Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - VSV-EBOPLUS (SYSTEMS ANALYSIS OF ADULT AND PEDIATRIC RESPONSES TO THE VSV-ZEBOVEBOLA VACCINE - Sofia ref.: 116068)

Teaser

The overall objective of 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...

Summary

The overall objective of 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 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” , collectc and distribute clinical samples to partners for immunogenicity and gene expression studies
• Characterize the innate and adaptive immune responses elicited by various doses of VSV-ZEBOV in adults and children and define how they correlate to vaccine reactogenicity and viral control
• Identify the contribution of specific cells to VSV-ZEBOV-induced innate responses and adverse reactions (inflammation, arthritis, dermatitis, vasculitis)
• Determine the 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 VSV-ZEBOV activities and results
• Generate and exploit synergies with other relevant Ebola vaccination projects in Europe and beyond

Work performed

Work performed and main achievements of the VSV-EBOPLUS project include:
• Collection and storage of samples (serum, plasma and Paxgene tubes) from US Phase I trial (NCT02314923) for conduction of transcriptomic and metabolomic analysis
• Ethical Clearance to extend Phase I/II trial of the VSV-ZEBOV candidate vaccine in healthy adults in Switzerland (NCT02287480) to include 4 additional yearly visits
• Ethical Clearance to extend Phase I/II trial of the VSV-ZEBOV candidate vaccine in healthy adults in Lambaréné/Gabon (PACTR201410000893222) to include 4 additional yearly visits
• Performance of the first two follow-up visits (year 2 and 3) for clinical trial NCT02287480 in Switzerland
• Performance of the first two follow-up visits (year 2 and 3) for clinical trial PACTR201410000893222 in Gabon
• Preparation of the safety/reactogenicity database for integrative analysis
• Distribution of samples collected in clinical trials in USA between Partners
• Characterization and publication of the persistence of antibody responses up to 2 years after immunization (Lancet Infect. Dis. 18:738-748, 2018)
• RNA isolation from 719 samples from US dose-response Phase I trial
• Generation of extended dcRT-MLPA sets for innate and adaptive immune profiling
• Implementation of protocols for transcriptomic analysis in the R-Bioconductor software environment
• Initiation of transcriptomic analysis on samples from US Phase I trial to analyse the transcriptomic signature induced by different vaccine doses
• Establishment of technologies to study affinity and kinetics of ZEBOV GP specific antibodies following a vaccination with rVSV-ZEBOV
• Establishment and validation of the protocol for the Pseudovirion Neutralisation Test (PsNT)
• Optimization of the Focus Reduction Neutralisation Test (FRNT) and Serum-Neutralization Test (SNT)
• Testing in a comparative study of the 3 neutralization tests (FRNT, SNT and PsNT assay)
• Identification of a group of MicroRNAs from serum extracellular vesicles whose expression at the baseline correlates with GP specific IgG response
• Methodologies for BioLayer Interferometry to analyse affinity and epitope binning of ZEBOV-GP specific IgG
• VSV-EBOPLUS website publication and preparation of dissemination material
• Effective management, dissemination and communication

Final results

VSV-EBOPLUS 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 VSV-ZEBOV Ebola vaccine, thus addressing an urgent need and 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.
Close interactions with other relevant Ebola vaccine efforts will be pro-actively pursued by VSV-EBOPLUS to ensure maximum coordination and harmonization.
The VSV-EBOPLUS will also contribute significantly to capacity building at the African site by intimately involving scientists from these institutions, providing training as well as exchanging critical information.
The development of a protective vaccine against Ebola is expected to have a major impact on preventing and controlling Ebola epidemics, particularly in areas most affected 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.

Website & more info

More info: http://www.vsv-eboplus.eu.