Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial.
OBJECTIVE
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).


METHODS
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.


METHODS
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.


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT02313077.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Iain D
ID
Milligan
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Malick M
MM
Gibani
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Richard
R
Sewell
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Elizabeth A
EA
Clutterbuck
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Danielle
D
Campbell
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Emma
E
Plested
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Elizabeth
E
Nuthall
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom2Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.
Merryn
M
Voysey
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
Laura
L
Silva-Reyes
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
M Juliana
MJ
McElrath
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Stephen C
SC
De Rosa
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Nicole
N
Frahm
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Kristen W
KW
Cohen
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Georgi
G
Shukarev
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Nicola
N
Orzabal
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Wilbert
W
van Duijnhoven
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Carla
C
Truyers
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Nora
N
Bachmayer
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Daniel
D
Splinter
Bavarian Nordic, Martinsried, Germany.
Nathaly
N
Samy
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Maria Grazia
MG
Pau
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Hanneke
H
Schuitemaker
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Kerstin
K
Luhn
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Benoit
B
Callendret
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Johan
J
Van Hoof
Janssen, Pharmaceutical Companies of Johnson & Johnson, Leiden, the Netherlands.
Macaya
M
Douoguih
Jenner Institute, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom7National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
Katie
K
Ewer
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Brian
B
Angus
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom7National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
Andrew J
AJ
Pollard
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom7National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
Matthew D
MD
Snape
D000328:Adult; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D029043:Ebolavirus / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors; D064368:Healthy Volunteers; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D008297:Male; D029024:Marburgvirus / Q000276:immunology; D008875:Middle Aged; D016037:Single-Blind Method; D013601:T-Lymphocytes / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014615:Vaccinia / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
D046129:Ebola Vaccines; D014614:Vaccines, Synthetic; D014764:Viral Proteins