DESIGN OF VACCINE TRIALS DURING OUTBREAKS WITH AND WITHOUT A DELAYED VACCINATION COMPARATOR

• 成果类型: Article
• 署名作者: Dean, Natalie E.; Halloran, M. Elizabeth; Longini, Ira M.
• 署名单位: State University System of Florida; University of Florida; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle
• 刊物名称: ANNALS OF APPLIED STATISTICS
• ISSN/ISSBN: 1932-6157
• DOI: 10.1214/17-AOAS1095
• 发表日期: 2018
• 页码: 330-347
• 关键词: efficacy

摘要

Conducting vaccine efficacy trials during outbreaks of emerging pathogens poses particular challenges. The Ebola ca suffit trial in Guinea used a novel ring vaccination cluster randomized design to target populations at highest risk of infection. Another key feature of the trial was the use of a delayed vaccination arm as a comparator, in which clusters were randomized to immediate vaccination or vaccination 21 days later. This approach, chosen to improve ethical acceptability of the trial, complicates the statistical analysis as participants in the comparison arm are eventually protected by vaccine. Furthermore, for infectious diseases, we observe time of illness onset and not time of infection, and we may not know the time required for the vaccinee to develop a protective immune response. As a result, including events observed shortly after vaccination may bias the per protocol estimate of vaccine efficacy. We provide a framework for approximating the bias and power of any given analysis period as functions of the background infection hazard rate, disease incubation period, and vaccine immune response. We use this framework to provide recommendations for designing standard vaccine efficacy trials and trials with a delayed vaccination comparator. Briefly, narrower analysis periods within the correct window can minimize or eliminate bias but may suffer from reduced power. Designs should be reasonably robust to mis-specification of the incubation period and time to develop a vaccine immune response.