EBioMedicine (May 2017)

Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization

  • Christine Dahlke,
  • Rahel Kasonta,
  • Sebastian Lunemann,
  • Verena Krähling,
  • Madeleine E. Zinser,
  • Nadine Biedenkopf,
  • Sarah K. Fehling,
  • My L. Ly,
  • Anne Rechtien,
  • Hans C. Stubbe,
  • Flaminia Olearo,
  • Saskia Borregaard,
  • Alen Jambrecina,
  • Felix Stahl,
  • Thomas Strecker,
  • Markus Eickmann,
  • Marc Lütgehetmann,
  • Michael Spohn,
  • Stefan Schmiedel,
  • Ansgar W. Lohse,
  • Stephan Becker,
  • Marylyn M. Addo,
  • Marylyn M. Addo,
  • Stephan Becker,
  • Verena Krähling,
  • Selidji Todagbe Agnandji,
  • Sanjeev Krishna,
  • Peter G. Kremsner,
  • Jessica S. Brosnahan,
  • Philip Bejon,
  • Patricia Njuguna,
  • Claire-Anne Siegrist,
  • Angela Huttner,
  • Marie-Paule Kieny,
  • Kayvon Modjarrad,
  • Vasee Moorthy,
  • Patricia Fast,
  • Barbara Savarese,
  • Olivier Lapujade

DOI
https://doi.org/10.1016/j.ebiom.2017.03.045
Journal volume & issue
Vol. 19, no. C
pp. 107 – 118

Abstract

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Background: The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date. Methods: We recruited 30 healthy subjects aged 18–55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3 × 105 plaque-forming units (PFU), 3 × 106 PFU, 2 × 107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay. Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides. Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2 × 107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine. VEBCON trial Hamburg, Germany (NCT02283099).

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