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H2020

VSV-EBOPLUS Report Summary

Project ID: 116068
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - VSV-EBOPLUS (SYSTEMS ANALYSIS OF ADULT AND PEDIATRIC RESPONSES TO THE VSV-ZEBOV EBOLA VACCINE)

Reporting period: 2016-04-01 to 2017-09-30

Summary of the context and overall objectives of the project

The overall objective of this project, VSV-EBOPLUS, is to comprehensively decipher, using systems biology approaches, the immune and molecular signatures of the human response elicited in adults and children by the highly protective vesicular stomatitis virus (VSV)‐vectored Zaire Ebola vaccine (VSV-ZEBOV), which was developed by Public Health Canada (BPSC1001), licensed to NewLink Genetics and subsequently to Merck for further development. In the VSV-EBOPLUS project, we characterize responses from VSV-ZEBOV phase I/Ib/II clinical trials including (i) dose-ranging, (ii) a pediatric cohort, and (iii) long-term follow-up studies.
Among prophylactic Ebola vaccine candidates, the VSV-ZEBOV vaccine has shown to be reactogenic but safe, immunogenic and protective in human studies [Agnandji et al, 2015; Regules et al, 2017; Huttner et al, 2015, Henao-Restrepo et al 2017]. VSV-ZEBOV is a recombinant VSV vector in which the VSV envelope glycoprotein was replaced with the Zaire strain Ebola virus glycoprotein (ZEBOV-GP), giving rise to rVSVΔG-ZEBOV-GP (VSV-ZEBOV) [Garbutt et al, 2004].

VSV-EBOPLUS will thus significantly accelerate and bring innovation to Ebola vaccine development through an ambitious programme combining clinical and cutting-edge systems biology approaches that together address the safety and immunogenicity of VSV-ZEBOV. By providing immune monitoring beyond the demonstrated (short) duration of protection and comparing responses and signatures from children (in whom efficacy could not be assessed in the current absence of an outbreak) to those identified in adults, it is anticipated to overcome critical bottlenecks in furthering Ebola vaccine development towards clinical application. VSV-EBOPLUS is therefore expected to have a significant impact on Ebola vaccine development addressing an extremely important unmet medical need.

The overall objectives of VSV-EBOPLUS are:
• Build upon and extend up to M60 the WHO and Wellcome-Trust sponsored VEBCON (VSV Ebola CONsortium) “Phase I/II dose‐finding randomized, single‐center, double‐blind, placebo controlled safety and immunogenicity trial of the VSV-ZEBOV in healthy adults” in Switzerland and Gabon to obtain information on the duration of immune responses and signatures of long lasting vaccine-induced immunological memory in 160 adults
• Organize the distribution of samples from subjects enrolled in the MSD-sponsored “Phase 1 Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Dose-Response Study to Evaluate the Safety and Immunogenicity of the BPSC1001 (VSVΔG-ZEBOV) Ebola Virus Vaccine Candidate in Healthy Adult Subjects” to partners performing the immunogenicity and gene expression studies
• Implement two early visits for children and adolescents who will be enrolled in the Lambaréné (Gabon) site of a “Phase 2 randomized, double-blind, active vaccine-controlled study of the safety and immunogenicity of the V920 (VSV-ZEBOV) Ebola Virus Vaccine Candidate in healthy children 6 months – 17 years of age” and collect, preserve and distribute clinical samples to partners performing the immunogenicity and gene expression studies
• Characterize at early and late time points the innate and adaptive immune responses elicited by various doses of VSV-ZEBOV in these adults and children, assessing the dynamic of the metabolomics and immunologic profiles to define how they correlate to vaccine reactogenicity, antibody responses and viral control
• Identify the contribution of specific cells to VSV-ZEBOV-induced innate responses and adverse reactions (inflammation, arthritis, dermatitis, vasculitis)
• Determine the dynamic transcriptomic profiles of adult and pediatric responses to VSV-ZEBOV vaccination at multiple time points
• Generate / exploit the clinical safety/reactogenicity and the immunology (metabolomics, immunomics, and transcriptomics) databases for integrative analysis
• Disseminate scientific information and communicate

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 year of activity, the VSV-EBOPLUS Consortium has met all the due deliverables and well beyond.
Major achievements include:
• Collection and storage of samples (serum, plasma and Paxgene tubes) for conduction of transcriptomic and metabolomic analysis
• Identification of samples (serum, plasma, Paxgene tubes) to be distributed from US Phase I trial
• MTA between Merck and the involved project partners for the transfer of samples collected in the clinical trials in the US.
• Ethical Clearance to extend the Phase I/II trial of the VSV-ZEBOV candidate vaccine in healthy adults in Switzerland to include 4 additional yearly visits
• Ethical Clearance to extend the Phase I/II trial of the VSV-ZEBOV candidate vaccine in healthy adults in Lambaréné/Gabon to include 4 additional yearly visits
• Establishment of technologies to study affinity and kinetics of ZEBOV GP specific antibodies raised following a vaccination with rVSV-ZEBOV
• Establishment and validation of the pseudovirion protocol for the Pseudovirion Neutralisation Test (PsNT)
• Initial organization of the inter-laboratory comparative study for Ebola neutralisation assays
• Generation of extended dcRT-MLPA sets for innate and adaptive immune profiling
• Implementation of protocols for transcriptomic analysis in the R-Bioconductor software environment
• Methodologies for purification and quality control of microRNA from serum extracellular vesicles
• Methodologies for BioLayer Interferometry technology to analyse the affinity and epitope binning of ZEBOV-GP specific IgG antibody
• Effective management, dissemination and communication

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)

VSV-EBOPLUS project will significantly accelerate and innovate the Ebola vaccine development field through an ambitious programme combining clinical and high tech cutting-edge technologies to address safety and immunogenicity of the new promising Ebola vaccine VSV-ZEBOV, thus overcoming a critical bottleneck in Ebola vaccine development. The VSV-EBOPLUS project will provide additional data to assess the safety, immunogenicity and efficacy of the VSV-ZEBOV in preventing EVD.
VSV-EBOPLUS addresses an urgent need. Close interactions with other relevant Ebola vaccine efforts will be pro-actively pursued by VSV-EBOPLUS to ensure maximum coordination and harmonisation, in order to have an impact on the worldwide capacity to quickly develop vaccines in situations of global public health emergencies.
The VSV-EBOPLUS will also contribute significantly to capacity building at the African site by intimately involving scientists from these institutions, training as needed as well as exchanging critical information.
The development of a protective vaccine against Ebola is expected to have a major impact on the Ebola epidemic, particularly in areas affected most by this rampant and often fatal disease. Vaccination will be able to prevent infection, disease and death, as well as major social and societal breakdown.

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