The effectiveness of influenza vaccine during 2015–2016 was reduced in some age groups as compared to that in previous 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09 virus)–predominant seasons. We hypothesized that the age at first exposure to specific influenza A(H1N1) viruses could influence vaccine effectiveness (VE).

We estimated the effectiveness of influenza vaccine against polymerase chain reaction–confirmed influenza A(H1N1)pdm09-associated medically attended illness from the 2010–2011 season through the 2015–2016 season, according to patient birth cohort using data from the Influenza Vaccine Effectiveness Network. Birth cohorts were defined a priori on the basis of likely immunologic priming with groups of influenza A(H1N1) viruses that circulated during 1918–2015. VE was calculated as 100 × [1 – adjusted odds ratio] from logistic regression models comparing the odds of vaccination among influenza virus–positive versus influenza test–negative patients.

A total of 2115 A(H1N1)pdm09 virus–positive and 14 696 influenza virus–negative patients aged ≥6 months were included. VE was 61% (95% confidence interval [CI], 56%–66%) against A(H1N1)pdm09-associated illness during the 2010–2011 through 2013–2014 seasons, compared with 47% (95% CI, 36%–56%) during 2015–2016. During 2015–2016, A(H1N1)pdm09-specific VE was 22% (95% CI, −7%–43%) among adults born during 1958–1979 versus 61% (95% CI, 54%–66%) for all other birth cohorts combined.

Findings suggest an association between reduced VE against influenza A(H1N1)pdm09-related illness during 2015–2016 and early exposure to specific influenza A(H1N1) viruses.