title: Real-time dynamic modelling for the design of a cluster-randomized phase 3 Ebola vaccine trial in Sierra Leone.
abstract: Declining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013-16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size.
  
  
  
  In real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning.
  
  
  
  EVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time.
  
  
  
  This analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined.
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Camacho
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Electronic address: r.eggo@lshtm.ac.uk.
authors.forename: R M
authors.initials: RM
authors.lastname: Eggo
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Goeyvaerts
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Vandebosch
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mogg
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: S
authors.initials: S
authors.lastname: Funk
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kucharski
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Watson
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Vangeneugden
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: W J
authors.initials: WJ
authors.lastname: Edmunds
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000276:immunology*; D019142:Hemorrhagic Fever, Ebola / Q000453:epidemiology* / Q000517:prevention & control* / Q000635:transmission; D006801:Humans; D015994:Incidence; D015233:Models, Statistical; D012807:Sierra Leone / Q000453:epidemiology
chemical_list: D046129:Ebola Vaccines
keywords: Collaboration; Ebola vaccine; Epidemic; Phase 3; Transmission modelling; Trial design