Vaccine Efficacy Trials During Ongoing Epidemics: Lessons from Ebola

Investigating the efficacy of vaccines during on-going epidemics poses numerous challenges, whether the infection is Middle East Respiratory Syndrome (MERS), novel influenza strains or Ebola. Beyond the public health urgency, there are issues such as variable and unpredictable incidence and limited vaccine supplies, which pose huge challenges for investigators (and governments). I wrote about some of these issues last October in a post titled, "Ebola vaccine - do we really need a placebo-controlled RCT." In the post, I described a stepped-wedge design, which we've used in health services research, but I made clear that I wasn't a vaccine trial expert.

Fortunately, more experienced vaccine trial experts have just published their thoughts on designing vaccine trials during emergencies with the ongoing West African Ebola outbreak providing context. Marc Lipsitch, Rebecca Grais and colleagues (COI - I'm a co-author), suggest three principles worth considering when designing vaccine trials during public health emergencies:

Principle 1: Block Randomization within small centers with analysis matched by center
    Some centers may have higher (or lower) incidence, so that it is better to randomize within a center (block randomization). In this way, exposed (vaccinated) and unexposed (controls) would be expected to have similar risk of infection.

Principle 2: Stepped Rollout
     This principle is a response to the urgency of the situation. An individual randomized trial would require waiting for all centers to come online before commencing a trial (see purple box in Figure A, above). In contrast, a stepped role-out allows each center to commence the trial as soon as they are ready (purple area in Figure B, above).

Principle 3: Adaptive Design
     Since vaccine trials require participants to be at some risk of infection after the've established immunity from vaccination, it is imperative to know if centers will have active transmission once they are included in the study. This is incredibly difficult to predict. Adaptive designs use pre-specified rules to add centers (green in Figure B) or extend follow-up periods (yellow in Figure B), which improve the chances that a trial will reach a successful conclusion.

There is more depth in the Science Policy Forum, if you're interested. A final note of thanks to Marc and the group for including me in this effort. I learned a great deal through many email discussions over the past 4-5 months.