title: Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study.
abstract: BACKGROUND
  The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z).
  
  
  METHODS
  We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027.
  
  
  RESULTS
  Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 μg/mL (25·8-56·3) in the low-dose group, and 5·2 μg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 μg/mL (19·3-28·6) in the low-dose group, and 3·2 μg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses.
  
  
  CONCLUSIONS
  ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa.
  
  
  BACKGROUND
  Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.
authors.affiliation: Policlinique Médicale Universitaire, Lausanne, Switzerland. Electronic address: olga.de-santis@hospvd.ch.
authors.forename: Olga
authors.initials: O
authors.lastname: De Santis
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Switzerland.
authors.forename: Régine
authors.initials: R
authors.lastname: Audran
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Pothin
authors.affiliation: Clinical Trial Unit, Lausanne University Hospital, Switzerland.
authors.forename: Loane
authors.initials: L
authors.lastname: Warpelin-Decrausaz
authors.affiliation: Clinical Trial Unit, Lausanne University Hospital, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Vallotton
authors.affiliation: Clinical Trial Unit, Lausanne University Hospital, Switzerland.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Wuerzner
authors.affiliation: Policlinique Médicale Universitaire, Lausanne, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Cochet
authors.affiliation: Policlinique Médicale Universitaire, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Estoppey
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Switzerland.
authors.forename: Viviane
authors.initials: V
authors.lastname: Steiner-Monard
authors.affiliation: Policlinique Médicale Universitaire, Lausanne, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lonchampt
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Thierry
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Mayor
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Olivier Tshiani
authors.initials: OT
authors.lastname: Mbaya
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ploquin
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Sullivan
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Roman
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: De Ryck
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.affiliation: WHO, Geneva, Switzerland.
authors.forename: Marie Paule
authors.initials: MP
authors.lastname: Kieny
authors.affiliation: WHO, Geneva, Switzerland.
authors.forename: Vasee
authors.initials: V
authors.lastname: Moorthy
authors.affiliation: Division of Immunology and Allergy, Lausanne University Hospital, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Spertini
authors.affiliation: Policlinique Médicale Universitaire, Lausanne, Switzerland; Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Switzerland; Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
mesh_terms: D000256:Adenoviridae / Q000145:classification*; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D004306:Dose-Response Relationship, Immunologic; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D029043:Ebolavirus / Q000276:immunology; D005260:Female; D005334:Fever / Q000139:chemically induced; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D008889:Military Personnel; D019444:Vaccines, DNA / Q000276:immunology; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D046129:Ebola Vaccines; D007074:Immunoglobulin G; D019444:Vaccines, DNA