Safety and Immunogenicity of the rVSV?G-SEBOV-GP Vaccine Administered at 2 Dose Levels in Healthy Ugandan Adults and Adolescents

Uganda recently declared the end of its seventh Ebola outbreak, with 14 cases and four deaths. Ebola is a severe febrile disease, sometimes with haemorrhagic manifestations, and with an average case fatality rate (CFR) of almost 50%. Sudan virus (SUDV) is one of four pathogenic orthoebolaviruses that causes Ebola disease in humans and is responsible for six of Uganda's Ebola outbreaks to date, including the most recent outbreak. The other pathogenic orthoebolaviruses are Ebola virus (EBOV), Tai Forest virus, and Bundibugyo virus. SUDV disease (SVD) has occurred unpredictably in South Sudan and Uganda since its discovery 50 years ago. Fruit bats are a suspected natural reservoir of infection; some non-human primate (NHP) and antelope species may be intermediate hosts. Human-to-human transmission occurs through contact with infectious body fluids. Orthoebolaviruses are major biosecurity threats due to their unpredictability, transmissibility, high CFRs, and epidemic/pandemic potential or risk of being weaponised for bioterrorism. SUDV is on the World Health Organisation's (WHO) recent list of pathogens that should be prioritised for R&D of medical countermeasures. There is currently no approved SUDV vaccine. However, IAVI is developing a vaccine candidate (rVSV?G-SUDV-GP) using the same recombinant vesicular stomatitis virus (rVSV) platform as Merck's licensed and highly efficacious rVSV?G-ZEBOV-GP vaccine (ERVEBO®). ERVEBO® has already had demonstrable impact in curbing viral transmission and reducing mortality during EBOV outbreaks in West and Central Africa. IAVI's SUDV vaccine (rVSV?G-SUDV-GP) is a genetically engineered, replication-competent, and attenuated live virus vaccine designed to induce potent immune responses with one dose. A single dose induced robust immune responses in NHPs and protected 90% of animals against lethal SUDV challenge. In a recent U.S. Phase 1 clinical trial (NCT05724472), intramuscular injection with a rVSV-based SUDV vaccine at 2x106-2x108 plaque-forming units (pfu) was well-tolerated and elicited antibody responses in all vaccinees. The vaccine used in that trial (rVSV?G-SEBOV-GP) was Merck-manufactured but genetically identical to IAVI's rVSV?G-SUDV-GP candidate. Building on the successful NHP and Phase 1 studies, the MRC/UVRI & LSHTM Uganda Research Unit (MUL), in collaboration with IAVI Africa, proposes a Phase 2a, randomised, double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of rVSV?G-SEBOV-GP in Uganda, a country where SUDV is regionally enzootic. This study of 156 adults and adolescents will address key priorities in the clinical development pathway, including generating safety data in relevant African populations and informing dose-selection for ongoing clinical development. Importantly, it will provide immunogenicity and safety data in a younger age-group to guide progression to future larger trials in children and adolescents. We will use the Merck-manufactured rVSV?G-SEBOV-GP vaccine, given dose availability. Upon availability of IAVI's rVSV?G-SUDV-GP candidate, a separate bridging trial will be conducted to demonstrate similarity in safety and immunogenicity of the two vaccines. The proposed Phase 2a trial in Uganda is a critical step to advance clinical development of a much-needed SUDV vaccine. Further, it will enhance regional familiarity with the investigational product of regulators and communities and facilitate effective collaboration between key stakeholders, strengthening preparedness for integration of vaccination into future SUDV outbreak response. The proposed partnership, together with plans for Africa-based vaccine manufacturing through collaboration with Institut Pasteur de Dakar, reinforces Africa's role and ownership in the development of vaccines targeting diseases that are endemic to the continent.