Intended for healthcare professionals

CCBY Open access
Research Methods & Reporting

The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3740 (Published 27 July 2015) Cite this as: BMJ 2015;351:h3740
  1. Ebola ça suffit ring vaccination trial consortium
  1. Correspondence to: Ana Maria Henao-Restrepo, Department of Immunization, Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland henaorestrepoa{at}who.int
  • Accepted 29 June 2015

Abstract

A World Health Organization expert meeting on Ebola vaccines proposed urgent safety and efficacy studies in response to the outbreak in West Africa. One approach to communicable disease control is ring vaccination of individuals at high risk of infection due to their social or geographical connection to a known case. This paper describes the protocol for a novel cluster randomised controlled trial design which uses ring vaccination.

In the Ebola ça suffit ring vaccination trial, rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation. Secondary objectives include vaccine effectiveness at the level of the ring, and incidence of serious adverse events.

Ring vaccination trials are adaptive, can be run until disease elimination, allow interim analysis, and can go dormant during inter-epidemic periods.

Footnotes

  • The authors (and members of the Ebola ça suffit ring vaccination trial consortium, who contributed to this article) are (in alphabetic order): Anton Camacho, Miles W Carroll, Natalie E Dean, Moussa Doumbia, W John Edmunds, Matthias Egger, Godwin Enwere, Yper Hall, Ana Maria Henao-Restrepo, Stefanie Hossmann, Sakoba Keita, Mandy Kader Kondé, Ira M Longini, Sema Mandal, Gunnstein Norheim, Ximena Riveros, John-Arne Røttingen, Sven Trelle, Andrea S Vicari, Sara V Watle, and Conall H Watson.

  • We thank Professor D A Henderson for helpful discussions regarding the use of surveillance and containment to eradicate smallpox and its application to the design of the ring vaccination trial. We also thank Bertrand Draguez, Rebecca Grais, Marie Paule Kieny, Myron Levine, Peter Smith, and Aboubacar Soumah for their advice and guidance, and to colleagues at CTU Bern for support with data management.

  • The development of the design of the Ebola ça suffit trial was supported by the Guinean authorities, WHO, Médecins Sans Frontières (MSF) Belgium and Epicentre, the Norwegian Institute of Public Health, the University of Florida, the London School of Hygiene and Tropical Medicine, the University of Bern, the University of Maryland, the Center for Vaccine Development Mali, Public Health England (Colindale and Porton Down), Public Health Agency of Canada, NewLink/Merck, and European Mobile Laboratory Guinea.

  • Contributors: All authors critically reviewed the manuscript for content. AC provided advice on trial design; extracted, cleaned, and analysed epidemiology data on Ebola in Guinea to inform sample size calculations; and helped draft the manuscript. MWC provided advice on trial design and protocol, supported and designed the process for documentation of laboratory confirmation of Ebola cases, and contributed to the drafting of the manuscript. NED provided advice on trial design, contributed to the protocol development, designed the statistical analysis plan, and helped write the first draft the manuscript. MD contributed to the protocol and provided inputs on operational issues regarding trial design and implementing the trial, and helped draft the manuscript. WJE conceived and designed the trial, analysed epidemiology data on Ebola in Guinea to inform sample size calculations, and helped draft the manuscript. ME conceived and designed the trial, prepared the first draft of the protocol, contributed to the statistical analysis plan, and prepared the first draft of and revised the manuscript. GE contributed to the design of the trial, contributed to the protocol development, designed trial safety procedures, implemented the trial, and helped draft the manuscript. YH provided inputs on trial design and protocol, supported process for documentation of laboratory confirmation of cases, and helped draft the manuscript. AMHR conceived and designed the trial, coordinated all aspects of the design and implementation of the trial, contributed to the protocol, contributed to the design of data collection systems, helped draft the manuscript, revised the manuscript, and is guarantor. SH contributed to the protocol, designed data collection systems, implemented data management, and helped draft the manuscript. SK contributed to the protocol, provided advice on operational issues regarding trial design, implemented the trial, and helped draft the manuscript. MKK contributed to the design of the trial, provided advice on operational issues regarding trial design and implementing the trial, and helped draft the manuscript. IML conceived and designed the trial, designed the statistical analysis plan, helped prepare the first draft the manuscript and revised the manuscript. SM contributed to the design of the trial, revised the protocol, contributed to the design of data collection systems, and helped draft the manuscript. GN conceived and designed the trial, prepared the first draft of the protocol, contributed to ethical and regulatory approval and community engagement planning, and helped draft the manuscript. XR contributed to the design of the trial, revised the protocol, coordinated implementation and logistics, and helped draft the manuscript. JAR contributed to the design of the trial and to the protocol and helped draft the manuscript. ST contributed to the protocol, designed data collection systems, implemented data management, and helped draft the manuscript. ASV contributed to the protocol and provided advice on operational issues regarding trial design, implemented the trial, and helped draft the manuscript. SVW contributed to the protocol and helped draft the manuscript. CHW conceived and designed the trial, contributed to the protocol, contributed to the design of data collection systems, contributed to the statistical analysis plan, and helped draft and revise the manuscript.

  • Funding: The trial is funded by the Research Council of Norway through the Norwegian Institute of Public Health; 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; and WHO, with support from the Wellcome Trust, United Kingdom. AC was funded by the Research for Health in Humanitarian Crises (R2HC) Programme, managed by Research for Humanitarian Assistance (Grant 13165). CHW is supported by the UK Medical Research Council grant MR/J003999/1. Role of the sponsor: the role of the sponsor is described in the accompanying protocol.

  • Competing interests: All authors have completed the unified competing interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). AC, WJE, and CHW have acted as unpaid advisors to the WHO on Ebola vaccination and report travel and accommodation paid for by the WHO to attend meetings. WJE is a co-investigator on the EBOVAC trial (funded by European Commission Innovative Medicines Initiative) of the Johnson & Johnson prime-boost Ebola vaccine candidate, and his partner is an epidemiologist at GlaxoSmithKline, in a role unrelated to the company’s development of an Ebola vaccine. AC and CHW have acted as unpaid advisors to the EBOVAC trial, for which CHW reports travel and accommodation paid for by the EBOVAC consortium to attend a meeting. All authors report no other financial relationships with any institutions that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Transparency: AMHR affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and registered) have been explained.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

View Full Text