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Vaccine safety and immunogenicity signatures of human responses to VSV-ZEBOV – Sofia ref.: 115842

Periodic Reporting for period 4 - VSV-EBOVAC (Vaccine safety and immunogenicity signatures of human responses to VSV-ZEBOV – Sofia ref.: 115842)

Reporting period: 2018-03-01 to 2019-02-28

Ebola virus disease (EVD) is a severe often fatal haemorrhagic fever with an average case fatality rate that ranges from 50 to 90%. Currently no licensed therapies or vaccines exist for EVD and correlates of protection are not yet fully established.
The overall objective of VSV-EBOVAC was to comprehensively characterize, using cutting-edge technologies, the immune and molecular signatures of the responses elicited in humans by the rVSV-ZEBOV Ebola vaccine which is based on the replication-competent recombinant vesicular stomatitis virus (VSV) expressing a Zaire ebolavirus (EBOV) glycoprotein (Medaglini D. and Siegrist C.S. Sci Transl Med. 2015). rVSV-ZEBOV, the only Ebola vaccine with demonstrated efficacy in ring vaccination human trials, was recently granted “Breakthrough Therapy Designation” by the FDA and PRIority Medicines (PRIME) status by EMA and is currently used to support outbreak control in Democratic Republic of Congo.
The specific VSV-EBOVAC objectives include:
- Build on and extend up to 12 months the Phase I/II dose‐finding randomized, single‐center, double‐blind, placebo controlled safety and immunogenicity trials of the rVSV- ZEBOV vaccine in healthy adults in Europe and Africa
- Characterize the innate and adaptive immune responses elicited by rVSV-ZEBOV
- Determine the transcriptomic & metabolomic profiles of the human immune response to rVSV-ZEBOV
- Generate and exploit synergies with other relevant Ebola projects in Europe and beyond
- Contribute data to the Central Ebola+ Information repository
VSV-EBOVAC has successfully acquired important information on the safety and immunogenicity signatures of the rVSV-ZEBOV vaccine.
Three clinical studies with rVSV-ZEBOV conducted in Switzerland, Gabon and Kenya were successfully extended to include 12 months visit to evaluate the persistence of the vaccine-induced immune response and its comparison between subjects in Europe and Africa.
The signature of the immune response and adverse events to rVSV-ZEBOV was identified examining longitudinal plasma samples from vaccine recipients in Europe and Africa (Huttner A. et al. Sci Transl Med. 2017). This rVSV-ZEBOV vaccine’s plasma signature of six monocyte-mediated cytokines/chemokines correlates with viraemia, hematologic changes induced by rVSV-ZEBOV. The signature reveals monocyte’s critical role in rVSV-ZEBOV safety and immunogenicity across doses and continents and provides first pathways for predicting immunologic and clinical responses to the vaccine.
The one year antibody persistence to single-dose rVSV-ZEBOV vaccination was demonstrated across dose ranges and settings, a key criterion in countries where booster vaccination would be impractical (Huttner A. et al. Lancet Infect Dis. 2018).
The avidity of rVSV-ZEBOV specific antibodies in sera collected longitiudinally from the 3 cohorts was determined and the impact of pre-existing antibodies was elucidated.
Transcriptomic and metabolomic profiles of human immune response to rVSV-ZEBOV vaccination were identified in samples collected at multiple time points in 3 different cohorts in subjects vaccinated with different doses. A panel of genes whose expression levels after vaccination are associated with long term antibody response was identified.
All together, these studies, applying cutting-edge technologies, provided critical knowledge on the safety and immunogenicity signatures of the human responses to rVSV-ZEBOV vaccination.
With an emphasis on systems analyses, VSV-EBOVAC harnessed state-of-the-art technologies that illuminated mechanisms behind the observed immunogenicity and reactogenicity of the rVSV-ZEBOV vaccine and ensured that such information was shared among stakeholders.
The VSV-EBOVAC project represents a critical step forward through harmonization and in-depth integrated analyses of data generated through a variety of clinical, immunological, and molecular readouts (safety, immunogenicity, innate and adaptive immunity, transcriptomics, and metabolomics) and ensured that all information resulting from the in-humans clinical studies was exploited and shared.
The VSV-EBOVAC results have contributed to the understanding of and confidence in the clinical use of the rVSV-ZEBOV vaccine and have supported and facilitated the advancement of the rVSV-ZEBOV vaccine in the clinical development path
Furthermore, the knowledge generated for rVSV-ZEBOV may inform correlates of protection of other Ebola vaccines.
The VSV-EBOVAC project have also pursued interactions with other relevant Ebola vaccine efforts to enhance the worldwide capacity to respond to future Ebolavirus disease outbreaks.
The sustainability of VSV-EBOVAC is ensured by the continued research efforts in characterization of rVSV-ZEBOV response in adults and children and by the progress towards licensure of the rVSV-ZEBOV vaccine providing worldwide capacity to respond to future EVD outbreaks.

VSV-EBOVAC Publications:

• The Medaglini D, Harandi AM, Ottenhoff TH, Siegrist CA; VSV-Ebovac Consortium. Ebola vaccine R&D: Filling the knowledge gaps. Sci Transl Med. 2015;7:317
• Huttner A, Christophe Combescure C, Grillet S, Haks MC, Quinten E, Modoux C, Agnandji ST, Brosnahan J, Dayer JA, Harandi AH, Kaiser L, Medaglini D, Monath T, the VEBCON and VSV-EBOVAC Consortia, Roux-Lombard P, Kremsner PG, Ottenhoff T, Siegrist CA. A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa. Sci Transl Med. 2017;9:385
• Medaglini D., Siegrist CA. Immunomonitoring of human responses to the rVSV-ZEBOV Ebola vaccine. Curr Opin Virol. 2017;23:88-94
• Huttner A, Agnandji ST, Combescure C, Fernandes JF, Bache EB, Kabwende L, Ndungu FM, Brosnahan J, Monath TP, Lemaître B, Grillet S, Botto M, Engler O, Portmann J, Siegrist D, Bejon P, Silvera P, Kremsner P, Siegrist CA, VEBCON, VSV-EBOVAC, VSV-EBOPLUS Consortia. Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study. Lancet Infect Dis. 2018;7:738-748
• Medaglini D, Santoro F, Siegrist CA. Correlates of vaccine-induced protective immunity against Ebola virus disease. Semin Immunol. 2018;39:65-72
• Huttner A., Siegrist CA. Durability of single-dose rVSV-ZEBOV vaccine responses: what do we know? Expert Rev Vaccines. 2018;17:1105-1110
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