title: A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa.
abstract: The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.
authors.affiliation: Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.|Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.|Center for Vaccinology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Angela
authors.identifier: 0000-0002-8380-368X
authors.initials: A
authors.lastname: Huttner
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: World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Grillet
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Mariëlle C
authors.identifier: 0000-0002-7538-1800
authors.initials: MC
authors.lastname: Haks
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Quinten
authors.affiliation: Division of Immunology and Allergy, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Modoux
authors.affiliation: Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.|Institut für Tropenmedizin, Universitätsklinikum Tübingen, and German Center for Infection Research, Tübingen, Germany.
authors.forename: Selidji Todagbe
authors.initials: ST
authors.lastname: Agnandji
authors.affiliation: Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brosnahan
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: Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Harandi
authors.affiliation: Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Laurent
authors.identifier: 0000-0002-0857-2252
authors.initials: L
authors.lastname: Kaiser
authors.affiliation: Laboratory of Molecular Microbiology and Biotechnology, Department of Medical Biotechnologies, University of Siena, Siena, Italy.|Sclavo Vaccines Association, Siena, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Medaglini
authors.affiliation: NewLink Genetics Corp., 94 Jackson Road, Devens, MA 01439, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Monath
authors.affiliation: Division of Immunology and Allergy, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Roux-Lombard
authors.affiliation: Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.|Institut für Tropenmedizin, Universitätsklinikum Tübingen, and German Center for Infection Research, Tübingen, Germany.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Center for Vaccinology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. claire-anne.siegrist@unige.ch.|World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000349:Africa; D046129:Ebola Vaccines / Q000009:adverse effects / Q000276:immunology*; D005060:Europe; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000097:blood* / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male
chemical_list: D046129:Ebola Vaccines