Using simulation to aid trial design: Ring-vaccination trials

Background: The 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 findings: We 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. Conclusions: 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. Author summary: The urgency, as well as the logistical and sometimes ethical challenges of clinical trials for interventions during epidemics of emerging diseases prompts the need for novel designs and analytic strategies. The successful use of a novel cluster-randomized ring-vaccination trial to test an Ebola vaccine in Guinea raises the general question of what circumstances would favour the use of trials of similar design and how the properties of the population, the vaccine and the trial would influence the necessary sample size and the expected results. We present a generalized transmission dynamic model for a ring vaccination trial to address these questions. This work is an example of the general phenomenon that mechanistic, transmission-dynamic simulations can aid in the design and interpretation of intervention trials for infectious diseases, when the trial itself can have non-obvious effects on transmission dynamics that may not be fully captured by effect- and sample-size calculations for noncommunicable diseases.