Evaluating reduced effectiveness after repeat influenza vaccination while accounting for confounding by recent infection and within-season waning

medRxiv. 2023 Mar 17;2023.03.12.23287173. doi: 10.1101/2023.03.12.23287173. Preprint


Background: Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees in a given season. Understanding the underlying causes requires consideration of within-season waning and recent infection.

Methods: Using the US Flu Vaccine Effectiveness (VE) Network data over 8 influenza seasons (2011-2012 to 2018-2019), we estimated the effect of prior-season vaccination on the odds of clinical infection in a given season, after accounting for waning vaccine protection using regression methods. We adjusted for potential confounding by recent clinical infection using inverse-probability weighting. We investigated theoretically whether unmeasured subclinical infection in the prior season, which is more likely in the non-repeat vaccinees, could explain the repeat vaccination effect.

Results: Repeat vaccinees vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for influenza A(H3N2) (OR=1.11, 95% CI:1.02-1.21) but not for influenza B (OR=1.03, 95% CI:0.89-1.18) or A(H1N1) (OR=1.03, 95% CI:0.90-1.19) compared to those vaccinated in the given season only. Recent clinical infection with the homologous (sub)type protected against clinical infection with A(H3N2) or B. Individuals with clinical infection in one season had 1.11 (95% CI:1.03-1.19) times the odds of switching vaccination status in the following season. Adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. Adjusting for subclinical infection could theoretically attenuate this effect.

Conclusion: Waning protection and recent clinical infection were insufficient to explain observed reduced VE in repeat vaccinees with a test-negative design.

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