Elsevier

EBioMedicine

Volume 19, May 2017, Pages 107-118
EBioMedicine

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

https://doi.org/10.1016/j.ebiom.2017.03.045Get rights and content
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open access

Highlights

  • A phase I clinical trial was conducted to investigate the live-attenuated Ebola vaccine rVSV-ZEBOV.

  • Ebola-specific humoral and cell-mediated immune responses show a favorable profile for subjects immunized with 2 × 107 PFU of rVSV-ZEBOV.

  • The highest dose cohort induced stronger antigen-specific CTL-responses and interlocked cytokine networks compared to lower dose groups.

rVSV-ZEBOV is the first Ebola vaccine with human efficacy data, currently undergoing an accelerated licensing process. Nevertheless, to date no human immunological correlate of protection has been identified and mechanisms of immune responses elicited by rVSV-ZEBOV remain incompletely understood.

We conducted a phase I trial to test rVSV-ZEBOV in 30 healthy subjects using three dosage levels. We here present a comprehensive evaluation of humoral and cell-mediated responses with an in-depth analysis of signaling molecules following ex vivo stimulation with Ebola GP peptides. Our data suggest a favorable immune response profile for subjects immunized with 2 × 107 PFU.

These data address critical knowledge gaps with respect to mechanisms of immuneprotection in the context of Ebola vaccines and may provide additional evidence to support the current dosage used in later stage clinical trials.

Abstract

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).

Keywords

rVSV-ZEBOV
Ebola vaccine
Phase I study
T-cell responses
Cytokines
Humoral and cell-mediated immune responses

Cited by (0)

Funding: Wellcome Trust through WHO (SPHQ14-LOA-311), BMG (ZMVI5-2514NIK005), BMBF and DZIF (TTU01.905).

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These authors contributed equally to this work.