Titel: Deciphering immune signatures induced by viral vector vaccines against the Ebola virus
Sprache: Englisch
Autor*in: Bartels, Etienne
Schlagwörter: Ebola Virus (EBOV); Viral Vector Vaccines; In Vitro Stimulation; VSV-EBOV; MVA-EBOV; Immune Signature; CD86
GND-Schlagwörter: Ebola-VirusGND
Erscheinungsdatum: 2021-05
Tag der mündlichen Prüfung: 2021-08-20
The Ebola virus disease (EVD) is a severe, often fatal illness in humans. EVD is caused by the Ebola virus (EBOV) and is responsible for about 50−90 % deaths in diagnosed cases. The largest EVD outbreaks occurred in West Africa from 2013–2016 and in the Democratic Republic of the Congo (DRC) from 2018–2020. Vaccines are effective countermeasures against deadly diseases. The vector platforms vesicular stomatitis virus (VSV) and modified vaccinia virus Ankara (MVA) were used to develop viral vector vaccines against EBOV. While VSV can replicate in humans to some extent, MVA is replication deficient. Both carry the immunogenic EBOV glycoprotein (EBOV-GP). VSV-EBOV expresses the EBOV-GP on its surface instead of the VSV-GP, whereas MVA-EBOV only encodes for the EBOV-GP gene. Although VSV-EBOV was frequently used in the second largest outbreak in the DRC, exact mechanisms of induced immune signatures, especially innate immune responses, remain inadequately understood. However, innate immune responses can shape and influence adaptive immunogenicity and therefore contribute to vaccine efficacy. Since innate immunity is difficult to analyze comprehensively in clinical trials due to its early manifestation, it has not been well investigated so far.

To elucidate specific innate immune mechanisms induced by MVA-EBOV and VSV-EBOV, in vitro stimulation assays of hPBMCs were implemented. Early immune responses were comprehensively monitored by longitudinal sampling and application of different methods. In the first 24 hours post stimulation, the immune responses were investigated on mRNA level (RNA-Seq) and protein level (flow cytometry/cytokine secretion).
Flow cytometry approaches revealed a significantly secretion of IP-10 and a trend to altered expression of CD40, CD83, and CD86 on monocyte and DC subsets post VSV-EBOV stimulation. On the mRNA level VSV-EBOV stimulations resulted in an elevated expression of genes belonging to chemokine signaling. In contrast, MVA-EBOV showed mainly significantly decreased expression of CD86 on pDCs, CD1c+CD11c+ DCs, and CD1c-CD141+ DCs. Induced transcriptomic changes by MVA-EBOV included mainly interferon signaling and the defense response to viruses. Compared to VSV-EBOV, MVA-EBOV exhibited more differentially expressed genes with higher gene expression rates.

The decreased expression of CD86 on monocytes and DCs suggests an elevated immune response due to a lower suppressive effect of activated CD86+ monocytes and DCs post MVA-EBOV stimulation. Both viral vector vaccines led to specific innate signatures, where MVA-EBOV seemed to induce a stronger anti viral immune response than VSV-EBOV due to a higher number of DEG and the induction of anti viral pathways. Thus, this dissertation deciphered distinct immune signatures of VSV-EBOV and MVA-EBOV emphasizing specific early transcriptomic changes which might contribute to different immunogenicity in vaccinees.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/9224
URN: urn:nbn:de:gbv:18-ediss-95547
Dokumenttyp: Dissertation
Betreuer*in: Addo, Marylyn Martina
Gilberger, Tim-Wolf
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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