Safety and immunogenicity of a bivalent Ebola virus and Sudan virus ChAdOx1 vectored vaccine in adults in the UK: an open-label, non-randomised, first-in-human, phase 1 clinical trial.

BACKGROUND: Four Orthoebolavirus species can cause Ebola disease, with Ebola virus (species Orthoebolavirus zairense) and Sudan virus (species Orthoebolavirus sudanense) responsible for the majority of outbreaks and cases. No vaccines have been approved against orthoebolaviruses other than Ebola virus. We aimed to evaluate the safety and immunogenicity of a non-replicating single-adenoviral vaccine (ChAdOx1 biEBOV) encoding both Ebola virus and Sudan virus glycoproteins. METHODS: In this open-label, non-randomised, first-in-human, phase 1, dose-escalation clinical trial of ChAdOx1 biEBOV, participants aged 18-55 years without clinically significant medical comorbidities or previous adenovirus vaccine exposure were recruited at a single site (Oxford, UK). Participants were non-randomly enrolled to a low-dose group (5 × 10⁹ viral particles [vp] of ChAdOx1 biEBOV), a medium-dose group (2·5 × 101⁰ vp), and a high-dose group (5 × 101⁰ vp). All doses were administered intramuscularly. After recruitment of all participants, the protocol was amended so that a subgroup from the high-dose group received a second high dose of vaccine 12 weeks after the first dose. Primary outcome measures were assessment of solicited adverse events for 7 days after vaccinations, unsolicited adverse events for 28 days after vaccinations, changes in clinical laboratory measures within 28 days after vaccination, and serious adverse events and adverse events of special interest for the study duration. Secondary outcomes were assessment of humoral and cellular immunity to Ebola virus and Sudan virus glycoprotein. This study is registered with ClinicalTrials.gov, NCT05079750. FINDINGS: Between Nov 11, 2021, and April 7, 2022, 40 individuals attended the trial screening visit, of whom 26 were enrolled (six in the low-dose group, six in the medium-dose group, and 14 in the high-dose group). Seven participants in the high-dose group received one vaccine dose and seven received two vaccine doses. Local solicited adverse events were reported by 17 (65%) of 26 participants after dose 1 and five (71%) of seven after dose 2. Systemic solicited adverse events were reported by 23 (88%) participants after dose 1 and five (71%) after dose 2. All solicited adverse events were mild or moderate, with no severe events reported. No serious adverse reactions were reported. Unsolicited adverse events related to vaccination were mostly mild or moderate and short-lived, such as joint pain or upper respiratory symptoms. One adverse event of special interest, thrombocytopenia, occurred transiently in one participant in the high-dose group. Rapidly resolving lymphopenia was common at the early post-vaccination timepoint. A single 5 × 101⁰ vp dose vaccination elicited seropositivity to Ebola virus in 14 (100%) participants in the high-dose group and elicited seropositivity to Sudan virus in 12 (86%) participants in the high-dose group; antibody titres were boosted in the two-dose group. INTERPRETATION: Our results suggest that the ChAdOx1 biEBOV vaccine was safe and well tolerated. Safety and tolerability data are consistent with other vaccines using the same vaccine backbone. A single 5 × 101⁰ vp dose of the vaccine was immunogenic, generating binding antibodies against both Ebola virus and Sudan virus glycoproteins, with antibody responses boosted in the subgroup receiving a second immunisation. Future research should focus on approaches to enhance antibody responses and to elicit neutralising antibodies to Sudan virus. FUNDING: UK Research and Innovation.