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Vaccine efficacy trials for Crimean-Congo haemorrhagic fever: Insights from modelling different epidemiological
Juan F Vesga1, Raphaelle Métras2, Madeleine H A Clark3
1Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
Insights
Conducting Crimean-Congo haemorrhagic fever (CCHF) vaccine trials is feasible in Afghanistan and Turkey, but not South Africa, due to transmission levels. Higher vaccine efficacy reduces required trial endpoints and follow-up time.
Area of Science:
- Epidemiology
- Vaccinology
- Public Health
Background:
- Crimean-Congo haemorrhagic fever (CCHF) is a priority emerging pathogen with no licensed vaccine.
- Assessing the feasibility of phase III vaccine efficacy trials is crucial.
Purpose of the Study:
- To evaluate the feasibility of conducting phase III CCHF vaccine efficacy trials.
- To determine the role of transmission dynamics in trial feasibility.
- To estimate necessary sample sizes and follow-up durations for vaccine trials.
Main Methods:
- Calibrated models of CCHF virus (CCHFV) transmission in Afghanistan, Turkey, and South Africa.
- Simulated individual randomized controlled trials in high-risk populations.
- Estimated minimum required cases (trial endpoints) for a 60% vaccine efficacy.
Main Results:
- Afghanistan and Turkey require approximately 160,000-175,000 person-months of follow-up for 150 trial endpoints.
- South Africa's low transmission levels make trials infeasible within realistic follow-up times.
- Using infection as an endpoint, rather than clinical cases, reduces required person-months by 70-80% in Afghanistan and Turkey.
Conclusions:
- Endemic transmission levels are central to the feasibility of phase III CCHF vaccine trials.
- Afghanistan and Turkey present feasible settings for conducting such trials.
- Optimizing trial endpoints and considering higher vaccine efficacy can enhance feasibility.
Background:
Crimean-Congo haemorrhagic fever (CCHF) is a priority emerging pathogen for which a licensed vaccine is not yet available. We aim to assess the feasibility of conducting phase III vaccine efficacy trials and the role of varying transmission dynamics.
Methods:
We calibrate models of CCHF virus (CCHFV) transmission among livestock and spillover to humans in endemic areas in Afghanistan, Turkey and South Africa. We propose an individual randomised controlled trial targeted to high-risk population, and use the calibrated models to simulate trial cohorts to estimate the minimum necessary number of cases (trial endpoints) to analyse a vaccine with a minimum efficacy of 60%, under different conditions of sample size and follow-up time in the three selected settings.
Results:
A mean follow-up of 160,000 person-month (75,000-550,000) would be necessary to accrue the required 150 trial endpoints for a target vaccine efficacy of 60 % and clinically defined endpoint, in a setting like Herat, Afghanistan. For Turkey, the same would be achieved with a mean follow-up of 175,000 person-month (50,000-350,000). The results suggest that for South Africa the low endemic transmission levels will not permit achieving the necessary conditions for conducting this trial within a realistic follow-up time. In the scenario of CCHFV vaccine trial designed to capture infection as opposed to clinical case as a trial endpoint, the required person-months is reduced by 70 % to 80 % in Afghanistan and Turkey, and in South Africa, a trial becomes feasible for a large number of person-months of follow-up (>600,000). Increased expected vaccine efficacy > 60 % will reduce the required number of trial endpoints and thus the sample size and follow-time in phase III trials.
Conclusions:
Underlying endemic transmission levels will play a central role in defining the feasibility of phase III vaccine efficacy trials. Endemic settings in Afghanistan and Turkey offer conditions under which such studies could feasibly be conducted.
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