Improving vaccine trials in infectious disease emergencies

Abstract

Unprecedented global effort is under way to facilitate the testing of countermeasures in infectious disease emergencies. Better understanding of the various options for trial design is needed in advance of outbreaks, as is preliminary global agreement on the most suitable designs for the various scenarios. What would enhance the speed, validity, and ethics of clinical studies of such countermeasures? Focusing on studies of vaccine efficacy and effectiveness in emergencies, we highlight three needs: for formal randomized trials-even in most emergencies; for individually randomized trials-even in many emergencies; and for six areas of innovation in trial methodology. These needs should inform current updates of protocols and roadmaps.

Fig. 1. Comparing stepped wedge and individual randomization for vaccine protection of trial participants

Top: Stepped-wedge designs offer vaccine candidates to all eligible trial participants at some point during the trial (dark shading) if they remain uninfected and alive. Bottom: Individually randomized trials, where control participants do not receive the experimental vaccine during data collection, ordinarily take less time or fewer participants or fewer disease cases than other designs to achieve a given degree of statistical power, so data collection can end sooner (vertical dashed line). If control participants in such a trial are offered the vaccine at the end of data collection (light shading), this can permit all trial participants to have access to the vaccine earlier than all stepped-wedge participants (24).

Figure 2. Time-sensitivity of testing countermeasures at different stages of the epidemic, illustrated with the epidemic curve of Ebola cases in Guinea and Sierra Leone

During the ascending phase of an epidemic, case numbers accumulate at an accelerating rate, meaning that each added week of delay in identifying effective prevention or treatment measures brings a larger number of new infections. Once an epidemic is brought under control dwindling case numbers threaten trial power, because lower disease incidence ordinarily makes more trial participants necessary for statistically robust results. In sum, a race to identify countermeasures to stop the epidemic in the early stage is replaced in the late stage by a race to test the countermeasures before a research opportunity for developing countermeasures for future outbreaks is missed.