Abstract
BackgroundThe 2014–6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.Methods and findingsWe present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design.ConclusionsIncorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the measurement window, as well as the epidemiologic setting.
Highlights
Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the measurement window, as well as the epidemiologic setting
The West African Ebola epidemic highlighted the need to identify a range of trial designs to evaluate vaccine effects rapidly, efficiently and rigorously during emerging disease outbreaks
Other approaches considered include individual randomization and a steppedwedge design [3, 4]. In such trials it is difficult to estimate the likely effect of an infectious disease intervention because of indirect effects, and this issue is compounded by complex trial design
Summary
The West African Ebola epidemic highlighted the need to identify a range of trial designs to evaluate vaccine effects rapidly, efficiently and rigorously during emerging disease outbreaks. By creating a transmission dynamic model for a ring vaccination trial, we show that we can make sample size calculations based on disease characteristics and individual intervention efficacy. With this framework in place we are able to examine the estimated vaccine effect and sample size under a range of assumptions about the properties of the vaccine, the trial, and the study population. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination
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