Abstract
BACKGROUND: The test-negative control study design is the basis for observational studies of influenza vaccine effectiveness (VE). Recent studies have suggested that influenza vaccination increases the risk of noninfluenza respiratory virus infection. Such an effect could create bias in VE studies using influenza-negative controls. We investigated the association between influenza infection, vaccination, and detection of other respiratory viruses among children <5 years old and adults ≥50 years old with acute respiratory illness who participated in seasonal studies of influenza vaccine effectiveness. METHODS: Nasal/nasopharyngeal samples collected from 2004–2005 through 2009–2010 were tested for 19 respiratory virus targets using a multiplex reverse-transcription polymerase chain reaction (RT-PCR) platform. Vaccination status was determined using a validated registry. Adjusted odds ratios for influenza and vaccination status were calculated using three different control groups: influenza-negative, other respiratory virus positive, and pan-negative. RESULTS: Influenza was detected in 12% of 2010 children and 20% of 1738 adults. Noninfluenza respiratory viruses were detected in 70% of children and 38% of adults without influenza. The proportion vaccinated did not vary between virus-positive controls and pan-negative controls in children (P = .62) or adults (P = .33). Influenza infection was associated with reduced odds of vaccination, but adjusted odds ratios differed by no more than 0.02 when the analysis used influenza-negative or virus-positive controls. CONCLUSIONS: Influenza vaccination was not associated with detection of noninfluenza respiratory viruses. Use of influenza-negative controls did not generate a biased estimate of vaccine effectiveness due to an effect of vaccination on other respiratory virus infections.