Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses

Abstract

Background: Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012-13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses.

Methods/findings: Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33-63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17-59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16-80%) against A(H1N1)pdm09, 67% (95%CI: 30-85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29-91%) against B/Victoria (non-vaccine-lineage) viruses.

Conclusions: These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Conflict of interest statement

Competing Interests: Within 36 months of manuscript submission, GDS received research grants from GlaxoSmithKline (GSK) and Sanofi Pasteur for unrelated vaccine studies and travel fee reimbursement to attend an ad hoc GSK Advisory Board, without honorarium. JBG has received research grants from GSK and Hoffmann-LaRoche for antiviral resistance studies. MK has received research grants from Roche, Merck, Gen-Probe and Siemens. SMM has received research grants from GSK, Sanofi Pasteur and Pfizer. SMM is a Canada Research Chair in Pharmaco-epidemiology and Vaccine Evaluation; and the Great-West Life, London Life and Canada Life Junior Investigator of the Canadian Cancer Society [grant # 2011-700644]. SS and TLK are funded by the Canadian Institutes of Health Research Grant (TPA-90193). The other authors declare that they have no competing interests to report. This does not alter adherence to all PLOS policies on sharing data and materials.

Figures

Figure 1. Specimen exclusion for influenza vaccine effectiveness analysis, Canada, 2012–13 sentinel surveillance system.

NOTE: exclusions shown here in stepwise fashion to arrive at total case and control tally (i.e. those meeting multiple exclusion criteria are counted on the basis of the first exclusion criterion met in the list shown). Missing collection dates were imputed as the laboratory accession date minus two days, the average time period between collection date and laboratory accession date for records with valid data for both fields.

Figure 2. Influenza specimens by week and subtype, 2012–13 sentinel surveillance period (N = 1682).

NOTE: excludes specimens from patients failing to meet the influenza-like illness case definition or unknown; specimens collected >7 days after influenza-like illness onset or interval unknown; comorbidity unknown; age unknown or

Figure 3. Three-dimensional model of antigenic-site differences between circulating H3N2 viruses and the 2012–13 egg-adapted A/Victoria/361/2011 IVR-165 high growth reassortant vaccine strain.

One HA1 monomer is shown with five previously defined antigenic site residues of A–E colored in light green, dark green, light blue, dark blue and purple, respectively, mapped onto a related crystal structure (A/X-31(H3N2), PDB, 1HGG) using PyMOL . The most prevalent antigenic site amino acid differences between circulating clade 3C viruses in Canada relative to the egg-adapted A/Victoria/361/2011 IVR-165 vaccine reassortant strain are shown in red and labelled with coloured font representing their antigenic sites, viewed from the front (A) or side (B). Three amino acid differences (Q156H, V186G and Y219S) are owing to mutation in the egg-adapted IVR-165 vaccine strain rather than circulating viruses which instead share identity with the MDCK-passaged WHO reference prototype at these positions. RBS indicates approximate location of the receptor-binding site.