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

Abstract

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.

Keywords: antigenic drift; genomics; influenza vaccines; sentinel surveillance; vaccine effectiveness.

Figure 1.

Vaccine effectiveness study inclusion and exclusion criteria for the 2014–2015 season, Canadian Sentinel Practitioner Surveillance Network. ^aExclusions are not mutually exclusive; specimens may have >1 exclusion criterion that applies. Counts for each criterion will sum to more than the total number of specimens excluded. Abbreviations: ILI, influenza-like illness; PCR, polymerase chain reaction.

Figure 2.

Effect of prior 2012–2013 and/or 2013–2014 season influenza vaccine receipt on current 2014–2015 influenza vaccine effectiveness for influenza A(H3N2). Analyses are based on the same exclusion criteria as primary analysis, adjusted for age group (<9, 9–19, 20–49, 50–64, ≥65 years), sex, comorbidity, province, collection interval, and calendar time (spline). Calendar time was modeled by week of specimen collection using cubic B-spline functions with 3 equally spaced knots. A, The effect of prior 2013–2014 vaccine receipt in participants aged ≥2 years in 2014–2015 and with complete data for 2013–2014 and 2014–2015 influenza vaccine receipt. B, The effect of prior 2013–2014 and/or 2012–2013 vaccine receipt in participants aged ≥3 years in 2014–2015 and those with complete data for 2012–2013, 2013–2014, and 2014–2015 influenza vaccine receipt. Abbreviations: CI, confidence interval; VE, vaccine effectiveness.

Figure 3.

Effect of prior 2012–2013 and/or 2013–2014 season influenza vaccine receipt on current 2014–2015 influenza vaccine effectiveness for influenza B(Yamagata). Analyses are based on the same exclusion criteria as primary analysis, adjusted for age group (<9, 9–19, 20–49, 50–64, ≥65 years), sex, comorbidity, province, collection interval, and calendar time (spline). Calendar time was modeled by week of specimen collection using cubic B-spline functions with 3 equally spaced knots. A, The effect of prior 2013–2014 vaccine receipt in participants aged ≥2 years in 2014–2015 and with complete data for 2013–2014 and 2014–2015 influenza vaccine receipt. B, The effect of prior 2013–2014 and/or 2012–2013 vaccine receipt in participants aged ≥3 years in 2014–2015 and those with complete data for 2012–2013, 2013–2014, and 2014–2015 influenza vaccine receipt. Abbreviations: CI, confidence interval; VE, vaccine effectiveness.

Figure 4.

Crystal structure of hemagglutinin (HA) of circulating A(H3N2) clade 3C.2a and clade 3C.3b viruses relative to the 2014–2015 egg-adapted high-growth reassortant (HGR) vaccine strain. Three-dimensional structural model shows antigenic site substitutions in the HA1 of representative sentinel influenza A(H3N2) viruses compared with the 2014–2015 egg-adapted A/Texas/50/2012-like (clade 3C.1) HGR vaccine strain (X-223A) for (A) clade 3C.2a and (B) clade 3C.3b. The homology models of HA were generated using the SWISS-MODEL web-based automated modeling server [34]. The final images of the HA structures were generated using Pymol (Schrödinger, LLC) [35]. The trimeric HA protein of A(H3N2) was constructed using the A/Victoria/361/2011 human A(H3N2) virus (PDB accession number 4WE8.1) with 97% identity to circulating strains. Antigenic sites (A–E) are shown in pastel colors. Substitutions in antigenic sites are labelled, and those identifying clade designations are shown in cyan, those arising from egg passage and/or in the HGR are shown in red, and other substitutions in sentinel viruses are shown in darker shading of the corresponding antigenic site color. Mutations at pivotal antigenic site B positions 159 (a cluster-transition position) and 160 (associated with a potential gain of glycosylation) are indicated with a red star, present in clade 3C.2a viruses but absent from clade 3C.3b viruses relative to X-223A. (Panel A republished with modifications on permission of Oxford University Press from Skowronski DM et al [11], J Infect Dis 2015; 212(5).)