Beyond Antigenic Match: Possible Agent-Host and Immuno-epidemiological Influences on Influenza Vaccine Effectiveness During the 2015–2016 Season in Canada

BACKGROUND: Vaccine effectiveness (VE) estimates for 2015–2016 seasonal influenza vaccine are reported from Canada’s Sentinel Practitioner Surveillance Network (SPSN). This season was characterized by a delayed 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) epidemic and concurrent influenza B(Victoria) virus activity. Potential influences on VE beyond antigenic match are explored, including viral genomic variation, birth cohort effects, prior vaccination, and epidemic period. METHODS: VE was estimated by a test-negative design comparing the adjusted odds ratio for influenza test positivity among vaccinated compared to unvaccinated participants. Vaccine-virus relatedness was assessed by gene sequencing and hemagglutination inhibition assay. RESULTS: Analyses included 596 influenza A(H1N1)pdm09 and 305 B(Victoria) cases and 926 test-negative controls. A(H1N1)pdm09 viruses were considered antigenically related to vaccine (unchanged since 2009), despite phylogenetic clustering within emerging clade 6B.1. The adjusted VE against A(H1N1)pdm09 was 43% (95% confidence interval [CI], 25%–57%). Compared to other age groups, VE against A(H1N1)pdm09 was lower for adults born during 1957–1976 (25%; 95% CI, −16%–51%). The VE against A(H1N1)pdm09 was also lower for participants consecutively vaccinated during both the current and prior seasons (41%; 95% CI, 18%–57%) than for those vaccinated during the current season only (75%; 95% CI, 45%–88%), and the VE among participants presenting in March–April 2016 (19%; 95% CI, −15%–44%) was lower than that among those presenting during January–February 2016 (62%; 95% CI, 44%–74%). The adjusted VE for B(Victoria) viruses was 54% (95% CI, 32%–68%), despite lineage-level mismatch to B(Yamagata) vaccine. The further variation in VE as observed for A(H1N1)pdm09 was not observed for B(Victoria). CONCLUSIONS: Influenza VE findings may require consideration of other agent-host and immuno-epidemiologic influences on vaccine performance beyond antigenic match, including viral genomic variation, repeat vaccination, birth (immunological) cohort effects, and potential within-season waning of vaccine protection.