Centre 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.
Centre 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; INSERM, Sorbonne Université, Institut Pierre Louis d'Épidémiologie et de Santé Publique (Unité Mixte de Recherche en Santé 1136), Paris, France.
Vaccine. 2022 Sep 22;40(40):5806-5813. doi: 10.1016/j.vaccine.2022.08.061. Epub 2022 Sep 1.
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.
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.
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.
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.
克里米亚-刚果出血热（CCHF）是一种优先出现的病原体，目前尚无许可疫苗。我们旨在评估进行 III 期疫苗功效试验的可行性以及不同传播动态的作用。
我们校准了在阿富汗、土耳其和南非流行地区家畜和溢出到人类的 CCHFV 传播模型。我们提出了一项针对高危人群的个体随机对照试验，并使用校准模型模拟试验队列，以估计在三种选定环境下，在不同的样本量和随访时间条件下，分析最低疗效为 60%的疫苗所需的最小病例数（试验终点）。
在阿富汗赫拉特这样的环境中，要达到 150 个试验终点，目标疫苗效力为 60%，临床定义的终点，需要 160000 人月的平均随访（75000-550000）。对于土耳其，同样的随访时间为 175000 人月（50000-350000）。结果表明，南非的低流行传播水平将不允许在现实的随访时间内达到进行这项试验的必要条件。在设计用于捕获感染而不是临床病例作为试验终点的 CCHFV 疫苗试验中，在阿富汗和土耳其，所需的人月数减少了 70%至 80%，在南非，对于大量的人月随访（>600000），试验变得可行。预期疫苗效力增加>60%将减少 III 期试验所需的试验终点数量，从而减少样本量和随访时间。
基础流行传播水平将在定义 III 期疫苗功效试验的可行性方面发挥核心作用。阿富汗和土耳其的流行环境提供了进行此类研究的可行条件。
