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VSV-EBOVAC Report Summary

Project ID: 115842
Funded under: H2020-EU.

Periodic Reporting for period 2 - VSV-EBOVAC (Vaccine safety and immunogenicity signatures of human responses to VSV-ZEBOV)

Reporting period: 2016-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

"The overall objective of VSV-EBOVAC is to comprehensively characterize the immune and molecular signatures of immune responses elicited in humans by rVSV-ZEBOV, a promising Ebola vaccine candidate based on the replication-competent recombinant vesicular stomatitis virus (VSV) expressing a Zaire ebolavirus (EBOV) glycoprotein.
rVSV-ZEBOV was selected by the World Health Organization (WHO) as one of the most promising vaccine candidates for further development. To accelerate its clinical development, the WHO initiated a consortium (VEBCON) to support parallel first-in-man Phase I clinical trials in Europe and Africa. Preliminary results have documented that rVSV-ZEBOV is immunogenic albeit reactogenic at high doses. Remarkably, high doses of rVSV-ZEBOV proved highly efficacious in preventing Ebola virus
disease within a few days in a Guinea Phase III trial. The VSV-EBOVAC project capitalizes upon this
innovative effort by acquiring new and critical in depth knowledge of innate and adaptive immune responses elicited in humans by rVSV-ZEBOV vaccine, with special emphasis on transcriptomic and metabolomic signatures.
VSV-EBOVAC offers an ambitious program using cutting-edge technologies in performing in depth characterization of clinical samples collected longitudinally before and after rVSV-ZEBOV immunization from about 200 volunteers in Switzerland, Gabon and Kenya, and extending the WHO initiated Phase I clinical studies to identify the signatures and determinants of persistent, long-term ""memory"" immune responses up to 12 months. VSV-EBOVAC thus ensures that the maximum possible information will be ""retrieved"" from the ongoing rVSV-ZEBOV clinical studies, exploited and shared, to facilitate and enhance knowledge of the vaccine's safety and immunogenicity, thus filling a critical knowledge gap in Ebola vaccine development.
VSV-EBOVAC is a public private consortium of 12 partners involving experts from academic institutions, scientists of the 3 main clinical sites (Switzerland, Gabon, Kenya), the representative from the vaccine manufacturer, a small and medium-sized enterprise (SME) and research institutes.

The specific objectives of VSV-EBOVAC are:
- Build on and extend up to 12 months the Phase I/II dose-finding randomized, single-center, double- blind, placebo controlled safety and immunogenicity trial of the rVSV-ZEBOV vaccine in healthy adults in Switzerland, Kenya and Gabon
- Characterize the innate and adaptive immune responses elicited by various doses of rVSV-ZEBOV and define how they contribute to vaccine reactogenicity, antibody responses and viral control
- Characterize rVSV-ZEBOV induced humoral immune response
- Perform a direct comparison of the long-term immunity (antibodies, memory B cells, memory CD8 and CD4 T cells) generated in volunteers vaccinated with the rVSV-ZEBOV vaccine compared to individuals that have survived Ebola infection
- Determine the dynamic transcriptomic and metabolomic profiles of the human immune response to VSV-ZEBOV vaccination at multiple time points
- Disseminate scientific information and communicate VSV-ZEBOV activities and results
- Generate and exploit synergies with other relevant Ebola vaccination projects in Europe and beyond"

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During its first two years of activity, the VSV-EBOVAC Consortium has met all the due deliverables and well beyond.
Major achievements include:
- Extension of the three clinical trials (Geneva, Lambaréné, Gabon) to include a month 12 follow-up visit
- Distribution of early, intermediate and late samples (>28) from the 3 clinical study sites to partners in Europe and the US
- Identification of a first innate response signature in the plasma of VSV-ZEBOV vaccinees, associated with biological and clinical outcomes (Huttner A. et al. Science Translational Medicine, in press; Attachment 1). Six monocyte-associated cytokines/chemokines have been identified as correlating with viraemia and biological responses to VSV-ZEBOV, with D28 antibody responses and with the frequency and intensity of early reactogenicity and of arthritis in high-dose vaccinees.
- Characterization of rVSV-ZEBOV induced humoral immune response
- First comprehensive transcriptomic profiles of VSV-ZEBOV vaccination at multiple time points in EU (Swiss) population
- First transcriptomic profiles of VSV-ZEBOV vaccination in Kenian population
- Identification of a strong early response IFN-inducible gene signature in both cohorts
- Identification of plasma metabolites induced within 7 days after VSV-ZEBOV vaccination in healthy volunteers.
- Effective management, dissemination and communication
- Collaboration with other relevant Ebola vaccine projects in Europe and beyond to fully exploit synergies

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

With an emphasis on systems analyses, the VSV-EBOVAC project harnesses state-of-the-art technologies that illuminate mechanisms behind the observed immunogenicity and reactogenicity of the rVSV-ZEBOV vaccine and ensures that such information is shared among stakeholders.
The 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, immunological memory, transcriptomics, and metabolomics-and ensures that all information resulting from the ongoing first-in-humans clinical studies is exploited and shared. The results obtained from this project should enhance and accelerate the development of a safe and efficacious vaccine to counter Ebola infection in humans but could also provide a blueprint for the development of other future vaccines.
The VSV-EBOVAC project will pursue interactions with other relevant Ebola vaccine efforts to ensure maximum coordination and harmonization, in order to enhance the worldwide capacity to respond swiftly to future Ebolavirus disease outbreaks.

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