Abstract
ABSTRACT
Many epidemic-prone infectious diseases present challenges that the current West African Ebola outbreak brings into sharp relief. Specifically, the urgency to evaluate vaccines, initially limited vaccine supplies, and large and unpredictable spatial and temporal fluctuations in incidence have presented huge logistical, ethical, and statistical challenges to trial design.
In the Ebola outbreak, long and intense discussion led to broad agreement on the need to evaluate the efficacy of Ebola vaccines through an individually randomized controlled trial (iRCT) (1), with cluster-randomized designs providing supplemental information. However, by the time an iRCT began in Liberia, the ability to estimate vaccine efficacy was threatened by the otherwise welcome declining incidence of Ebola virus infection (2). Other trials, planned to provide evidence on vaccines’ direct and indirect (herd immunity) effects, might not be able to include enough Ebola cases to provide statistically robust efficacy estimates (2, 3).
Similar challenges may arise when evaluating vaccines for diseases such as meningococcal meningitis, cholera, Middle East Respiratory Syndrome and other coronavirus infections, vector-borne viral diseases such as dengue and chikungunya, and novel influenza strains. Resource-poor populations continue to be at particularly high risk for such infections (4). We suggest three principles, all well-established in the clinical trials literature and applied to varying degrees in the Ebola vaccine trials, that will be of general use in designing vaccine trials during emergencies [Trials of therapies for infected persons arguably involve a different set of logistical and ethical challenges (5)]. Each principle is mainly responding to a challenge identified in the Ebola context: block randomization with matching is a response to heterogeneity of incidence; stepped rollout is a response to urgency; and adaptive design is a response to uncertainty.