Syddansk Universitet DOI: / ES Publication date: 2016

Transcription

1 Syddask Uiversitet Pademic vacciatio strategies ad iflueza severe outcomes durig the iflueza A(H1N1)pdm pademic ad the post-pademic iflueza seaso the Nordic experiece Gil Cuesta, Julita; Aavitslad, Prebe; Eglud, Hélèe; Gudlaugsso, Olafur; Hauge, Siri Helee; Lyytikäie, Outi; Sigmudsdóttir, Guðrú; Tegell, Aders; Virtae, Mikko; Krause, Tyra Grove; Nordic iflueza compariso group; Fischer, Thea Kølse Published i: Eurosurveillace (Olie Editio) DOI: 1.287/-7.ES Publicatio date: 1 Documet versio Publisher's PDF, also kow as Versio of record Citatio for pulished versio (APA): Gil Cuesta, J., Aavitslad, P., Eglud, H., Gudlaugsso, O., Hauge, S. H., Lyytikäie, O.,... Fischer, T. K. (1). Pademic vacciatio strategies ad iflueza severe outcomes durig the iflueza A(H1N1)pdm pademic ad the post-pademic iflueza seaso: the Nordic experiece. Eurosurveillace (Olie Editio), 21(1), [38]. DOI: 1.287/-7.ES Geeral rights Copyright ad moral rights for the publicatios made accessible i the public portal are retaied by the authors ad/or other copyright owers ad it is a coditio of accessig publicatios that users recogise ad abide by the legal requiremets associated with these rights. Users may dowload ad prit oe copy of ay publicatio from the public portal for the purpose of private study or research. You may ot further distribute the material or use it for ay profit-makig activity or commercial gai You may freely distribute the URL idetifyig the publicatio i the public portal? Take dow policy If you believe that this documet breaches copyright please cotact us providig details, ad we will remove access to the work immediately ad ivestigate your claim. Dowload date: 31. aug.. 18

2 Surveillace ad outbreak report Pademic vacciatio strategies ad iflueza severe outcomes durig the iflueza A(H1N1)pdm pademic ad the post-pademic iflueza seaso: the Nordic experiece J Gil Cuesta 1 7, P Aavitslad 2, H Eglud 3, Ó Gudlaugsso 4, SH Hauge 5, O Lyytikäie, G Sigmudsdóttir 4, A Tegell 3, M Virtae, the Nordic iflueza compariso group 8, T Grove Krause 1 1. States Serum Istitut, Copehage, Demark 2. Epidemi, Kristiasad, Norway 3. Public Health Agecy Swede, Stockholm, Swede 4. Cetre for Health Security ad Commuicable Disease Cotrol, Reykjavik, Icelad 5. Norwegia Istitute of Public Health, Oslo, Norway. Natioal Istitute for Health ad Welfare, Helsiki, Filad 7. Europea Programme for Itervetio Epidemiology Traiig (EPIET), Europea 8. Cetre for Disease Prevetio ad Cotrol (ECDC), Stockholm, Swede.. The Nordic iflueza compariso group members are listed at the ed of the article Correspodece: Julita Gil Cuesta (giljulita@gmail.com) Citatio style for this article: Gil Cuesta J, Aavitslad P, Eglud H, Gudlaugsso Ó, Hauge SH, Lyytikäie O, Sigmudsdóttir G, Tegell A, Virtae M, the Nordic iflueza compariso group, Grove Krause T. Pademic vacciatio strategies ad iflueza severe outcomes durig the iflueza A(H1N1)pdm pademic ad the post-pademic iflueza seaso: the Nordic experiece. Euro Surveill. 1;21(1):pii=38. DOI: Article submitted o 14 April / accepted o 3 December / published o 21 April 1 Durig the /1 iflueza A(H1N1)pdm pademic, the five Nordic coutries adopted differet approaches to pademic vacciatio. We compared pademic vacciatio strategies ad severe iflueza outcomes, i seasos /1 ad 1/11 i these coutries with similar iflueza surveillace systems. We calculated the cumulative pademic vacciatio coverage i /1 ad cumulative icidece rates of laboratory cofirmed A(H1N1)pdm ifectios, itesive care uit (ICU) admissios ad deaths i /1 ad 1/11. We estimated icidece risk ratios (IRR) i a Poisso regressio model to compare those idicators betwee Demark ad the other coutries. The vacciatio coverage was lower i Demark (.1%) compared with Filad (48.2%), Icelad (44.1%), Norway (41.3%) ad Swede (.%). I /1 Demark had a similar cumulative icidece of A(H1N1) pdm ICU admissios ad deaths compared with the other coutries. I 1/11 Demark had a sigificatly higher cumulative icidece of A(H1N1)pdm ICU admissios (IRR: 2.4; 5% cofidece iterval (CI): 1. 3.) ad deaths (IRR: 8.3; 5% CI: ). Compared with Demark, the other coutries had higher pademic vacciatio coverage ad experieced less A(H1N1)pdm-related severe outcomes i 1/11. Pademic vacciatio may have had a impact o severe iflueza outcomes i the post-pademic seaso. Surveillace of severe outcomes may be used to compare the impact of iflueza betwee seasos ad support differet vacciatio strategies. Backgroud I, the World Health Orgaizatio recommeded adjuvated vaccies i respose to the A(H1N1)pdm pademic [1]. The five Nordic coutries (Demark, Filad, Icelad, Norway ad Swede) all used the moovalet AS3-adjuvated pademic iflueza vaccie Pademrix [2]. Several studies have estimated the effectiveess of the pademic vaccie i prevetig A(H1N1)pdm durig the pademic [3-7]. I additio, others have show a effect agaist iflueza A(H1N1)pdm i the postpademic seaso as well as persistece of atibodies i childre at sub-atioal or atioal level [8-1]. It is therefore possible that a high pademic vacciatio coverage i a populatio would affect the distributio of circulatig iflueza subtypes ad disease severity for a loger period after a pademic. We are ot aware of ay studies that assessed how differet pademic vacciatio strategies may have affected the iflueza type/subtype distributio ad the epidemiology of severe iflueza i the post-pademic seaso. The five Nordic coutries are comparable with regards to demography [11], uiversal ad equal access to the healthcare system [], ad healthcare practices [13]. They also had similar surveillace systems durig the pademic [14-18]. Furthermore, all Nordic coutries established or stregtheed their surveillace of severe iflueza cases through reportig of iflueza 1

3 Figure 1 Cumulative pademic vacciatio coverage ad laboratory-cofirmed iflueza A(H1N1)pdm, iflueza B ad A(H3N2) cases by week, iflueza seasos /1 ad 1/11, Demark, Filad, Icelad, Norway ad Swede A. Demark B. Filad Number of cases 1, 1, 1, 1, Vacciatio coverage (%) Number of cases 2,5 2, 1,5 1, Vacciatio coverage (%) Week ad seaso Week ad seaso Number of cases Number of cases 3,5 3, 2,5 2, 1,5 1, C. Icelad D. Norway Vacciatio coverage (%) 5 Vacciatio coverage (%) Week ad seaso 1 11 Week ad seaso E. Swede Number of cases 3, 2,5 2, 1,5 1, Vacciatio coverage (%) Iflueza B Iflueza A (H3N2) Iflueza A (H1N1)pdm Vaccie coverage Week ad seaso Filad data refers to A(H1N1)pdm (i blue), ot subtyped iflueza A (i gree) ad iflueza B (grey) 2

4 Figure 2 Iflueza A(H1N1)pdm ad iflueza B distributio by age group ad coutry, Demark, Filad, Icelad, Norway ad Swede, iflueza seasos /1 ad 1/11 Percetage of cases by age group 1% % 8% 7% % 5% % 3% % 1% % Demark A(H1N1)pdm-related itesive care uit (ICU) admissios ad deaths i the /1 ad 1/11 iflueza seasos [14-1]. The objective of this study was to compare the five Nordic coutries i terms of circulatig iflueza types/ subtypes ad severe outcomes of iflueza i the seasos /1 ad 1/11 i relatio to the pademic vacciatio coverage ad the timig of vacciatio. Methods Filad Icelad Norway A(H1N1)pdm - 4 years 5-14 years Swede Study desig ad period We coducted a ecological study where we retrospectively compared aggregated data from two cosecutive iflueza seasos: the pademic seaso /1 (week week 1) ad the post-pademic seaso 1/11 (week 1 week 11) i the five Nordic coutries. Data collectio The atioal public health istitutes of the five coutries provided iformatio about the recommedatios for (i) pademic vacciatio such as target groups, begiig of vacciatio campaigs ad umber Demark Filad Iflueza subtypes by coutries - 24 years 25-4 years Icelad Norway Iflueza B 5 years Distributio of iflueza A(H3N2) ot show due to small umber of cases. Swede of doses idicated, ad (ii) virological samplig of patiets with suspected iflueza i.e. target groups ad samplig protocols. Each of the coutries uses atioal uique persoal idetificatio umbers which eables the likage of differet atioal health registers but oly aggregated data were provided for the curret study. The public health istitutes provided data o laboratorycofirmed iflueza cases by type/subtype, iflueza A(H1N1)pdm-related ICU admissios, ifluezarelated deaths, ad the percetage of samples that tested positive for iflueza from laboratories as well as the umber of persos vacciated. These umerator data were stratified by week of the iflueza seaso. We obtaied populatio deomiators from Eurostat [11]. Defiitios The weekly ad cumulative pademic vacciatio coverages were calculated based o the idividual registratio of vacciated idividuals from each coutry by dividig the umber of vacciated idividuals by the coutry populatio. Notificatio of cofirmed iflueza A(H1N1)pdm cases was madatory i Filad, Icelad, Norway ad Swede [,1,]. I Demark, otificatio was oly madatory i the /1 seaso []. I seaso 1/11, iformatio o laboratory-cofirmed cases was obtaied from a ewly established atioal database comprisig all iflueza test results [21]. Therefore, all laboratories i each of the Nordic coutries were icluded i the reportig. The weekly ad cumulative icideces of laboratory-cofirmed iflueza A(H1N1)pdm, A(H3N2) ad iflueza B cases were calculated by dividig the umber of cases by 1, coutry populatio for each seaso. We defied severe outcomes of iflueza A(H1N1) pdm as iflueza-related ICU admissios ad deaths. Durig the pademic, the surveillace of the A(H1N1)pdm cases icluded all ICUs i each of the five Nordic coutries. The testig recommedatios at hospital level were to swab all patiets hospitalised with iflueza-like illess symptoms or lower airway ifectios durig the pademic [22-24]. The A(H1N1) pdm testig recommedatios did ot chage durig the 1/11 seaso [25,2]. The cumulative icideces of iflueza-related ICU admissios were calculated by dividig the umber of patiets admitted to the ICUs ad diagosed with iflueza A(H1N1)pdm by 1, coutry populatio for each seaso. The umber of iflueza-related deaths was idetified by obtaiig iformatio from the civil registry o date of death amog the A(H1N1)pdm cofirmed cases i Demark, Filad ad Swede. Deaths that occurred withi 3 days after the last iflueza positive sample were cosidered. Each case was the reviewed ad validated by atioal medical officers. I Icelad ad 3

5 Table 1 Timig of recommedatios of pademic vacciatio to target groups i Demark, Filad, Icelad, Norway ad Swede, durig the /1 iflueza A(H1N1)pdm pademic Coutry Demark Uderlyig coditios a Week 43: < 5 years of age Week 4: 5 years of age Target groups recommeded by week Healthcare workers ad key Pregat wome commuity professios b Week 43 Week 45: 2 d ad 3 rd trimester Healthy populatio moths of age Not recommeded Filad Week 45 Week 43 Week 44 Week 4: 35 moths Week 47: 3 24 years Icelad Week 45 Week Week 45 Week 48 Norway Week 38 Week 38 Week 38 Week 43 Swede Week 42 Week 42 Week 42 Week 44 4 c a The coutries icluded oe or more of the followig: pulmoary diseases, cardiovascular diseases, haemoglobiopathies, diabetes type 1 or 2, cogeital or acquired immue deficiecies, euromuscular coditios, chroic liver or real failure, other diagoses which pose a serious health risk i cojuctio with iflueza. b The coutries icluded oe or more of the followig: police, fireme, firefighters, etc. c Accordig to regioal plaig. Norway, a case-based reportig of all deaths associated with A(H1N1)pdm was i place from hospitals ad healthcare facilities. The iflueza-related mortality was calculated by dividig the umber of iflueza cofirmed deaths by 1, coutry populatio for each seaso. Data aalysis The pademic vacciatio coverage durig the pademic seaso was compared betwee the five coutries. I each iflueza seaso, we compared the coutry icidece of laboratory-cofirmed iflueza by type/ subtype, A(H1N1)pdm-related ICU-admissios ad the A(H1N1)pdm-related mortality. These idicators were also compared by age groups. A Poisso regressio model was used to compare the idicators betwee the Nordic coutries for each iflueza seaso. We estimated the icidece risk ratio (IRR) ad correspodig 5% cofidece itervals (CI) for Demark vs the other four coutries, usig the other coutries as a referece. The statistical aalysis was carried out usig Stata software. Ethical cosideratios The study oly icluded aggregated surveillace data without persoal idetifiers. Therefore, o ethical approval was eeded accordig to each coutry s atioal regulatios. Results Vacciatio recommedatios ad coverage durig the pademic I, all coutries recommeded pademic vacciatio for healthcare workers, pregat wome ad idividuals aged six moths or more with oe or more chroic medical coditio which icreased the risk for iflueza-related complicatios, from week 38 to 45 (Table 1). I additio, Filad, Icelad, Norway ad Swede but ot Demark, recommeded vacciatio to the whole populatio aged six moths of age or more from week 43 to 48. Filad, Icelad ad Norway recommeded oe vaccie dose for idividuals aged 1 years or more. Swede ad Demark started by recommedig two doses ad chaged to oe dose i week 4 ad 4 of, respectively, for idividuals aged above 1 years old with a fuctioig immue system. Demark, Icelad, Norway ad Swede recommeded two doses for childre below 1 years of age, while Filad recommeded oly oe dose i this age group. Norway chaged the recommedatio to oe dose i the same age group i week 51. The Nordic coutries started to admiister the vaccie i September i Filad ad i October i Demark, Icelad, Norway ad Swede. The cumulative coverage of admiistered vaccies by the ed of the pademic was sigificatly lower i Demark,.1%, compared with Filad, 48.2%, Icelad 44.1%, Norway 41.3% ad Swede.%. The percetage of vacciated childre below five years of age i Demark was.3%, i Filad 73%, i Icelad 43% ad i Norway 47%; data for Swede was ot available. The percetage of vacciated populatio above 5 years of age i Demark was 18%, compared with 4% i Filad, 5% i Icelad ad 53% i Norway. I the 1/11 seaso, the trivalet seasoal iflueza vaccie (TIV) icluded A(H1N1)pdm as oe of the three viruses, ad this vaccie type was used i all five coutries; Pademrix was ot i use durig this seaso. 4

6 Table 2 Rates of laboratory-cofirmed iflueza A(H1N1)pdm ad ICU admissios ad deaths related to iflueza A(H1N1) pdm, iflueza seasos /1 ad 1/11, Demark, Filad, Icelad, Norway ad Swede Coutry Demark 5,47 Filad 7, Icelad Norway 13,77 Swede 11,2 Laboratory-cofirmed A(H1N1)pdm A(H1N1)pdm-related ICU admissios A(H1N1)pdm-related deaths Seaso /1 Seaso 1/11 Seaso /1 Seaso 1/11 Seaso /1 Seaso 1/11 /1, (5%CI).3 (.7 11.) ( ) 21.1 ( ) ( ) 1.7 (1. 1.) 1, ,35 1,5 /1, (5% CI) 3.2 ( ) 1.3 (.3.5) 7.5 ( ) 28. (2. 2.). (11.3.7) /1, (5%CI) 1. (1.3 2.) 2.4 (2. 2.) 5.3 (3.3 8.) 3. ( ) 1.2 (1. 1.4) /1, (5%CI) /1, (5%CI) 1 1. ( ) 3.5 (.3.7) (.7 1.2) 44.8 (..1) 13 /1, (5%CI). (.7 1.2).2 (.1.4) 1.3 (.4 2.2) 2. (.1 2.5) 43.8 (. 1.1) 32. (.4.) 1 4. (.5.8) 3.3 (.2.5).2 (..1). (.5.2) p value <.1 p value <.1 p value <.1 p value <.1 p value <.5 p value <.1 : umber; CI: cofidece iterval; ICU: itesive care uit. p values were calculated through Poisso regressio. of laboratory-cofirmed iflueza ad recommedatios for testig The weekly icidece of reported laboratory cofirmed A(H1N1)pdm cases peaked i week 42 of i Icelad, week 45 i Norway, week 4 i Demark ad Filad ad week 47 i Swede. At the peak i each coutry, the cumulative pademic vaccie coverage was below 1% for all coutries except Swede, where it was 3% (Figure 1). Durig the pademic, the iflueza A(H1N1)pdm virus was predomiat amog laboratory-cofirmed iflueza cases compared with iflueza B ad A(H3N2) viruses i the five Nordic coutries. I Filad there was oly iformatio o A(H1N1)pdm, but ot o other subtypes of iflueza A (Figure 1). I the 1/11 seaso, iflueza B was predomiat i Filad, Icelad, Norway ad Swede, cotrary to Demark where A(H1N1)pdm was predomiat (Figure 1). I /1, the icidece of laboratory-cofirmed A(H1N1)pdm iflueza was sigificatly lower i Demark compared with the other four Nordic coutries (IRR:.; 5% CI:..; p value <.1) (Table 2, 3). I 1/11, the cumulative icidece of A(H1N1) pdm iflueza was lower i all coutries compared with /1 (Table 2). I cotrast to the previous seaso, it was sigificatly higher i Demark tha i the other four Nordic coutries (IRR: 1.8; 5% CI: ; p value <.1) (Table 2, 3). Recommeded target groups for testig were similar i the five coutries. The swabbig of cases ad their cotacts started i week i Swede, week 18 i Demark, Filad ad Norway ad week 21 i Icelad. The swabbig recommedatios chaged to oly risk group patiets or close cotacts of cofirmed cases i all coutries from week 2 i Demark ad Swede, week 3 i Norway, week 31 i Filad ad week 33 i Icelad (Table 4). The umber of positive A(H1N1)pdm cases amog the total tested was available i Icelad (1.%), Norway (21.4%) ad Swede (23.%) i the /1 seaso. I seaso 1/11, the percetage of positives decreased i the three coutries ad was 3.5% i Icelad,.4% i Norway ad.2% i Swede. Iflueza A(H1N1)pdm-related ICU admissios ad mortality Durig the pademic seaso, the icidece of A(H1N1) pdm-related ICU admissios was statistically sigificatly lower i Demark ad Swede tha i Filad, Icelad ad Norway (Table 2). I the 1/11 seaso, the icidece was lower tha durig the pademic i all coutries except for Demark. I 1/11, Demark had a higher icidece of A(H1N1)pdm-related ICU admissios (IRR: 2.4; 5% CI: 1. 3.; p value <.1) compared with the other Nordic coutries (Table 2,3). I the /1 seaso, there were o statistically sigificat differeces betwee the iflueza A(H1N1) pdm-related mortality i the five coutries (Table 2,3). I 1/11, the iflueza A(H1N1)pdm-related mortality was sigificatly higher i Demark compared 5

7 Table 3 Rates of laboratory-cofirmed iflueza A(H1N1)pdm ad iflueza B cases, ICU admissios ad mortality due to iflueza A(H1N1)pdm i Demark compared with the other coutries (Filad, Icelad, Norway ad Swede), iflueza seasos /1 ad 1/11 Rates of laboratorycofirmed iflueza A(H1N1)pdm ad iflueza B cases, A(H1N1)pdm ICU admissios ad mortality /1, Seaso /1 Seaso 1/11 Demark Other coutries a Demark Other coutries a 5% CI IRR b (5% CI) p value /1, 5% CI /1, 5% CI IRR b p value /1, 5% CI A(H1N1)pdm (..) p < Iflueza B NA NA NA NA NA NA 23.4 A(H1N1)pdm-related ICU admissios A(H1N1)pdm-related mortality (. 1.). (. 1.4) 3.2 p = p = (1.7 1.).5 (.5.5) 2.4 (1. 3.) 8.3 ( ) p <.1 1. NA 43.7 p <.1.8 p < CI: cofidece iterval; ICU: itesive care uit; IRR: icidece risk ratio; NA: ot available. a Other coutries: Filad, Icelad, Norway ad Swede. b Referece group: Other coutries. with the other coutries (IRR: 8.3; 5% CI: ; p value <.1). Discussio There was a wide variatio i pademic vacciatio strategies durig the pademic i Europe, ad the iflueza A(H1N1)pdm pademic vacciatio coverage previously reported for the etire populatio raged from.5% to 5% across Europea coutries [27]. We evaluated how the pademic ad the post-pademic iflueza seasos progressed i the Nordic coutries ad preset the results i light of the differet vacciatio strategies used. A similar approach would have bee difficult at the Europea level due to the heterogeeous populatios, differet healthcare ad differet iflueza surveillace systems. The Nordic coutries are comparable regardig these factors which gave us a uique opportuity to study differeces i severe outcomes of iflueza A(H1N1)pdm i the pademic ad post-pademic seasos i relatio to the vacciatio coverage durig the pademic. The pademic vacciatio coverage was % i Demark where vacciatio was oly recommeded for at-risk groups, compared with 41 to % i the other four Nordic coutries where vacciatio was recommeded for the whole populatio. The timeliess of vacciatio varied by a few weeks with Swede havig the highest proportio of the populatio vacciated before the epidemic peak. All Nordic coutries reported that the most frequet iflueza type durig the pademic was A(H1N1) pdm, with Demark ad Swede havig the lowest rates of laboratory-cofirmed A(H1N1)pdm cases overall ad cases admitted to ICU. However, i the followig iflueza seaso, 1/11, A(H1N1)pdm domiated i Demark, whereas iflueza type B was the predomiat virus i the other four Nordic coutries. Furthermore, i the 1/11 seaso, Demark experieced a higher icidece of A(H1N1)pdm-related ICU admissios ad deaths tha the other Nordic coutries. The higher icidece of laboratory-cofirmed iflueza A(H1N1)pdm cases ad related ICU admissios ad deaths i Demark i the 1/11 seaso could be due to less atural or vaccie-iduced immuity i the populatio i the post-pademic seaso compared with the other coutries. Studies o the burde of the pademic iflueza i Demark have estimated a cliical attack rate of 5% [28] which is ideed lower tha the cliical attack rate of 3% estimated i Norway [2]. However, the latter umber was obtaied by usig a differet method [2]. Cliical attack rates were ot available for the other Nordic coutries. Other Europea coutries have reported fidigs similar to those observed i Demark. I 1/11, the Uited Kigdom (UK) reported a higher level of daily umber of cofirmed ad suspected iflueza cases i critical care ad a higher umber of deaths compared with the /1 pademic seaso [3,31]. Pademic vacciatio coverage was estimated to be % for the geeral populatio i Scotlad [32]. The coverage was 35% for the risk groups i the UK where it provided some protectio agaist laboratory-cofirmed iflueza A(H1N1)

8 Table 4 Timig of recommedatios of iflueza testig, Demark, Filad, Icelad, Norway ad Swede, /1 iflueza A(H1N1)pdm pademic Coutry Groups recommeded for testig ad week Cases a ad their cotacts Cases at risk of severe disease ad their cotacts Demark Week 18 Week 2 Filad Week 18 Week 31 Icelad Week 21 Week 33 Norway Week 18 Week 3 Swede Week Week 2 a Idividuals fulfillig the atioal case defiitio for suspected case of iflueza A(H1N1)pdm. pdm i the 1/11 seaso accordig to a vaccie effectiveess study [1]. I Greece, where a 3% populatio pademic vacciatio coverage was reported, higher ICU admissio rates ad higher overall populatio mortality due to iflueza A(H1N1)pdm was also reported i 1/11 compared with the previous seaso [33]. I Irelad, 23% of the populatio eligible for vacciatio was vacciated durig the pademic ad the umber of iflueza A(H1N1)pdm-related ICU admissios ad deaths icreased from the /1 to the 1/11 iflueza seaso [34]. Adjuvated vaccies have show to provide loger lastig immuity i childre, adults ad populatios with chroic coditios compared with o-adjuvated vaccies [8,,35]. They iduce atibodies that show higher levels of haemagglutiatio ihibitio ad iflueza-eutralisig activity tha o-adjuvated vaccies [3-38]. I additio, the pademic vaccie strai closely matched the iflueza A(H1N1)pdm virus strai that circulated durig the seaso 1/11. Thus, i 1/11 the populatio of the Nordic coutries could have bee protected to some extet by the pademic vaccie admiistered more tha oe year earlier. Several atioal ad sub-atioal studies have reported the prevailig effectiveess of the pademic vaccie i /1 i prevetig iflueza A(H1N1)pdm durig seaso 1/11. I Swede, the pademic vaccie effectiveess (VE) was 72% agaist hospitalisatio i 1/11 [8]. I Filad, the VE agaist A(H1N1)pdm iflueza was 81% if vacciated with pademic vaccie ad 88% if vacciated with either pademic vaccie or TIV i 1/11 [3]. I UK, the VE agaist A(H1N1) pdm i 1/11 was 34% if vacciated with pademic vaccie; 4% if vacciated with TIV i 1/11 ad 3% if vacciated with both [1]. These results are i lie with our fidigs of a lower icidece of severe iflueza outcomes i 1/11 i the four coutries with higher pademic vacciatio coverage compared with Demark. Limitatios Although the five Nordic coutries have similar healthcare systems, they may have had differet testig practices for iflueza cofirmatio ad subtypig, ad thus ascertaimet of the diagosis. This would have affected the comparability of the data betwee coutries ad betwee the two seasos. This limitatio is however miimised due to three facts. Firstly, testig recommedatios were similar i the five coutries from the begiig of the pademic ad chaged to oly risk group patiets or close cotacts of laboratorycofirmed cases i all coutries from week 2 to 32. Furthermore, testig bias probably did ot affect the ICU admissio rates, as the testig recommedatios at hospital level (icludig ICU uits) i all coutries were to swab all patiets hospitalised with iflueza symptoms or lower airway ifectio [22-2]. Secodly, the proportio of specimes positive for iflueza was similar amog the three coutries with available iformatio which may additioally idicate that the case ascertaimet was comparable throughout this period. The percetage of positive samples reflects the iflueza trasmissio if systematically sampled e.g. i setiel systems. But differet criteria for diagostic swabbig of symptomatic patiets (e.g. more severely ill patiets with higher likelihood of beig iflueza positive) could also have accouted for differeces i the percetage betwee coutries. Thirdly, the age distributio of laboratory-cofirmed iflueza A(H1N1) pdm ad iflueza B was similar (Figure 2) betwee the coutries i the two seasos which also poits towards a comparable case ascertaimet. I additio, the testig practices may have chaged due to differet disease awareess durig the pademic ad the followig year. However, there is o evidece that chages i disease awareess betwee the two seasos would have differed markedly betwee the coutries cocered. Data o the TIV coverage i the five coutries i /1 ad 1/11 seasos was ot icluded i the aalysis, as it was ot available for all coutries. This could have iflueced the morbidity ad mortality due to iflueza i both seasos, as i Caada, where studies have show a icreased risk of iflueza A(H1N1) pdm i /1 amog TIV recipiets i 8/ []. Therefore, the TIV i /1 ad 1/11 could have iflueced the morbidity ad mortality due to iflueza i both seasos. However, i the Nordic coutries the TIV was oly offered to the risk groups ad ot to the geeral populatio, ad it is therefore likely to have had a mior impact o the overall icidece of disease. I additio, the coverage i 1/11 would oly have had a impact o the results if there were differeces i the risk groups or coverages i the other Nordic coutries compared with Demark. This is ot the case sice the seasoal vacciatio recommedatios were similar i the Nordic coutries ad icluded the same risk groups, except for the recommedatio of vacciatig healthy childre i Filad [41]. Moreover, vacciatio coverages i the seaso 7

9 1/11 were similar i three of the Nordic coutries i the elderly populatio: 5% i Demark, 47% i Norway amog elderly ad risk groups, ad 54% i Swede [42]. The optimal desig to address a prologed effect of the pademic vaccie would have bee a multi-coutry register-based study with idividual level iformatio o pademic ad seasoal vacciatios ad iflueza A(H1N1)pdm outcomes. If this data had bee available it would have bee possible to coduct pademic VE aalysis with stratificatio o previous TIV vacciatio i the two seasos. Fially, it is a limitatio that we oly icluded iformatio o vacciatio coverage as a predictor of severe outcomes of iflueza, whe iflueza trasmissio is kow to be iflueced by a rage of factors other tha vacciatio such as populatio desity, social factors, weather coditios ad latitude which were ot take ito accout i this study. Coclusios ad recommedatios Our observatioal study allowed a comprehesive descriptio of timig ad coverage of the pademic vacciatios ad severe outcomes of iflueza A(H1N1) pdm durig the pademic ad followig seaso i the five Nordic coutries. I respose to the A(H1N1)pdm pademic, Filad, Icelad, Norway ad Swede recommeded vacciatio to the whole populatio at a certai time of the pademic ad reached coverages of 41 to %, whereas Demark throughout the pademic oly recommeded to vacciate risk groups, leadig to a coverage of % of the populatio. This differece does ot seem to have iflueced the timig of the epidemic or the disease burde i the /1 pademic seaso, probably because the vaccies were distributed too late relative to the epidemic peak. However, i the followig iflueza seaso 1/11, the four coutries with higher pademic vacciatio coverage experieced a seaso domiated by iflueza B ad had less iflueza A(H1N1)pdm-related severe outcomes compared with Demark. Our results idicate that the adjuvated pademic vacciatio may have had a impact o iflueza type/subtype distributio ad iflueza-related severe outcomes i the seaso followig the pademic, although other factors may have also played a role. We did ot aim to aswer the questio about the most appropriate vacciatio strategy durig a pademic. However, the study idicates that differet vacciatio strategies may have had cosequeces for the iflueza seaso followig the pademic seaso ad this should be part of a overall assessmet of a pademic respose. I such a assessmet the risk of severe ad uexpected rare adverse evets also eeds to be take ito cosideratio whe evaluatig the risk/beefit of a pademic vacciatio campaig. I order to support the assessmet of vacciatio strategies, we recommed the use of comprehesive iflueza surveillace systems that, i additio to surveillace of iflueza itesity ad circulatig subtypes, also iclude severe iflueza-related outcomes to moitor chages i the impact of iflueza betwee seasos across coutries. We also recommed to keep the same surveillace systems i place i the seasos followig the pademic, i order to eable full evaluatio of the impact of pademic vacciatio campaigs. The Nordic iflueza compariso group Kåre Mølbak ad Thea Kølse Fischer, States Serum Istitut, Copehage, Demark, Aika Lide, Public Health Agecy Swede, Stockholm, Swede ad Haraldur Briem, Cetre for Health Security ad Commuicable Disease Cotrol, Reykjavik, Icelad. Ackowledgemets We thak Jes Nielse, Hae-Dorthe Emborg ad Sophie Gubbels for their support durig the aalysis ad Pawel Stefaoff ad Yva Huti for their critical review of the mauscript. Coflict of iterest Noe declared Authors cotributios Julita Gil Cuesta wrote the study protocol, coordiated the data collectio, aalysed the data ad wrote the mauscript. Kåre Mølbak ad Aika Lide coceived the study. Tyra Grove Krause coceived the study, cotributed with the data from her respective coutry ad wrote the mauscript. Prebe Aavitslad, Hélèe Eglud, Ólafur Gudlaugsso, Siri Helee Hauge, Outi Lyytikäie, Guðrú Sigmudsdóttir, Aders Tegell, ad Mikko Virtae cotributed to the study desig, cotributed with the data from their respective coutries ad wrote the mauscript. The Nordic iflueza compariso group cotributed to the study desig ad critical review of the mauscript. All authors reviewed ad approved the fial versio of the mauscript. Refereces 1. Pademic iflueza A (H1N1) virus vaccie - coclusios ad recommedatios from the October meetig of the immuizatio Strategic Advisory Group of Experts. Wkly Epidemiol Rec. ;84(4):55-8.PMID: Johase K, Nicoll A, Ciacio BC, Kramarz P. Pademic iflueza A(H1N1) vaccies i the Europea Uio.Euro Surveill. ;14(41):131. ViewArticle.aspx?ArticleId=131PMID: Wichma O, Stöcker P, Poggesee G, Altma D, Walter D, Hellebrad W, et al. Pademic iflueza A(H1N1) breakthrough ifectios ad estimates of vaccie effectiveess i Germay -1. Euro Surveill. 1;(18):1. aspx?articleid=1pmid: Puig-Barberà J, Aredo-Pea A, Pardo-Serrao F, Tirado- Balaguer MD, Pérez-Vilar S, Silvestre-Silvestre E, et al., Surveillace ad Vaccie Evaluatio Group durig the autum H1N1 pademic wave i Castelló, Spai. Effectiveess of seasoal 8-, -1 ad pademic vaccies, to prevet iflueza hospitalizatios durig the autum iflueza pademic wave i Castelló, Spai. A testegative, hospital-based, case-cotrol study.vaccie. 8

10 1;28(47):74-7. DOI: 1.11/j.vaccie PMID: Valeciao M, Kisslig E, Cohe JM, Oroszi B, Barret AS, Rizzo C, et al. Estimates of pademic iflueza vaccie effectiveess i Europe, -1: results of Iflueza Moitorig Vaccie Effectiveess i Europe (I-MOVE) multicetre case-cotrol study. PLoS Med. 11;8(1):e1388. DOI: /joural.pmed.1388 PMID: Hardelid P, Flemig DM, McMeami J, Adrews N, Robertso C. Sebastia Pillai P, et al. Effectiveess of pademic ad seasoal iflueza vaccie i prevetig pademic iflueza A(H1N1) ifectio i Eglad ad Scotlad -1. Euro Surveill. 11;1(2):pii=3. Available from: eurosurveillace.org/viewarticle.aspx?articleid=3 7. Wu J, Xu F, Lu L, Lu M, Miao L, Gao T, et al. Safety ad effectiveess of a H1N1 vaccie i Beijig. N Egl J Med. 1;33(25): DOI: 1./NEJMoa3 PMID: Widgre K, Magusso M, Hagstam P, Widerström M, Örtqvist Å, Eiemo IM, et al. Prevailig effectiveess of the iflueza A(H1N1)pdm vaccie durig the 1/11 seaso i Swede. Euro Surveill. 13;18():447. eurosurveillace.org/viewarticle.aspx?articleid=447pmid: Castilla J, Mora J, Martiez-Artola V, Reia G, Martiez-Baz I, Garcia Ceoz M, et al. Effectiveess of trivalet seasoal ad moovalet iflueza A(H1N1) vaccies i populatio with major chroic coditios of Navarre, Spai: 1/11 midseaso aalysis. Euro Surveill. 11;1(7):. eurosurveillace.org/viewarticle.aspx?articleid=pmid: Pebody R, Hardelid P, Flemig D, McMeami J, Adrews N, Robertso C, et al. Effectiveess of seasoal 1/11 ad pademic iflueza A(H1N1) vaccies i prevetig iflueza ifectio i the Uited Kigdom: mid-seaso aalysis 1/11. Euro Surveill. 11;1():1. eurosurveillace.org/viewarticle.aspx?articleid=1pmid: Eurostat. Available from: portal/page/portal/populatio/data/database. Kristiase IS, Pederse KM. [Health care systems i the Nordic coutries--more similarities tha differeces?]. Tidsskr Nor Laegefore. ;1():23-.PMID: Nordic Medico-Statistical Committee 13: (NOMESCO). Health Statistics i the Nordic Coutries. Copehage: NOMESCO;. Available from: smash/get/diva2:8741/fulltext1.pdf. 14. Mølbak K, Widgre K, Jese KS, Ethelberg S, Aderse PH, Christiase AH, et al. Burde of illess of the pademic of iflueza A (H1N1) i Demark. Vaccie. 11;2(Suppl 2):B3-. DOI: 1.11/j.vaccie PMID: 257. Lyytikaie O, Kuusi M, Sellma M, Virtae M, Eskola J, Rokko E, et al. Surveillace of iflueza i Filad durig the pademic, 1 May to 8 March 1. Euro Surveill. 11;1(27):18. ViewArticle.aspx?ArticleId=18PMID: Sigmudsdottir G, Gudaso T, Ólafsso Ö, Baldvisdóttir GE, Atladottir A, Löve A, et al. Surveillace of iflueza i Icelad durig the pademic. Euro Surveill. 1;(4):42. aspx?articleid=42pmid: The Swedish Istitute for Commuicable Disease Cotrol (Smittskyddsistitutet). The Iflueza A(H1N1) Pademic i Swede, Available from: folkhalsomydighete.se/ 18. Direktoratet for samfussikkerhet of beredskap. Rapport Ny iflueza A(H1N1). 1. Available from: o/global/publikasjoer/1/rapporter/pademirapport.pdf 1. Gubbels S, Krause TG, Bragstad K, Perer A, Mølbak K, Glisma S. Burde ad characteristics of iflueza A ad B i Daish itesive care uits durig the /1 ad 1/11 iflueza seasos.epidemiol Ifect. 13;141(4): DOI: 1.1/S PMID: Guzmá Herrador BR, Aavitslad P, Feirig B, Riise Bergsaker MA, Borge K. Usefuless of health registries whe estimatig vaccie effectiveess durig the iflueza A(H1N1)pdm pademic i Norway.BMC Ifect Dis. ;(1):3. DOI: 1.118/ PMID: Voldstedlud M, Haarh M, Mølbak K, the MiBa Board of Represetatives. The Daish Microbiology Database (MiBa) 1 to 13. Euro Surveill. 14;1(1):pii=7. DOI: dx.doi.org/1.287/-7.es States Serum Istitut. Iflueza-News - week 18,. April. Available from: EN%-%egelsk/EPI-NEWS//pdf/EPI-NEWS%-% %-%No%18.ashx 23. States Serum Istitut. Iflueza-News - week 27,. July. Available from: EN%-%egelsk/EPI-NEWS//pdf/EPI-NEWS%-% %-%No%27-2.ashx 24. Aavitslad B, Blystad H, Hauge B, Borge K, Huges F, Feirig B, et al. Folkehelseistituttet uder ifluesapademie Delrapport: Rådgivig. April 13. Available from: Mai_7=24::25,548&MaiCotet_24=53::25,5 58&Cotet_53=25:1:25,558::25:1:::: 25. Daish Society for Ifectious Diseases. Guidelies for maagemet of iflueza. Dec 11. Daish. Available from: 2DA452CFAE3.ashx 2. The Swedish Istitute for Commuicable Disease Cotrol (Smittskyddsistitutet). Iflueza i Swede. Seaso Feb. Available from: folkhalsomydighete.se/pagefiles/28/iflueza-iswede-1-11.pdf 27. O Flaaga. Cotter S, Mereckiee J. Pademic A(H1N1) Iflueza Vacciatio Survey, Iflueza seaso /1. Veice II cosortium. Available from: Fial_Report_VENICE_Pademic_Iflueza_.pdf 28. Mølbak K, Widgre K, Jese KS, Ethelberg S, Aderse PH, Christiase AH, et al. Burde of illess of the pademic of iflueza A (H1N1) i Demark. Vaccie. 11;2(Suppl 2):B3-. DOI: 1.11/j.vaccie PMID: Blasio BF, Iverse BG, Tomba GS. Effect of vaccies ad ativirals durig the major A(H1N1) pademic wave i Norway--ad the ifluece of vacciatio timig.plos Oe. ;7(1):e318. DOI: /joural.poe.318 PMID: Health Protectio Agecy. Surveillace of iflueza ad other respiratory viruses i the UK; 11. Available from: Mytto OT, Rutter PD, Doaldso LJ, Iflueza A. Iflueza A(H1N1)pdm i Eglad, to 11: a greater burde of severe illess i the year after the pademic tha i the pademic year.euro Surveill. ;(14):13. eurosurveillace.org/viewarticle.aspx?articleid=13pmid: Simpso CR, Ritchie LD, Robertso C, Sheikh A, McMeami J. Effectiveess of H1N1 vaccie for the prevetio of pademic iflueza i Scotlad, UK: a retrospective observatioal cohort study.lacet Ifect Dis. ;():-72. DOI: 1.11/ S1473-3()7133- PMID: Athaasiou M, Baka A, Adreopoulou A, Spala G, Karageorgou K, Kostopoulos L, et al. Iflueza surveillace durig the postpademic iflueza 1/11 seaso i Greece, 4 October 1 to 22 May 11. Euro Surveill. 11;1(44):4. eurosurveillace.org/viewarticle.aspx?articleid=4pmid: Health Protectio Surveillace Cetre. Iflueza surveillace i Irelad weekly update Iflueza week 1 (th to 23rd May 1). Dubli: Health Protectio Surveillace Cetre, May 1. Available from: Respiratory/Iflueza/SeasoalIflueza/Surveillace/ IfluezaSurveillaceReports/PreviousIfluezaSeasosSurve illacereports/1seaso/file,4348,e.pdf 35. Skowroski DM, Jajua NZ, Hottes TS, De Serres G. Mechaism for seasoal vaccie effect o pademic H1N1 risk remais ucertai. Cli Ifect Dis. 11;52():831-2, author reply DOI: 1.13/cid/cir3 PMID: Hardelid P, Adrews NJ, Hoschler K, Staford E, Bagueli M, Waight PA, et al. Assessmet of baselie age-specific atibody prevalece ad icidece of ifectio to ovel iflueza A/ H1N1. Health Techol Assess. 1 Dec;14(55):1-2. doi:. 37. Waddigto CS, Walker WT, Oeser C, Reier A, Joh T, Wilkis S, et al. Safety ad immuogeicity of AS3B adjuvated split virio versus o-adjuvated whole virio H1N1 iflueza vaccie i UK childre aged moths- years: ope label, radomised, parallel group, multicetre study. BMJ. 1;3(may27 1):c24. DOI: 1.113/bmj.c24 PMID: Vesikari T, Kuf M, Wutzler P, Karvoe A, Kieiger- Baum D, Schmitt HJ, et al. Oil-i-water emulsio adjuvat with iflueza vaccie i youg childre. N Egl J Med. 11;35():1-1. DOI: 1./NEJMoa11331 PMID: Syrjäe RK, Jokie J, Ziegler T, Sudma J, Lahdekari M, Julkue I, et al. Effectiveess of pademic ad seasoal iflueza vaccies i prevetig laboratory-cofirmed iflueza i adults: a cliical cohort study durig epidemic seasos -1 ad 1-11 i Filad. PLoS Oe. 14;():e DOI: /joural.poe PMID:

11 . Skowroski DM, De Serres G, Crowcroft NS, Jajua NZ, Bouliae N, Hottes TS, et al., Caadia SAVOIR Team. Associatio betwee the 8- seasoal iflueza vaccie ad pademic H1N1 illess durig Sprig-Summer : four observatioal studies from Caada.PLoS Med. 1;7(4):e58. DOI: /joural.pmed.58 PMID: Mereckiee J, Cotter S, Nicoll A, Lopalco P, Noori T, Weber JT, D Acoa F, Lévy-Bruhl D, Dematte L, Giambi C, Valetier- Brath P, Stakiewicz I, Appelgre E, O Flaaga D, the VENICE project gatekeepers group. Seasoal iflueza immuisatio i Europe. Overview of recommedatios ad vacciatio coverage for three seasos: pre-pademic (8/), pademic (/1) ad post-pademic (1/11). Euro Surveill. 14;1(1):pii=78. DOI: org/1.287/-7.es O Flaaga. Cotter S, Mereckiee J. Seasoal Iflueza Vacciatio i EU/EEA, iflueza seaso 1-11 VENICE II Cosortium. Available from: Seasoal_Iflueza_1-11.pdf Licese ad copyright This is a ope-access article distributed uder the terms of the Creative Commos Attributio (CC BY 4.) Licece. You may share ad adapt the material, but must give appropriate credit to the source, provide a lik to the licece, ad idicate if chages were made. This article is copyright of the authors,