Abstract
Background
Outbreaks of Marburg virus disease (MVD) are rare and small in size, with only 18 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. In a sensitivity analysis, increasing
by 25% and 50% led to an estimated VE after 200 outbreaks of 69% (95% CIs: 53–85%) and 70% (95% CIs: 59–82%), respectively.
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.
Outbreaks of Marburg virus disease (MVD) are rare and small in size, with only 18 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. In a sensitivity analysis, increasing
by 25% and 50% led to an estimated VE after 200 outbreaks of 69% (95% CIs: 53–85%) and 70% (95% CIs: 59–82%), respectively.
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.
| Original language | English |
|---|---|
| Article number | 100321 |
| Journal | Vaccine: X |
| Volume | 14 |
| Early online date | 28 Jun 2023 |
| DOIs | |
| Publication status | Published - 1 Aug 2023 |
Bibliographical note
Funding Information:This study was part funded by the Department of Health and Social Care using UK Aid funding and is managed by the National Institute for Health and Care Research (VEEPED: PR-OD-1017-20002) and the Japan Agency for Medical Research and Development (AMED; grant number JP223fa627004). TJ acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO concordat agreement and is also part of the EDCTP2 programme supported by the European Union. The views expressed in this publication are those of the authors and not necessarily those of the funders.
Publisher Copyright:
© 2023 The Author(s)
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
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