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

Abstract

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.

Keywords: Influenza; birth cohort effects; hemagglutination inhibition; influenza A subtype; influenza B lineage; influenza vaccine; original antigenic sin; repeat vaccination; sequencing; vaccine effectiveness.

Figure 1.

Crystal structure (trimer) of hemagglutinin (HA) of dominant clade 6B.1 2009 pandemic influenza A(H1N1) viruses (A[H1N1]pdm09) detected by the Canadian Sentinel Practitioner Surveillance Network, during the 2015–2016 season, with key substitutions relative to the egg-adapted X-179A high-growth reassortant (HGR) vaccine strain. Three-dimensional structural model shows key substitutions in the HA1 of dominant sentinel A(H1N1)pdm09 clade 6B.1 viruses as compared to the 2015–2016 egg-adapted A/California/07/2009-like HGR vaccine strain (namely X-179A most used in Canada). The trimeric HA protein of A(H1N1)pdm09 was constructed using the crystal structure of the A/Washington/05/2011 HA (Protein Data Bank accession number 4LXV) with substitutions relevant to clade 6B.1 viruses added in the PyMOL Molecular Graphics System (version 1.6; Schrödinger), using the Mutagenesis Wizard. Antigenic sites Sa, Sb, Ca1, Ca2, and Cb are shown in pastel colors. Substitutions are labelled and the involved antigenic site is indicated in parentheses and darker shading. Nonantigenic site substitutions arising from egg passage and/or in the HGR (both X-179A and X-181) are shown in red; a third such substitution (N129D) in relation to X-181 alone is not displayed. The dotted line from S203T (Ca1) indicates that the highlighted mutation is not visible from the point of view shown in the crystal structure. Note that amino acid numbering is based on the H1 scheme and begins with the signal peptide removed. RBS, receptor-binding site; +CHO, potential gain of glycosylation site.

Figure 2.

Adjusted vaccine effectiveness (VE) estimates for 2015–2016 seasonal influenza vaccine, by influenza type and subtype or lineage (primary analysis), Canadian Sentinel Practitioner Surveillance Network. Abbreviation: CI, confidence interval. ^aAdjusted for age group, sex, comorbidity, province, collection interval, and calendar time (week of specimen collection as modeled using cubic B spline functions with 3 equally spaced knots). Details are specified in Supplement 3 and Supplement 11.

Figure 3.

Adjusted vaccine effectiveness (VE) for 2015–2016 (current) and/or 2014–2015 (prior) seasonal influenza vaccines against 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) and influenza B(Victoria), during the 2015–2016 season, Canadian Sentinel Practitioner Surveillance Network. The exclusion criteria were the same as in the primary analysis but limited to participants ≥9 years old and with complete information for 2014–2015 and 2015–2016 vaccine receipt. CI, confidence interval. ^aAdjusted for age group, sex, comorbidity, province, collection interval, and calendar time (week of specimen collection was modeled using cubic B spline functions with 3 equally spaced knots). Details are specified in Supplement 3 and Supplement 13.

Figure 4.

Adjusted vaccine effectiveness (VE) for 2015–2016 seasonal influenza vaccine against 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09), stratified by age group (A) and birth year (B), among Canadian Sentinel Practitioner Surveillance Network participants 1–76 years old. A, Adjusted VE stratified by age groups adapted to reflect potential variation in K163-priming specificity as per Supplement 1, with stratification by age group based on an interaction model as detailed in Supplement 3 and Supplement 15. B, Adjusted VE stratified by single year of age (or derived year of birth), with age smoothed as a restricted cubic-spline function with 5 knots based on percentiles as detailed in Supplement 3 and Supplement 16. Color shading was performed as per Supplement 1 and corresponds to birth year, as follows: orange, pronounced K163 specificity predicted; pink, K163 specificity anticipated but conditional upon age of first A(H1N1) exposure; and gray, K163 specificity not predicted. Birth years without color shading are for children or older adults for whom priming in relation to position 163 varies for additional reasons specified in Supplement 1. CI, confidence interval. ^aAdapted from the work by Linderman et al [18]. ^bPeriod of no A(H1N1) circulation (ie, 1957–1976) for which heterosubtypic priming with A(H2N2) (ie, 1957–1967) and/or A(H3N2) (ie, 1968–1976) is likely before reemergence of A(H1N1) viruses (K163 bearing) in 1977.

Figure 5.

Adjusted vaccine effectiveness (VE) for 2015–2016 seasonal influenza vaccine against 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) and B(Victoria) virus, by epidemic period, Canadian Sentinel Practitioner Surveillance Network. Stratified estimates were derived using an interaction model based on the entire analytic sample for A(H1N1)pdm09 and B(Victoria); sample sizes for epidemic subgroups are displayed for interest. Abbreviation: CI, confidence interval. ^aAdjusted for age group, sex, comorbidity, province, collection interval, epidemic period (based on month of specimen collection), and vaccination status*epidemic period interaction. Details are provided in Supplement 11.