Influenza live viral challenges in humans are valuable models for testing the efficacy of vaccines and antiviral agents. Volunteers are treated with an investigational agent, and their clinical outcomes postchallenge are compared to those of placebo-treated volunteers. Despite using a common protocol, similar recruitment criteria, and similar doses of the same challenge strain, we noticed differences in disease severity outcomes between the placebo groups from different studies. We investigated whether these differences were significant and, if so, whether any pattern and its possible causes could be identified. We compared the clinical outcomes postchallenge in placebo groups from five clinical studies carried out between 2008 and 2013. Correlations between the prechallenge heterosubtypic cellular response (gamma interferon [IFN-γ]) and postchallenge clinical outcomes were also investigated in one study. Placebo groups from studies carried out between 2009 and 2010 attained significantly reduced (P < 0.05) symptom scores postchallenge compared to those of placebo groups from studies carried out in either 2008 or 2013. Also, in a 2010 study, the frequency of high-influenza heterosubtypic cellular responders prevaccination was significantly lower in the test group (FLU-v) than that in the placebo group (P = 0.04). Moreover, the increased preexisting heterosubtypic cellular response of the placebo group correlated with reductions in symptom score and viral shedding postchallenge (P ≤ 0.023). Only postvaccination did the test group display an equivalent correlation. The last influenza pandemic coincided with a significant reduction in disease severity outcomes. This reduction also appears to correlate with increased preexisting influenza heterosubtypic cellular responses. (This study is registered at ClinicalTrials.gov under registration number NCT01226758.).
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