title: The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.
abstract: BACKGROUND
  Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold.
  
  
  METHODS
  The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480.
  
  
  RESULTS
  Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×10(7) pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7-516·4] vs 1064·2 [757·6-1495·1]; p<0·0001; and 35·1 [24·7-50·7] vs 127·0 [86·0-187·6]; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality.
  
  
  CONCLUSIONS
  Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa.
  
  
  BACKGROUND
  Wellcome Trust through WHO.
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Huttner
authors.affiliation: Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Julie-Anne
authors.initials: JA
authors.lastname: Dayer
authors.affiliation: Virology Laboratory, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Yerly
authors.affiliation: Division of Clinical Epidemiology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Combescure
authors.affiliation: WHO Collaborating Centre for Vaccinology, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Floriane
authors.initials: F
authors.lastname: Auderset
authors.affiliation: Centre for Clinical Research, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
authors.affiliation: Philipps University Marburg, Institute for Virology, Marburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Eickmann
authors.affiliation: Division of Rheumatology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Finckh
authors.affiliation: Virology Laboratory, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Goncalves
authors.affiliation: Department of Molecular Virology and Department of Translational Sciences, US Army Medical Research, Institute for Infectious Diseases (USAMRIID), Frederick, MD, USA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Hooper
authors.affiliation: Division of Dermatology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
authors.affiliation: Philipps University Marburg, Institute for Virology, Marburg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krähling
authors.affiliation: Department of Molecular Virology and Department of Translational Sciences, US Army Medical Research, Institute for Infectious Diseases (USAMRIID), Frederick, MD, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Kwilas
authors.affiliation: WHO Collaborating Centre for Vaccinology, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lemaître
authors.affiliation: Centre for Clinical Research, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Matthey
authors.affiliation: Department of Molecular Virology and Department of Translational Sciences, US Army Medical Research, Institute for Infectious Diseases (USAMRIID), Frederick, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Silvera
authors.affiliation: Philipps University Marburg, Institute for Virology, Marburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Becker
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Fast
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Vasee
authors.initials: V
authors.lastname: Moorthy
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Marie Paule
authors.initials: MP
authors.lastname: Kieny
authors.affiliation: Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; Virology Laboratory, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kaiser
authors.affiliation: WHO Collaborating Centre for Vaccinology, Faculty of Medicine, Geneva, Switzerland; Center for Vaccinology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. Electronic address: claire-anne.siegrist@unige.ch.
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000235:genetics; D001168:Arthritis / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D003872:Dermatitis / Q000453:epidemiology / Q000473:pathology; D004311:Double-Blind Method; D004337:Drug Carriers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D046129:Ebola Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D029043:Ebolavirus / Q000235:genetics; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D013557:Switzerland; D014611:Vaccination / Q000009:adverse effects* / Q000379:methods*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014657:Vasculitis / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D018116:Vesiculovirus / Q000235:genetics; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D004337:Drug Carriers; D046129:Ebola Vaccines; D010919:Placebos; D014614:Vaccines, Synthetic