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Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial

Tuesday, 27th of December 2016

Summary below; full text is at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32621-6/fulltext

Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial

Dr Ana Maria Henao-Restrepo et al.

WHO, Geneva, Switzerland

Correspondence

Correspondence to: Dr Ana Maria Henao-Restrepo, World Health Organization, 1211 Geneva 27, Switzerland

Published: 22 December 2016 orologi audemars piguet replica

Publication stage: In Press Corrected Proof

Trial profile

The vaccine effects analyses set included all eligible contacts and contacts of contacts and the safety analysis set included all participants who had received the vaccine. Participants were analysed in the group corresponding to the allocated arm. *Including two non-randomised rings from Sierra Leone with 325 contacts and 255 contacts of contacts. †Including three pilot rings.

 

Figure 2

Kaplan-Meier plots for all confirmed cases of Ebola virus disease among all contacts and contacts of contacts in immediate, delayed, and non-randomised clusters

Arrows show time of vaccination (at day 0 or day 21). The shaded area denotes the a priori defined lag time of 0–9 days. *Individuals aged 6–18 years were eligible for immediate vaccination in non-pilot, non-randomised rings. Description of Ebola virus disease cases 10 days or more after randomisation: A (allocated to delayed vaccination): 22 cases; six were children (aged <18 years); one was eligible and did not consent; four were absent; 11 were eligible and consented, including seven eligible and consented with illness onset on days 10–20 after randomisation plus four eligible, consented, and delayed vaccinated with onset on days 21–30 after randomisation (0, 2, 6, and 6 days after their delayed vaccination). B: ten cases, all unvaccinated; two were children (aged <18 years); four were eligible and did not consent; three were absent; one was not eligible (ie, pregnant, breastfeeding, or severely ill). C: two cases, both were children (aged <6 years and hence unvaccinated).

 

Figure 3

Kaplan-Meier plots for confirmed cases of Ebola virus disease in different study populations

Arrows show time of vaccination (at day 0 or day 21); the plus signs denote cases among non-eligible children and the stars denote cases among vaccinated individuals; the shaded area denotes the a priori defined lag time of 0–9 days.

Summary

Background

rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.

Methods

We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.

Findings

In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae.

Interpretation

The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.

Funding

WHO, UK Wellcome Trust, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norways GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).