title: Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo).
  
  
  METHODS
  In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian).
  
  
  RESULTS
  Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 10(10) pu, 35 [38%] to 2·5 × 10(10) pu, 35 [38%] to 5 × 10(10) pu, and 11 [12%] to 1 × 10(11) pu) and 20 in the USA (ten [50%] to 1 × 10(10) pu and ten [50%] to 1 × 10(11) pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 10(10) and two [2%] received 1 × 10(11) pu) and four (20%) of 20 in the USA (all received 1 × 10(11) pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness.
  
  
  CONCLUSIONS
  1 × 10(11) pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers).
  
  
  BACKGROUND
  Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA; Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Milagritos D
authors.initials: MD
authors.lastname: Tapia
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Samba O
authors.initials: SO
authors.lastname: Sow
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Lyke
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Fadima Cheick
authors.initials: FC
authors.lastname: Haidara
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Fatoumata
authors.initials: F
authors.lastname: Diallo
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Moussa
authors.initials: M
authors.lastname: Doumbia
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Awa
authors.initials: A
authors.lastname: Traore
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Flanon
authors.initials: F
authors.lastname: Coulibaly
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Mamoudou
authors.initials: M
authors.lastname: Kodio
authors.affiliation: Centre pour le Développement des Vaccins du Mali, Bamako, Mali, West Africa.
authors.forename: Uma
authors.initials: U
authors.lastname: Onwuchekwa
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Rezwanul
authors.initials: R
authors.lastname: Wahid
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Kieny
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Vasee
authors.initials: V
authors.lastname: Moorthy
authors.affiliation: Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Egeruan B
authors.initials: EB
authors.lastname: Imoukhuede
authors.affiliation: Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Tommy
authors.initials: T
authors.lastname: Rampling
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Francois
authors.initials: F
authors.lastname: Roman
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: De Ryck
authors.affiliation: The EMMES Corporation, Rockville, MD, USA.
authors.forename: Abbie R
authors.initials: AR
authors.lastname: Bellamy
authors.affiliation: The EMMES Corporation, Rockville, MD, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Dally
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 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, Bethesda, MD, USA.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ploquin
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Stanley
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Ledgerwood
authors.affiliation: Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Adrian V S
authors.initials: AVS
authors.lastname: Hill
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Sullivan
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Barney
authors.initials: B
authors.lastname: Graham
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: mlevine@medicine.umaryland.edu.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D046129:Ebola Vaccines / Q000008:administration & dosage*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007117:Immunization, Secondary; D008297:Male; D008302:Mali; D008875:Middle Aged; D016037:Single-Blind Method; D014481:United States; D055815:Young Adult
chemical_list: D000956:Antigens, Viral; D046129:Ebola Vaccines; D006023:Glycoproteins