Abstract:
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.
