Vaccine efficacy trials for Crimean-Congo haemorrhagic fever: Insights from modelling different epidemiological settings.

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.

Transmission dynamics and vaccination strategies for Crimean-Congo haemorrhagic fever virus in Afghanistan: A modelling study.

BACKGROUND: Crimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic virus for which a safe and effective vaccine is not yet available, despite being considered a priority emerging pathogen. Understanding transmission patterns and the use of potential effective vaccines are central elements of the future plan against this infection. METHODS: We developed a series of models of transmission amongst livestock, and spillover infection into humans. We use real-world human and animal data from a CCHFV endemic area in Afghanistan (Herat) to calibrate our models. We assess the value of environmental drivers as proxy indicators of vector activity, and select the best model using deviance information criteria. Finally we assess the impact of vaccination by simulating campaigns targeted to humans or livestock, and to high-risk subpopulations (i.e, farmers). FINDINGS: Saturation deficit is the indicator that better explains tick activity trends in Herat. Recent increments in reported CCHFV cases in this area are more likely explained by increased surveillance capacity instead of changes in the background transmission dynamics. Modelling suggests that clinical cases only represent 31% (95% CrI 28%-33%) of total infections in this area. Vaccination campaigns targeting humans would result in a much larger impact than livestock vaccination (266 vs 31 clinical cases averted respectively) and a more efficient option when assessed in courses per case averted (35 vs 431 respectively). Targeted vaccination of farmers is impactful and more efficient, resulting in 19 courses per case averted (95% CrI 7-62) compared to targeting the general population (35 courses 95% CrI 16-107). CONCLUSIONS: CCHFV is endemic in Herat, and transmission cycles are well predicted by environmental drivers like saturation deficit. Vaccinating humans is likely to be more efficient and impactful than animals, and importantly targeted interventions to high risk groups like farmers can offer a more efficient approach to vaccine roll-out.

Crimean-Congo hemorrhagic fever, Afghanistan, 2009.

In response to an outbreak of Crimean-Congo hemorrhagic fever in western Afghanistan, we measured immunoglobulin G seroprevalence among household members and their animals. Seroprevalence was 11.2% and 75.0% in humans (n = 330) and livestock (n = 132), respectively. Persons with frequent exposure to cattle had an elevated risk of being immunoglobulin G positive.