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

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.

Fig 1 Development of cases arising in two hypothetical, simplified, example trial rings, which are identical but for receipt of immediate or delayed (by 21 days) vaccination. Case boxes indicate the presence of symptoms and infectiousness. Arrows indicate disease incubation periods after infection. Because disease onset is detected rather than the point of infection, the shaded areas show periods in which any cases arising would be excluded from an analysis of vaccine efficacy against infection. This example shows a window which assesses the vaccine’s ability to offer protection from the day of administration. Three cases arise during the trial; one contributes to the analysis

Fig 2 Schematic presentation of the design of a ring vaccination trial during an outbreak of an infectious disease