Ebola virus disease is caused by an infection with a virus known as the Ebolavirus. The disease is characterized by symptoms such as fever, body aches, diarrhoea, bleeding, and vomiting. According to the World Health Organization, the number of people who die among the population having Ebola virus disease ranges from 25% to 90%. Vaccination is one of the most effective ways to prevent illness caused by viruses. A vaccine contains a non-functional part of the virus that is recognized by the body's protective immune system. The body then produces a response that prevents illness if the person is exposed to that virus again. This process is known as an immune response. The investigational treatment consists of a 2 dose vaccine regimen, 1 dose of Ad26.ZEBOV and 1 dose of MVA-BN-Filo vaccine, for the prevention of Ebola virus disease (Zaire ebolavirus species). This combination will be given at 2 different intervals between the 2 vaccine doses. The first schedule will include MVA-BN-Filo as the first dose followed by Ad26.ZEBOV as the second dose. The second schedule will include Ad26.ZEBOV as the first dose followed by MVA-BN-Filo as the second dose. In this study, researchers want to know the safety of the Ebola vaccine regimen in healthy adults and in human immunodeficiency virus (HIV*)-infected adults when administered using different vaccination schedules and interval. In addition, researchers want to understand the immune responses induced by the Ebola vaccine regimen by performing some tests. *HIV infection affects cells of the immune system and decreases their ability to fight infections. Participants can take part in this study if they have never received an Ebola vaccine, have not been diagnosed with Ebola virus disease, and have not travelled to any place where Ebola virus disease was confirmed up to 1 month before the study starts. Participants in the HIV-infected cohort should have a documented HIV infection within 6 months before the study start and be taking medicines for the treatment of HIV infection for the duration of the study. During the study, all participants will go through screening to confirm if they can take part in the study. Once enrolled, participants will be divided into 2 groups, healthy adults and participants with HIV infection between 18 to 70 years of age. All participants will receive either study vaccine (Ad26.ZEBOV, MVA-BN-Filo) or placebo, which does not contain the study vaccine, but looks like it. All vaccines will be given as an injection in the muscle. This study will be conducted in 2 parts: • • In Part 1 performed in the USA, participants will receive MVA-BN-Filo or placebo on Day 1 followed by Ad26.ZEBOV or placebo on Day 15. • • In Part 2 performed in Africa, participants will be further divided into 2 groups. • o Participants in Group 1 will receive Ad26.ZEBOV or placebo on Day 1 followed by MVA-BN-Filo or placebo on Day 29. • o Participants in Group 2 will receive MVA-BN-Filo or placebo on Day 1 followed by Ad26.ZEBOV or placebo on Day 15. During the study, participants will undergo different study assessments and tests. These include blood tests, vital signs (such as pulse, blood pressure, and temperature), electrocardiograms, physical exams, and pregnancy test for women. Any side effects reported by the participants will also be recorded throughout the study. Blood samples will be taken at several time points to understand how many participants responded to the vaccine regimen and to what extent. There will be a follow-up phase up to 1 year after the second dose to monitor the participants’ health and to collect blood samples for immune response assessments. The overall duration of the study will be approximately 3 years.

SYNOPSIS A Randomized, Observer-blind, Placebo-controlled, Two-part, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Two Prime-boost Regimens of the Candidate Prophylactic Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo. The sponsor, in collaboration with Bavarian Nordic (BN) and Walter Reed Army Institute of Research (WRAIR), is investigating the potential of a prophylactic Ebola vaccine regimen comprised of the following 2 candidate Ebola vaccines: Ad26.ZEBOV is a monovalent vaccine expressing the full length Ebola virus (EBOV, formerly known as Zaire ebolavirus) Mayinga glycoprotein (GP), and is produced in the human cell line PER.C6®. MVA-mBN226B, further referred to as Modified Vaccinia Ankara (MVA)-BN-Filo®, is a multivalent vaccine expressing the Sudan virus (SUDV) GP, the EBOV GP, the Marburg virus (MARV) Musoke GP, and the Tai Forest virus (TAFV, formerly known as Côte d’Ivoire ebolavirus) nucleoprotein (NP), and is produced in chicken embryo fibroblast cells. The EBOV GP expressed by MVA-BN-Filo has 100% homology to the one expressed by Ad26.ZEBOV. Two populations will be studied in this protocol: healthy adults and human immunodeficiency virus (HIV)-infected adults, ages 18-70 years inclusive, will be enrolled. Ad26.ZEBOV and MVA-BN-Filo will be evaluated as a heterologous prime-boost regimen. The first schedule to be evaluated is prime vaccination with MVA-BN-Filo followed by a boost with Ad26.ZEBOV 14 days later. In the second schedule, Ad26.ZEBOV is used to prime a filovirus-specific immune response and MVA-BN-Filo is used to boost the immune response 28 days later. The EBOV GP that is currently circulating in West Africa has 97% homology to the EBOV GP used in this vaccine regimen. STUDY RATIONALE • Enlarge the safety and immunogenicity database for the Ad26.ZEBOV/MVA-BN-Filo 1, 29-day prime-boost regimen in healthy adults. • Assess the safety and immunogenicity of Ad26.ZEBOV/MVA-BN-Filo 1, 29-day prime-boost regimen in HIV-infected subjects and determine the effect of vaccination on HIV disease. • Enlarge the safety and immunogenicity database for MVA-BN-Filo/Ad26.ZEBOV 1, 15 day prime-boost regimen in healthy adults and HIV-infected adults.