title: 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.
  
  
  RESULTS
  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.
authors.affiliation: Communicable Disease Prevention and Control Service, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Danuta M
authors.initials: DM
authors.lastname: Skowronski
authors.affiliation: School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada; Clinical Prevention Services, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
authors.forename: Naveed Z
authors.initials: NZ
authors.lastname: Janjua
authors.affiliation: Department of Biological and Occupational Risks, Institut National de Santé Publique du Québec, Québec (Québec), Canada; Department of Social and Preventive Medicine, Laval University, Québec (Québec), Canada.
authors.forename: Gaston
authors.initials: G
authors.lastname: De Serres
authors.affiliation: Communicable Disease Prevention and Control Service, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
authors.forename: Suzana
authors.initials: S
authors.lastname: Sabaiduc
authors.affiliation: Department of Molecular Research, Public Health Ontario, Toronto, Ontario, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Eshaghi
authors.affiliation: Family Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Dickinson
authors.affiliation: Department of Virology, Provincial Laboratory of Public Health, Calgary, Alberta, Canada; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fonseca
authors.affiliation: Communicable Disease Prevention and Control, Public Health Ontario, Toronto, Ontario, Canada.
authors.forename: Anne-Luise
authors.initials: AL
authors.lastname: Winter
authors.affiliation: Department of Microbiology, Public Health Ontario, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology and Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Gubbay
authors.affiliation: Communicable Disease Prevention and Control Service, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; Clinical Prevention Services, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
authors.forename: Mel
authors.initials: M
authors.lastname: Krajden
authors.affiliation: Communicable Disease Prevention and Control Service, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; Clinical Prevention Services, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Petric
authors.affiliation: Laboratoire de Santé Publique du Québec, Institut National de Santé Publique du Québec, Sainte-Anne-de-Bellevue, Québec, Canada; Département De Microbiologie, Infectiologie et Immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Hugues
authors.initials: H
authors.lastname: Charest
authors.affiliation: Influenza and Respiratory Virus Section, National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bastien
authors.affiliation: School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Trijntje L
authors.initials: TL
authors.lastname: Kwindt
authors.affiliation: Community Health Sciences and Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Salaheddin M
authors.initials: SM
authors.lastname: Mahmud
authors.affiliation: Cadham Provincial Laboratory, Manitoba Health, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Caeseele
authors.affiliation: Influenza and Respiratory Virus Section, National Microbiology Laboratory, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002170:Canada; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007114:Immunization; D007223:Infant; D007231:Infant, Newborn; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D012621:Seasons; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines