Abstract
Ebolavirus Disease (EVD) is a severe haemorrhagic fever that occurs in epidemic outbreaks, with a high fatality rate and no specific therapies available. rVSVΔG-ZEBOV-GP (Ervebo®), a live-attenuated recombinant vesicular stomatitis virus vector expressing the glycoprotein G of Zaire Ebolavirus, is the first vaccine approved for prevention of EVD. Both innate and adaptive responses are deemed to be involved in vaccine-induced protection, yet the mechanisms are not fully elucidated. A global transcriptomic approach was used to profile the blood host-response in 51 healthy volunteers enrolled in a phase 1/2 clinical trial. Signatures of the host responses were investigated assessing the enrichment in differentially expressed genes (DEGs) of specific “blood transcription modules” (BTM). Comparison of gene-expression levels showed that vaccination produces a peak of 5469 DEGs at day one, representing 38.6% of the expressed genes. Out of 346 BTMs, 144 were significantly affected by vaccination. Innate immunity pathways were induced from day 1 to day 14. At days 2 and 3, neutrophil modules were downregulated and complement-related modules upregulated. T-cell and cell-cycle associated modules were upregulated at days 7 and 14, while at day 28, no modules remained activated. At day 14, a direct correlation was observed between ZEBOV glycoprotein-specific antibody titres and activation of seven BTMs, including two related to B-cell activation and B cell receptor signalling. Transcriptomic analysis identified an rVSVΔG-ZEBOV-GP-induced signature and demonstrated a direct correlation of blood transcriptomic changes with ZEBOV glycoprotein-specific antibody titres.
Highlights
Ebolavirus Disease (EVD) is a severe haemorrhagic fever that affects both humans and non-human primates and occurs in epidemic outbreaks
We investigated whether a transcriptomic signal could be correlated with the magnitude of total anti-ZEBOV GP IgGs after vaccination using the blood transcription modules framework
We showed that rVSV∆G-ZEBOV-GP vaccination: (i) had a tremendous impact on the blood transcription in vaccinees, hijacking the host transcriptional homeostasis; (ii) had a sustained impact on innate immunity associated gene modules which possibly resulted in increased protection from viral infection; and (iii) induced a transcriptional signature of adaptive immune response that correlated with anti-GP antibody titers
Summary
Ebolavirus Disease (EVD) is a severe haemorrhagic fever that affects both humans and non-human primates and occurs in epidemic outbreaks. Using a systems biology approach, high-dimensional RNA-expression data can be integrated with clinical and immunologic phenotypes to identify transcriptional signatures of immunogenicity and reactogenicity, and to elucidate possible vaccine associated mechanisms of immune response [26,27]. This approach has been employed to dissect the mechanism of action of different vaccines in clinical trials [28,29] and in pre-clinical models [30,31,32]. The blood transcriptomic response to high dose vaccination (107 and 5 × 107 pfu) with rVSV∆GZEBOV-GP was analysed in 51 volunteers of the phase 1/2 randomised controlled trial (NCT02287480) conducted in Geneva and transcriptomic data were integrated with clinical and immunological data
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