Research Article: Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial

Date Published: October 6, 2017

Publisher: Public Library of Science

Author(s): Selidji T. Agnandji, José F. Fernandes, Emmanuel B. Bache, Régis M. Obiang Mba, Jessica S. Brosnahan, Lumeka Kabwende, Paul Pitzinger, Pieter Staarink, Marguerite Massinga-Loembe, Verena Krähling, Nadine Biedenkopf, Sarah Katharina Fehling, Thomas Strecker, David J. Clark, Henry M. Staines, Jay W. Hooper, Peter Silvera, Vasee Moorthy, Marie-Paule Kieny, Akim A. Adegnika, Martin P. Grobusch, Stephan Becker, Michael Ramharter, Benjamin Mordmüller, Bertrand Lell, Sanjeev Krishna, Peter G. Kremsner, Lorenz von Seidlein

Abstract: BackgroundThe rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data.Methods and findingsA randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)–glycoprotein (GP)–specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%–100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264–908), 556 (95% CI: 280–1,101), 1,245 (95% CI: 899–1,724), and 1,503 (95% CI: 931–2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647–1,591), 1,887 (1,154–3,085), 1,445 (1,013–2,062), and 3,958 (2,249–6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025–1,989), and children, 1,620 (95% CI: 806–3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study.ConclusionsOur data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting.Trial registrationPan African Clinical Trials Registry PACTR201411000919191

Partial Text: The western African Ebola virus disease (EVD) public health emergency of international concern ended in June 2016 [1], after infecting approximately 28,650 individuals, of whom 11,323 died [2,3]. Global commitment led to landmarks in vaccine development against EVD, with 8 candidates out of 15 undergoing evaluation in phase I–III clinical trials worldwide by the end of 2015 [4–6]. A live-attenuated recombinant vaccine consisting of the vesicular stomatitis virus (VSV), strain Indiana, with the gene for the Kikwit-95 Zaire Ebola virus (ZEBOV) glycoprotein (GP) replacing the VSV glycoprotein (G) had given acceptable results in non-human primate challenge models and was selected for accelerated clinical development. In European and African populations, the VEBCON Consortium (VSV-EBola CONsortium) carried out parallel dose-escalation phase I trials of the recombinant VSV (rVSV)–ZEBOV candidate vaccine in Germany (NCT02283099), Kenya (NCT02296983), and Gabon (PACTR2014000089322) and a double-blind phase I/II randomised controlled trial in Switzerland (NCT02287480). Three further phase II/III trials were later launched in Guinea, Sierra Leone, and Liberia. Results from phase I trials in the US [7] and preclinical data supported selection of the 2 × 107 plaque-forming units (PFU) dose as the most immunogenic for phase IIb/III trials in Guinea, Sierra Leone, and Liberia. A final analysis of the Guinea trial showed that a single dose of 2 × 107 PFU given immediately after contact with an index case was 100% (95% CI: 70%–100%, P = 0.0045) efficacious in preventing EVD in individuals, and protected the population through a ring vaccination strategy 10 days or more post-vaccination [8].

From 21 November 2014 to 13 April 2015, 115 adults were vaccinated with a single injection of rVSVΔG-ZEBOV-GP at 5 different doses. Twenty adolescents and 20 children were vaccinated between 8 May and 7 July 2015 (Fig 1).

Although the 2014–2016 EVD emergency in western Africa has ended, the increasing mobility of people between remote and urban areas and the weak health systems in Ebolavirus endemic countries suggest that a future outbreak could reassert itself as a major international threat [17,18]. Risks include increased human-to-human secondary transmission as in the recent epidemic [19] as well as continuing transmission after recovery. Halting transmission by vaccination will be key in curbing future outbreaks [20]. The rVSVΔG-ZEBOV-GP and ChAd3-ZEBOV vaccine candidates were selected by WHO in August 2014 for fast track clinical evaluation [6]. As part of these efforts, we examined a range of doses for rVSVΔG-ZEBOV-GP in adults as well as safety and immunogenicity in children.

Source:

http://doi.org/10.1371/journal.pmed.1002402

 

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