Immunogenicity and reactogenicity of novel adenovirus type 26 and modified vaccinia Ankara-vectored Ebola vaccines: A randomized clinical trial

Importance Developing effective vaccines against Ebola virus is a global priority. Objective To evaluate an adenovirus-type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus and Tai Forest virus nucleoprotein (MVA-BN-Filo). Design, Setting and Participants Single-center, randomized, placebo-controlled, observer-blind, phase I trial performed in Oxford, UK, enrolling healthy 18 to 50 year-olds from December 2014; 8-month follow-up completed October 2015. Intervention Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to study vaccines/placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5x10^10 viral particles) or MVA-BN-Filo (1x10^8 median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56-days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14-days later. Outcome and Measures The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days following each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7-days following each immunization until 8-months following priming immunization. Results Among 87 study participants (median age 38.5 years, 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile following MVA-BN-Filo compared with 3/60 (5%; 95% CI 1%-14%) of participants receiving Ad26.ZEBOV in the randomized groups. In the open-label group 4/15 (27%; 8%-55%) Ad26.ZEBOV recipients experienced fever. In the randomized groups, 28/29 (97%; 82%-99.9%) of Ad26.ZEBOV and 7/30 (23%; 10%-42%)MVA-BN-Filo recipients had detectable Ebola glycoprotein-specific IgG 28-days following primary immunization. All vaccine recipients had specific IgG detectable 21-days post-boost and at 8-month follow-up. Within randomized groups, at day 7 post-boost at least 86% of vaccine recipients showed Ebola-specific T cell responses. Conclusions and Relevance In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed following primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies.