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Influenza vaccine effectiveness against influenza-related hospitalization during a season with mixed… Andrew, Melissa K; Shinde, Vivek; Hatchette, Todd; Ambrose, Ardith; Boivin, Guy; Bowie, William; Chit, Ayman; Dos Santos, Gael; ElSherif, May; Green, Karen; Haguinet, François; Halperin, Scott A; Ibarguchi, Barbara; Johnstone, Jennie; Katz, Kevin; Langley, Joanne M; LeBlanc, Jason; Loeb, Mark; MacKinnon-Cameron, Donna; McCarthy, Anne; McElhaney, Janet; McGeer, Allison; Nichols, Michaela K; Powis, Jeff; Richardson, David; Semret, Makeda; Stiver, Grant; Trottier, Sylvie; Valiquette, Louis; Webster, Duncan; Ye, Lingyun; McNeil, Shelly A Dec 29, 2017

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RESEARCH ARTICLE Open AccessInfluenza vaccine effectiveness againstinfluenza-related hospitalization during aseason with mixed outbreaks of fourinfluenza viruses: a test-negative case-control study in adults in CanadaMelissa K. Andrew1, Vivek Shinde2, Todd Hatchette1, Ardith Ambrose1, Guy Boivin3, William Bowie4, Ayman Chit5,Gael Dos Santos6, May ElSherif1, Karen Green7, François Haguinet8, Scott A. Halperin1, Barbara Ibarguchi9,Jennie Johnstone10, Kevin Katz11, Joanne M. Langley1, Jason LeBlanc1, Mark Loeb10, Donna MacKinnon-Cameron1,Anne McCarthy12, Janet McElhaney13, Allison McGeer7, Michaela K. Nichols1, Jeff Powis14, David Richardson15,Makeda Semret16, Grant Stiver4, Sylvie Trottier3, Louis Valiquette17, Duncan Webster18, Lingyun Ye1, andShelly A. McNeil1* on behalf of the Public Health Agency of Canada/Canadian Institutes of Health ResearchInfluenza Research Network (PCIRN) Serious Outcomes Surveillance Network and the Toronto Invasive BacterialDiseases Network (TIBDN)AbstractBackground: The Serious Outcomes Surveillance (SOS) Network was established to monitor seasonal influenzacomplications among hospitalized Canadian adults and to assess the effectiveness of influenza vaccination againstsevere outcomes. Here we report age- and strain-specific vaccine effectiveness (VE) in preventing severe outcomesduring a season characterized by mixed outbreaks of four different influenza strains.Methods: This prospective, multicentre, test-negative case-control study evaluated the VE of trivalent influenzavaccine (TIV) in the prevention of laboratory-confirmed influenza-hospitalization in adults aged ≥16 years (all adults)and adults aged 16–64 years (younger adults). The SOS Network identified hospitalized patients with diagnosespotentially attributable to influenza during the 2011/12 influenza season. Swabs collected at admission were testedby reverse transcriptase polymerase chain reaction (RT PCR) or viral culture to discriminate influenza cases (positive)from controls (negative). VE was calculated as 1-odds ratio (OR) of vaccination in cases versus controls × 100.(Continued on next page)* Correspondence: Shelly.McNeil@nshealth.ca1Canadian Center for Vaccinology, IWK Health Centre and Nova Scotia HealthAuthority, Dalhousie University, 5850/5980 University Ave, Halifax, NovaScotia B3K 6R8, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Andrew et al. BMC Infectious Diseases  (2017) 17:805 DOI 10.1186/s12879-017-2905-8(Continued from previous page)Results: Overall, in all adults, the unadjusted and adjusted VEs of TIV against influenza-hospitalization were 41.8% (95%Confidence Interval [CI]: 26.0, 54.3), and 42.8% (95% CI: 23.8, 57.0), respectively. In younger adults (16–64 years), theunadjusted and adjusted VEs of TIV against influenza-hospitalization were 35.8% (95% CI: 4.5, 56.8) and 33.2% (95% CI: −6.7, 58.2), respectively. In the all adults group, adjusted VE against influenza A/H1N1 was 72.5% (95% CI: 30.5, 89.1), againstA/H3N2 was 86.1% (95% CI: 40.1, 96.8), against B/Victoria was 40.5% (95% CI: −28.9, 72.6), and against B/Yamagata was 32.3% (95% CI: −8.3, 57.7). The adjusted estimate of early season VE (from November 1 to March 11) was 54.4% (95% CI: 29.7–70.4), which was higher than late season (from March 11 to May 25) VE estimate (VE: 29.7%, 95% CI: -5.3, 53.1).Conclusions: These results suggest that TIV was highly effective against A viruses and moderately effective against Bviruses during a mild season characterised by co-circulation of four influenza strains in Canada. Findings underscore theneed to provide VE assessment by subtype/lineage as well as the timing of vaccination (early season vs late season) toaccurately evaluate vaccine performance and thus guide public health decision-making.Trial registration: ClinicalTrials.gov Identifier: NCT01517191. Registration was retrospective and the date of registrationwas January 17, 2012.Keywords: Influenza, Vaccine, Effectiveness, Adults, Hospitalization,BackgroundNumerous countries provide publicly-funded influenzavaccination programs. In addition to advocating for a par-ticular focus on people at high risk of influenza-relatedcomplications or hospitalization, some countries, such asAustralia, Canada, and United States (US) now recom-mend universal vaccination for those aged 6 months andolder [1–3]. Despite these recommendations, the benefitsof influenza vaccination remain controversial due to thevariability of effectiveness of the vaccine between seasonsand among individuals. Furthermore, although the sea-sonal influenza vaccine is expected to provide benefit, par-ticularly against severe outcomes relating to influenza,evaluating the effect of influenza vaccination on hospitali-zations and deaths in observational studies is challenging.Hospital-based surveillance networks are used bymany countries to monitor influenza disease and to as-sess vaccine effectiveness (VE) against severe outcomesattributable to influenza to guide public health decision-making. Prospective observational studies in adultsconducted between 2010 and 2015 following the H1N1pandemic in 2009 mostly report moderate adjusted VEagainst influenza-hospitalization (37–61%), although onestudy provided an unadjusted estimate of 33%, and an-other reported that influenza vaccination did not reducethe risk of influenza-related hospital admission in adultsaged ≥20 years [4–10]. This variability may be due to thedegree of vaccine match with the circulating strainsacross seasons and between regions, the virulence of theviruses circulating, unmeasured confounders, and/or dif-ferences in study design such as screening case defini-tions, laboratory diagnostics used, outcomes assessed,and the selection of controls.The Serious Outcomes Surveillance (SOS) Network ofthe Public Health Agency of Canada/Canadian Institutesof Health Research Influenza Research Network(PCIRN) was established in 2009, at the time of theH1N1 pandemic. The objectives were to prospectivelymonitor serious outcomes associated with seasonal influ-enza, burden of influenza disease, and VE in the preven-tion of laboratory-confirmed influenza-hospitalization inhospitalized adults aged ≥16 years using data collectionprotocols designed to overcome some of the limitationsof previous observational VE studies [11, 12].In the current paper, we describe a multicentre, multi-province, test-negative case-control study of seasonal in-fluenza VE during the 2011/12 influenza season, whereCanadian national surveillance reported mixed outbreaksof four influenza strains [13]. The main objectives of thisstudy were to evaluate the VE of trivalent influenzavaccine (TIV) in the prevention of laboratory-confirmedinfluenza-hospitalization both overall and by influenzastrain for all adult patients (≥16 years) and for youngeradults (16–64 years). Secondary objectives were to assessVE of TIV against influenza-related hospitalization (for allstrains and specifically for influenza B) by month ofhospital admission (early season/late season). Results fromthe SOS Network this season focusing specifically oninfluenza VE and the role of frailty in older adult patients(≥65 years) have been reported elsewhere [14].MethodsThis prospective, multicentre, test-negative case-controlstudy assessed the VE of seasonal TIV among hospitalizedpatients admitted from 1 November 2011 to 25 May 2012.This study was conducted by the PCIRN SOS Network incollaboration with the Toronto Invasive Bacterial DiseasesNetwork (TIBDN) [11, 12]. Influenza surveillance wasperformed in 38 academic and community sentinelhospitals in Nova Scotia, New Brunswick, Quebec,Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 2 of 11Ontario, and British Columbia, accounting for approxi-mately 16,000 adult acute care beds. The aim of the ana-lysis was to assess VE of seasonal influenza vaccine againstlaboratory-confirmed influenza-related hospitalization andto characterize the burden of influenza disease in hospital-ized patients during the 2011/12 influenza season. TheSOS Network (now part of the Canadian ImmunizationResearch Network; CIRN) surveillance is ongoing.ParticipantsSOS Network surveillance monitors reviewed dailyadmissions to medical and coronary intensive care unitsand medical wards. Admitted patients were eligible forthe study if aged ≥16 years with community-acquiredpneumonia (CAP), acute exacerbation of chronicobstructive pulmonary disease or asthma, unexplainedsepsis, any other respiratory infection or diagnosis, orany respiratory or influenza-like symptoms, and scree-ning was performed within 5 days of admission. Naso-pharyngeal (NP) swabs were collected from eligiblepatients either as part of their clinical care or by SOSNetwork monitors, and tested for influenza viruses.The study was conducted during the winter respiratoryseason. When the study site reported ≥two positive influ-enza tests or when the laboratory reported one or morepositive influenza tests in two consecutive weeks, SOSmonitors began screening hospital admissions 1 day perweek. Patients were screened who were admitted on thatday with a triage temperature ≥ 37.5 °C associated with oneof the following: acute coronary syndrome, any other car-diac diagnosis, or stroke. Cardiac and stroke patients werescreened in order to assess the potential burden of influ-enza as a precipitant. A temperature of ≥37.5 °C was usedin this subgroup in an attempt to minimise false-negativeinfluenza laboratory results associated with lag between in-fluenza infection and related cardiac and stroke hospitaliza-tions. This enhanced surveillance was stopped when thelocal laboratory reported no positive tests for influenza intwo consecutive weeks. In hospitals associated with theTIBDN, influenza testing was performed 7 days per weekas routine clinical practice for cardiac and stroke care.Patients were considered an influenza case if theyfulfilled the eligibility criteria and tested positive forinfluenza (hereafter, ‘cases’), or a test-negative controlif they fulfilled the eligibility criteria and tested nega-tive for influenza within 7 days of hospital admission(hereafter, ‘controls’). Each case was age-matched withthe next ≥1 sequentially enrolled control(s) admittedto the same site 14 days before or after the admissionof the case.Patients were defined as vaccinated if they reported re-ceipt of a 2011/12 seasonal influenza vaccine more than14 days before the onset of their symptoms. Patientswho received the 2011/2012 seasonal influenza vaccineand whose onset of illness date was unknown wereinitially defined as status unknown until after 14 January2012, when they were defined as vaccinated, since thevast majority of adults in Canadian immunization pro-grams are vaccinated before the end of the calendar year.Vaccines used in Canada contained the influenza strainsrecommended by the World Health Organization (WHO)for inclusion in the 2011/12 influenza season vaccines inthe Northern Hemisphere: A/California/7/2009 (H1N1)-like virus; A/Perth/16/2009 (H3N2)-like virus; B/Brisbane/60/2008-like virus (Victoria lineage) [15].Data collectionData were collected by SOS Network monitors via pa-tient interview and medical record review. Standardizedcase report forms were used to collect detailed demo-graphic information, medical and surgical history, detailsof presenting illness, hospitalization details includingmanagement, healthcare use, and ultimately dischargeand 30-day post-discharge outcomes. Information aboutseasonal influenza vaccination status was collected byinterview with the patient or their caregiver; self-reported immunization history was verified with theimmunization provider or an immunization registry,provided that information was available. Study monitorscontacted patients’ primary care physician/familyphysician and, where possible, Provincial Public Healthrecords, to collect data on product, lot number, and dateadministered.The study protocol was approved by the Research EthicsBoards of all participating institutions. All patientsprovided written informed consent for data and samplecollection, and medical record screening in accordancewith the local Research Ethics Boards requirements.Laboratory methodsInitial influenza testing was performed at the hospitals’laboratory or Provincial Public Health Laboratories ac-cording to local protocols. All SOS Network sites usedRT PCR, apart from one site which used viral culture.After local testing, specimens were transported to theSOS Network central laboratory at the Canadian Centerfor Vaccinology in Halifax, Nova Scotia where they werere-tested for influenza using RT PCR to confirm locallaboratory results and for further influenza A subtype orB lineage determination.Statistical methodsVE was calculated as 1 minus the odds ratio (OR) ofvaccination in cases compared with controls multipliedby 100. ORs were estimated by conditional logistic re-gression. The characteristics of cases versus controls andvaccinated versus unvaccinated cases were described andassessed using Mantel-Haenszel methods for discreteAndrew et al. BMC Infectious Diseases  (2017) 17:805 Page 3 of 11variables and linear mixed model methods for conti-nuous variables with matched sets as random effect. Noadjustment was made for multiple comparisons.Conditional logistic regression was used to identifyrisk factors for influenza disease; the adjustment covari-ates of the VE analyses were partly selected post-hoc. VEestimates were adjusted for age and any antiviral usageprior to hospital admission. The VE estimates for theprevention of influenza-hospitalization in the final modelwere also adjusted using multivariate logistic regressionwith stepwise backward selection of covariates with p-values of <0.1 by univariate analysis. All matched setswith at least one case and one control without missingdata for the final set of covariates were considered in theestimation of the final adjusted VE. Unadjusted andadjusted VE estimates were provided with a 95% Confi-dence Interval (CI).VE against influenza-related hospitalization due to anyinfluenza strain and also specifically due to influenza Bwas estimated for cases and controls admitted early inthe influenza season (defined as admissions prior to theadmission date of the median influenza case enrolled)and late in the influenza season (defined as admissionsafter the date of admission of the median influenza caseenrolled).In an exploratory analysis to assess residual bias,the final logistic regression model was used to assessVE of TIV for the prevention of respiratory virusesother than influenza. In this exploratory analysis,cases were those testing positive for a non-influenzarespiratory virus by multiplex PCR and controls werethose negative for both influenza and other respira-tory viruses by multiplex PCR.All analyses were performed using SAS Softwareversion 9.2 or later (SAS Institute Inc. NC, USA).ResultsThe first patient was enrolled on 20 December 2011 andthe last patient contact was on 15 July 2012. A total of7044 patients (age ≥ 16) were screened, of whom 20.9%(n = 1474) were enrolled in the overall cohort, and 19.3%(n = 1363) were included in the VE assessment, as theyhad known influenza immunization status (528 casesand 835 controls). The mean age of cases and controlsin the overall cohort was 67.1 years and 69.2 years, re-spectively. A total of 208 cases and 271 controls wereaged 16–64 years (younger adult group), with a meanage of 46.3 years and 49.2 years, respectively. Demo-graphic and clinical characteristics are shown in Table 1.Test-negative controls were more likely to have ≥1underlying co-morbidity (p = 0.04), underlying cardiacdisease (p = 0.005), and pulmonary disease (p = 0.021).Controls were also more likely than cases to have a bodymass index (BMI) of ≥30 kg/m2 (p = 0.016) and to havebeen past smokers (p < 0.001). Influenza cases weremore likely to be pregnant (p = 0.006). Baseline charac-teristics of vaccinated and unvaccinated patients areshown in Table 2. A total of 776/1363 (56.9%) patients(age ≥ 16 years) had received 2011/12 TIV.In the overall cohort, the specific 2011/12 influenzavaccine brand received could not be ascertained in64.6% (n = 164) of vaccinated cases and 67.6% (n = 353)of vaccinated controls. Among cases/controls for whomthis information was available, 30.0%/39.1% had receivedFluviral™ (GSK), 34.4%/32.5% had received Agriflu™(Novartis Vaccines), 28.9%/24.9% had received Vaxigrip™Table 1 Demographic and clinical characteristics of patientsaged ≥16 years (all adults group)CasesN = 528ControlsN = 835p-valueAge, yearsMean (SD) 67.11 (20.05) 69.17 (16.94) 0.732Median (range) 70 (18–104) 73 (18–99)Age subgroups, n (%)16–49 years 107 (20.3) 107 (12.8) 0.11850–64 101 (19.1) 164 (19.6)65–75 years 101 (31.6) 206 (36.5)> 75 years 219 (68.4) 358 (63.5)Female, n (%) 288 (54.5) 469 (56.2) 0.580BMI, kg/m2Mean (SD) 26.51 (6.74) 26.81 (7.07) 0.407Median (range) 25.39(9.64–60.35)25.73(10.7–63.77)Obese (BMI ≥30 kg/m2), n (%) 103 (19.5) 229 (27.4) 0.016≥1 co-morbidity, n (%)Cardiac disease 210 (39.8) 415 (49.7) 0.005Vascular disease 317 (60.0) 557 (66.7) 0.093Pulmonary disease 231 (43.8) 426 (51.0) 0.021Smoking, n (%)Current 89 (16.9) 143 (17.1) 0.529Past 143 (27.1) 334 (40.0) <0.001Children aged <5 years inhousehold, n (%)0 456 (86.3) 763 (91.4) 0.0011 or more 54 (10.2) 46 (5.5)Received 2011/12 seasonalinfluenza vaccine, n (%)262 (49.6) 529 (63.4) <0.001Received 2010/11 seasonalinfluenza vaccine, n (%)248 (47.0) 515 (61.7) <0.001N number of patients, BMI body mass index, SD standard deviationMissing data: BMI: 40 cases (7.6%), 15 controls (1.8%); Obesity: 40 cases (7.6%),15 controls (1.8%); Current smoking: 5 cases (0.9%), 7 controls (0.8%); Pastsmoking: 105 cases (19.9%), 156 controls (18.7%); Children aged <5 years inthe household: 18 cases (3.4%), 26 controls (3.1%); Received 2010/11 seasonalinfluenza vaccine: 47 cases (8.9%), 42 controls (5.0%)Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 4 of 11(Sanofi Pasteur), 3.3%/2.4% had received Fluad™ (Novar-tis Vaccines), one vaccinated control had received Flu-zone™ (Sanofi Pasteur), and two vaccinated controls hadreceived FluMist™ (MedImmune). Two vaccinated caseshad received another approved TIV.Influenza profileA summary of the temporal distribution of influenza-related hospitalizations admitted to SOS Network hospi-tals is shown in Fig. 1. Overall, in all patients ≥16 years,among the 182 cases of influenza A, 56 (30.8%) were at-tributable to A/H3N2, 89 (48.9%) to A/H1N1, and 37(20.3%) were not subtyped; among the 346 influenza Bcases, 188 (54.3%) were linked to B/Yamagata lineage, 81(23.4%) to B/Victoria lineage, and 77 (22.3%) were notlineage-typed. In younger adults (16–64 years), amongthe 86 cases of influenza A, 13 (15.1%) were A/H3N2,and 55 (63.9%) were A/H1N1, and among the 122 casesof influenza B, 53 (43.4%) were B/Yamagata lineage and37 (30.3%) were B/Victoria lineage.Vaccine effectivenessA summary of the VE estimates for TIV in the preven-tion of influenza-hospitalization overall and for youngeradults, respectively, are shown in Tables 3 and 4. Over-all, the matched unadjusted VE for the prevention ofinfluenza-hospitalization was 41.8% (95% CI: 26.0, 54.3),and the matched adjusted VE estimate was 42.8% (95%CI: 23.8, 57.0). In younger adults (16–64 years), theunadjusted VE for the prevention of influenza-hospitalization was 35.8% (95% CI: 4.5, 56.8) and theadjusted VE estimate was 33.2% (95% CI: −6.7, 58.2).Overall, adjusted VE against influenza A/H1N1 strainswas 72.5% (95% CI: 30.5, 89.1), against influenza A/H3N2 was 86.1% (95% CI: 40.1, 96.8), against the B/Victoria lineage strain (B-lineage included in the 2011/12 TIV) was 40.5% (95% CI: −28.9, 72.6), and against theB/Yamagata lineage strain (B-lineage not included in the2011/12 TIV) was 32.3% (95% CI: −8.3, 57.7).VE of TIV against influenza-related hospitalizationduring early-season and during late-season are shown inTable 5. VE against influenza-related hospitalizationduring early-season was 54.4% (95% CI: 29.7, 70.4), andduring late-season was 29.7% (95% CI: −5.3, 53.1); VEagainst influenza-related hospitalization due to influenzaB during early-season was 44.8% (95% CI: 0.3, 69.5), andduring late-season was 33.1% (95% CI: −5.2, 57.5).Among younger adults (16–64 years), VE against influ-enza B years during early-season was 67.1% (95% CI: 2.7,88.9), and during late-season was −52.3% (95% CI:−251.6, 34.0).The unadjusted VE for TIV against hospitalization inpatients with non-influenza respiratory viruses (n = 140cases) compared with patients who were negative for in-fluenza and other viruses (n = 469 controls) was −5.0%(95% CI: -54.9, 28.8), and the adjusted VE was −19.9%(95% CI: -83.6, 21.6).DiscussionIn this study, the adjusted VE estimate of TIV againstinfluenza-hospitalization in all adults aged ≥16 years wasmoderate (42.8%; 95% CI: 23.8, 57.0), although VEtended to be lower in younger adults aged 16–64 years(33.2%; 95% CI: −6.7, 58.2). More than three-quarters ofthe influenza-hospitalizations occurred later in the sea-son during February, March and April, and VE of TIVfor preventing influenza-related hospitalizations waslower in late-season relative to early-season (VE: 29.7%,Table 2 Demographics and clinical characteristics of TIV-vaccinated vs unvaccinated patients ≥16 years (all adults group)Not vaccinatedN = 587TIVN = 776p-valueAge, yearsMean (SD) 61.35 (19.76) 73.68 (14.94) <0.001Median (range) 64 (18–98) 76 (18–104)Age subgroups, n (%)16–49 years 161 (27.4) 53 (6.8) <0.00150–64 143 (24.4) 122 (15.7)65–75 years 112 (19.1) 195 (25.1)> 75 years 171 (29.1) 406 (52.3)Female, n (%) 337 (57.4) 420 (54.1) 0.248BMI, kg/m2Mean (SD) 26.72 (6.66) 26.68 (7.16) 0.915Median (range) 25.49(11.38–60.35)25.67(6.64–63.77)Obese (BMI ≥30 kg/m2),n (%)136 (23.2) 196 (25.3) 0.480≥ 1 co-morbidity, n (%)Cardiac disease 195 (33.2) 568 (73.2) <0.001Vascular disease 427 (55.0) 241 (41.1) <0.001Pulmonary disease 297 (50.6) 401 (51.7) <0.001Smoking, n (%)Current 127 (21.6) 105 (13.5) <0.001Past 162 (27.6) 315 (40.6) <0.001Admitted from a LTCF 15 (2.6) 70 (9.0) <0.001≤4 prescribed medicationsbefore admission287 (48.9) 169 (21.8) <0.001N number of patients, TIV trivalent influenza vaccine, SD standard deviation,BMI body mass index, LTCF long-term care facilityMissing data: BMI: 29 not vaccinated (4.9%), 26 TIV-vaccinated (3.4%); Obesity:29 not vaccinated (4.9%), 26 TIV-vaccinated (3.4%); Current smoking: 1 notvaccinated (0.2%), 11 TIV-vaccinated (1.4%); Past smoking: 131 not vaccinated(22.3%), 130 TIV-vaccinated (16.7%); Admitted from a LTCF: 0 not vaccinated(0.0%), 1 TIV-vaccinated (0.1%); ≤4 prescribed medications before admission:10 not vaccinated (1.7%), 7 TIV-vaccinated (0.9%)Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 5 of 1195% CI: −5.3, 53.1 and VE: 54.4%, 95% CI: 29.7, 70.4,respectively).The 2011/2012 season in Canada represented anunusual opportunity to assess VE because in addition tothe two influenza A strains (H1N1 and H3N2), influenzaB strains from both the Yamagata-lineage and Victorialineages were also co-circulating. The season was rela-tively mild, peaked late between February and April, andwas characterized by a fairly balanced circulation of bothinfluenza A and B viruses [13]. About 53.4% of virusesdetected by national surveillance in Canada during the2011/12 season were influenza B, and about half of theB viruses tested by Canada’s National MicrobiologyLaboratory (NML) were antigenically similar to the vac-cine strain (B/Brisbane/60/2008-like virus), while theother half were similar to the B lineage not included inthe TIV (B/Wisconsin/01/2010-like virus) [13]. Amonginfluenza A viruses tested by the NML, more than 90%of influenza A viruses were antigenically similar to thevaccine strains (A/California/07/2009 H1N1-like virusand A/Perth/16/2009 H3N2-like virus) [13].Compared to national surveillance in Canada, in theSOS Network during the 2011/2012 season the viruspredominantly leading to hospitalisation was influenzaB, with the co-circulation of B/Victoria (81 cases) and B/Yamagata (188 cases) lineage viruses, as well as bothinfluenza A viruses; A/H1N1 (89 cases) and A/H3N2 (56cases). Although the adjusted VE of TIV against influ-enza B-related hospitalization was statistically significantin the all adults cohort (≥16 years) (VE: 36.2%; 95% CI:10.0, 54.7), the VE against influenza B-relatedhospitalization in younger adults (16–64 years) was not(VE: 25.4%; 95% CI: −35.4, 58.9). The adjusted VE esti-mates in all adults cohort (≥16 years) against B/Victoria(vaccine-matched) and B/Yamagata (not included inTIV) related hospitalizations were 40.5% and 32.3%,respectively, and in younger adults were 9.7 and 36.9%,respectively, but none of these B lineage VE estimateswere statistically significant. While the B/Yamagata com-ponent was not included in the TIV, VE estimates forpreventing B/Yamagata-related hospitalizations weresimilar to VE estimates for preventing B/Victoria-relatedhospitalizations, suggesting a possibility of cross-protection of TIV between influenza B lineages, howeverthis was not statistically significant. It is possible that in-dividuals could have been exposed to the B/Yamagatalineage during natural infection in the preceding sea-sons. Adjusted VE estimates were statistically significantfor protection against hospitalization with A/H1N1 inthe all adults cohort (72.5%) and in younger adults(68.7%), and against A/H3N2 in the all adults cohort(86.1%). There were too few cases of A/H3N2 inyounger adults (13 cases) to estimate VE.Other sentinel surveillance studies conducted duringthe 2011/12 season in North America and Europe alsoreported the co-circulation of influenza A viruses andboth influenza B lineage viruses. [16–18]. In a test-negative case-control study conducted in Canada in the010203040506070809044 45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21WEEKB (lineage unknown) (n=89) B (Yamagata) (n=204)B (Victoria) (n=89) A (Subtype unknown) (n=47)A (H1N1) (n=99) A (H3N2) (n=60)Test-Negative Controls (n=833)NUMBER OF PATIENTSFig. 1 Laboratory-confirmed influenza cases and test-negative controls by week and virus subtype, November 1, 2011 to May 25, 2012Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 6 of 112011/12 season, the adjusted VE against medically-attended influenza for TIV versus unvaccinated subjectsagainst any influenza strain was 59%, for A/H1N1 was80%, and for vaccine-matched B/Victoria was 71%;however, protection was suboptimal for the circulatingA/H3N2 variants and the B/Yamagata strain (not in-cluded in TIV), with adjusted VE estimates of 51 and27%, respectively [18]. Sub-optimal protection against A/H3N2-hospitalization during the 2011/12 season wasalso observed in Europe, where the circulating A/H3N2virus was reported to have drifted genetically and anti-genically away from the vaccine strain [19].Prospective studies of laboratory-confirmed influenzainfections have suggested that influenza vaccination mayprovide higher protection against more severe influenzaoutcomes such as hospitalization and intensive care unit(ICU) admission. During the 2006/2007–2008/2009influenza seasons, in community-dwelling people aged≥50 years in the US, the adjusted VE of influenza vaccin-ation against influenza-hospitalization was 61.2% [20].Furthermore, in a European study in 2010/11, amongthe general population, the adjusted VE estimate of TIVagainst medically-attended influenza was 75%, againstinfluenza-hospitalization was 60%, while against severeinfluenza cases resulting in ICU admission or death, theVE was 89% [21]. In our study, although VE of TIV wassignificant for the prevention of hospitalization in theoverall adult cohort, it was not statistically significant inyounger adults. The increased VE observed in theelderly may have been associated with better vaccineprotection against severe cases of influenza in olderadults compared with less-severe influenza complica-tions in younger adults. Additionally, the proportionof immunocompromised patients in the younger co-hort was particularly high in the SOS Network thisseason (22.6% were considered immunocompromised),and given that studies have demonstrated decreasedimmune responses to influenza vaccination in im-munocompromised patients, this could potentially becontributing to the decreased VE observed in thisgroup [22]. This analysis was not powered to compareVE against intensive care unit (ICU) admission,mechanical ventilation or death, and the VE estimateof TIV was not significant in either cohort for theprevention of death or ICU admission/mechanicalventilation (data not shown).Table 3 Vaccine effectiveness (VE) of TIV against influenza-relatedhospitalization in patients ≥16 years (all adults group)Cases Controls Unadjusted AdjustedN N VE, % 95% CI VE, % 95% CIAll strains 528 835 41.8 26.0, 54.3 42.8a 23.8, 57.0Influenza A 182 301 50.4 23.9, 67.6 55.6b 23.4, 74.3A/H1N1 89 142 71.7 41.7, 86.3 72.5c 30.5, 89.1A/H3N2 56 105 31.0 −45.9, 67.5 86.1d 40.1, 96.8Influenza B 346 534 37.3 16.0, 53.2 36.2e 10.0, 54.7B/Victoria 81 126 47.1 3.4, 71.0 40.5f −28.9, 72.6B/Yamagata 188 292 28.7 −5.4, 51.8 32.3g −8.3, 57.7N number of patients, CI Confidence Interval, TIV trivalent influenza vaccine, VEvaccine effectivenessCovariate (p-value in model):a Influenza vaccination (<0.001), age (0.378), anti-viral use before admission(0.902), admission from long term care facility (0.005), obesity (0.119), exposedto children aged <5 years in household (0.034), current or past smoker (0.000),medications before onset of illness (0.011);b Influenza vaccination (0.004), age (0.264), anti-viral use before admission(0.766), admission from long term care facility (0.592), obesity (0.633), exposedto children aged <5 years in household (0.157), current or past smoker (0.376),medications before onset of illness (0.191);c Influenza vaccination (0.006), age (0.093), anti-viral use before admission(0.814), admission from long term care facility (0.993), obesity (0.199), exposedto children aged <5 years in household (0.311), current or past smoker (0.188),medications before onset of illness (0.046);d Influenza vaccination (0.008), age (0.022), admission from long term carefacility (0.419), obesity (0.998), exposed to children aged <5 years inhousehold (0.046), current or past smoker (0.571), medications before onset ofillness (0.560);e Influenza vaccination (0.010), age (0.791), anti-viral use before admission(0.471), admission from long term care facility (0.001), obesity (0.143), exposedto children aged <5 years in household (0.096), current or past smoker (0.000),medications before onset of illness (0.023);f Influenza vaccination (0.188), age (0.215), admission from long term carefacility (0.794), obesity (0.750), exposed to children aged <5 years inhousehold (0.184), current or past smoker (0.025), medications before onset ofillness (0.093);g Influenza vaccination (0.103), age (0.021), anti-viral use before admission(0.456), admission from long term care facility (0.002), obesity (0.319), exposedto children aged <5 years in household (0.005), current or past smoker (0.004),medications before onset of illness (0.087);Table 4 Vaccine effectiveness (VE) of TIV against influenza-relatedhospitalization in patients ≥16–64 years (younger adults group)Cases Controls Unadjusted AdjustedN N VE, % 95% CI VE, % 95% CIAll strains 208 271 35.8 4.5, 56.8 33.2a −6.7, 58.2Influenza A 86 110 48.5 1.4, 73.1 42.2b −24.2, 73.1A/H1N1 55 68 57.8 2.7, 81.7 68.7c 6.4, 89.5A/H3N2 13 18 38.2 −599.5, 94.5 – –Influenza B 122 161 26.2 −22.2, 55.4 25.4d −35.4, 58.9B/Victoria 37 48 25.6 −82.8, 69.7 9.7e −161.6, 68.9B/Yamagata 53 70 16.6 −81.1, 61.6 36.9f −72.5, 76.9N number of patients, CI Confidence Interval, TIV trivalent influenza vaccine, VEvaccine effectivenessCovariate (p-value in model):a Influenza vaccination (0.092), age (0.018), anti-viral use before admission(0.881), seniors including patient living in dwelling (0.020), pregnancy (0.045);b Influenza vaccination (0.160), age (0.192), anti-viral use before admission(0.874) seniors including patient living in dwelling (0.188), pregnancy (0.991);c Influenza vaccination (0.038), age (0.173), anti-viral use before admission(0.895) seniors including patient living in dwelling (0.201), pregnancy (0.994);d Influenza vaccination (0.335), age (0.045), seniors including patient living indwelling (0.046), pregnancy (0.099);e Influenza vaccination (0.850), age (0.054), seniors including patient living indwelling (0.888), pregnancy (0.996);f Influenza vaccination (0.370), age (0.783), seniors including patient living indwelling (0.037), pregnancy (0.740)Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 7 of 11Differences in TIV early-season VE (VE: 54.4%, 95%CI: 29.7, 70.4) versus late-season VE (VE: 29.7%, 95% CI:−5.3, 53.1) are likely attributed to the delayed influenzaB peak that Canada often sees during its influenza sea-sons. Generally, in Canada, influenza A peaks earlier inthe season, followed by a later influenza B peak. Giveninfluenza B Yamagata circulated more heavily in thelate-season and it was not included in the TIV, this dis-crepancy in VE by time in the season is understandable.Although influenza A has often been hypothesized tocontribute to more serious influenza infections, a recentreport over eight influenza seasons in the US demon-strated no significant differences in proportions ofserious outcomes in patients hospitalized with influenzaA vs B, despite influenza B contributing far fewer casesthan influenza A [23]. Among younger adults, VEagainst influenza B years during late-season was notsignificantly protective at −52.3% (95% CI: −251.6, 34.0),Table 5 Vaccine effectiveness (VE) of TIV against influenza-related hospitalization by early/late season in patients ≥16 years,≥16–64 years, and ≥65 yearsInfluenza Type Cases Controls Unadjusted AdjustedN N VE, % 95% CI VE, % 95% CIAge≥ 16 years (all ages) Early seasonAll strains 265 423 48.6 27.9, 63.3 54.4a 29.7, 70.4Influenza B 148 230 41.0 8.4, 62.1 44.8b 0.3, 69.5Late seasonAll strains 263 412 33.8 6.6, 53.0 29.7c −5.3, 53.1Influenza B 198 304 34.1 2.8, 55.4 33.1d −5.2, 57.5Age≥ 16–64 years (younger adults) Early seasonAll strains 109 131 59.0 27.6, 76.8 65.7e 28.2, 83.6Influenza B 55 68 60.1 12.7, 81.8 67.1f 2.7, 88.9Late seasonAll strains 99 140 −8.5 −95.0, 39.6 −36.1g −171.2, 31.7Influenza B 67 93 −27.7 −175.5, 36.7 −52.3h −251.6, 34.0Age≥ 65 years (older adults) Early seasonAll strains 156 292 41.2 9.8, 61.7 52.5i 8.0, 75.5Influenza B 93 162 27.4 −25.9, 58.2 36.3j −45.1, 72.0Late seasonAll strains 164 272 48.6 21.3, 66.4 62.4k 29.9, 79.9Influenza B 131 211 50.9 21.2, 69.4 69.3l 37.4, 84.9N number of patients, CI Confidence Interval, TIV trivalent influenza vaccineEarly season defined as admissions prior to the admission date of the median influenza case enrolled; Late season defined as admissions after the date ofadmission of the median influenza case enrolledCovariate (p value in model):a Influenza vaccination (<0.001), age (0.116), antiviral use before onset of illness (0.821), admission from long term care facility (0.001), obesity (0.017), exposed tochildren aged <5 years in household (0.536), current or past smoker (0.015), medications before onset of illness (0.325);b Influenza vaccination (0.049), age (0.099), antiviral use before onset of illness (0.992), admission from long term care facility (<0.001), obesity (0.020), exposed tochildren aged <5 years in household (0.447), current or past smoker (0.001), medications before onset of illness (0.515);c Influenza vaccination (0.088), age (0.383), antiviral use before onset of illness (0.988), admission from long term care facility (0.960), obesity (0.859), exposed tochildren aged <5 years in household (0.030), current or past smoker (0.003), medications before onset of illness (0.007);d Influenza vaccination (0.082), age (0.150), antiviral use before onset of illness (0.992), admission from long term care facility (0.884), obesity (0.764), exposed tochildren aged <5 years in household (0.060), current or past smoker (0.002), medications before onset of illness (0.018);e Influenza vaccination (0.005), age (0.035), antiviral use before onset of illness (0.998), seniors including patient living in the dwelling (0.129), pregnancy (0.994);f Influenza vaccination (0.045), age (0.021), seniors including patient living in the dwelling (0.061), pregnancy (0.995), (no patients used antivirals before onsetof illness);g Influenza vaccination (0.381), age (0.383), antiviral use before onset of illness (0.992), seniors including patient living in the dwelling (0.046), pregnancy (0.264);h Influenza vaccination (0.324), age (0.993), seniors including patient living in the dwelling (0.173), pregnancy (0.188), (no patients used antivirals before onsetof illness);i Influenza vaccination (0.027), age (0.151), antiviral use before onset of illness (0.991), frailty index prior to admission (0.057), exposed to children aged <5 years inhousehold (0.179), medications before onset of illness (0.051);j Influenza vaccination (0.283), age (0.220), antiviral use before onset of illness (0.995), frailty index prior to admission (0.030), exposed to children aged <5 years inhousehold (0.399), medications before onset of illness (0.031);k Influenza vaccination (0.002), age (0.992), antiviral use before onset of illness (0.993), frailty index prior to admission (0.076), exposed to children aged <5 years inhousehold (0.107), medications before onset of illness (0.397);l Influenza vaccination (0.001), age (0.673), antiviral use before onset of illness (0.993), frailty index prior to admission (0.043), exposed to children aged <5 years inhousehold (0.467), medications before onset of illness (0.339)Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 8 of 11although a lack of power contributed to the wide CIsobserved. However, approximately 22.6% of adults 16–64 years were immunocompromised (had cancer,haematopoetic or solid organ transplant, HIV, or weretaking immunosuppressive medications). About 12.1% ofthese patients had cancer, and 13.6% were on immuno-suppressive medications (data not shown), which couldbe contributing to decreased VE in this age bracket.Conversely, late-season VE against all-strain influenzaand influenza B was highly effective in older adults≥65 years (VE: 62.4%, VE: 69.3%, respectively). One ex-planation for this could be that the older adult age grouphad residual immunity to the B Yamagata lineage thatwas not included in the TIV and circulated late-season,while younger adults may have lacked this previously ac-quired immunity to B Yamagata and had no protectionconferred by vaccine, resulting in the poor and non-effective VE observed.One of the strengths of this study was the assessmentof influenza VE for the prevention of non-influenza re-spiratory viruses. Given the observational nature of thestudy, there is potential for unmeasured confounders toinfluence VE estimates. We were unable to demonstrateany impact of TIV on hospitalization for non-influenzarespiratory viruses (VE: −19.9%, 95% CI: -83.6, 21.6).This suggests that there is little important residual biasin the study design, as one would not expect to observeprotection of TIV against other laboratory-confirmednon-influenza respiratory viruses. Other strengths to ourstudy include the sentinel approach, which providesconsistency within a large-scale observational setting,and in Canada has been used to develop a rigorous test-negative case-control design over multiple seasons [24–28]. Further strengths were the use of multiplex RT PCRmethods to characterize influenza viruses as well asother respiratory co-infections, including the determin-ation of influenza B lineages, and the collection of de-tailed information on confounding factors withsubsequent adjustment of VE estimates.The main limitations of the study were the observa-tional design and the relative infrequency ofhospitalization for influenza among younger healthyadults, which limit the ability to generate sufficientlypowered data. Further factors which limit thegeneralizability of the results across seasons include theinability to entirely predict viral circulation and subse-quently vaccine strain match or mismatch within a givenseason in light of differences in viral epidemiology acrossregions.ConclusionsThis study evaluated the VE of TIV for preventinginfluenza-related hospitalizations in Canada using alarge, prospective, sentinel surveillance network and atest-negative case-control study design. These resultssuggest that TIV was highly effective against A virusesand moderately effective against B viruses during a mildseason in Canada which was characterised by co-circulation of four influenza strains, including both Ya-magata and Victoria B-lineages. These findings under-score the need to provide VE assessment by subtype/lineage as well as the timing of vaccination (early seasonvs late season) to accurately evaluate vaccine perform-ance and thus guide public health decision-making. TheSOS Network surveillance provides a unique opportun-ity for ongoing evaluation of seasonal influenza VE forpreventing hospitalizations and other severe outcomesin Canada.AbbreviationsCAP: Community-acquired pneumonia; ICU: Intensive care unit;NML: National Microbiology Laboratory; NP: Nasopharyngeal; PCIRN: PublicHealth Agency of Canada/Canadian Institutes of Health Research InfluenzaResearch Network; PCR: Polymerase chain reaction; RT PCR: Reversetranscription polymerase chain reaction; SOS: Serious Outcomes Surveillance;TIBDN: Toronto Invasive Bacterial Diseases Network; TIV: Trivalent influenzavaccine; VE: Vaccine effectiveness; WHO: World Health OrganizationAcknowledgementsThis study was funded by the Canadian Institutes of Health Research andthrough a Collaborative Research Agreement with GlaxoSmithKlineBiologicals SA. We also thank Annick Moon (Moon Medical CommunicationsLtd., UK; on behalf of GSK, Wavre, Belgium) for providing medical writingservices and Bruno Dumont (Business and Decision Life Sciences; on behalfof GSK, Wavre, Belgium) for editorial assistance and manuscript coordination.Finally, the authors wish to thank the dedicated SOS Network Surveillancemonitors whose tremendous efforts make this study possible.FundingFunding for this study was provided by GlaxoSmithKline Biologicals SA andthe Public Health Agency of Canada/Canadian Institutes of Health ResearchInfluenza Research Network (PCIRN). GlaxoSmithKline Biologicals SAcontributed to the conception and design of the study, validation of dataanalysis, as well as review of the manuscript. PCIRN contributed to theconception and the design of the study, data collection and analysis and thedevelopment of the manuscript. The authors are solely responsible for finalcontent and interpretation. The authors received no financial support orother form of compensation related to the development of the manuscript.Availability of data and materialsThe datasets generated and/or analysed during the current study are notpublically available due to the confidential nature of the data obtained frompatients, however, datasets are available through the corresponding authoron reasonable request.Authors’ contributionsThe CIRN SOS principal investigator (SAM) and co-principal investigator(MKA), CIRN SOS site investigators (AMcC, AMcG, DW, GB, KK, KG, GS, JJ, JM,JP, LV, ML, MS, ST, WB, DR), GSK collaborators (GDS, FH, BI, VS), and other col-laborators (AC) were involved in the conception and design of the study; Siteinvestigators, principal investigator (SAM) and co-principal investigator (MKA)supervised CIRN SOS Network sentinel sites and staff, and were involved indata collection and recruitment; SAM, JL, TH, and ME conducted/supervisedthe CIRN SOS Network central laboratory; SAM, ME, and AA were involved inCIRN SOS site coordination. LY, DM-C, FH, and MKN were involved in datamanagement and statistical support. MKA, MKN, VS, TH, and SAM drafted themanuscript and interpreted the data. All authors (MKA, SAM, TH, MKN, AMcC,AMcG, DW, GB, KK, KG, GS, JJ, JM, JP, LV, ML, MS, ST, WB, DR, SAH, JML, AC,GDS, FH, BI, VS, JL, ME, AA, LY, DM-C) revised the manuscript critically for im-portant intellectual content. All authors had full access to the data and gavefinal approval before submission.Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 9 of 11Ethics approval and consent to participateThe protocol was approved by the Research Ethics Boards of participatinginstitutions. The full names of individual Research Ethics Boards for each SOSNetwork participating center are listed here: Halifax site: Capital HealthResearch Ethics Board; Mount Sinai and TIBDN sites: Mount Sinai HospitalResearch Ethics Board; Hamilton site: Hamilton Health Sciences/ McMasterHealth Sciences Research Ethics Board; Vancouver site: The University ofBritish Columbia Clinical Research Ethics Board; Ottawa site: Ottawa HealthScience Network Research Ethics Board; Quebec City site: Comité d’éthiquede la recherché du CHU de Québec; Sherbrooke site: Comité d’éthique de larecherché sur l’human du Centre Hospitalier universitaire de Sherbrooke;Saint John site: Horizon Health Network Research Ethics Board; Montreal site:Montreal General Hospital BMD Research Ethics Committee; North York site:North York General Research Ethics Board; Toronto East site: Toronto EastGeneral Hospital Research Ethics Board; William Osler site (Brampton, On):William Osler Health System Research Ethics Board; Sudbury site: HealthSciences North Research Ethics Board. All patients provided written informedconsent for data and sample collection, and medical record screening inaccordance with the local Research Ethics Boards requirements.Consent for publicationN/ACompeting interestsMKA reports grant funding from the GSK group of companies, Pfizer andSanofi Pasteur. VS reports he was employed by GSK Vaccines at the time ofthe study and is now employed by Novavax Vaccines, and holds shares inthe GSK group of companies. TH reports grant funding from the GSK groupof companies, and payments from Pfizer and Abbvie, outside the submittedwork. AA has nothing to disclose. GB has nothing to disclose. WB hasnothing to disclose. AC reports payments from Sanofi, outside the submittedwork. GDS reports he was external consultant at Business & Decision LifeSciences (on behalf of GSK) at the time of the study, and is currentlyemployed by the GSK group of companies and holds shares in the GSKgroup of companies. ME has nothing to disclose. KG has nothing to disclose.FH reports he is employed by the GSK group of companies. SAH reportspayments from the GSK group of companies, during the conduct of thestudy and outside the submitted work. BI reports she was employed by theGSK group of companies at the time of the study. JJ has nothing to disclose.KK has nothing to disclose. JML reports payments from the GSK group ofcompanies and CIHR, during the conduct of the study; and reports paymentfrom the GSK group of companies, outside the submitted work. JL hasnothing to disclose. ML has nothing to disclose. DM-C has nothing to dis-close. AMcC has nothing to disclose. JM reports payments to her institutionfrom GlaxoSmithKline Group of Companies, and Sanofi Pasteur, outside ofthe submitted work. AMcG reports payments to her institution from the GSKgroup of companies for the conduct of this study, and payments from Hoff-man La Roche and Sanofi Pasteur, outside the submitted work. MKN hasnothing to disclose. JP reports payments from the GSK group of companies,Merck, Roche and Synthetic Biologics, outside the submitted work. DR hasnothing to disclose. MS reports payments from the GSK group of companiesand Pfizer, during the conduct of the study. GS has nothing to disclose. STreports payments from CIHR, during the conduct of the study. LV reportspayments from the GSK group of companies, during the conduct of thestudy. DW has nothing to disclose. LY has nothing to disclose. SAM reportspayments from the GSK group of companies, during the conduct of thestudy; and reports payments from Pfizer, Merck, Novartis and Sanofi, outsidethe submitted work.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Canadian Center for Vaccinology, IWK Health Centre and Nova Scotia HealthAuthority, Dalhousie University, 5850/5980 University Ave, Halifax, NovaScotia B3K 6R8, Canada. 2GSK, King of Prussia, Current affiliation: NovavaxVaccines, Washington, DC, USA. 3Centre Hospitalier Universitaire de Québec,2705 Boulevard Laurier, RC-709, Québec, Québec G1V 4G2, Canada.4University of British Columbia, 452D, Heather Pavilion East, VGH, 2733Heather Street, Vancouver, British Columbia V5Z 3J5, Canada. 5Leslie DanFaculty of Pharmacy, University of Toronto, Current affiliation: Sanofi Pasteur,Swiftwater, Pennsylvania, USA. 6Business & Decision Life Sciences, Bruxelles,Belgium, on behalf of GSK (Wavre, Belgium), Current affiliation: GSK, Wavre,Belgium. 7Mount Sinai Hospital, 600 University Ave, Room 210, Toronto,Ontario M5G 1X5, Canada. 8GSK, Wavre, Belgium. 9GSK, Mississauga, Ontario,Canada, Current affiliation: Bayer Inc, Mississauga, Ontario, Canada.10McMaster University, Michael G. DeGroote Centre for Learning, 1200 MainStreet West, Room 3208, Hamilton, Ontario L8S 4K1, Canada. 11North YorkGeneral Hospital, 4001 Leslie St, Toronto, Ontario M2K 1E1, Canada. 12TheOttawa Hospital, Ottawa Hospital Civic Campus, 1053 Carling Ave, Ottawa,Ontario K1Y 4E9, Canada. 13Health Sciences North Research Institute, 41Ramsey Lake Rd, Sudbury, Ontario P3E 5J1, Canada. 14Michael GarronHospital, 825 Coxwell Ave, Toronto, Ontario M4C 3E7, Canada. 15William OslerHealth System, Department of Infectious Diseases and Medical Microbiology,2100 Bovaird Dr East, Brampton, Ontario L6R 3J7, Canada. 16McGill University,McGill University Health Centre, Glen Site, 1001 Decarie Blvd, Montreal,Quebec H4A 3J1, Canada. 17Université de Sherbrooke, 3001 12th Ave North,Sherbrooke, Quebec J1H 5N4, Canada. 18Saint John Regional Hospital,Dalhousie University, 400 University Ave, Saint John, New Brunswick E2L 4L2,Canada.Received: 22 June 2017 Accepted: 11 December 2017References1. Public Health Agency of Canada. National Advisory Committee on immunization.Statement on seasonal influenza vaccine for 2014–2015. 2014. http://www.phac-aspc.gc.ca/naci-ccni/flu-grippe-eng.php. Accessed 15 Jan 2017.2. Australian Government Department of Health. Australian Technical AdvisoryGroup on Immunisation (ATAGI) advice for immunisation providersregarding the administration of seasonal influenza vaccines in 2017. 2017.http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/DA045106A3499384CA257E2D001A1FA3/$File/ATAGI-Providers-Influenza-Statement.pdf. Accessed 10 Dec 2017.3. United States Centers for Disease Control and Prevention. CDC’s advisorycommittee on immunization practices (ACIP) recommends universal annualinfluenza vaccination. 2010. http://www.cdc.gov/media/pressrel/2010/r100224.htm. Accessed 10 June 2016.4. Cheng AC, Holmes M, Irving LB, Brown SGA, Waterer GW, Korman TM, et al.Influenza vaccine effectiveness against hospitalisation with confirmedinfluenza in the 2010-11 seasons: a test-negative observational study. PLoSOne. 2013;8:1–8. doi: 10.1371/journal.pone.0068760.5. Cowling BJ, Feng S, Finelli L, Steffens A, Fowlkes A. Assessment of influenzavaccine effectiveness in a sentinel surveillance network 2010–13. U SVaccine. 2015;34:61–6. doi: 10.1016/j.vaccine.2015.11.016.6. McLean HQ, Meece JK, Belongia EA. Influenza vaccination and risk ofhospitalization among adults with laboratory confirmed influenza illness.Vaccine. 2014;32:453–7. doi: 10.1016/j.vaccine.2013.11.060.7. Puig-Barbera J, Mira-Iglesias A, Tortajada-Girbes M, Lopez-Labrador FX,Belenguer-Varea A, Carballido-Fernandez M, et al. Effectiveness of influenzavaccination programme in preventing hospital admissions, Valencia, 2014/15 early results. Euro Surveill Bull Eur Sur Les Mal Transm = Eur CommunDis Bull. 2015;20:1–6. doi: 10.2807/1560-7917.ES2015.20.8.21044.8. Puig-Barberà J, Natividad-Sancho A, Launay O, Burtseva E, Ciblak MA,Tormos A, et al. 2012-2013 seasonal influenza vaccine effectiveness againstinfluenza hospitalizations: results from the global influenza hospitalsurveillance network. PLoS One. 2014; doi: 10.1371/journal.pone.0100497.9. Puig-Barberà J, Díez-Domingo J, Arnedo-Pena A, Ruiz-García M, Pérez-Vilar S,Micó-Esparza JL, et al. Effectiveness of the 2010-2011 seasonal influenzavaccine in preventing confirmed influenza hospitalizations in adults: a case-case comparison, case-control study. Vaccine. 2012;30:5714–20. doi: 10.1016/j.vaccine.2012.07.006.10. Cheng A, Kotsimbosc T, Kelly P. On behalf of the FluCAN investigators.Influenza vaccine effectiveness against hospitalisation with influenza inadults in Australia in 2014. Vaccine. 2015;33:7352–6. https://doi.org/10.1016/j.vaccine.2015.10.016.11. McNeil SA, Shinde V, Andrew M, Hatchette TF, Leblanc J, Ambrose A, et al.Interim estimates of 2013/14 influenza clinical severity and vaccineeffectiveness in the prevention of laboratory-confirmed influenza-relatedhospitalisation, Canada, February 2014. Eur Secur. 2014;19:1–6.Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 10 of 1112. McNeil SA, Andrew MK, Ye L, Haguinet F, Hatchette TF, Elsherif M, et al.Interim estimates of 2014/15 influenza vaccine effectiveness in preventinglaboratory-confirmed influenza-related hospitalisation from the seriousoutcomes surveillance network of the Canadian immunization researchnetwork, January 2015. Eur Secur. 2015;20:1–7. doi: 10.2807/1560-7917.ES2015.20.5.21024.13. Public Health Agency of Canada. National Advisory Committee onimmunization. FluWatch: august 12 to august 25, 2012 (weeks 33 & 34).2012. http://publications.gc.ca/site/eng/9.507424/publication.html. Accessed17 Feb 2017.14. Andrew MK, Shinde V, Ye L, Hatchette TF, Haguinet F, Dos Santos G, et al.The importance of frailty in the assessment of influenza vaccineeffectiveness against influenza-related hospitalization in elderly people. JInfect Dis. 2017;216(4):405–14.15. World Health Organization. Recommended composition of influenza virusvaccines for use in the 2011–2012 northern hemisphere influenza season.2011. www.who.int/influenza/vaccines/virus/2011_12north/en/. Accessed 10June 2016.16. Ohmit SE, Thompson MG, Petrie JG, Thaker SN, Jackson ML, Belongia EA, etal. Influenza vaccine effectiveness in the 2011-2012 season: protectionagainst each circulating virus and the effect of prior vaccination onestimates. Clin Infect Dis. 2014;58:319–27. doi: 10.1093/cid/cit736.17. Dos Santos G, Neumeier E, Bekkat-Berkani R. Influenza: can we cope betterwith the unpredictable? Hum Vaccines Immunother. 2016;12:699–708. doi:10.1080/21645515.2015.1086047.18. Skowronski DM, Janjua NZ, Sabaiduc S, De Serres G, Winter AL, Gubbay JB,et al. Influenza a/subtype and B/lineage effectiveness estimates for the2011-2012 trivalent vaccine: cross-season and cross-lineage protection withunchanged vaccine. J Infect Dis. 2014;210:126–37. doi: 10.1093/infdis/jiu048.19. Rondy M, Puig-Barbera J, Launay O, Duval X, Castilla J, Guevara M, et al. 2011-12 seasonal influenza vaccines effectiveness against confirmed a(H3N2)influenza hospitalisation: pooled analysis from a European network ofhospitals. A pilot study. PLoS One. 2013;8 doi: 10.1371/journal.pone.0059681.20. Talbot HK, Griffin MR, Chen Q, Zhu Y, Williams JV, Edwards KM. Effectivenessof seasonal vaccine in preventing confirmed influenza-associatedhospitalizations in community dwelling older adults. J Infect Dis. 2011;203:500–8. doi: 10.1093/infdis/jiq076.21. Castilla J, Godoy P, Domínguez Á, Martínez-Baz I, Astray J, Martín V, et al.Influenza vaccine effectiveness in preventing outpatient, inpatient, andsevere cases of laboratory-confirmed influenza. Clin Infect Dis. 2013;57:167–75. doi: 10.1093/cid/cit194.22. Beck CR, McKenzie BC, Hashim AB, Harris RC, Zanuzdana A, Agboado G, etal. Influenza vaccination for immunocompromised patients: systematicreview and meta-analysis from a public health policy perspective. PLoS One.2011;6 doi: 10.1371/journal.pone.0029249.23. Su S, Chaves SS, Perez A, D’Mello T, Kirley PD, Yousey-Hindes K, et al.Comparing clinical characteristics between hospitalized adults withlaboratory-confirmed influenza a and B virus infection. Clin Infect Dis. 2014;59:252–5. doi: 10.1093/cid/ciu269.24. Skowronski DM, Janjua NZ, De Serres G, Winter AL, Dickinson JA, Gardy JL,et al. A sentinel platform to evaluate influenza vaccine effectiveness andnew variant circulation, Canada 2010-2011 season. Clin Infect Dis. 2012;55:332–42. doi: 10.1093/cid/cis431.25. Skowronski D, Gilbert M, Tweed S, Petric M, Li Y, Mak A. Effectiveness ofvaccine against medical consultation due to laboratory-confirmed influenza:results from a sentinel physician pilot project in British Columbia, 2004-2005.Canada Commun Dis Rep. 2005;31:181–91.26. Skowronski DM, Masaro C, Kwindt TL, Mak A, Petric M, Li Y, et al. Estimatingvaccine effectiveness against laboratory-confirmed influenza using asentinel physician network: results from the 2005–2006 season of dual aand B vaccine mismatch in Canada. Vaccine. 2007;25:2842–51.27. Skowronski DM, De Serres G, Dickinson J, Petric M, Mak A, Fonseca K, et al.Component-specific effectiveness of trivalent influenza vaccine asmonitored through a sentinel surveillance network in Canada, 2006–2007. JInfect Dis. 2009;199:168–79. doi: 10.1086/595862.28. Janjua NZ, Skowronski DM, De Serres G, Dickinson J, Crowcroft NS, Taylor M,et al. Estimates of influenza vaccine effectiveness for 2007-2008 fromCanada’s sentinel surveillance system: cross-protection against major andminor variants. J Infect Dis. 2012;205:1858–68. doi: 10.1093/infdis/jis283.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Andrew et al. BMC Infectious Diseases  (2017) 17:805 Page 11 of 11


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