LAUSR

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 trial endpoints necessary to analyse vaccine efficacy, sample size and follow-up time in the three settings. Results: Under assumptions of a minimum vaccine efficacy of 60%, the minimum sample size needed to accrue the required 150 clinical endpoints in a minimum follow-up time of 6 months is estimated to be 34,000 (CrI 95%, 16,750 , 88,725) and 37,000 (CrI 95%, 13,000 , 77,250) in Afghanistan and Turkey, respectively. 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 a scenario of CCHFV infection (rather than clinical case) as trial endpoint, the required sample size is reduced by 70% to 80% in Afghanistan and Turkey, and in South Africa, a trial becomes feasible for large sample sizes (>75,000) and vaccine efficacy of >70%. 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.