The 2013/14 influenza season to date in Canada has been characterised by predominant (90%) A(H1N1)pdm09 activity. Vaccine effectiveness (VE) was assessed in January 2014 by Canada’s sentinel surveillance network using a test-negative case–control design. Interim adjusted-VE against medically-attended laboratory-confirmed influenza A(H1N1)pdm09 infection was 74% (95% CI: 58–83). Relative to vaccine, A(H1N1)pdm09 viruses were antigenically similar and genetically well conserved, with most showing just three mutations across the 50 amino acids comprising antigenic sites of the haemagglutinin protein.
Since the 2009 pandemic, influenza A(H1N1)pfdm09 viruses have comprised a small proportion (<20%) of seasonal influenza virus detections each year in Canada . However, A(H1N1)pdm09 activity has recently resurged in North America, comprising more than 90% of detected influenza strains in both Canada and the United States (US) to mid-January of the 2013/14 season [1,2]. This profile is in contrast to that of the same period last season in Canada, when 90% of detected strains instead belonged to the A(H3N2) subtype .
The 2013/14 trivalent influenza vaccine (TIV) for the northern hemisphere retains the same A(H1N1)pdm09 (A/California/07/2009-like) strain recommended since 2009 by the World Health Organization (WHO) . In response to substantial A(H1N1)pdm09 resurgence, interim 2013/14 vaccine effectiveness (VE) was assessed in January 2014 using Canada’s sentinel surveillance network. VE estimates are discussed in the context of antigenic and genetic characterisation of circulating A(H1N1)pdm09 viruses.
Estimating influenza vaccine effectiveness
As previously described [3,5-12], a test-negative case–control design was used to estimate VE. Patients presenting with influenza-like illness (ILI) and testing positive for influenza viruses were considered cases, and those testing negative were considered controls.
Community-based practitioners at sentinel surveillance sites across participating provinces (British Columbia, Alberta, Manitoba, Ontario and Quebec) may offer nasal or nasopharyngeal swabbing to any patient presenting within seven days of symptom onset of ILI, defined as acute onset of respiratory illness with fever and cough and one or more of the following: sore throat, arthralgia, myalgia or prostration.
The analysis period included specimens collected from 1 November 2013 (week 44: 27 October 2013–2 November 2013) to 23 January 2014 (week 4: 19–25 January 2014), selected to account for influenza activity beginning in early November (Figure 1) and immunisation campaigns typically commencing in October. Epidemiological information was obtained from consenting patients or their parents/guardians using a standard questionnaire at specimen collection. Ethics review boards in participating provinces approved this study.
Figure 1. Laboratory detection of influenza by week and virus subtype, 2013/14 sentinel surveillance system, Canada, 29 September 2013–23 January 2014 (n=918)a
Specimens were tested for influenza A (by subtype) and B viruses at provincial reference laboratories using real-time RT-PCR. Odds ratios (OR) for medically-attended, laboratory-confirmed influenza were estimated by multivariable logistic regression. VE was calculated as (1−OR)x100%. Patients for whom comorbidity status was unknown or for whom the timing of vaccination was unknown or less than two weeks before symptom onset were excluded from the primary analysis but explored in sensitivity analyses. Age-stratified analysis and a study period beginning from week 49 (1–7 December 2013) to allow for additional vaccine uptake were also explored.
Genetic characterisation of sentinel influenza A(H1N1)pdm09 viruses
The haemagglutinin (HA) genes (HA1/HA2) from a convenience sample of sentinel influenza A(H1N1)pdm09 viruses from original patient specimens were sequenced for phylogenetic analysis and pair-wise amino acid (aa) identity based on antigenic maps spanning the 50 aa residues across HA1 antigenic sites Sa, Sb, Ca1, Ca2 and Cb [12,13]. Findings were expressed as percentage identity to vaccine, calculated as (1−(number of aa substitutions in antigenic sites)/(total antigenic site aa residues))x100%. After removal of the signal peptide (residues 1–17), the approximate likelihood method was used to generate the phylogenetic tree of aligned nucleotide sequences in FastTree , visualised in FigTree , including reference HA sequences shown in Table 1.
Table 1. Reference haemagglutinin sequences obtained from the EpiFlu database of the Global Initiative on Sharing Avian Influenza Data (GISAID) and used in phylogenetic analysis, 2013/14 sentinel surveillance network, Canada
Interim estimates of influenza vaccine effectiveness
A total of 1,091 specimens were submitted between 1 November 2013 and 23 January 2014. After exclusion criteria were applied (Figure 2), 792 specimens were included in the primary analysis.
Figure 2. Specimen exclusion, interim 2013/14 influenza vaccine effectiveness evaluation, Canada, 1 November 2013–23 January 2014 (n=1,091)
As in previous seasons, adults 20–49 years old contributed the largest proportion of specimens (50%) (Table 2) [3,6-12]. However, compared with the 2012/13 mid-season publication , a greater proportion of cases in 2013/14 were adults aged 20–49 years (53% versus 42%; p<0.01) or 50–64 years (22% versus 17%; p=0.13) (p<0.01 combined); proportions were more comparable among controls (48% versus 43%; p=0.17 and 20% versus 21%; p=0.86, respectively) (Table 2). Conversely, individuals younger than 20 years (21% versus 32%; p<0.01) and those 65 years and older (4% versus 9%; p<0.01) comprised a smaller proportion of cases compared with 2012/13 (Table 2) . Adults aged 20–49 years and 50–64 years also comprised a greater proportion of cases in 2013/14 compared with the 2009 monovalent influenza A(H1N1)pdm09 VE analysis (53% versus 46%; p=0.14 and 22% versus 10%; p<0.01, respectively) .
Of the 792 specimens tested to date and included in primary VE analysis, 325 (41%) were positive for influenza, and 287 of 318 typed/subtyped viruses (90%) were A(H1N1)pdm09 (Table 3; Figure 1). Overall, 155 of 487 controls (32%) and 41 of 332 cases (12%) reported receipt of 2013/14 TIV (p<0.01). After applying exclusions related to immunisation timing, 29% of controls and 10% of cases were considered immunised (p<0.01) (Table 2). The proportion of controls reporting TIV receipt in 2013/14 and earlier seasons was comparable to that reported in previous VE analyses and other community-based surveys in Canada (ca 30%) [3,7-9,11,12,16]. Proportions comparable to previous community surveys were also observed in 2013/14 for receipt of the 2009 monovalent A(H1N1)pdm09 vaccine (43% versus 41%) . The proportion of participants with co-morbidity was comparable to previous Canadian estimates (15–20%) [3,6-12,18] (Table 2).
Table 2. Profile of participants included in primary analysis, interim 2013/14 influenza vaccine effectiveness evaluation, Canada, 1 November 2013–23 January 2014 (n=792)
Table 3. Laboratory profile of specimens included in primary analysis, interim 2013/14 influenza vaccine effectiveness evaluation, Canada, 1 November 2013–23 January 2014 (n=792)
The majority of participants immunised in 2013/14 also reported prior immunisation: 30 of 31 cases (97%) and 103 of 119 controls (87%) were immunised in 2012/13 (p=0.11); 26 of 29 cases (90%) and 89 of 116 controls (77%) were immunised in both 2012/13 and 2011/12 (p=0.12); and 21 of 26 cases (81%) and 83 of 108 controls (77%) received the 2009 monovalent A(H1N1)pdm09 vaccine (p=0.67).
The adjusted VE estimate for any influenza, driven predominately by A(H1N1)pdm09, was 71% (95% CI: 54–81), and for A(H1N1)pdm09 alone was 74% (95% CI: 58–83) (Table 4). In sensitivity analyses, VE estimates remained within 1–7% of primary analysis.
Table 4. Interim 2013/14 influenza vaccine effectiveness evaluation, influenza A(H1N1)pdm09 and influenza (any), Canada, 1 November 2013–23 January 2014 (n=792)
All A(H1N1)pdm09 isolates from Canada this season through week 4 (n=473, including 84 sentinel submissions) were identified by haemagglutination inhibition (HI) assay as antigenically similar to the A/California/07/2009 reference virus . Only two A(H1N1)pdm09 isolates and none of the tested sentinel viruses, showed eightfold or higher reduction in HI titres against the reference strain, signalling sporadic antigenic change in only a very small proportion (<0.5%) [1,19].
HA1/HA2 sequences of a subset of 76 of 287 (26%) sentinel A(H1N1)pdm09 viruses were also assessed, including four collected in November, 45 in December and 27 in January (Figure 3; Table 5). All 76 sequences clustered within the European Centre for Disease Prevention and Control (ECDC)-described clade 6B (Figure 3) , representing a switch from clade 6C viruses that predominated among A(H1N1)pdm09 viruses during the 2012/13 season, albeit at substantially lower levels than A(H3N2) viruses .
Figure 3. Phylogenetic tree of influenza A(H1N1)pdm09 viruses, 2013/14 sentinel surveillance network, Canada, 1 November 2013–23 January 2014 (n=76)
Table 5. Amino acid changes in the haemagglutinin (HA1) genes (antigenic regions)a of a subset of 2013/14 Canadian sentinel influenza A(H1N1)pdm09 strains relative to vaccine reference strainsb, Canada, 1 November 2013–23 January 2014 (n=76)
Two egg-adapted A/California/07/2009 seed strains, NYMC X-179A and X-181, have been available to manufacturers for vaccine production since 2009, both identical in their antigenic site aa sequence to the WHO-recommended A/California/07/2009 reference strain (with a single substitution in a non-antigenic site (N129D) in X-181). Of the publicly supplied TIV in Canada, 70% was derived from X-179A and 30% from X-181. Sentinel viruses shared 90%-94% aa identity with the vaccine across antigenic sites, the majority showing 94% identity with the vaccine. All 76 sentinel sequences had the same three antigenic site mutations: K163Q (site Sa), a clade 6B marker, as well as S185T (site Sb) and S203T (site Ca1), both of which were also identified among dominant circulating A(H1N1)pdm09 viruses of the past two seasons [12,21]. Five of 76 sequences bore a fourth aa substitution unique to each virus, and one Quebec sequence bore five substitutions (Table 5). Other than S185T, present in all 76 sequences, A186T, present in the single Quebec sequence, and possibly N156K and S157L , each present in a single and different Alberta sequence, none of the other substitutions were located within or adjacent to the receptor-binding site. With the exception of the single Quebec sequence, antigenic site mutations R205K, A141T, and A186T, which are located close to the receptor-binding site [22-25] and which occurred in 37%, 30% and 14%, respectively, of sentinel sequences during the 2012/13 season , were not evident in 2013/14.
To date, the 2013/14 influenza season in North America has been characterised by substantial A(H1N1)pdm09 activity. This dramatic resurgence after only low-level circulation in the years since the 2009 pandemic has raised questions about possible virus evolution (i.e. antigenic drift) and reduced VE (i.e. vaccine failure). Our interim 2013/14 virological and VE analysis provides timely reassurance against both of these concerns. We show that circulating A(H1N1)pdm09 viruses are well-conserved based on genotypic and phenotypic characterisation, and that vaccine protection is substantial, reducing the risk of medically-attended laboratory-confirmed A(H1N1)pdm09 illness by about three quarters.
Our point estimate of ca 75% VE for the 2013/14 non-adjuvanted TIV against influenza A(H1N1)pdm09 is comparable, if not exceeding, 2009 estimates for non-adjuvanted formulations of the monovalent pandemic vaccine used in the US (ca 60%) [26,27], albeit lower than the 93% VE estimated by our sentinel system for the 2009 AS03-adjuvanted pandemic vaccine used in Canada . The 2013/14 mid-season VE estimate against influenza A(H1N1)pdm09 of ca 75% is in the upper range of recent seasons’ VE estimates for non-adjuvanted TIV against A(H1N1)pdm09 reported since 2010 from Canada [11,12,21], Europe [28-32] and the US [33-35], which span ca 60–80%. With several times more influenza A(H1N1)pdm09 cases already contributing thus far in 2013/14 than in previous seasons in Canada, we are likely to converge upon a more stable and accurate estimate of TIV protection against A(H1N1)pdm09 infection this season.
Although a switch from clade 6C to clade 6B* occurred between the 2012/13 and 2013/14 seasons , A(H1N1)pdm09 viruses remain genetically and antigenically similar to the A/California/07/2009 vaccine strain, a somewhat surprising finding given that this virus has circulated globally since 2009. Historically, however, H1N1 compared with H3N2 subtype viruses generally have shown a slower pace of HA antigenic change, judging at least by the recommended updates to vaccine composition made by the WHO between 1990/91 and 2008/09 (five H1N1 versus 11 H3N2 vaccine strain switches), with two H1N1 (but no H3N2) strains retained as TIV components for at least seven consecutive years during that period [4,36]. Genetic conservation of A(H1N1)pdm09 viruses may also be surprising in the context of population-level immune pressure. A recent serosurvey conducted in May 2013 in Canada showed that levels of seroprotective antibody to A/California/07/2009 were high among school-aged children and the elderly; however, seroprotection was lower among very young children and adults between 20 and 69 years of age . These findings may explain why conserved A(H1N1)pdm09 viruses resurged in 2013/14 and why there has been an apparent shift in the age distribution toward 20–64 year-old adults among medically-attended laboratory-confirmed influenza cases identified through the sentinel surveillance network this season. Such a demographic shift in disease burden toward adults following the 2009 pandemic was previously predicted in mathematical models from Canada  and warrants further empiric evaluation in additional surveillance datasets.
Limitations of the Canadian sentinel surveillance network for VE estimation have been described previously [3,5-12]. Although the validity of VE estimates derived by the test-negative approach has been demonstrated theoretically and in relation to randomised clinical trial analysis [39,40], the design remains observational, and bias and confounding cannot be ruled out. VE estimates for 2013/14 may vary at the end of the season, particularly since A(H1N1)pdm09 activity is still peaking in some regions of Canada . However, end-of-season estimates for the 2012/13 VE differed by less than 5% from interim results presented in mid-season, even though the number of contributing cases increased by more than one third [3,21]. Ongoing monitoring is nevertheless warranted for changes in virus and/or VE with further time across the season. Variable efficacy of repeated immunisation has previously been described, with differential effects depending upon the antigenic distance between successive vaccine components and circulating strains . In that context, as in previous years, we emphasise that a substantial proportion of our immunised participants are repeat recipients of unchanged A(H1N1)pdm09 vaccine antigen. Generalisability to regions with a different profile of vaccine uptake may be limited on that basis. In recent analyses, we  and others [29,30,42] have noted a trend toward improved VE with recurrent receipt of the A(H1N1)pdm09 antigen, although other studies have reported contrary findings [28,31,35]. Assessment of these effects may benefit from the additional power available in end-of-season analysis.
In summary, our interim findings indicate that the 2013/14 TIV provides substantial protection against resurgent but conserved A(H1N1)pdm09 viruses circulating in Canada during the 2013/14 season, reducing the risk of medically-attended laboratory-confirmed A(H1N1)pdm09 illness by about three quarters. Neither antigenic drift nor homologous vaccine failure can account for resurgent A(H1N1)pdm09 activity this season in Canada. Other factors involved in agent–host interaction, including pre-existing antibody, should be considered in explaining the current epidemiology of this virus.
The authors gratefully acknowledge the contribution of sentinel sites whose regular submission of specimens and data provide the basis of our analyses. We wish to acknowledge the coordination and technical support provided by epidemiologic and laboratory staff in all participating provinces. We acknowledge Dr Naveed Janjua for his contribution to previous analyses. We wish to thank the following for network coordination activities in each province including: Elaine Douglas for TARRANT in Alberta; Hazel Rona, Julia Paul and Erin Schillberg of the Winnipeg Regional Health Authority, Manitoba; Romy Olsha of Public Health Ontario; and Monique Douville-Fradet, Sophie Auger and Rachid Amini of the Institut national de santé publique du Québec. We thank those who provided laboratory support in each province including Virology staff of the British Columbia Public Health Microbiology and Reference Laboratory, the Alberta Provincial Laboratory, Public Health Ontario, the Cadham Provincial Laboratory (Roy Cole and Kerry Dust, Manitoba), and the Laboratoire de santé publique du Québec. We further acknowledge the virus detection and gene sequencing support provided by Kanti Pabbaraju, Sallene Wong and Danielle Zarra of the Alberta Provincial Laboratory; Aimin Li of Public Health Ontario; Joel Ménard and Lyne Désautels of the Laboratoire de santé publique du Québec; and the authors, originating and submitting laboratories of the reference virus sequences from GISAID’s EpiFlu Database (www.gisaid.org) (see Table 1).
Funding was provided by the Canadian Institutes of Health Research (CIHR grant # TPA-90193), the British Columbia Centre for Disease Control, Alberta Health and Wellness, Public Health Ontario, Ministère de la santé et des services sociaux du Québec and the Institut national de santé publique du Québec.
Conflict of interest
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. JG 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. 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.
Principal investigator (epidemiology): DMS (National and British Columbia); GDS (Québec); JAD (Alberta); ALW (Ontario); SMM (Manitoba). Principal investigator (laboratory): JBG (Ontario); HC (Québec); MPP and MK (British Columbia); KF (Alberta); PVC (Manitoba), YL and NB (national). National database coordination: TLK. Data analysis: CC and DMS (epidemiology); SS and AE (phylogenetic). Preparation of first draft: DMS. Draft revision and approval: all.
On request of the authors, this passage was changed on 7 February 2014 from "a switch from clade 6B to clade 6C occurred" to "a switch from clade 6C to clade 6B occurred".
- Public Health Agency of Canada (PHAC). FluWatch. Weekly reports 2013-2014 season. Ottawa: PHAC. [Accessed: 1 Feb 2014]. Available from: http://www.phac-aspc.gc.ca/fluwatch/13-14/index-eng.php
- Centers for Disease Control and Prevention (CDC). FluView. 2013-2014 influenza season week 4 ending January 25, 2014. U.S. Virologic Surveillance. Atlanta: CDC. [Accessed: 29 Jan 2014]. Available from: http://www.cdc.gov/flu/weekly/pastreports.htm
- Skowronski DM, Janjua NZ, De Serres G, Dickinson JA, Winter AL, Mahmud SM, et al. Interim estimates of influenza vaccine effectiveness in 2012/13 from Canada's sentinel surveillance network, January 2013. Euro Surveill. 2013;18(5):pii=20394.
- World Health Organization (WHO). WHO recommendations on the composition of influenza virus vaccines. Geneva: WHO. [Accessed: 29 Jan 2014]. Available from: http://www.who.int/influenza/vaccines/virus/recommendations/en/index.html
- Skowronski DM, Gilbert M, Tweed SA, Petric M, Li Y, Mak A, et al. Effectiveness of vaccine against medical consultation due to laboratory-confirmed influenza: results from a sentinel physician pilot project in British Columbia, 2004-2005. Can Commun Dis Rep. 2005;31(18):181-91.
- Skowronski DM, Masaro C, Kwindt TL, Mak A, Petric M, Li Y, et al. Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: results from the 2005-2006 season of dual A and B vaccine mismatch in Canada. Vaccine. 2007;25(15):2842-51.
- Skowronski DM, De Serres G, Dickinson J, Petric M, Mak A, Fonseca K, et al. Component-specific effectiveness of trivalent influenza vaccine as monitored through a sentinel surveillance network in Canada, 2006-2007. J Infect Dis. 2009;199(2):168-79.
- Janjua NZ, Skowronski DM, De Serres G, Dickinson J, Crowcroft NS, Taylor M, et al. Estimates of influenza vaccine effectiveness for 2007-08 from Canada's sentinel surveillance system: cross-protection against major and minor variants. J Infect Dis. 2012;205(12):1858-68.
- Skowronski DM, De Serres G, Crowcroft NS, Janjua NZ, Boulianne N, Hottes TS, et al. Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during spring-summer 2009: four observational studies from Canada. PLoS Med. 2010;7(4):e1000258.
- Skowronski DM, Janjua NZ, De Serres G, Hottes TS, Dickinson JA, Crowcroft N, et al. Effectiveness of AS03-adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009. BMJ. 2011;342:c7297.
- Skowronski DM, Janjua NZ, De Serres G, Winter AL, Dickinson JA, Gardy JL, et al. A sentinel platform to evaluate influenza vaccine effectiveness and new variant circulation, Canada 2010-2011 season. Clin Infect Dis. 2012;55(3):332-42.
- Skowronski DM, Janjua NZ, Sabaiduc S, De Serres G, Winter A-L, Gubbay JB, et al. Influenza A/subtype and B/lineage effectiveness estimates for the 2011-12 trivalent vaccine: cross-season and cross-lineage protection with unchanged vaccine. J Infect Dis. 2014 Jan 19. [Epub ahead of print].
- Brownlee GG, Fodor E. The predicted antigenicity of the haemagglutinin of the 1918 Spanish influenza pandemic suggests an avian origin. Philos Trans R Soc Lond B Biol Sci. 2001;356(1416):1871-6.
- Price MN, Dehal PS, Arkin AP. FastTree 2 – approximately maximum-likelihood trees for large alignments. PLoS One. 2010;5:e9490.
- Rambaut A. FigTree v1.4.0: a graphical viewer of phylogenetic trees. Edinburgh: University of Edinburgh. [Accessed: 29 Jan 2014]. Available from: http://tree.bio.ed.ac.uk/software/figtree/
- Statistics Canada. Influenza immunization, less than one year ago by sex, by province and territory (Percent). Ottawa: Statistics Canada. [Accessed: 29 Jan 2014]. Available from: http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health102b-eng.htm
- Gilmour H and Hofmann N. H1N1 vaccination. Health Reports. 2010;21(4). Catalogue no. 82-003-XPE. Ottawa: Statistics Canada. [Accessed: 29 Jan 2014]. Available from: http://www.statcan.gc.ca/pub/82-003-x/2010004/article/11348-eng.pdf
- Broemeling AM, Watson DE, Prebtani F. Population patterns of chronic health conditions, co-morbidity and healthcare use in Canada: implications for policy and practice. Healthc Q. 2008;11(3):70-6.
- Katz JM, Hancock K, Xu X. Serologic assays for influenza surveillance, diagnosis and vaccine evaluation. Expert Rev Anti Infect Ther. 2011;9(6):669-83.
- European Centre for Disease Prevention and Control (ECDC). Influenza virus characterisation. Summary Europe, December 2013. Surveillance report. Stockholm: ECDC. 2014. Available from: http://ecdc.europa.eu/en/publications/Publications/influenza-virus-characterisation-dec-2013.pdf
- Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLOS One. 2014. Forthcoming.
- Yang H, Carney P, Stevens J. Structure and receptor binding properties of a pandemic H1N1 virus hemagglutin. Version 2. PLoS Curr. 2010 March 22 [revised 2010 March 23];2:RRN1152.
- Koel BF, Burke DF, Bestebroer TM, van der Vliet S, Zondag GC, Vervaet G, et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science. 2013;342(6161):976-9.
- Soundarajan V, Zheng S, Patel N, Warnock K, Raman R, Wilson IA, et al. Networks link antigenic and receptor-binding sites of influenza hemagglutinin: mechanistic insight into fitter strain propagation. Sci Rep. 2011;1:200.
- Khandaker I, Suzuki A, Kamigaki T, Tohma K, Odagiri T, Okada T, et al. Molecular evolution of the hemagglutinin and neuraminidase genes of pandemic (H1N1) 2009 influenza viruses in Sendai, Japan, during 2009-2011. Virus Genes. 2013 Sep 29. [Epub ahead of print].
- Griffin MR, Monto AS, Belongia EA, Treanor JJ, Chen Q, Chen J, et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities. PLoS One. 2011;6(8):e23085.
- Uzicanin A, Thompson M, Smith P, Chaves SS, Foster L, Dube N, et al. Effectiveness of 1 dose of influenza A(H1N1) 2009 monovalent vaccines in preventing reverse-transcription polymerase chain reaction-confirmed H1N1 infection among school-aged children in Maine. J Infect Dis. 2012;206(7):1059-68.
- Kissling E, Valenciano M, Cohen JM, Oroszi B, Barret AS, Rizzo C, et al. I-MOVE multi-centre case control study 2010-11: overall and stratified estimates of influenza vaccine effectiveness in Europe. PLoS One. 2011;6(11):e27622.
- Martínez-Baz I, Martinez-Argola V, Reina G, Guevara M, Cenoz MG, Moran J, et al. Effectiveness of the trivalent influenza vaccine in Navarre, Spain, 2010–2011: a population-based test-negative case–control study. BMC Public Health. 2013;13:191.
- Jiménez-Jorge S, Savulescu C, Pozo F, de Mateo S, Casas I, Ledesma J, et al. Effectiveness of the 2010-11 seasonal trivalent influenza vaccine in Spain: cycEVA study. Vaccine 2012;30(24):3595-602.
- Pebody RG, Andrews N, Fleming DM, McMenamin J, Cottrell S, Smyth B, et al. Age-specific vaccine effectiveness of seasonal 2010/2011 and pandemic influenza A(H1N1) 2009 vaccines in preventing influenza in the United Kingdom. Epidemiol Infect. 2012 Jun 13:1-11. [Epub ahead of print].
- Valenciano M, Kissling E, I-MOVE case–control study team. Early estimates of seasonal influenza vaccine effectiveness in Europe: results from the I-MOVE multicentre case–control study, 2012/13. Euro Surveill. 2013;18(7):pii=20400.
- Treanor JJ, Talbot K, Ohmit SE, Coleman LA, Thompson MG, Cheng PY, et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. Clin Infect Dis. 2012;55(7):951-9.
- Ohmit SE, Thompson MG, Petrie JG, Thaker SN, Jackson ML, Belongia EA, et al. Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates. Clin Infect Dis. 2014;58(3):319-27.
- Bateman AC, Kieke BA, Irving SA, Meece JK, Shay DK, Belongia EA. Effectiveness of monovalent 2009 pandemic influenza A virus subtype H1N1 and 2010-2011 trivalent inactivated influenza vaccines in Wisconsin during the 2010-2011 influenza season. J Infect Dis. 2013;207(8):1262-9.
- Influenza Research Database. World Health Organization recommendations for composition of influenza vaccines. [Accessed: 5 Feb 2014]. Available from: http://www.fludb.org/brc/vaccineRecommend.do?decorator=influenza
- Skowronski DM, Chambers C, Janjua NZ, Petric M, Krajden M. A(H1N1)pdm09 – Canada: (British Columbia) primary data and analysis. ProMED Archive Number 20140101.2146429. 1 Jan 2014. Available from: http://www.promedmail.org/direct.php?id=2146429
- Bansal S, Pourbohloul B, Hupert N, Grenfell B, Meyers LA. The shifting demographic landscape of pandemic influenza. PLoS One. 2010;5(2):e9360.
- Orenstein EW, De Serres G, Haber MJ, Shay D K, Bridges C B, et al. Methodologic issues regarding the use of three observational study designs to assess influenza vaccine effectiveness. Int J Epidemiol. 2007;36(3):623-31.
- De Serres G, Skowronski DM, Wu XW, Ambrose CS. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised double-blind placebo-controlled trials. Euro Surveill. 2013;18(37):pii:20585.
- Smith DJ, Forrest S, Ackley DH, Perelson AS. Variable efficacy of repeated annual influenza vaccination. Proc Natl Acad Sci USA. 1999;96(24):14001-6.
- Pebody R, Hardelid P, Fleming DM, McMenamin J, Andrews N, Robertson C, et al. Effectiveness of seasonal 2010/11 and pandemic influenza A(H1N1)2009 vaccines in preventing influenza infection in the United Kingdom: mid-season analysis 2010/11. Euro Surveill. 2011;16(6):pii=19791.
- National Advisory Committee on Immunization. Statement on seasonal influenza vaccine for 2013–2014. Can Commun Dis Rep. 2013;39:1-37. ISSN 1481–8531. Available from: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/13vol39/acs-dcc-4/index-eng.php