Ebola vaccine tested on adults and children in Africa

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Data confirms the acceptable safety and immunogenicity profile of the rVSV-ΔGP-ZEBOV Eboal virus in adults and support consideration of lower doses for paediatric populations, a University of London found.

The worst Ebola virus disease outbreak in history ended in 2016 after infecting 28,600 people and killing about 11,300 worldwide. The outbreak led to urgent action by medical experts across the world to combat this devastating disease; including the setting up of trials of vaccines to stop the disease taking hold.

This global commitment to develop a vaccine against the disease suggested eight options, out of a starting pool of 15 candidates, should be evaluated in clinical trials worldwide by the end of 2015.

Professor Sanjeev Krishna, of St George’s University of London’s Institute for Infection and Immunity, said: “An unprecedented Ebola outbreak showed how it is possible for academics, non-governmental organisations, industry and funders to work effectively together very quickly in times of medical crisis. The results of the trial show how a vaccine could best be used to tackle this terrible disease effectively. We need a system of specialists, medical experts and organisers that maintains vigilance against outbreak diseases like Ebola. We should continue to improve ways to make, evaluate and deliver vaccines when they are needed, often in parts of the world lacking in infrastructure for diagnosing infections and providing treatments.”

He explained that considering the persistent replication of the vaccine which is called rVSV-ΔGP-ZEBOV in children and adolescents, further studies investigating lower doses in this population are warranted.

The vaccine contains a non-infectious portion of a gene from the Zaire Ebola virus. The St George’s researchers worked with colleagues on a vaccine trial in Gabon. In addition, lower vaccine doses should be considered when boosting individuals with pre-existing antibodies to Ebolavirus glycoprotein, a finding that has emerged after the vaccine was tested in a country that has experienced Ebolavirus outbreaks in the past.

The vaccine was one of two being examined as a ‘candidate’ option by the World Health Organisation to identify urgently a vaccine to combat the Ebola virus outbreak in West Africa.

The clinical trial was led by colleagues at University of Tübingen in Germany, coordinated by Professor Peter Kremsner with their partner institute CERMEL in Lambaréné, Gabon.

Krishna was among a consortium of experts called VEBCON convened by the WHO in August 2014 in Geneva to discuss solutions and strategies for combatting the EVD crisis.

He acted as a scientific advisor to the new studies in Gabon, He is also affiliated with the Institute of Tropical Medicine in Tübingen and has carried out collaborative work for many years in Lambaréné.

Abstract
Background: The 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 findings: A 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.
Conclusions: Our 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.

Authors
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

St George’s, University of London material
PLOS Medicine abstract


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