Selidji T Agnandji, José F Fernandes, Emmanuel B Bache, Régis M Obiang Mba, Jessica S Brosnahan, Lumeka Kabwende, Paul Pitzinger, Pieter Staarink, Marguerite Massinga-Loembe, Verena Krähling, Nadine Biedenkopf, Sarah Katharina Fehling, Thomas Strecker, David J Clark, Henry M Staines, Jay W Hooper, Peter Silvera, Vasee Moorthy, Marie-Paule Kieny, Akim A Adegnika, Martin P Grobusch, Stephan Becker, Michael Ramharter, Benjamin Mordmüller, Bertrand Lell, VEBCON Consortium, Sanjeev Krishna, Peter G Kremsner, AII - Infectious diseases, APH - Global Health, Infectious diseases, APH - Aging & Later Life, and AII - Amsterdam institute for Infection and Immunity
Background The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. Methods and findings A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)–glycoprotein (GP)–specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%–100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264–908), 556 (95% CI: 280–1,101), 1,245 (95% CI: 899–1,724), and 1,503 (95% CI: 931–2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647–1,591), 1,887 (1,154–3,085), 1,445 (1,013–2,062), and 3,958 (2,249–6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025–1,989), and children, 1,620 (95% CI: 806–3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. Conclusions Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. Trial registration Pan African Clinical Trials Registry PACTR201411000919191, Sanjeev Krishna and colleagues present a phase I randomised trial for safety and immunogenicity of an Ebola vaccine in both adults and children in Gabon., Author summary Why was this study done? The worst Ebola outbreak in history ended in 2016 after killing about 11,323 individuals and infecting 28,650 individuals worldwide. This public health emergency accelerated efforts to develop a vaccine as part of the strategy to contain the outbreak. Two vaccine candidates with preclinical safety and efficacy data obtained from non-human primates entered human trials. The one used in our study is the rVSVΔG-ZEBOV-GP vaccine, containing a non-infectious portion of a gene from the Zaire Ebola virus introduced into a recombinant vesicular stomatitis virus (rVSV), which itself is unlikely to cause disease in humans. To generate data for deployment of the vaccine, several dose-ranging phase I trials were initiated across centres in the United States, Europe, and Africa. What did the researchers do and find? We allocated 115 adults aged 18–50 years to receive 1 of the 5 doses used in the trial. A single intramuscular dose ranging from 3 × 103 to 2 × 107 plaque-forming units (PFU) was given, and participants were followed up until 6 months post-injection for safety and immunogenicity. Preliminary results led to the selection of the 2 × 107 PFU dose for further development. We also included 20 adolescents (13–17 years) and 20 children (6–12 years), who received the 2 × 107 PFU dose and were followed-up in a similar way as the adults. No vaccine-related serious or severe adverse event was reported by any participant. A high proportion of our population—even though residing in an area with no history of Ebola outbreak—had pre-vaccination antibodies specific to the Zaire Ebola virus. In adults, antibodies persisted up to 6 months post-injection at doses of 3 × 105 to 2 × 107 PFU. In participants with baseline antibodies, a dose as low as 3 × 104 PFU could induce high antibody titres up to day 56 post-injection. Higher vaccine replication, leading to shedding of the vaccine in saliva and urine, occurred in children and adolescents. What do these findings mean? Our results and other findings show that this vaccine is safe and immunogenic. Lower vaccine doses may be needed in paediatric populations as well as for boosting after primary vaccination or naturally acquired immunity.