Researchers offer guidelines for vaccine study design during public health emergencies

A public health emergency creates a challenging environment for the study of experimental vaccines, necessitating the need for novel, flexible and responsive trial designs. In a paper published July 3 in the journal Science Translational Medicine, a group of researchers led by University of Florida biostatistics faculty describes key considerations for the design and analysis of such trials.

“The most significant challenge during a public health emergency is that it is hard to design a study that places the vaccine in populations at high risk for the disease,” said lead author Natalie Dean, Ph.D., an assistant professor in the department of biostatistics at the UF College of Public Health and Health Professions and the UF College of Medicine. “In order to tell if the vaccine works, populations need to be naturally exposed, but for outbreaks, disease incidence is very unpredictable. Outbreaks may end quickly, before there is time to implement a clinical trial. We need new trial design strategies to address these challenges.”

The new recommendations come from a group of statisticians, clinical trialists, infectious disease modelers and researchers, which include the paper’s senior author, Ira Longini, Ph.D., a UF professor of biostatistics. They were convened by the World Health Organization’s Research and Development Blueprint and charged with establishing standard procedures to rapidly evaluate experimental vaccines during public health emergencies while maintaining the highest scientific and ethical standards. The team used the Blueprint’s priority diseases as a framework for discussion. The 2018 list of priority diseases includes Crimean-Congo hemorrhagic fever, Ebola and Marburg viruses, Lassa fever, MERS-CoV, SARS, Nipah, Rift Valley Fever, Zika and Disease X, a future unknown threat.

In their paper, the team outlines major study design elements and challenges specific to the Blueprint priority diseases and to the context of public health emergencies. They also illustrate some of the trade-offs and methodological options.

“We emphasize the need for flexibility in trial design,” Dean said. “Some proposed strategies include responsive designs in which the vaccine trial population is not defined in advance, but rather the vaccine is deployed where outbreaks are observed. This type of strategy was used for the Ebola ring vaccination trial in Guinea where the vaccine was provided to the contacts of confirmed cases.”

Dean said another proposed strategy is multi-outbreak trials, in which trials start, stop, and restart and continue across outbreaks until the scientific question of whether or not the vaccine works is addressed.

To navigate the various study design elements and options outlined in the team’s paper, and to promote scientific discussion among methodologists, members developed an interactive, web-based decision support tool called InterVax, available at The team describes the goals and features of the InterVax Tool, as well as its application to the design of a Zika vaccine efficacy trial, in a paper published this month in the journal Vaccine.

Dean currently leads a National Institute of Allergy and Infectious Diseases-funded R01 study aimed at developing innovative study designs and analytical methods to estimate vaccine efficacy and effectiveness. The five-year study focuses on emerging infectious diseases, such as Ebola, Lassa fever, MERS and pandemic influenza.