Passive enhanced safety surveillance for Vaxigrip and Intanza 15 µg in the United Kingdom and Finland during the northern hemisphere influenza season 2015/16.

Bricourt, H; Chabanon, AL; Souverain, A; Vesikari, T; Caroe, TD

Passive enhanced safety surveillance for Vaxigrip and Intanza 15 µg in the United Kingdom and Finland during the northern hemisphere influenza season 2015/16.

Bricourt, H,Chabanon, AL,Souverain, A,Vesikari, T,Caroe, TD

Published: 2017
Repository: trepo.tuni.fi
Language: en

Full text

1www.eu osu eillance.o g Su eillance and ou b eak epo Passi e enhanced sa e y su eillance o Vaxig ip and In anza 15 µg in he Uni ed Kingdom and Finland du ing he no he n hemisphe e in luenza season 2015/16 H B icou ¹ , AL Chabanon ¹ , A Sou e ain ¹ , C Sado ge ¹ , T Vesika i ² , TD Ca oe ³ 1. Sano i Pas eu MSD, Lyon, F ance 2. Vaccine Resea ch Cen e , Uni e si y o Tampe e, School o Medicine, Tampe e, Finland 3. Ligh house Medical P ac ice, Eas bou ne, Eas Sussex, Uni ed Kingdom Co espondence: Hélène B icou (h_b icou @ho mail. ) Ci a ion s yle o his a icle: B icou H, Chabanon AL, Sou e ain A, Sado ge C, Vesika i T, Ca oe TD. Passi e enhanced sa e y su eillance o Vaxig ip and In anza 15 µg in he Uni ed Kingdom and Finland du ing he no he n hemisphe e in luenza season 2015/16. Eu o Su eill. 2017;22(18):pii=30527. DOI: h p://dx.doi.o g/10.2807/1560-7917. ES.2017.22.18.30527 A icle submi ed on 28 July 2016 / accep ed on 13 Decembe 2016 / published on 04 May 2017 Enhanced sa e y su eillance (ESS) was conduc ed in he Uni ed Kingdom and Finland o Vaxig ip and In anza 15 µg o comply wi h he Eu opean Medicines Agency in e im guidance aimed o de ec any po en- ial inc ease in eac ogenici y in nea eal ime ollow- ing he annual upda e o he in luenza accine s ain composi ion. This pilo passi e ESS was es ablished o s eng hen sa e y moni o ing by acili a ing spon a- neous accinee epo s and es ima ing nea eal- ime accinee exposu e. The p ima y objec i e was o es i- ma e he epo ing a es o suspec ed ad e se eac- ions (ARs) occu ing wi hin 7 days pos accina ion du ing he no he n hemisphe e 2015/16 in luenza season. Among he Vaxig ip accinees (n = 1,012), 32 (3.2%) epo ed a o al o 122 suspec ed ARs, includ- ing 110 suspec ed ARs ha occu ed wi hin 7 days pos accina ion. Among he In anza 15 µg accinees (n = 1,017), 31 (3.0%) epo ed a o al o 114 suspec ed ARs, including 99 ha occu ed wi hin 7 days pos - accina ion. These esul s we e consis en wi h he known sa e y p o ile o he wo accines and did no show any change in eac ogenici y o sa e y conce ns. This passi e ESS showed imp o ed da a epo ing and demons a ed i s sui abili y o heal h au ho i ies’ equi emen s; u he ine uning o he me hodology is unde discussion be ween all s akeholde s. In oduc ion In luenza is an acu e i al espi a o y in ec ion ha a ec s 5% o 20% o he global popula ion annually [1]. This a e amoun s o ca 25 o 100 million pe sons each in luenza season in Eu ope. The epidemiology o seasonal in luenza has been well cha ac e ised, pa - icula ly in he no he n hemisphe e (NH), whe e he in luenza season ypically alls be ween No embe and Ap il [2]. Vaccina ion is he only p e en i e measu e o sea- sonal in luenza. As ecommended by he Wo ld Heal h O ganiza ion (WHO), he cu en i alen o quad i a- len ma ke ed in luenza accines a e composed o an igens om wo in luenza A s ains and one o wo in luenza B i us s ain [1]. The ecommenda ion is based on ex ensi e su eillance o in luenza s ains h ough he WHO Global In luenza Su eillance ne - wo k as he in luenza s ains con inue o e ol e, caus- ing an an igenic misma ch be ween he i us s ains in he accine and he ci cula ing i uses in he subse- quen in luenza season [3,4]. Consequen ly, he s ain composi ion o he in luenza accine is adap ed o he epidemiological si ua ion o p o ide op imal p o ec ion o he popula ion. The Eu opean Medicines Agency (EMA) eques s annual enhanced sa e y su eillance (ESS) o all seasonal in luenza accines. The pu pose o his equi emen is o apidly de ec a clinically signi ican change (beyond wha was known o expec ed wi h he p e ious accine composi ion) in he equency and/o se e i y o eac- ogenici y (local, sys emic o alle gic eac ions) ha may indica e he po en ial o mo e se ious isks as exposu e o he accine inc eases. To a oid alse a i- bu ion o such a signal o he gene al in insic sa e y p o ile o a p oduc , i is ecommended ha ESS should in ol e subanalysis o mo e han one ba ch [5]. In e im guidance was issued by he Pha maco igilance Risk Assessmen Commi ee (PRAC) in Ap il 2014 o ou line he p inciples o be ollowed o imp o ed con inuous ou ine su eillance o in luenza accines [5]. Expe iences and limi a ions aced du ing he NH 2014/15 pilo in luenza season we e discussed be ween he accine ma ke ing au ho isa ion holde s (MAHs) 2www.eu osu eillance.o g h ough a dedica ed sa e y ask o ce wi hin Vaccines Eu ope (Eu opean Vaccines Manu ac u e s Associa ion wi hin he Eu opean Fede a ion o Pha maceu ical Indus ies and Associa ions (EFPIA)) and we e p e- sen ed o he EMA/PRAC/Vaccine Wo king Pa y in No embe 2014. By Decembe 2014, he PRAC ecom- mended es ablishing a passi e ESS o he NH 2015/16 in luenza season o he MAHs. Thus, a new design was de eloped o moni o Vaxig ip (in amuscula i- alen spli - i ion inac i a ed in luenza accine) and In anza 15 µg (in ade mal i alen spli - i ion inac i- a ed in luenza accine) eac ogenici y ha elied on enhanced ou ine pha maco igilance ea ly in he in lu- enza season. In he Uni ed Kingdom (UK), Vaxig ip is ecommended o adul s olde han 65 yea s, isk g oups be ween 18 and 64 yea s and child en be ween 6 mon hs and 2 yea s o age. In Finland, Vaxig ip is ecommended o be used in child en 6 mon hs o 2 yea s o age and in a - isk g oups om 3 o 18 yea s o age. Child en aged 2 o 3 yea s in Finland and 2 yea s and olde in he UK p e e en ially ecei e ano he in luenza accine (li e a enua ed in luenza accine) pe espec i e na ional ecommenda ions [6,7]. In anza 15 µg is only used in he UK and ecommended o indi iduals 60 yea s and olde . No ably, he Vaxig ip ade name in he UK is Inac i a ed In luenza (spli i ion) BP accine, bu i will be e e ed o as Vaxig ip in his manusc ip . The p inciple o his passi e ESS was o apidly es i- ma e accine usage o co e age (numbe o accinees o doses adminis e ed) and o acili a e passi e epo - ing o suspec ed ad e se eac ions (ARs) om ac- cinees in o de o de i e AR epo ing a es om he same sou ce o popula ion. Fo hese spon aneous epo s, causali y assessmen was no eques ed om he accinee o heal hca e p o essionals (HCPs) and was no pe o med by he MAH. The p ima y objec i e was o es ima e he epo ing a es o suspec ed ARs occu ing wi hin 7 days ollow- ing ou ine accina ion wi h Vaxig ip o In anza 15 µg du ing he NH 2015/16 in luenza season. The second- a y objec i es we e o es ima e he epo ing a es o suspec ed ARs occu ing wi hin 7 days ollowing ou- ine accina ion wi h Vaxig ip o In anza 15 µg acco d- ing o age g oup and o se ious suspec ed ARs pos accina ion no limi ed o 7 days. This ESS also aimed o p o ide e e ence epo ing a es o compa ison in he nex in luenza season (2016/17). As an explo a o y objec i e, a ba ch analysis would be pe o med i a signal was de ec ed, whene e possible, o a oid alse a ibu ion o he signal o he gene al in insic sa e y p o ile o he p oduc . Me hods Design This was a mul icen e, non-in e en ional, obse a- ional, passi e ESS conduc ed in he UK and Finland o ensu e he ep esen a i eness o all age g oups indica ed o each accine and he use o a leas wo di e en ba ches. The passi e ESS elied on enhanced ( acili a ed) epo ing o suspec ed ARs by inc easing he awa eness o accinees, h ough ained HCPs, ega ding he impo ance o epo ing suspec ed ARs pos accina ion (especially hose occu ing wi hin 7 days pos accina ion) and by dis ibu ing sa e y epo ca ds (SRCs) ha allowed accinees o epo suspec ed ARs h ough a dedica ed oll- ee elephone numbe . Nea eal- ime, age-speci ic, b and-speci ic in luenza accina ion co e age was achie ed in addi- ion o nea eal- ime analysis es ima ing suspec ed AR epo ing a es wi hin 7 days pos accina ion du ing he NH 2015/16 in luenza season. Se ing The passi e ESS s a ed on 13 Oc obe 2015 o Vaxig ip and 17 Oc obe 2015 o In anza 15 µg and ended when 1,000 SRCs each had been dis ibu ed (on 2 Decembe 2015 o Vaxig ip and on 8 Decembe 2015 o In anza 15 µg). Any epo s ecei ed ou side he ESS pe iod we e handled as ou ine spon aneous epo s bu we e no included in he analysis. Pa icipan s Vaccinees who ecei ed Vaxig ip o In anza 15 µg in ou ine p ac ice du ing he NH 2015/16 in luenza sea- son and who accep ed he SRC (o hei pa en s, in cases o child accinees) we e eligible o pa icipa ion in his ESS. The e we e no exclusion c i e ia. P ocedu es and da a collec ion me hod A pape SRC speci ic o Vaxig ip o In anza 15 µg p o- ided he ollowing in o ma ion o he accinee: de ails ega ding he ESS, ins uc ions on how o epo sus- pec ed ARs, he dedica ed local oll- ee elephone numbe , he si e iden i ie , a unique SRC iden i ica ion numbe , accine b and and ba ch, accina ion da e and name o he ea ing physician. Table1 Sa e y epo ca ds dis ibu ed o Vaxig ip and In anza 15 µg accinees, by age g oup, Uni ed Kingdom and Finland, 2015/16 (n = 2,029) Age g oup Sa e y epo ca ds dis ibu ed Numbe Pe cen age Vaxig ip 6 mon hs o < 6 yea s 496 49.0 ≥ 6 o < 13 yea s 111 11.0 ≥ 13 o < 18 yea s 19 1.9 ≥ 18 o ≤ 65 yea s 149 14.7 > 65 yea s 237 23.4 To al Vaxig ip 1,012 100.0 In anzaa To al In anza 1,017 100.0 a All In anza 15 µg accinees we e ≥ 60 yea s-old. 3www.eu osu eillance.o g Vaccine co e age da a we e collec ed a p ac ice le el by he HCP/ accina o (s) on a eal- ime basis (a leas once a day) using an elec onic da a cap u e sys em. Vaccinees we e encou aged o epo any suspec ed pos - accina ion ARs, especially hose occu ing wi hin 7 days (al hough epo s o ARs a e 7 days we e also conside ed o he analysis). A s uc u ed elephone in e iew was de eloped o ensu e he app op ia e- ness and comple eness o da a collec ion when ac- cinees called o epo suspec ed ARs. All e en s epo ed spon aneously by accinees we e conside ed suspec ed ARs and we e eco ded and epo ed acco ding o Good Pha maco igilance P ac ice module VI [8]. All suspec ed ARs we e desc ibed. PRAC Ad e se E en s o In e es (AEIs), as lis ed in he guid- ance, we e also speci ically desc ibed [5]. Pe p o ocol, side e ec s epo ed by a accinee o HCP we e consid- e ed suspec ed ARs (unless he epo e s speci ically s a ed he e en s o be un ela ed o excluded a causal ela ionship). Sa e y signals we e de ined pe Good Pha maco igilance P ac ice Annex I e ision 3 [9]. Table2 Summa y o suspec ed ad e se eac ions by age g oup, ime o onse and b and, Uni ed Kingdom and Finland, 2015/16 (n = 2,029) Time o onse a e accina ion ≤ 7 days > 7 days To ala n % n % n % Vaxig ip (n = 1,012) To al numbe o suspec ed AR 110 10.9 12 1.2 122 12.1 To al numbe o PRAC AEI 42 4.1 40.4 46 4.5 To al numbe o accinees wi h a leas 1 suspec ed AR 31 3.1 30.3 32 3.2 To al numbe o accinees wi h PRAC AEI 22 2.2 30.3 25 2.5 6 mon hs o < 6 yea s (n = 496) Numbe o suspec ed AR 40 8.1 20.4 42 8.5 Numbe o PRAC AEI 20 4.0 10.2 21 4.2 Numbe o accinees wi h a leas 1 suspec ed AR 14 2.8 10.2 14 2.8 Numbe o accinees wi h PRAC AEI 11 2.2 10.2 12 2.4 ≥ 6 o < 13 yea s (n = 111) Numbe o suspec ed AR 87.2 0 0 8 7.2 Numbe o PRAC AEI 76.3 0 0 7 6.3 Numbe o accinees wi h a leas 1 suspec ed AR 21.8 0 0 2 1.8 Numbe o accinees wi h PRAC AEI 21.8 0 0 2 1.8 ≥ 13 o < 18 yea s (n = 19) No da a epo ed o his age g oup ≥ 18 o ≤ 65 yea s (n = 149) Numbe o suspec ed AR 12 8.0 0 0 12 8.0 Numbe o PRAC AEI 42.7 0 0 4 2.7 Numbe o accinees wi h a leas 1 suspec ed AR 42.7 0 0 4 2.7 Numbe o accinees wi h PRAC AEI 21.3 0 0 2 1.3 > 65 yea s (n = 237) Numbe o suspec ed AR 50 21.1 10 4.2 60 25.3 Numbe o PRAC AEI 11 4.6 31.3 14 5.9 Numbe o accinees wi h a leas 1 suspec ed AR 11 4.6 20.8 12 5.1 Numbe o accinees wi h PRAC AEI 73.0 20.8 93.8 In anzab (n = 1,017) To al numbe o suspec ed AR 99 9.7 15 1.5 114 11.2 To al numbe o PRAC AEI 53 5.2 30.3 56 5.5 To al numbe o accinees wi h a leas 1 suspec ed AR 29 2.9 30.3 31 3.0 To al numbe o accinees wi h PRAC AEI 26 2.6 30.3 28 2.8 AEI: ad e se e en o in e es ; AR: ad e se eac ion; PRAC: pha maco igilance isk assessmen commi ee. a No all numbe s add up as accinees could epo suspec ed AR in bo h ime in e als. b All In anza 15 µg accinees we e ≥ 60 yea s-old. 4www.eu osu eillance.o g Popula ion size The numbe o SRCs needed o be dis ibu ed pe b and (n = 1,000) was es ima ed based on he expec ed AR epo ing a e and he abili y o de ec common o e y common ARs. The numbe o si es (six in Finland and 14 in he UK) was based on he expec ed olume o accina ions wi h Vaxig ip and In anza 15 µg and hei abili y o dis ibu e SRCs wi hin a sho ime pe iod. Age ep esen a i eness o he popula ion was ensu ed h ough coun y/si e selec ion (in Finland, only paedi- a ic accina ion cen es we e selec ed); ne e heless, he SRC dis ibu ion a si e le el ollowed ou ine ac- cina ion p ac ices. The numbe o accinees who would po en ially epo suspec ed ARs could only be s imu- la ed bu no con olled. S a is ical analysis The ESS popula ion included all accinees who we e accina ed in ou ine p ac ice wi h ei he Vaxig ip o In anza 15 µg and who ecei ed he SRC. No con i ma- o y hypo hesis es ing was conduc ed o he analy- ses. All analyses we e desc ip i e and we e p oduced using SAS e sion 9.2. Ve ba im ARs we e coded wi h Medical Dic iona y o Regula o y Ac i i ies e minology ( e sion 18.0) and p ocessed acco ding o ou ine pha - maco igilance p ocesses. ESS epo ing a es we e calcula ed pe b and using he ollowing o mula: ESS epo ing a e = (Numbe o accinees epo - ing ARs wi hin 7 days x 100) / o al numbe o SRCs dis ibu ed Suspec ed AR epo ing a es we e es ima ed pe b and using he ollowing me hod: Suspec ed AR epo ing a e = (Numbe o ARs wi hin 7 days x 100) / o al numbe o SRCs dis ibu ed Con idence in e als (CIs) o ESS epo ing a es we e compu ed using he Wald me hod i he AR coun was ≥ 5 and using exac me hod i he AR coun was < 5. All suspec ed ARs (including PRAC AEIs, se ious sus- pec ed ARs and o he suspec ed ARs) and co espond- ing AR epo ing a es we e epo ed and summa ised by accine, age g oups (Vaxig ip: 6 mon hs o < 6 yea s; Table3 Mos equen ly epo ed suspec ed ad e se eac ions (wi h epo ing a es ≥ 1% ) by age g oup and ime o onse , Uni ed Kingdom and Finland, 2015/16 (n = 2,029) P e e ed e m Time o onse ≤ 7 days > 7 days To al n % CI n % CI n % CI Vaxig ip (n = 1,012) 6 mon hs o < 6 yea s (n = 496) Cough 51.0 0.1–1.9 0 5 1.0 0.1–1.9 Py exia 71.4 0.4–2.4 10.2 0.0–1.1 81.6 0.5–2.7 Rhino hoea 51.0 0.1–1.9 10.2 0.0–1.1 61.2 0.2–2.2 ≥ 6 o < 13 yea s (n = 111) Vaccina ion si e e y hema 21.8 0.2–6.4 0 2 1.8 0.2–6.4 ≥ 13 o < 18 yea s (n = 19) No da a epo ed o his g oup ≥ 18 o ≤ 65 yea s (n = 149) No suspec ed AR ≥ 1% o o al epo ed o his g oup > 65 yea s (n = 237) Cough 31.3 0.3–3.7 10.4 0.0–2.3 41.7 0.5–4.3 Fa igue 20.8 0.1–3.0 10.4 0.0–2.3 31.3 0.3–3.7 Headache 31.3 0.3–3.7 10.4 0.0–2.3 41.7 0.5–4.3 In luenza-like illness 52.1 0.3–3.9 0 5 2.1 0.3–3.9 Malaise 31.3 0.3–3.7 20.8 0.1–3.0 52.1 0.3–3.9 Nasopha yngi is 31.3 0.3–3.7 0 3 1.3 0.3–3.7 O opha yngeal pain 20.8 0.1–3.0 10.4 0.0–2.3 31.3 0.3-3.7 In anza b 15 µg (n = 1,017) Vaccina ion si e pain 10 1.0 0.4–1.6 010 1.0 0.4-1.6 AR: ad e se eac ion; CI: con idence in e al. a No all numbe s add up as accinees could epo suspec ed AR in bo h ime in e als. b All In anza 15 µg accinees we e ≥ 60 yea s-old. 5www.eu osu eillance.o g ≥ 6 yea s o < 13 yea s; ≥ 13 yea s o < 18 yea s, ≥ 18 yea s o ≤ 65 yea s, and > 65 yea s; In anza 15 µg: ≥ 60 yea s), se iousness (Yes/No), se e i y (G ade 1 (mild), G ade 2 (mode a e), G ade 3 (se e e), and unknown pe p o ocol se e i y de ini ion), and day o onse since accina ion (≤ 7 and > 7 days). A simila analysis was also pe o med on se ious suspec ed ARs. The mean numbe o ARs pe accinee who epo ed a leas one suspec ed AR was also calcula ed. Fo each b and, weekly epo s o signal de ec ion we e gene - a ed and analysed. A 1-mon h in e im epo (1 mon h a e he i s SRCs we e dis ibu ed) and a inal epo we e compiled and submi ed o he ele an heal h au ho i ies. AR epo ing a es we e calcula ed and compa ed wi h he equency o he AEIs epo ed du - ing he NH 2014/15 in luenza season clinical ials and wi h he expec ed a es based on cu en p oduc -spe- ci ic da a om he Summa y o P oduc Cha ac e is ics (SmPC) [10]. No s a is ical es s we e pe o med [11]. E hics The ESS was conduc ed in acco dance wi h Good Epidemiological P ac ice, he Eu opean Ne wo k o Cen es o Pha macoepidemiology and Pha maco igilance Guide on Me hodological S anda ds in Pha macoepidemiology [12,13] and Good Pha maco igilance P ac ices [8]. The ESS was submi - ed o na ional au ho i ies as equi ed by he local egula ions and was app o ed by na ional e hics commi ees. Resul s Exposu e da a A o al o 1,012 SRCs o Vaxig ip and 1,017 SRCs o In anza 15 µg we e dis ibu ed o di e en age g oups in he UK and Finland du ing he 8-week pe iod om 13 Oc obe o 8 Decembe 2015 (Table 1). We also consid- e ed in he analysis addi ional SRCs dis ibu ed on he same day he 1,000 h SRC was eached. The ESS co e ed 21 di e en ba ches o Vaxig ip and h ee di e en ba ches o In anza 15 µg. App oxima ely hal (51%) o he Vaxig ip accinees ecei ed he same ba ch; he o he hal (49%) ecei ed Vaxig ip om 20 di e en ba ches. Almos all o he In anza accinees (excep h ee accinees) ecei ed he same ba ch. Because no sa e y signal was de ec ed o ei he Vaxig ip o In anza 15 µg, no speci ic ba ch analysis was conduc ed. Vaxig ip sa e y da a Among he Vaxig ip accinees, 32 (3.2%) epo ed a o al o 122 suspec ed ARs (mean o 3.8 ARs/ accinee who epo ed a leas one AR), including 110 suspec ed ARs ha occu ed wi hin 7 days pos - accina ion (Table 2). The highes epo ing a e o suspec ed ARs occu - ing wi hin 7 days pos accina ion was obse ed in accinees olde han 65 yea s; 11 o hese accinees epo ed 50 suspec ed ARs (4.5 ARs wi hin 7 days/ ac- cinee who epo ed a leas one AR; Table 2). Table4 Mos equen ly epo ed PRAC ad e se e en s o in e es (e en s epo ed a leas wice) wi h onse wi hin 7 days, by se e i y, Uni ed Kingdom and Finland, 2015/16 (n = 2,029) P e e ed e m Mild Mode a e Se e e Unknown To al n % 95%CI n % 95%CI n % 95%CI n % 95%CI n % 95%CI Vaxig ip (n = 1,012) Numbe o accinees wi h PRAC AEI 90.9 0.3–1.5 30.3 0.1–0.9 50.5 0.1–0.9 90.9 0.3–1.5 22 2.2 1.3–3.1 Headache 0 0 0 0 0 0 1 0.1 0.0–0.5 40.4 0.1–1.0 50.5 0.1–0.9 Py exia 30.3 0.1–0.9 10.1 0.0–0.5 20.2 0.0–0.7 30.3 0.1–0.9 90.9 0.3–1.5 Vaccina ion si e e y hema 10.1 0.0–0.5 10.1 0.0–0.5 20.2 0.0–0.7 10.1 0.0–0.5 50.5 0.1–0.9 In anza 15 µg (n = 1,017) Numbe o accinees wi h PRAC AEI 18 1.8 1.0–2.6 20.2 0.0–0.7 30.3 0.1–0.9 70.7 0.2–1.2 26 2.6 1.6–3.5 Malaise 30.3 0.1–0.9 0 0 0 1 0.1 0.0–0.5 20.2 0.0–0.7 60.6 0.1–1.1 Vaccina ion si e e y hema 60.6 0.1–1.1 10.1 0.0–0.5 0 0 0 2 0.2 0.0–0.7 90.9 0.3–1.5 Vaccina ion si e pain 90.9 0.3–1.5 0 0 0 0 0 0 1 0.1 0.0–0.5 10 1.0 0.4–1.6 Vaccina ion si e p u i us 40.4 0.1–1.0 0 0 0 1 0.1 0.0–0.5 0 0 0 5 0.5 0.1–0.9 Vaccina ion si e swelling 50.5 0.1–0.9 0 0 0 0 0 0 0 0 0 5 0.5 0.1–0.9 AEI: ad e se e en o in e es ; PRAC: pha maco igilance isk assessmen commi ee. No e: PRAC AEIs as lis ed in he guidance we e speci ically desc ibed as ollows: Injec ion si e eac ions (pain, e y hema, p u i us, swelling, indu a ion and ecchymosis) and sys emic eac ions ( e e >38°C, headache, malaise, myalgia, shi e ing, ash, omi ing, nausea, a h algia, dec eased appe i e, i i abili y ( o accinees younge han 5 yea s), c ying ( o accinees younge han 5 yea s), and e en s indica i e o alle gic and hype sensi i i y eac ions including ocula symp oms). 6www.eu osu eillance.o g The e was no ob ious dis ibu ion pa e n in he ype o suspec ed ARs ac oss age g oups, wi h he majo i y o indi idual ARs occu ing a a equency o less han 1%. The o al numbe o suspec ed ARs ha occu ed a a equency o 1% o highe a e p esen ed by age g oup and ime o onse in Table 3. One se ious suspec ed AR was epo ed ollowing Vaxig ip accina ion. A pe son in hei la e 70s expe- ienced a ches in ec ion (lowe espi a o y ac in ec- ion, which was conside ed o be an impo an medical e en ) 18 days a e accina ion, which s a ed wi h so e h oa , headache, coughing and eeling ‘unpleas- an ’ and ho . The accinee’s medical his o y included a p e ious ches in ec ion 2 weeks be o e he in luenza accina ion. The accinee was la e epo ed o be eco e ing om he second ches in ec ion ollowing accina ion. O e all, 46 suspec ed PRAC AEIs we e epo ed by 25 accinees (1.8 suspec ed AEIs/ accinee who epo ed a leas one AR). O hese AEIs, 42 suspec ed AEIs occu ed wi hin 7 days pos accina ion (Table 2). The mos equen (n ≥ 2) PRAC AEIs wi h an onse wi hin 7 days pos accina ion a e p esen ed by se e i y in Table 4. The e was no ob ious dis ibu ion pa e n in he ype o AEIs, hei se e i y o hei equency obse ed ac oss age g oups o Vaxig ip. All AEIs we e consid- e ed no se ious. In anza sa e y da a Among he In anza 15 µg accinees, 31 (3.0%) epo ed 114 suspec ed ARs (3.7 ARs/ accinee who epo ed a leas one AR), including 99 suspec ed ARs ha occu ed wi hin 7 days pos accina ion (Table 2). All o he suspec ed ARs we e non-se ious. One ac- cinee could no be included in he analysis because o insu icien in o ma ion o iden i y he SRC numbe . This accinee had epo ed he non-se ious suspec ed ARs o cough and pain. The mos equen ly epo ed suspec ed ARs wi hin 7 days pos accina ion ( hose epo ed by ≥ 1% o accinees) a e lis ed in Table 3. O e all, 56 suspec ed PRAC AEIs we e epo ed by 28 accinees (2 AEIs/ accinee who epo ed a leas one AR). O hese AEIs, 53 AEIs occu ed wi hin 7 days pos accina ion (Table 2). All AEIs we e conside ed non- se ious. The mos equen (n ≥ 2) PRAC AEIs wi h an onse wi hin 7 days pos - accina ion a e p esen ed by se e i y in Table 4. Compa ison o he epo ed equencies wi h he e e ence da a om he no he n hemisphe e 2014/15 enhanced sa e y su eillance No inc ease was no ed in he obse ed AEI equencies o Vaxig ip o In anza 15 μg du ing he NH 2015/16 ESS when compa ed wi h he equencies obse ed du ing he NH 2014/15 ESS (da a no shown). Compa ison o he epo ed equencies wi h he Summa y o P oduc Cha ac e is ics Vaxig ip In luenza-like illness (ILI) was ound o ha e a highe epo ing equency in his ESS compa ed wi h he Vaxig ip SmPC. ILI was epo ed by i e accinees Table5 Compa ison o o he eac ions (no solici ed in he no he n hemisphe e 2014/15 clinical ial) wi h he Vaxig ip Summa y o P oduc Cha ac e is ics, Uni ed Kingdom and Finland, 2015/16 (n = 2,029) Ad e se eac iona ESS 2015/16 (≤ 7 days) Vaxig ip SmPC (≤ 7 days) F equencybCompa ison esul Ageg oup Obse ed equency pe age g oup Ageg oup SmPC ESS 2015/16 Highe o equal o lowe han SmPC Dia hoea 6 mon hs o < 6 yea s 0.2% 6 o 35 mon hs Ve y common Uncommon Lowe Dia hoea ≥ 18 yea sc0.3% ≥ 18 yea s Uncommon Uncommon Equal Dizziness ≥ 18 yea sc0.5% ≥ 18 yea s Uncommon Uncommon Equal In luenza- like illness ≥ 18 yea sc1.3% ≥ 18 yea s Uncommon Common Highe As henia ≥ 18 yea sc0.3% ≥ 18 yea s Ve y common Uncommon Lowe Swea ing inc eased ≥ 18 yea sc0.3% ≥ 18 yea s Common Uncommon Lowe ESS: enhanced sa e y su eillance; SmPC: summa y o p oduc cha ac e is ics. No e: A accinee wi h mul iple occu ences o an ad e se eac ion is coun ed only once unde he applicable sys em o gan class/p e e ed e m. a Only no solici ed ad e se eac ions in he no he n hemisphe e 2014/15 clinical ial and epo ed in his ESS a e compa ed wi h he SmPC and included in his able. b Ve y common (≥ 1/10 o ≥ 10%); common (≥ 1/100 o < 1/10 o ≥ 1% o < 10%); uncommon (≥ 1/1,000 o < 1/100 o ≥ 0.1% o < 1%); a e (≥ 1/10,000 o < 1/1,000 o ≥ 0.01% o < 0.1%); e y a e (< 1/10,000 o < 0.01%). c Combined age g oups o adul and elde ly accinees. 7www.eu osu eillance.o g (2.1%; 95% CI: 0.3–3.9%) olde han 65 yea s bu was no epo ed by accinees aged 18–65 yea s, which led o a combined ILI epo ing a e o 1.3%. This obse ed equency was sligh ly highe han he ‘uncommon’ (≥ 0.1% o < 1%) equency o ILI in he g oups o adul s and elde ly people in he SmPC. Howe e , he sligh ly highe epo ing a e obse ed was no conside ed clinically ele an upon medical e iew. The o he sus- pec ed ARs had equencies lowe han o equal o he SmPC equencies (Table 5). In anza 15 µg Fa igue and swea ing (hype hyd osis) we e epo ed ollowing In anza accina ion, and he epo ed e- quencies in he ESS we e simila o hose e e enced in he SmPC (Table 6). Discussion In his ESS, accinees we e encou aged o epo any suspec ed ARs ha hey expe ienced, wi h an empha- sis on hose occu ing wi hin 7 days pos accina ion. Hence, he epo ing o suspec ed ARs was s imula ed bu emained spon aneous in na u e (i.e. no solic- i ed). We obse ed highe epo ing a es when spon- aneous no i ica ion was s imula ed (3.2% o Vaxig ip and 3.0% o In anza 15 µg) compa ed wi h epo ing a es in ou ine pha maco igilance (passi e spon ane- ous non-s imula ed sys em). Spon aneous epo ing a es a e seasonal in luenza accina ion ange om 20 o 90 epo s pe 1,000,000 people accina ed [14- 19]. Passi e ESS has been shown o inc ease epo ing a es wo- o i e old when swi ched om ou ine pha - maco igilance [20,21]. This s udy was execu ed in a ime-e icien manne . App oxima ely 1.5–2 hou s pe HCP we e dedica ed o p o ocol aining, p ocesses o be used, managemen o accinees, si e managemen and he end o he ESS p ocess, depending on s a in ol ed. The con ac cen- e needed ca 15 min pe accinee o eco d he sus- pec ed AR. Howe e , in o ma ion on he ime spen pe accinee by he HCP o explain he ESS, dis ibu e he SRCs, and explain how ARs we e o be epo ed was no collec ed as pa o his ESS. The s eng hs o his ESS we e ha he numbe o SRCs dis ibu ed was consis en wi h he es ima ed sample size and ha weekly analyses we e pe o med, which allowed o nea eal- ime in es iga ion o he eac- ogenici y o Vaxig ip and In anza 15 µg. The sa e y epo s ecei ed we e well documen ed in e ms o exposu e da a (b and, ba ch and da e o accina ion), which is no always he case wi h ou ine pha maco ig- ilance. The o e all epo ing a es o he wo p oduc s we e o he same o de o magni ude. By conside ing wo coun ies and using a ho ough si e selec ion p o- cess, we we e able o ga he da a ac oss all age g oups as ecommended by he guidance, including da a in paedia ic age g oups, o e - ep esen ed compa ed wi h paedia ic ou ine co e age a e. O e all, he mean numbe s o suspec ed ARs pe ac- cinee who epo ed a leas one AR wi hin 7 days pos - accina ion we e 3.8 o Vaxig ip and 3.7 o In anza 15 µg, anging be ween 0 ( o accinees in he 13–18 yea s age g oup owing o he small numbe o SRCs dis ib- u ed) and 13 ( o accinees olde han 65 yea s). The highe a e age numbe o suspec ed ARs in he g oup o elde ly people could be due o he well-known co - ela ion be ween inc easing age and AR epo ing a e. F ail y, medical his o y and concomi an use o medica- ion a e common causes o his phenomenon [22]. No ob ious dis ibu ion pa e n in he ype and equency o suspec ed ARs was obse ed ac oss age g oups o ei he accine. All o he epo ed ARs we e non-se ious, excep o one se ious AR epo ed a e Vaxig ip accina ion. The passi e ESS esul s do no aise any conce ns abou he sa e y o Vaxig ip and In anza 15 µg. None o he obse ed equencies o AEIs in he cu en ESS we e abo e he equencies obse ed du ing he NH 2014/15 Table6 Compa ison o o he eac ions (no solici ed in he no he n hemisphe e 2014/15 clinical ial) wi h In anza 15 µg summa y o p oduc cha ac e is ics, Uni ed Kingdom and Finland, 2015/16 (n = 2,029) Ad e se eac ion ESS 2015/16 (≤ 7 days + > 7 days) In anza15µgSmPC (≤ 7 days + > 7 days) F equencybCompa ison esul Ageg oupcRepo ed equency pe age g oup Age g oup SmPC ESS 2015/16 Highe o equal o lowe han SmPC Fa igue ≥ 18 yea s 0.2% > 60 yea s Uncommon Uncommon Equal Swea ing ≥ 18 yea s 0.2% > 60 yea s Uncommon Uncommon Equal ESS: enhanced sa e y su eillance; SmPC: summa y o p oduc cha ac e is ics. No e: A accinee wi h mul iple occu ences o an ad e se eac ion is coun ed only once unde he applicable sys em o gan class/p e e ed e m. a Only no solici ed ad e se eac ions in he no he n hemisphe e 2014/15 clinical ial and epo ed in his ESS a e compa ed wi h he SmPC and included in his able. b Ve y common (≥ 1/10 o ≥ 10%); common (≥ 1/100 o < 1/10 o ≥ 1% o < 10%); uncommon (≥ 1/1,000 o < 1/100 o ≥ 0.1% o < 1%); a e (≥ 1/10,000 o < 1/1,000 o ≥ 0.01% o < 0.1%); e y a e (< 1/10,000 o < 0.01%). c Combined age g oups o adul and elde ly accinees. 8www.eu osu eillance.o g clinical s udy [11]. No sa e y issues we e obse ed, and he sa e y p o ile o he wo accines was consis en wi h wha is known o bo h p oduc s. Pe EMA in e im guidance, da a was o be gene a ed om a leas wo ba ches o he accines. This equi emen was ul illed o Vaxig ip bu was no easible o In anza 15 µg owing o he agmen ed ma ke sha e. The passi e ESS had he ollowing po en ial limi a ions: i s ly, he e was no con ol o e he ac ual epo ing (unde - epo ing was s ill possible) o he iming o a suspec ed AR epo ela i e o he ime since accina- ion (suspec ed ARs ha occu ed wi hin 7 days could s ill be epo ed ou side he ESS pe iod). Secondly, he age g oups in which he accine was used could no be con olled and depended on na ional ecommen- da ions o in luenza accina ion, as well as he ac- cine co e age a es pe age g oup obse ed in ou ine p ac ice. In addi ion, he choice o conduc he ESS in wo coun ies, wi h Finland dedica ed o he dis ibu- ion o paedia ic SRCs, a ec ed he age g oup dis- ibu ion o he SRC. Du ing he ESS, all age g oups we e ep esen ed. Howe e , o Vaxig ip, mos o he SRCs we e dis ibu ed in he age g oups 6 mon hs o < 6 yea s (n = 496) and in he age g oup olde han 65 yea s (n = 237). Only 19 SRCs we e dis ibu ed in he age g oup 13 o 18 yea s. The e o e, da a om his speci ic paedia ic age g oup we e di icul o cap u e owing o low in luenza accine co e age. Thi dly, some deg ee o selec ion bias may ha e occu ed because accinees who accep ed he SRC migh ha e epo ed mo e (o ewe ) ARs han hose who e used he SRC. Mo eo e , HCPs could ha e p eselec ed he accinees o whom he SRC was p oposed, e en i he ins uc ions we e o dis ibu e he SRC on an ongoing basis o all eligible accinees. In addi ion, he accinees who ecei ed he accine ea ly in he season migh ha e been di e en om hose who ecei ed he accine la e in he sea- son. Howe e , his bias is mos p obably limi ed, as some si es dis ibu ed he SRCs e y quickly o la ge accinee g oups on days o massi e o ganised in lu- enza accina ions. Finally, some ope a ional cons ain s we e aced be o e ini ia ing his ESS a he si e le el. In he UK, he e was no o icial s a da e and in luenza accina ion s a ed by he middle o Oc obe in he con ex o ESS a he selec ed si es. In Finland, he na ional o icial s a da e o he in luenza accina ion was 9 No embe 2015. The s a da e a he si e le el o he ESS depended on HCP a ailabili y o ini ia ion, con ac signa u e, local p ac ice o ganisa ion o seasonal in luenza accina- ion and di e en local app o al da es. The i s si e in Finland s a ed SRC dis ibu ion on 10 No embe 2015, immedia ely a e he o icial na ional s a da e o in luenza accina ion. The ESS s a ed as closely as possible o he ime o he i s in luenza accina ions in he selec ed si es in bo h coun ies; howe e , hese s a da es may ha e been some weeks a e he i s adminis a ion o Vaxig ip doses elsewhe e in Eu ope and may ha e a ec ed he speed a which po en ial sa e y issues could ha e been de ec ed. The es ima ed AR epo ing a es will p o ide base- line AR epo ing a es o imp o e compa ison du ing he nex NH in luenza season (2016/17) using a simi- la passi e me hodology. A limi a ion in he cu en compa ison is ha he e e ence da a om ESS NH 2014/15 we e ob ained om ac i e sa e y su eillance (clinical ial) and no om spon aneous epo ing. The inalisa ion o he guidance ela ed o ESS is cu en ly unde discussion a EMA, and cu en passi e ESS pilo expe iences will p o ide da a o u he suppo ecom- menda ions. Despi e he his o ic success o immunisa- ion in educing he mo bidi y and mo ali y o se e al diseases, some public conce ns abou he sa e y o accines emain. These conce ns occasionally e ode public con idence in immunisa ion and some imes lead o accine hesi ancy and disease ou b eaks. The e o e, enhanced in luenza accine sa e y moni o ing can con- ibu e o inc ease public con idence in accine sa e y. In he absence o a mo e sys emic, cen alised, pan- Eu opean sa e y su eillance sys em, we belie e ha he passi e ESS expe ience p esen s a sui able model o enhanced passi e su eillance o seasonal in lu- enza accines. Conclusions The cu en pilo ESS used a passi e app oach and showed highe AR epo ing a es han p e iously shown o ou ine spon aneous epo ing. The e was no ob ious dis ibu ion pa e n in he ype and e- quency o suspec ed ARs o Vaxig ip o In anza 15 µg. We did no obse e any clinically signi ican changes compa ed wi h wha is known o expec ed o ei he accine, no any sa e y conce ns du ing he cu en ESS pe iod. The ESS esul s ha e imp o ed da a epo ing and demons a ed i s sui abili y o heal h au ho i ies’ equi emen s; u he ine uning o he me hodology is unde discussion be ween all s akeholde s. A con- inuous dialogue be ween he MAHs ( h ough Vaccines Eu ope) and he Eu opean heal h au ho i ies will help op imise and scale up he ESS sys em o u u e seasons. Acknowledgemen s The au ho s acknowledge all o he accinees, physicians and nu ses who pa icipa ed in he ESS in Finland and in he UK. Con lic o in e es The s udy was sponso ed and unded by Sano i Pas eu MSD. 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