Assessing vaccine durability in randomized trials following placebo crossover

Fintzi, Jonathan; Follmann, Dean

Randomized vaccine trials are used to assess vaccine efficacy (VE) and to characterize the durability of vaccine‐induced protection. If efficacy is demonstrated, the treatment of placebo volunteers becomes an issue. For COVID‐19 vaccine trials, there is broad consensus that placebo volunteers should be offered a vaccine once efficacy has been established. This will likely lead to most placebo volunteers crossing over to the vaccine arm, thus complicating the assessment of long term durability. We show how to analyze durability following placebo crossover and demonstrate that the VE profile that would be observed in a placebo controlled trial is recoverable in a trial with placebo crossover. This result holds no matter when the crossover occurs and with no assumptions about the form of the efficacy profile. We only require that the VE profile applies to the newly vaccinated irrespective of the timing of vaccination. We develop different methods to estimate efficacy within the context of a proportional hazards regression model and explore via simulation the implications of placebo crossover for estimation of VE under different efficacy dynamics and study designs. We apply our methods to simulated COVID‐19 vaccine trials with durable and waning VE and a total follow‐up of 2 years.