title: Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial.
abstract: BACKGROUND
  Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein.
  
  
  METHODS
  RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18-50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov, number NCT00997607.
  
  
  RESULTS
  108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37-75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28-66) in the group that received both vaccines. 15 of 30 (50%, 31-69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31-69) in the group that received both vaccines. Nine of 29 (31%, 15-51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10-42) in the group that received both vaccines. 19 of 30 (63%, 44-80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 13 of 30 (43%, 25-63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 15 of 29 (52%, 33-71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25-63) in the group that received both vaccines.
  
  
  CONCLUSIONS
  This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa.
  
  
  BACKGROUND
  US Department of Defense Infectious Disease Clinical Research Program and US National Institutes of Health Intramural Research Program.
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kibuuka
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Berkowitz
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda.
authors.forename: Monica
authors.initials: M
authors.lastname: Millard
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Enama
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda.
authors.forename: Allan
authors.initials: A
authors.lastname: Tindikahwa
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda.
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Sekiziyivu
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Costner
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sitar
authors.affiliation: US Military HIV Research Program, Bethesda, MD, USA.
authors.forename: Deline
authors.initials: D
authors.lastname: Glover
authors.affiliation: Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Gyan
authors.initials: G
authors.lastname: Joshi
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daphne
authors.initials: D
authors.lastname: Stanley
authors.affiliation: The EMMES Corporation, Rockville, MD, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Kunchai
authors.affiliation: US Military HIV Research Program, Bethesda, MD, USA.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Eller
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: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Sanofi, Cambridge, MA, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
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: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.affiliation: US Military HIV Research Program, Bethesda, MD, USA; Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: US Military HIV Research Program, Bethesda, MD, USA.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: Ledgerwood@mail.nih.gov.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Ledgerwood
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D004311:Double-Blind Method; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D029043:Ebolavirus / Q000276:immunology*; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D029024:Marburgvirus / Q000276:immunology*; D014454:Uganda; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D014760:Viral Fusion Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D046129:Ebola Vaccines; D019444:Vaccines, DNA; D014760:Viral Fusion Proteins