best to deploy the vaccine to fight Ebola in ways that are tailored to communities and meet the capacities of governments and regulatory authorities. The economic and social costs of combatting an Ebola epidemic are significant for all affected countries and international responders, including countries in the European Union who provide humanitarian aid. One estimate of the total economic and social burden from the 2014-2016 West Africa Ebola outbreak was $53 billion. An effective vaccine offering long-lasting protection against Ebola could therefore have a significant impact in at-risk countries and also for Europeans.