Assessing the feasibility of Phase 3 vaccine trials against Marburg Virus Disease: a modelling study

Abstract

Background: Outbreaks of Marburg virus disease (MVD) are rare and small in size, with only 16 recorded outbreaks since 1967, only two of which involved more than 100 cases. It has been proposed, therefore, that Phase 3 trials for MVD vaccines should be held open over multiple outbreaks until sufficient end points accrue to enable vaccine efficacy (VE) to be calculated. Here we estimate how many outbreaks might be needed for VE to be estimated. Methods: We adapt a mathematical model of MVD transmission to simulate a Phase 3 individually randomised placebo controlled vaccine trial. We assume in the base case that vaccine efficacy is 70% and that 50% of individuals in affected areas are enrolled into the trial (1:1 randomisation). We further assume that the vaccine trial starts two weeks after public health interventions are put in place and that cases occurring within 10 days of vaccination are not included in VE calculations. Results: The median size of simulated outbreaks was 2 cases. Only 0.3% of simulated outbreaks were predicted to have more than 100 MVD cases. 95% of simulated outbreaks terminated before cases accrued in the placebo and vaccine arms. Therefore the number of outbreaks required to estimate VE was large: after 100 outbreaks, the estimated VE was 69% but with considerable uncertainty (95% CIs: 0% - 100%) while the estimated VE after 200 outbreaks was 67% (95% CIs: 42% - 85%). Altering base-case assumptions made little difference to the findings. Conclusions: It is unlikely that the efficacy of any candidate vaccine can be calculated before more MVD outbreaks have occurred than have been recorded to date. This is because MVD outbreaks tend to be small, public health interventions have been historically effective at reducing transmission, and vaccine trials are only likely to start after these interventions are already in place. Hence, it is expected that outbreaks will terminate before, or shortly after, cases start to accrue in the vaccine and placebo arms. Manufacturers may want to consider alternative routes to licensure than Phase 3 trials for MVD vaccines.

Advancements in Marburg (MARV) Virus Vaccine Research With Its Recent Reemergence in Equatorial Guinea and Tanzania: A Scoping Review

“…Most outbreaks are relatively small and need to be controlled quickly using existing infection control and public health measures. Therefore, it is suggested that multiple outbreaks could be used to conduct Phase 3 trials for MVD vaccines until sufficient endpoints have been accumulated to assess vaccine efficacy (VE) and can be estimated by estimating the number of outbreaks required [ 77 ].…”