title: Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.
abstract: BACKGROUND
  A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa.
  
  
  METHODS
  For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.
  
  
  RESULTS
  Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing.
  
  
  CONCLUSIONS
  The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy.
  
  
  BACKGROUND
  WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; 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.
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Henao-Restrepo
authors.affiliation: Department of Biostatistics, University of Florida, Gainesville, FL, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Longini
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa.
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.affiliation: Department of Biostatistics, University of Florida, Gainesville, FL, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Dean
authors.affiliation: Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: W John
authors.initials: WJ
authors.lastname: Edmunds
authors.affiliation: Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Camacho
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK; The European Mobile Laboratory Consortium, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Miles W
authors.initials: MW
authors.lastname: Carroll
authors.affiliation: Centre pour Développement des Vaccins, Bamako, Mali.
authors.forename: Moussa
authors.initials: M
authors.lastname: Doumbia
authors.affiliation: Médecins Sans Frontières, Brussels, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Draguez
authors.affiliation: The European Mobile Laboratory Consortium, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Duraffour
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Godwin
authors.initials: G
authors.lastname: Enwere
authors.affiliation: Epicentre, Paris, France.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Grais
authors.affiliation: WHO Collaborating Centre for Arboviruses and Hemorrhagic Fever Reference and Research, Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gunther
authors.affiliation: Clinical Trials Unit, University of Bern, Bern, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hossmann
authors.affiliation: CEFORPAG, Conakry, Guinea.
authors.forename: Mandy Kader
authors.initials: MK
authors.lastname: Kondé
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Souleymane
authors.initials: S
authors.lastname: Kone
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK; The European Mobile Laboratory Consortium, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Eeva
authors.initials: E
authors.lastname: Kuisma
authors.affiliation: Center for Vaccine Development, University of Maryland, Baltimore, MD, USA.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Public Health England, London, UK.
authors.forename: Sema
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Gunnstein
authors.initials: G
authors.lastname: Norheim
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Ximena
authors.initials: X
authors.lastname: Riveros
authors.affiliation: Epicentre, Paris, France.
authors.forename: Aboubacar
authors.initials: A
authors.lastname: Soumah
authors.affiliation: Clinical Trials Unit, University of Bern, Bern, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Trelle
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Vicari
authors.affiliation: Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Conall H
authors.initials: CH
authors.lastname: Watson
authors.affiliation: Ebola Response, Ministry of Health, Conakry, Guinea.
authors.forename: Sakoba
authors.initials: S
authors.lastname: Kéïta
authors.affiliation: World Health Organization, Geneva, Switzerland. Electronic address: kienym@who.int.
authors.forename: Marie Paule
authors.initials: MP
authors.lastname: Kieny
authors.affiliation: Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway; Department of Health and Society, University of Oslo, Oslo, Norway; Department of Global Health and Population, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: John-Arne
authors.initials: JA
authors.lastname: Røttingen
mesh_terms: D000328:Adult; D046129:Ebola Vaccines; D029043:Ebolavirus / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D016701:Guinea / Q000453:epidemiology; D019142:Hemorrhagic Fever, Ebola / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D014611:Vaccination / Q000379:methods; D018116:Vesiculovirus / Q000378:metabolism; D055815:Young Adult
chemical_list: D046129:Ebola Vaccines; D008562:Membrane Glycoproteins