A Perfect Storm: Impact of Genomic Variation and Serial Vaccination on Low Influenza Vaccine Effectiveness During the 2014-2015 Season

Using an integrated surveillance platform, we incorporated genetic, antigenic, and epidemiologic indicators to evaluate agent–host factors that contributed to low vaccine effectiveness during the 2014–2015 influenza season, including variation in the viral genome and negative effects of serial vaccination.
Background. The 2014–2015 influenza season was distinguished by an epidemic of antigenically-drifted A(H3N2) viruses and vaccine components identical to 2013–2014. We report 2014–2015 vaccine effectiveness (VE) from Canada and explore contributing agent–host factors. Methods. VE against laboratory-confirmed influenza was derived using a test-negative design among outpatients with influenza-like illness. Sequencing identified amino acid mutations at key antigenic sites of the viral hemagglutinin protein. Results. Overall, 815/1930 (42%) patients tested influenza-positive: 590 (72%) influenza A and 226 (28%) influenza B. Most influenza A viruses with known subtype were A(H3N2) (570/577; 99%); 409/460 (89%) sequenced viruses belonged to genetic clade 3C.2a and 39/460 (8%) to clade 3C.3b. Dominant clade 3C.2a viruses bore the pivotal mutations F159Y (a cluster-transition position) and K160T (a predicted gain of glycosylation) compared to the mismatched clade 3C.1 vaccine. VE against A(H3N2) was −17% (95% confidence interval [CI], −50% to 9%) overall with clade-specific VE of −13% (95% CI, −51% to 15%) for clade 3C.2a but 52% (95% CI, −17% to 80%) for clade 3C.3b. VE against A(H3N2) was 53% (95% CI, 10% to 75%) for patients vaccinated in 2014-2015 only, significantly lower at −32% (95% CI, −75% to 0%) if also vaccinated in 2013–2014 and −54% (95% CI, −108% to −14%) if vaccinated each year since 2012–2013. VE against clade-mismatched B(Yamagata) viruses was 42% (95% CI, 10% to 62%) with less-pronounced reduction from prior vaccination compared to A(H3N2). Conclusions. Variation in the viral genome and negative effects of serial vaccination likely contributed to poor influenza vaccine performance in 2014–2015.