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Preliminary Communication |

Safety and Immunogenicity of Novel Adenovirus Type 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines A Randomized Clinical Trial

Iain D. Milligan, MRCP1; Malick M. Gibani, MRCP1; Richard Sewell, BA1; Elizabeth A. Clutterbuck, PhD1; Danielle Campbell, BScN1; Emma Plested1; Elizabeth Nuthall, BSc1; Merryn Voysey, MBiostat1,2; Laura Silva-Reyes, MSc1; M. Juliana McElrath, MD, PhD3; Stephen C. De Rosa, MD3; Nicole Frahm, PhD3; Kristen W. Cohen, PhD3; Georgi Shukarev, MD4; Nicola Orzabal, BSc4; Wilbert van Duijnhoven, MSc4; Carla Truyers, PhD4; Nora Bachmayer, PhD4; Daniel Splinter, PhD4; Nathaly Samy, MD5; Maria Grazia Pau, PhD4; Hanneke Schuitemaker, PhD4; Kerstin Luhn, PhD4; Benoit Callendret, PhD4; Johan Van Hoof, MD4; Macaya Douoguih, MD, MPH4; Katie Ewer, PhD6,7; Brian Angus, MD8; Andrew J. Pollard, FRCPCH, PhD1,7; Matthew D. Snape, FRCPCH, MD1,7
[+] Author Affiliations
1Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom
2Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
4Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands
5Bavarian Nordic, Martinsried, Germany
6Jenner Institute, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom
7National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom
8Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
JAMA. 2016;315(15):1610-1623. doi:10.1001/jama.2016.4218.
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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 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.

Interventions  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 × 1010 viral particles) or MVA-BN-Filo (1 × 108 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.

Main Outcomes and Measures  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.

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 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.

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 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.

Trial Registration  clinicaltrials.gov Identifier: NCT02313077

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Figure 1.
Participant Flow Diagram

Numbers with blood samples at the 1-month visit after each vaccination event are shown. Follow-up at days 180 and 240 was not planned for those who received placebo. Ad26.ZEBOV indicates adenovirus-type 26 vector vaccine encoding Ebola glycoprotein; MVA-BN-Filo, modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein.

aParticipants could be excluded for >1 reason.

bParticipants who did not receive boosts are described in the Results section.

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Figure 2.
Ebola Glycoprotein-Specific Antibody Responses for Vaccine Recipients in Randomized Groups

These data, along with those for recipients of Ad26.ZEBOV prime and MVA-BN-Filo boost at 14-day interval and for placebo recipients, are in Table 3 and eFigure 1 in Supplement 2. Day 1 is baseline, the day of first vaccination. For numbers of participants included at each time point, see Table 3. Error bars indicate 95% confidence intervals; Ad26.ZEBOV, adenovirus-type 26 vector vaccine encoding Ebola glycoprotein; MVA-BN-Filo, modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein.

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