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

Abstract

BackgroundThe 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).

Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study

“…28 Studies are in progress to elucidate immune mechanisms of protection, including the roles of antibody-dependent cellular cytotoxicity, innate immunity, and T cells. 29,30 Data from this study support several important conclusions. First, we confirm the previously described pattern of early onset, mild to moderate, well tolerated, transient, and dose-dependent local and systemic adverse events induced by rVSVΔG-ZEBOV-GP.…”

Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

“…Here, EBOV GP specific T-cells secreted mainly CD107a and TNFα, while lower dose groups showed antigen-specific T-cell responses. 70 Recent advances in our understanding of the innate immune system and the use of systems biology approaches are beginning to reveal the fundamental mechanisms by which the innate immune system orchestrates protective immune responses to vaccination. We investigated innate immune responses following VSV-EBOV immunization and our data revealed an innate immune signature that correlated with antibody responses in the Hamburg VSV-EBOV vaccine trial.…”

The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials

“…All participants were injected with vaccine doses ranging from 3 × 10 5 to 5 × 10 7 PFU or placebo (NCT02283099, NCT02296983). 34 , 35 The results from these three trials demonstrated good antibody responses in all vaccinees and neutralizing antibodies were elicited by day 28 in 107 out of 126 vaccinees (85%). 36 , 37 However, during one trial in Geneva, 11 out of 51 (22%) participants without any previous history of joint disease had an onset of arthralgia in the second week after vaccination.…”

“…39 In-depth analysis of samples from one trial corroborated this finding of increased IP-10 levels after vaccination and found a general activation of T cells with a significant induction of Th1 cytokines in response to vaccination. 35 A different study found a correlation between the antibody response to vaccination and an increase in the circulation of a specific subset of CD4+ T cells, cTfh17 cells. 40 …”