Randomized controlled trials for influenza drugs and vaccines: a review of controlled human infection studies

•Controlled human infection studies can down-select antiviral and vaccine candidates for further development.•Relatively small sample sizes can address questions on efficacy.•The safety record of controlled human infection studies with influenza is very good.

SummaryObjectivesControlled human infection, the intentional infection of healthy volunteers, allows disease pathogenesis to be studied and vaccines and therapeutic interventions to be evaluated in a controlled setting. A systematic review of randomized controlled trials of countermeasures for influenza that used the experimental human infection platform was performed. The primary objective was to document the scope of trials performed to date and the main efficacy outcome in the trials. The secondary objective was to assess safety and identify serious adverse events.MethodsThe PubMed database was searched for randomized controlled influenza human challenge studies with predetermined search terms. Review papers, papers without outcomes, community-acquired infections, duplicated data, pathogenesis studies, and observational studies were excluded.ResultsTwenty-six randomized controlled trials published between 1947 and 2014 fit the study inclusion criteria. Two-thirds of these trials investigated antivirals and one-third investigated influenza vaccines. Among 2462 subjects inoculated with influenza virus, the incidence of serious adverse events was low (0.04%). These challenge studies helped to down-select three antivirals and one vaccine that were subsequently approved by the US Food and Drug Administration (FDA).ConclusionsControlled human infection studies are an important research tool in assessing promising influenza vaccines and antivirals. These studies are performed quickly and are cost-effective and safe, with a low incidence of serious adverse events.