Abstract
BackgroundInfluenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis.MethodsTwenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR.Results1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = −16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = −36.1%).ConclusionsWe developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies.Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013
Highlights
Influenza challenge trials are important for vaccine efficacy testing
Seasonal influenza vaccines are licensed based on their ability to induce a haemagglutination inhibition (HI) titre of 1:40, but for novel vaccines that are designed to act through alternative immune mechanisms it will be necessary to demonstrate efficacy of the vaccine in preventing disease caused by influenza viruses, in humans
Challenge study outcome A human influenza challenge trial was conducted where 21 healthy adult volunteers were intranasally challenged with live influenza A virus
Summary
Disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. Seasonal influenza vaccines cannot provide protection against influenza pandemics caused by novel subtypes, and much research effort has been directed towards producing a ‘universal’ influenza A vaccine that will protect against any subtype of influenza A. This has resulted in a number of different approaches to vaccination against influenza which have entered early phase clinical development [5,6,7,8]. Symptom scoring may be influenced by many factors such as the mood of the volunteer, the time elapsed since waking, or drinking, or the perception that the volunteer should be feeling better in the later part of the quarantine period
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