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Design of Vaccine Trials during Outbreaks with and without a Delayed Vaccination Comparator

View ORCID ProfileNatalie E. Dean, M. Elizabeth Halloran, Ira M. Longini
doi: https://doi.org/10.1101/074088
Natalie E. Dean
1Department of Biostatistics, University of Florida
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M. Elizabeth Halloran
2Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
3Department of Biostatistics, University of Washington
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Ira M. Longini
1Department of Biostatistics, University of Florida
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Abstract

Conducting vaccine efficacy trials during outbreaks of emerging pathogens poses particular challenges. The ‘Ebola ça 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 per protocol 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 misspecification of the incubation period and time to develop a vaccine immune response.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 08, 2016.
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Design of Vaccine Trials during Outbreaks with and without a Delayed Vaccination Comparator
Natalie E. Dean, M. Elizabeth Halloran, Ira M. Longini
bioRxiv 074088; doi: https://doi.org/10.1101/074088
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Design of Vaccine Trials during Outbreaks with and without a Delayed Vaccination Comparator
Natalie E. Dean, M. Elizabeth Halloran, Ira M. Longini
bioRxiv 074088; doi: https://doi.org/10.1101/074088

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