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- Title
Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial.
- Authors
Milligan, Iain D.; Gibani, Malick M.; Sewell, Richard; Clutterbuck, Elizabeth A.; Campbell, Danielle; Plested, Emma; Nuthall, Elizabeth; Voysey, Merryn; Silva-Reyes, Laura; Juliana McElrath, M.; De Rosa, Stephen C.; Frahm, Nicole; Cohen, Kristen W.; Shukarev, Georgi; Orzabal, Nicola; Duijnhoven, Wilbert van; Truyers, Carla; Bachmayer, Nora; Splinter, Daniel; Samy, Nathaly
- Abstract
<bold>Importance: </bold>Developing effective vaccines against Ebola virus is a global priority.<bold>Objective: </bold>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).<bold>Design, Setting, and Participants: </bold>Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015.<bold>Interventions: </bold>Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10(10) viral particles) or MVA-BN-Filo (1 × 10(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.<bold>Main Outcomes and Measures: </bold>The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after 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 after each immunization until 8 months after priming immunizations.<bold>Results: </bold>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 participants 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 after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses.<bold>Conclusions and Relevance: </bold>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 after 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.<bold>Trial Registration: </bold>clinicaltrials.gov Identifier: NCT02313077.
- Subjects
VACCINE effectiveness; VACCINE safety; EBOLA virus disease vaccines; ENZYME-linked immunosorbent assay; IMMUNIZATION; GLYCOPROTEINS; CELLULAR immunity; COMPARATIVE studies; EBOLA virus disease; GENES; RESEARCH methodology; MEDICAL cooperation; POXVIRUS diseases; PROTEINS; RESEARCH; RESEARCH funding; RNA viruses; T cells; VIRAL vaccines; EVALUATION research; RANDOMIZED controlled trials; HUMAN research subjects; BLIND experiment; EBOLA virus; ANTIBODY formation
- Publication
JAMA: Journal of the American Medical Association, 2016, Vol 315, Issue 15, p1610
- ISSN
0098-7484
- Publication type
journal article
- DOI
10.1001/jama.2016.4218