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Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

ABSTRACT: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa.We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo.No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants.In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

SUBMITTER: Agnandji ST

PROVIDER: S-EPMC5490784 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

Agnandji Selidji T ST Huttner Angela A Zinser Madeleine E ME Njuguna Patricia P Dahlke Christine C Fernandes José F JF Yerly Sabine S Dayer Julie-Anne JA Kraehling Verena V Kasonta Rahel R Adegnika Akim A AA Altfeld Marcus M Auderset Floriane F Bache Emmanuel B EB Biedenkopf Nadine N Borregaard Saskia S Brosnahan Jessica S JS Burrow Rebekah R Combescure Christophe C Desmeules Jules J Eickmann Markus M Fehling Sarah K SK Finckh Axel A Goncalves Ana Rita AR Grobusch Martin P MP Hooper Jay J Jambrecina Alen A Kabwende Anita L AL Kaya Gürkan G Kimani Domtila D Lell Bertrand B Lemaître Barbara B Lohse Ansgar W AW Massinga-Loembe Marguerite M Matthey Alain A Mordmüller Benjamin B Nolting Anne A Ogwang Caroline C Ramharter Michael M Schmidt-Chanasit Jonas J Schmiedel Stefan S Silvera Peter P Stahl Felix R FR Staines Henry M HM Strecker Thomas T Stubbe Hans C HC Tsofa Benjamin B Zaki Sherif S Fast Patricia P Moorthy Vasee V Kaiser Laurent L Krishna Sanjeev S Becker Stephan S Kieny Marie-Paule MP Bejon Philip P Kremsner Peter G PG Addo Marylyn M MM Siegrist Claire-Anne CA

The New England journal of medicine 20150401 17

<h4>Background</h4>The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa.<h4>Methods</h4>We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Eu ...[more]

PMID: 25830326

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Project description:BackgroundA recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine.Methods354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 105 to 1 × 108 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity.FindingsOur results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 106 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis).InterpretationCollectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines.FundingInnovative Medicines Initiative 2 Joint Undertaking.

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Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

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Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

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