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)
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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.
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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.
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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. HB, ALC, and CS a e employees a Sano i Pas eu MSD.
Au ho s’ con ibu ions
HB and ALC con ibu ed o he design, se up, da a analysis,
in e p e a ion o esul s, and ou line and manusc ip w i ing.
9www.eu osu eillance.o g
CS pa icipa ed in he design and he ou line and manusc ip
e iew. AS con ibu ed o he s a is ical analysis plan w i -
ing, da a analysis, in e p e a ion o esul s, and ou line and
manusc ip e iew. TC and TV e iewed he design, pa ici-
pa ed in he se up and s udy conduc , and e iewed he con-
en o he manusc ip .
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