Concomi an adminis a ion o a ully liquid eady- o-use
DTaP-IPV-HB-PRP-T hexa alen accine wi h a meningococcal
ACWY conjuga e accine in oddle s
Timo Vesika i
a
, Ray Bo ow
b
, Xa ie Da Cos a
c
, S éphane Thomas
d
, Cécile Eymin
d,
⇑
, Flo ence Boisna d
d,1
,
S ephen Lockha
d,2
a
Vaccine Resea ch Cen e , FM3/Bioka u 10, 33014 Uni e si y o Tampe e, Tampe e, Finland
b
Vaccine E alua ion Uni , Public Heal h England, Clinical Sciences Building 2, Manches e Royal In i ma y, Ox o d Road, Manches e M13 9WL, UK
c
Sano i Pas eu Inc., Global Clinical Immunology, PO Box 187, Disco e y D i e, Swi wa e , PA 18370-0190, USA
d
Sano i Pas eu MSD, 162 A enue Jean Jau es, 69367 Lyon Cedex 07, F ance
a icle in o
A icle his o y:
Recei ed 4 Ap il 2018
Recei ed in e ised o m 2 Oc obe 2018
Accep ed 31 Oc obe 2018
A ailable online 22 No embe 2018
Keywo ds:
Co-adminis a ion
DTaP-IPV-HB-PRP-T
MenACWY-TT
Immunogenici y
Sa e y
Boos e accina ion
abs ac
In asi e meningococcal disease caused by Neisse ia meningi idis is a li e- h ea ening disease. Se e al coun-
ies now include meningococcal se og oup C (MenC) conjuga e and, mo e ecen ly, a meningococcal se -
og oup ACWY conjuga e (MenACWY) accina ion in hei na ional immuniza ion schedules. DTaP-IPV-
HB-PRP-T is a hexa alen accine ha p o ides p o ec ion agains six diseases. The phase III, open-label, an-
domised, mul icen e s udy en olled heal hy oddle s who ecei ed he DTaP-IPV-HB-PRP-T accine (a 2, 3
and 4 mon hs) wi ho wi hou a MenC accine (a 2 and 4 mon hs) in hep ima y se iess udy. A 12 mon hs
o age, 312 oddle s we e andomised o ecei e DTaP-IPV-HB-PRP-T co-adminis e ed wi h MenACWY-TT
accine (G oup A; n = 104); DTaP-IPV-HB-PRP-T accine alone (G oup B; n = 105); o MenACWY-TT accine
alone (G oup C; n = 103). A 12 mon hs o age, he e we e no no able di e ences in e ms o an ibody pe -
sis ence o any DTaP-IPV-HB-PRP-T accine an igen, whe he MenC-TT conjuga e accine was co-
adminis e ed o no du ing he p ima y se ies. Following boos e accina ion, immune esponses o
DTaP-IPV-HB-PRP-T and MenACWY-TT accines we e no a ec ed by co-adminis a ion. One mon h a e
accina ion, he immune esponses elici ed by bo h accines we e high, whe he adminis e ed concomi-
an ly o sepa a ely. The adminis a ion o MenC accine du ing in ancy did no p eclude he use o a
MenACWY-TT accine o boos e accina ion. E en hough he eac ogenici y a e co-adminis a ion
was somewha highe , he esul s o his s udy suppo he concomi an adminis a ion o he DTaP-IPV-
HB-PRP-T accine wi h a MenACWY-TT conjuga e accine when gi en om 12 mon hs o age.
The clinical ial egis a ion numbe s a e: clinical ial.go : NCT01839175; Eud aCT: 2012-005547-24.
Ó2018 The Au ho s. Published by Else ie L d. Thisis an open access a icle unde he CC BY-NC-NDlicense
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
1. In oduc ion
In asi e meningococcal disease is a con agious and li e-
h ea ening in ec ion caused by Neisse ia meningi idis, a G am-
nega i e endo oxin-p oducing bac e ium known o i s abili y
o cause epidemic disease [1,2]. Meningococcal disease occu s
wo ldwide, wi h conside able geog aphical a iabili y in
se og oup dis ibu ion [3,4]. Fa ali y a es o cases o in asi e
meningococcal disease a e be ween 5% and 15%, wi h 20% o su -
i o s su e ing pe manen sequelae including hea ing loss, neu-
ological impai men , seizu es and in ellec ual disabili ies [5].
Se e al coun ies including he UK o me ly in oduced
meningococcal se og oup C conjuga e (MenC)
3
accina ion and,
mo e ecen ly, a meningococcal se og oup ACWY conjuga e
h ps://doi.o g/10.1016/j. accine.2018.10.100
0264-410X/Ó2018 The Au ho s. Published by Else ie L d.
This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
⇑
Co esponding au ho a : Campus Sano i Lyon, 14 Espace Hen y Vallée, 69007 Lyon, F ance.
E-mail add esses: [email p o ec ed] (T. Vesika i), [email p o ec ed] (R. Bo ow), [email p o ec ed] (X. Da Cos a), [email p o ec ed] (S. Thomas),
[email p o ec ed] (C. Eymin), [email p o ec ed] (F. Boisna d), [email p o ec ed] (S. Lockha ).
1
Cu en add ess: Campus Sano i Lyon, 14 Espace Hen y Vallée, 69007 Lyon, F ance.
2
Cu en add ess: P ize Vaccine Clinical R&D, Ho izon Building, Honey Lane, Hu ley SL6 6RJ, Uni ed Kingdom.
3
Abb e ia ions: AE, ad e se e en ; AESI, ad e se e en o special in e es ; aP, acellula pe ussis; AR, ad e se eac ion; CI, con idence in e al; CRF, case eco d o ms; D,
diph he ia; FHA, ilamen ous haemagglu inin; GMC, geome ic mean concen a ion; GMT, geome ic mean i e; HB, hepa i is B; Hib, Haemophilus in luenzae ype b; IPV,
inac i a ed polio i us; ISR, injec ion si e eac ions; LLOQ, lowe limi o quan i a ion; LLT, lowes le el e m; MedDRA
Ò
, Medical Dic iona y o Regula o y Ac i i ies; Men C,
meningococcal se og oup C; MenACWY, meningococcal se og oups A, C, W and Y; NA, no applicable; PPS, pe -p o ocol se ; PRP, Haemophilus in luenzae ype b capsula
poly ibosyl- ibi ol-phospha e; PT, pe ussis oxoid; SAE, se ious ad e se e en ; SAR, se ious ad e se eac ion; SBA, se um bac e icidal an ibody; T, e anus; TT, e anus oxoid.
Vaccine 36 (2018) 8019–8027
Con en s lis s a ailable a ScienceDi ec
Vaccine
jou nal homepage: www.else ie .com/loca e/ accine
(MenACWY) accina ion, in o hei na ional immunisa ion sched-
ules [6].
The hexa alen diph he ia (D), e anus (T), acellula pe ussis
(aP), inac i a ed polio i us (IPV), hepa i is B (HB), Haemophilus
in luenzae ype-b (Hib) capsula poly ibosyl- ibi ol-phospha e
(PRP) accine (DTaP-IPV-HB-PRP-T; Hexyon
Ò
, Hexacima
Ò
, Hex-
axim
Ò
, Sano i Pas eu ; Lyon, F ance) is a ully liquid eady- o-use
combina ion accine ha p o ides p o ec ion agains six diseases.
A p ima y se ies accina ion s udy designed o assess he immuno-
genici y and sa e y o DTaP-IPV-HB-PRP-T when adminis e ed con-
comi an ly wi h a MenC accine du ing he i s yea o li e, and
whe he concomi an adminis a ion has any impac on he
immunogenici y and sa e y o ei he accine has al eady been pub-
lished [7]. The da a p esen ed he e epo he immunogenici y
esul s and sa e y indings om he boos e pa o he p e ious
wo– h ee- ou mon h p ima y se ies s udy ha assessed he co–
adminis a ion o a boos e dose o he DTaP-IPV-HB-PRP-T accine
wi h a MenACWY- e anus oxoid (TT) accine. In his s udy a boos-
e dose o a MenACWY accine ollowing a childhood MenC acci-
na ion was es ed as accina ion wi h MenACWY is al eady (o
likely o be in he nea u u e) he p e e ed ecommended immu-
nisa ion schedule agains meningococcal diseases.
1.1. Objec i es
The p ima y objec i e o his boos e pa o he p ima y s udy
was o desc ibe he immunogenici y o a boos e dose o he DTaP-
IPV-HB-PRP-T accine and a MenACWY-TT accine ei he co-
adminis e ed a 12 mon hs o age o gi en sepa a ely.
The seconda y objec i e was o desc ibe he an ibody pe sis-
ence a 12 mon hs o age o he DTaP-IPV-HB-PRP-T accine ol-
lowing a h ee–dose p ima y accina ion a wo, h ee and ou
mon hs o age (p io o adminis a ion o a boos e dose). The sec-
onda y objec i es included he desc ip ion o he sa e y o a boos-
e dose o he DTaP-IPV-HB-PRP-T accine and MenACWY-TT
accine ei he co–adminis e ed a 12 mon hs o age o gi en sepa-
a ely. The s udy was desc ip i e; no o mal hypo heses we e
es ed.
2. Ma e ials and me hods
2.1. S udy popula ion
Heal hy oddle s who ecei ed h ee doses o he DTaP-IPV-HB-
PRP-T accine in he p ima y se ies s udy we e eligible o
en olmen .
The main exclusion c i e ia we e:
p e ious boos e accina ion agains diph he ia, e anus, pe -
ussis, hepa i is B, poliomyeli is, Hib, o meningococcus wi h
ei he he DTaP-IPV-HB-PRP-T accine o ano he accine
p e ious (wi hin ou weeks) o planned accina ion du ing
s udy pa icipa ion,
any his o y o diph he ia, e anus, pe ussis, poliomyeli is, hep-
a i is B, Hib o meningococcal se og oup A, C, W o Y in ec ion
(s) con i med ei he clinically, se ologically o mic obiologically
known o suspec ed con aindica ion(s) o any o he s udy
accines
hype sensi i i y o alle gy o componen s o he s udy accines
 eceip o an icoagulan s in he p e ious h ee weeks, con-
aindica ing in amuscula injec ion
 eceip o high doses o sys emic co icos e oid he apy o o he
immunosupp essi e he apy in he p e ious h ee mon hs
any ecen his o y o ch onic disease o medical condi ion likely
o in e e e wi h he ial assessmen s.
2.2. Vaccines and accina ions
All accines we e adminis e ed acco ding o hei espec i e
summa ies o p oduc cha ac e is ics [8–12]. The hexa alen
DTaP-IPV-HB-PRP-T accine (0.5 mL; ba ch numbe : S4370) and/
o MenACWY-TT accine (0.5 mL; Nimen ix
Ò
manu ac u ed by
GlaxoSmi hKline Biologicals SA; ba ch numbe : A90CA032A) we e
adminis e ed in amuscula ly in he an e ola e al aspec o he
igh high. NeisVac-C
Ò
(Bax e AG; ba ch numbe : VNS1M04C)
and P e ena 13
Ò
(P ize ; ba ch numbe : G40914) wi h o wi hou
measles, mumps and ubella accine (li e) (M-M-R axP o
Ò
; Me ck
Sha p & Dohme Co po a ion; ba ch numbe : J011869) we e admin-
is e ed 5 cm apa in he le high.
Fu he de ails o he accines used a e p o ided in Supplemen-
a y Da a 1. The adminis a ion o MenACWY-TT was pe o med
ei he a leas one mon h be o e (G oup C; con ol g oup o
MenACWY-TT accine), o concomi an ly wi h (G oup A; es
g oup), a TT-con aining DTaP-IPV-HB-PRP-T accine. As adminis-
a ion o MenACWY-TT one mon h a e a TT-con aining accine
was no ecommended, and as Nimen ix did no ha e any co-
adminis a ion labelling claim wi h P e ena 13, MenC-TT accine
was adminis e ed ins ead o MenACWY-TT accine o subjec s in
G oup B (con ol g oup o he DTaP-IPV-HB-PRP-T accine) a
app oxima ely 13 mon hs o age o ensu e p o ec ion agains
MenC se og oup.
2.3. S udy design
This phase III, open-label, andomised, mul icen e s udy (clin-
ical ial.go : NCT01839175; Eud aCT: 2012-005547-24) was con-
duc ed a 11 accine esea ch clinics in Finland.
The andomisa ion was s a i ied by g oups om he p ima y
se ies (i.e., G oup 1: DTaP-IPV-HB-PRP-T accine co-adminis e ed
wi h MenC accine; G oup 2: DTaP-IPV-HB-PRP-T accine wi hou
MenC-TT accine). Pa icipan s en olled in he boos e phase we e
andomly assigned in a 1:1:1 a io o one o h ee accina ion
g oups i espec i e o hei p ima y se ies en olmen g oup. In
G oup A, pa icipan s ecei ed a dose o DTaP-IPV-HB-PRP-T ac-
cine wi h a dose o MenACWY-TT accine a app oxima ely
12 mon hs o age, and 28–42 days la e hey ecei ed a dose o
P e ena 13 (i.e., a app oxima ely 13 mon hs o age). In G oup B,
pa icipan s ecei ed a dose o DTaP-IPV-HB-PRP-T accine a
app oxima ely 12 mon hs o age, and doses o MenC-TT accine
and P e ena 13 a app oxima ely 13 mon hs o age. In G oup C,
pa icipan s ecei ed a dose o MenACWY-TT accine a app oxi-
ma ely 12 mon hs o age, and a dose o he DTaP-IPV-HB-PRP-T
accine plus a dose o P e ena 13 a app oxima ely 13 mon hs
o age. All pa icipan s we e o e ed an op ional dose o M-M-
R axP o a app oxima ely 13 mon hs o age.
The ial was conduc ed in acco dance wi h applicable local and
na ional equi emen s and guidelines, he In e na ional Council o
Ha monisa ion o Technical Requi emen s o Pha maceu icals o
Human Use, Good Clinical P ac ice s anda ds, he E hical P inciples
o Medical Resea ch In ol ing Human Subjec s o he Wo ld Med-
ical Associa ion, and he Decla a ion o Helsinki. The pa en (s) o
legal gua dian(s) o he pa icipa ing child en p o ided w i en
in o med consen p io o inclusion in he boos e pa .
2.4. Immunogenici y measu emen s
Se ology es s o DTaP-IPV-HB-PRP-T accine an igens and
MenC/MenACWY-TT accine an igens we e pe o med by wo di -
e en labo a o ies: Public Heal h England’s Vaccine E alua ion
Uni (Manches e , UK) o MenC, MenA, MenW and MenY; and
he Global Clinical Immunology pla o m (Sano i Pas eu Inc.,
8020 T. Vesika i e al. / Vaccine 36 (2018) 8019–8027
Swi wa e , PA, USA) o pe ussis, hepa i is B, Hib, diph he ia ox-
oid, e anus oxoid, and inac i a ed polio i us an igens. Labo a o y
s a we e blinded o he g oup o which pa icipan s we e
andomised.
The se ological analyses we e pe o med as desc ibed in he p i-
ma y se ies a icle [7]. The immunogenici y assessmen s used o
he DTaP-IPV-HB-PRP-T accine we e consis en wi h hose used
du ing he clinical de elopmen plan wi h ega ds o he assays
used, he endpoin s analysed, and he iming o he se ology
assessmen . The meningococcal se og oup A, W and Y an ibodies
we e es ed by he modi ied se um bac e icidal an ibody (SBA)
assay wi h baby abbi complemen , as p e iously desc ibed by
Maslanka e al. [13].
Blood samples o app oxima ely 5 mL each we e collec ed
be o e and one mon h a e he boos e accina ion (a 13 mon hs
o age). The an ibody co ela es o p o ec ion o each accine an i-
gen we e as desc ibed o he p ima y se ies, wi h he addi ion o
meningococcal se og oup A, W and Y endpoin s (SBA i e 8).
2.5. Sa e y assessmen s
Sa e y and ole abili y o ela ed se ious ad e se e en s (SAEs),
dea hs and ad e se e en s o special in e es (AESIs) we e moni-
o ed be ween he end o he p ima y se ies s udy and boos e ac-
cina ion day (a app oxima ely 12 mon hs o age). Wi hin 30 min
o boos e accina ion, in es iga o s moni o ed pa icipan s o
unsolici ed (spon aneously epo ed) sys emic ad e se e en s
(AEs) o SAEs.
A dia y ca d was p o ided a app oxima ely 12 mon hs o age
(boos e accina ion day, day 0) ha pa icipan s’ pa en s o legal
gua dians used on days 0–7 o eco d solici ed injec ion-si e
ad e se eac ions (injec ion-si e e y hema, injec ion-si e pain,
injec ion-si e swelling) and solici ed sys emic ad e se eac ions
(py exia, omi ing, c ying, somnolence, ano exia and i i abili y).
Unsolici ed injec ion-si e eac ions and sys emic AEs we e
eco ded on days 0–30. Pa en s o legal gua dians eco ded he
s a , end and in ensi y o any unsolici ed e en s; he in es iga o
assessed he ela ionship o hese e en s o he accina ion. Se i-
ous AEs, including dea hs, and AESIs we e eco ded om app oxi-
ma ely 12 o 13 mon hs o age. Fo child en andomised o G oup
C, a elephone con ac was made a app oxima ely 14 mon hs o
age o collec any ele an sa e y in o ma ion.
2.6. S a is ical me hods
2.6.1. Sample size
Sample size o he p ima y se ies was de e mined as p e i-
ously epo ed [7]. The maximum numbe o pa icipan s in he
p ima y se ies was expec ed o be 350; all child en who ecei ed
h ee doses o he DTaP-IPV-HB-PRP-T accine we e o be in i ed
o pa icipa e in he boos e s udy. We es ima ed ha a pa icipa-
ion a e in he boos e phase o 70–85% would esul in 245–298
pa icipan s being e aluable o he p ima y analysis. Wi h a sam-
ple size o 80 e aluable pa icipan s pe g oup, he hal -wid h o
he wo-sided 95% con idence in e al (CI) should no exceed 10%
o obse ed esponse a es abo e 80%.
2.6.2. Analyses
Desc ip i e s a is ics we e used o he immunogenici y and
sa e y analyses. The andomised se was de ined as all andomised
subjec s in he boos e pa o he s udy. The pe sis ence analysis
was pe o med on he pe sis ence analysis se (all child en an-
domised and who p o ided a blood sample on boos e accina ion
day).
The pos -boos e immunogenici y p ima y analyses we e pe -
o med on he pe -p o ocol se (PPS; andomised pa icipan s
excluding hose wi h p o ocol de ia ion(s) ha could in e e e
wi h he immunogenici y e alua ion).
The ull analysis se s (all andomised pa icipan s who ecei ed
a leas one dose o he s udy accines and who had any pos -
accina ion immunogenici y da a) we e used o suppo i e
analyses.
Sa e y analyses we e desc ibed o all pa icipan s wi h sa e y
ollow-up da a who ecei ed a leas one dose o s udy accine(s)
(sa e y analysis se ).
S a is ical analyses we e pe o med using SAS
Ò
so wa e e -
sion 9.1.3 (SAS
Ò
Ins i u e Inc., Ca y, NC, USA).
3. Resul s
3.1. Demog aphic and o he baseline cha ac e is ics
A 12 mon hs o age, 312 oddle s (mean age 376.5 days; ange:
366–415 days) p e iously p imed a wo, h ee and ou mon hs o
age wi h DTaP-IPV-HB-PRP-T accine wi h o wi hou MenC-TT
accine we e andomised as ollows:
104 oddle s ecei ed DTaP-IPV-HB-PRP-T co-adminis e ed
wi h MenACWY-TT (G oup A)
105 oddle s ecei ed DTaP-IPV-HB-PRP-T alone (G oup B)
103 oddle s ecei ed MenACWY-TT alone (G oup C).
Demog aphic and baseline cha ac e is ics we e simila ac oss
he h ee g oups in e ms o age, e hnic o igin and empe a u e
in he o e all andomised se (Table 1). The pa icipan disposi ion
is summa ised in Fig. 1. In he PPS, demog aphic and baseline cha -
ac e is ics we e simila ac oss he g oups.
3.2. P e-boos e an ibody pe sis ence o DTaP-IPV-HB-PRP-T accine
an igens (pe sis ence analysis se )
Following he h ee-dose p ima y accina ion se ies a wo,
h ee and ou mon hs o age, no no able di e ences we e obse ed
a 12 mon hs o age be ween G oup 1 (DTaP-IPV-HB-PRP-T accine
co-adminis e ed wi h he MenC-TT accine) and G oup 2 (DTaP-
IPV-HB-PRP-T accine wi hou MenC-TT accine) in e ms o an i-
body le els o he di e en DTaP-IPV-HB-PRP-T accine an igens,
wi h he excep ion o he p opo ion o pa icipan s wi h an an i-
T concen a ion 0.10 IU/mL, which was highe in G oup 1 e sus
G oup 2 (100%, 95% CI: 97.6; 100.0, and 92.0%, 95% CI: 86.4; 95.8,
espec i ely) (Table 2).
A 12 mon hs o age, he e we e no no able di e ences in geo-
me ic mean concen a ions (GMCs) o i es (GMTs) be ween
G oup 1 and G oup 2 o any DTaP-IPV-HB-PRP-T accine an igen
wi h he excep ion o an i-T GMC, which was signi ican ly highe
in G oup 1 e sus G oup 2 (0.61, 95%CI: 0.55; 0.68, and 0.34, 95%
CI: 0.29; 0.39, espec i ely) (Supplemen a y Da a 2).
3.3. Pos -boos e an ibody esponse o DTaP-IPV-HB-PRP-T accine
an igens (PPS)
One mon h a e he boos e dose, no no able di e ences we e
obse ed be ween G oup A (DTaP-IPV-HB-PRP-T wi h MenACWY-
TT) and G oup B (DTaP-IPV-HB-PRP-T alone) in e ms o se op o-
ec ion a es (G oup A: 97.7–100%; G oup B: 98.9–100%) o any
DTaP-IPV-HB-PRP-T accine an igen (PPS) (Table 3).
The p opo ions o pa icipan s wi h an i-D concen a-
ion 1.0 IU/mL and an i-T concen a ion 1.0 IU/mL we e also
high and compa able in bo h g oups. Fo pe ussis an igens, he
p opo ion o pa icipan s wi h accine esponse ( om
p e- accina ion [p e-dose 1] o pos -boos e ) o pe ussis oxoid
T. Vesika i e al. / Vaccine 36 (2018) 8019–8027 8021
and ilamen ous haemagglu inin we e 98.8% and 100%, espec-
i ely, in bo h G oup A and G oup B. The p opo ion o pa icipan s
wi h a ou - old- ise om p e- accina ion (p e-dose 1) o pos -
boos e o pe ussis oxoid and ilamen ous haemagglu inin we e
espec i ely 83.5% and 96.5% in G oup A, and 88.4% and 92.1% in
G oup B.
The e we e no no able di e ences in GMCs/GMTs o any DTaP-
IPV-HB-PRP-T accine an igen be ween G oup A and G oup B
excep o an i-IPV3 GMT and an i-PRP GMC, which ended o be
highe in G oup B bu deemed no o be clinically signi ican
(Table 3). Compa able esul s o se op o ec ion a es/ esponse
a es and GMCs/GMTs we e obse ed in he ull analysis se
DTaP-IPV-HB-PRP-T.
3.3.1. An ibody esponse o MenACWY-TT accine an igens (PPS)
In he PPS, one mon h a e accina ion no no able di e ences
we e obse ed be ween G oup A (DTaP-IPV-HB-PRP-T wi h
MenACWY-TT) and G oup C (MenACWY-TT alone) in e ms o se o-
p o ec ion a es o any meningococcal se og oup. The p opo ion
o pa icipan s wi h an an ibody i e 8 (1/dil) was high in bo h
g oups, anging om 98.9 o 100% in G oup A, and 95.7 o 100%
in G oup C (Table 4).
The e we e no no able di e ences in GMTs be ween G oup A
and G oup C o any meningococcal an igen excep o MenA SBA
GMT, which ended o be highe in G oup C (Table 4). Fo bo h
G oup A and G oup C, he subg oup o pa icipan s who had p e i-
ously ecei ed he MenC accine du ing he p ima y se ies pa
(G oup 1) displayed highe an i-MenC GMTs e sus he subg oup
o pa icipan s who did no (G oup 2) (da a no shown).
3.4. Sa e y
The sa e y p o ile o he DTaP-IPV-HB-PRP-T accine was gene -
ally compa able whe he co-adminis e ed wi h MenACWY-TT ac-
cine o no (Table 5). O e all, mos o he pa icipan s epo ed AEs
occu ing wi hin 30 days a e accina ion: 94.2% in G oup A
(DTaP-IPV-HB-PRP-T wi h MenACWY-TT), 92.4% in G oup B
(DTaP-IPV-HB-PRP-T alone), and 87.4% in G oup C (MenACWY-TT
alone). Two pa icipan s (0.6% o all pa icipan s), one in G oup A
(1.0%) and one in G oup B (1.0%), expe ienced an immedia e unso-
lici ed AE a e he boos e – g ade 1 u ica ia and g ade 2 dia -
hoea, espec i ely – bo h conside ed by he in es iga o o be
ela ed o he s udy accines.
Solici ed injec ion si e eac ions wi hin se en days a e DTaP-
IPV-HB-PRP-T accina ion we e epo ed by 66.0% o subjec s in
G oup A, and 60.0% o subjec s in G oup B.
Solici ed injec ion si e eac ions wi hin se en days a e
MenACW-TT accina ion we e epo ed by 47.6% o subjec s in
G oup A, and 32.0% o subjec s in G oup C, and injec ion si e pain
was epo ed mo e equen ly in G oup A (46.6% e sus 17.5%).
G ade 3 in ensi y eac ions we e obse ed in 11% in G oup A and
1% in G oup C.
Nea ly all solici ed injec ion si e eac ions occu ed be ween
day 0 and day 3 ollowing accina ion, and las ed no mo e han
h ee days (Table 5). The de ails o he in ensi y scales used o
sa e y pa ame e s a e shown in Supplemen a y Da a 3.
The equency o solici ed sys emic eac ions was highe in
G oup A e sus G oup C o c ying, i i abili y, py exia and somno-
lence ( espec i ely: 50.5% e sus 30.1%; 76.7% e sus 48.5%; 30.1%
e sus 10.7%; and 52.4% e sus 32.0%). No no able di e ences we e
obse ed be ween G oup A and G oup C in equencies o eac ions
o G ade 3 in ensi y. Py exia o g ade 3 in ensi y (>39.5 °C) was
epo ed by ou pa icipan s: wo who ecei ed DTaP-IPV-HB-
PRP-T and MenACWY-TT accine concomi an ly; one who ecei ed
DTaP-IPV-HB-PRP-T accine alone; and one who ecei ed
MenACWY-TT accine alone.
One AESI was epo ed du ing he boos e phase, a se ious
eb ile con ulsion ela ed o pneumonia caused by espi a o y
syncy ial i al in ec ion epo ed 24 days a e adminis a ion o
MenACWY-TT accine alone. The numbe o SAEs epo ed was
Table 1
Demog aphy and o he baseline cha ac e is ics ( andomised se ).
G oup A
DTaP-IPV-HB-PRP-T wi h MenACWY
(N = 104)
G oup B
DTaP-IPV-HB-PRP-T alone
(N = 105)
G oup C
MenACWY-TT alone
(N = 103)
To al
(N = 312)
Age (days) a accina ion
n 104 105 103 312
Mean (SD) 375.8 (8.8) 376.8 (9.4) 376.8 (9.2) 376.5 (9.1)
Median 373.0 374.0 374.0 373.0
Min; max 366; 406 366; 415 366; 410 366; 415
Sex
n 104 105 103 312
Female, n (%) 49 (47.1)
*
54 (51.4)
*
46 (44.7)
*
149 (47.8)
*
Male, n (%) 55 (52.9)
*
51 (48.6)
*
57 (55.3)
*
163 (52.2)
*
E hnic o igin
n 104 105 103 312
Asian, n (%) 0 1 (1.0)
*
0 1 (0.3)
*
Black, n (%) 1 (1.0)
*
0 0 1 (0.3)
*
Caucasian, n (%) 96 (92.3)
*
100 (95.2)
*
95 (92.2)
*
291 (93.3)
*
O he , n (%) 7 (6.7)
*
4 (3.8)
*
8 (7.8) 19 (6.1)
*
Tempe a u e (°C)
n 104 105 103 312
Mean (SD) 36.6 (0.6) 36.6 (0.6) 36.6 (0.6) 36.6 (0.6)
Median 36.6 36.6 36.6 36.6
Min; max 35.3; 37.9 35.4; 37.8 35.1; 37.7 35.1; 37.9
Disposi ion o subjec s acco ding o g oups in he p ima y se ies
y
Hexa alen co-adminis e ed wi h MenC
(G oup 1), n (%)
53 (51.0)
*
52 (49.5)
*
51 (49.5)
*
156 (50.0)
*
Hexa alen wi hou MenC (G oup 2), n (%) 51 (49.0)
*
53 (50.5)
*
52 (50.5)
*
156 (50.0)
*
Abb e ia ions: aP, acellula pe ussis; D, diph he ia; HB, hepa i is B; IPV, inac i a ed polio i us; MenACWY, meningococcal se og oups A, C, W and Y; PRP, Haemophilus
in luenzae ype-b capsula poly ibosyl- ibi ol-phospha e; SD, s anda d de ia ion; T, e anus; TT, e anus oxoid.
*
Pe cen ages a e based on he numbe o andomised subjec s.
y
Vaccines ac ually ecei ed du ing he p ima y se ies pa .
8022 T. Vesika i e al. / Vaccine 36 (2018) 8019–8027
low and none was conside ed o be ela ed o he s udy accines by
he in es iga o . No AE leading o s udy discon inua ion du ing he
boos e phase o he s udy we e epo ed du ing he cou se o ha
pa o he s udy.
4. Discussion
The esul s demons a e ha , one mon h a e accina ion wi h
a boos e dose, he immune esponses elici ed by he DTaP-IPV-
HB-PRP-T accine and he meningococcal se og oup ACWY
Fig. 1. Disposi ion o pa ien s h ough he s udy.
a
Pa icipan s who ecei ed h ee doses o he DTaP-IPV-HB-PRP-T accine du ing he p ima y se ies pa .
b
One pa icipan
andomised o G oup A (DTaP-IPV-HB-PRP-T accine co-adminis e ed wi h MenACWY-TT accine) had ecei ed he DTaP-IPV-HB-PRP-T accine p io o andomisa ion (and
ecei ed he MenC accine a app oxima ely 13 mon hs o age).
c
One pa icipan was los o ollow-up a e accina ion a app oxima ely 12 mon hs o age, wi h no sa e y
da a a ailable.
T. Vesika i e al. / Vaccine 36 (2018) 8019–8027 8023

Table 3
Summa y o pos -boos e an ibody le els (A) and geome ic means o an ibody concen a ions o i es (B) o DTaP-IPV-HB-PRP-T accine an igens (PPS).
G oup A
Hexa alen co-adminis e ed wi h MenACWY (N = 87)
G oup B
Hexa alen alone (N = 91)
A. Pos -boos e an ibody le els
Componen Endpoin M
*
n (%) 95% CI M
*
n (%) 95% CI
An i-D 0.10 IU/mL 87 87 (100.0) 95.8; 100.0 91 91 (100.0) 96.0; 100.0
1.0 IU/mL 87 78 (89.7) 81.3; 95.2 91 88 (96.7) 90.7; 99.3
An i-T 0.10 IU/mL 87 87 (100.0) 95.8; 100.0 91 91 (100.0) 96.0; 100.0
1.0 IU/mL 87 84 (96.6) 90.3; 99.3 91 88 (96.7) 90.7; 99.3
An i-IPV1 8 1/dil 87 86 (98.9) 93.8; 100.0 91 90 (98.9) 94.0; 100.0
An i-IPV2 8 1/dil 87 87 (100.0) 95.8; 100.0 91 91 (100.0) 96.0; 100.0
An i-IPV3 8 1/dil 87 87 (100.0) 95.8; 100.0 90 90 (100.0) 96.0; 100.0
An i-HBs 10 mIU/mL 87 86 (98.9) 93.8; 100.0 91 90 (98.9) 94.0; 100.0
100 mIU/mL 85 85 (97.7) 91.9; 99.7 91 87 (95.6) 89.1; 98.8
An i-PRP 0.15 mg/mL 87 87 (100.0) 95.8; 100.0 91 91 (100.0) 96.0; 100.0
1.0 mg/mL 87 85 (97.7) 91.9; 99.7 91 91 (100.0) 96.0; 100.0
An i-PT Vaccine esponse
y
85 84 (98.8) 93.6; 100.0 86 85 (98.8) 93.7; 100.0
4- old inc ease
à
85 71 (83.5) 73.9; 90.7 86 76 (88.4) 79.7; 94.3
An i-FHA Vaccine esponse
y
85 85 (100.0) 95.8; 100.0 89 89 (100.0) 95.9; 100.0
4- old inc ease
à
85 82 (96.5) 90.0; 99.3 89 82 (92.1) 84.5; 96.8
B. Pos -boos e GMTs/GMCs
Componen M Geome ic mean (GMC/GMT)
§
95% CI M Geome ic mean (GMC/GMT)
§
95% CI
An i-D (IU/mL) 87 3.07 2.49; 3.79 91 3.24 2.69; 3.91
An i-T (IU/mL) 87 6.89 5.78; 8.21 91 6.25 5.30; 7.37
An i-IPV1 (1/dil) 87 2174.05 1606.18; 2942.70 91 2040.21 1522.96; 2733.14
An i-IPV2 (1/dil) 87 1678.14 1203.60; 2339.77 91 1738.58 1242.59; 2432.56
An i-IPV3 (1/dil) 87 3086.91 2278.10; 4182.89 90 4127.67 3175.40; 5365.53
An i-HBs (mIU/mL) 87 2230.68 1597.48; 3114.87 91 2233.15 1597.30; 3122.13
An i-PRP (mg/mL) 87 22.70 17.20; 29.96 91 27.82 21.89; 35.35
An i-PT (EU/mL) 87 111.78 97.90; 127.63 91 114.72 102.68; 128.16
An i-FHA (EU/mL) 87 174.98 153.98; 198.86 91 184.57 162.43; 209.72
Abb e ia ions: CI, con idence in e al; D, diph he ia; FHA, ilamen ous haemagglu inin; GMC, geome ic mean concen a ion; GMT, geome ic mean i e; HBs, hepa i is B;
IPV, inac i a ed polio i us; LLOQ, lowe limi o quan i a ion; MenACWY, meningococcal se og oups A, C, W and Y; PRP, Haemophilus in luenzae ype b capsula poly ibosyl-
ibi ol-phospha e; PPS, pe -p o ocol se ; PT, pe ussis oxoid; T, e anus.
*
M: numbe o subjec s wi h a ailable da a.
y
Pe ussis accine esponse was de ined as:
i p e- accina ion (p e-dose 1) an ibody concen a ion < 4 LLOQ, hen pos -boos e an ibody concen a ion 4LLOQ
i p e- accina ion (p e-dose 1) an ibody concen a ion 4LLOQ, hen pos -boos e an ibody concen a ion > p e- accina ion an ibody concen a ion.
à
Inc ease om p e- accina ion (p e-dose 1) o pos -boos e .
§
GMCs o an i-D, an i-T, an i-HBs, an i-PRP, an i-PT, and an i-FHA; GMTs o an i-IPV1, an i-IPV2 and an i-IPV3.
Table 2
Summa y o an ibody le els a 12 mon hs o age o all DTaP-IPV-HB-PRP-T an igens ollowing he h ee-dose p ima y accina ion (p e-boos e ) (pe sis ence analysis se ).
G oup 1 (p ima y se ies pa )
DTaP-IPV-HB-PRP-T co-adminis e ed wi h MenC
(N = 152)
G oup 2 (p ima y se ies pa )
DTaP-IPV-HB-PRP-T wi hou MenC (N = 151)
Componen Endpoin M
*
n (%) 95% CI M
*
n (%) 95% CI
An i-D 0.01 IU/mL 151 148 (98.0) 94.3; 99.6 150 149 (99.3) 96.3; 100.0
0.10 IU/mL 151 62 (41.1) 33.1; 49.3 150 71 (47.3) 39.1; 55.6
An i-T 0.01 IU/mL 151 151 (100.0) 97.6; 100.0 150 150 (100.0) 97.6; 100.0
0.10 IU/mL 151 151 (100.0) 97.6; 100.0 150 138 (92.0) 86.4; 95.8
An i-IPV1 8 1/dil 151 122 (80.8) 73.6; 86.7 150 127 (84.7) 77.9; 90.0
An i-IPV2 8 1/dil 151 98 (64.9) 56.7; 72.5 150 114 (76.0) 68.4; 82.6
An i-IPV3 8 1/dil 150 123 (82.0) 74.9; 87.8 148 131 (88.5) 82.2; 93.2
An i-HB 10 mIU/mL 152 137 (90.1) 84.2; 94.4 151 138 (91.4) 85.7; 95.3
100 mIU/mL 152 72 (47.4) 39.2; 55.6 151 77 (51.0) 42.7; 59.2
An i-PRP 0.15 mg/mL 151 131 (86.8) 80.3; 91.7 150 116 (77.3) 69.8; 83.8
1.0 mg/mL 151 70 (46.4) 38.2; 54.6 150 71 (47.3) 39.1; 55.6
An i-PT LLOQ
y
151 151 (100.0) 97.6; 100.0 148 147 (99.3) 96.3; 100.0
2LLOQ
y
151 150 (99.3) 96.4; 100.0 148 147 (99.3) 96.3; 100.0
An i-FHA LLOQ
y
151 151 (100.0) 97.6; 100.0 149 149 (100.0) 97.6; 100.0
2LLOQ
y
151 151 (100.0) 97.6; 100.0 149 149 (100.0) 97.6; 100.0
Abb e ia ions: aP, acellula pe ussis; CI, con idence in e al; D, diph he ia; FHA, ilamen ous haemagglu inin; HB, hepa i is B; IPV, inac i a ed polio i us; LLOQ, lowe limi
o quan i a ion; MenC, meningococcal se og oup C; PRP, Haemophilus in luenzae ype b capsula poly ibosyl- ibi ol-phospha e; PT, pe ussis oxoid; T, e anus.
*
M: numbe o subjec s wi h a ailable da a.
y
LLOQ = 2 EU/mL o PT and FHA.
8024 T. Vesika i e al. / Vaccine 36 (2018) 8019–8027
conjuga e accine, ei he co-adminis e ed a 12 mon hs o age, o
when adminis a ion is s agge ed a di e en ime poin s, a e high
o any accine an igen.
O e all, concomi an adminis a ion o he DTaP-IPV-HB-PRP-T
and MenACWY-TT accines did no a ec he immune esponse o
ei he accine: he simila esponse a es and an ibody GMCs/
GMTs be ween he g oups a e suppo i e o concomi an adminis-
a ion o he wo accines when gi en a 12 mon hs o age in
heal hy oddle s. The se op o ec ion a es/ esponse a es and he
an ibody GMCs/GMTs epo ed o he di e en an igens con ained
in he DTaP-IPV-HB-PRP-T accine in he p esen s udy we e con-
sis en wi h hose p e iously epo ed and/o summa ised o he
accine used in boos e accina ion, i espec i e o he p ima y
immunisa ion schedule o DTaP-IPV-HB-PRP-T (including a wo-,
h ee-, ou -mon h schedule) [7,8,14–17]. Simila ly, he se op o-
ec ion a es/ esponse a es and he an ibody GMTs epo ed o
he meningococcal se og oup A, C, W and Y conjuga e accine
an igens we e consis en wi h hose p e iously epo ed wi h he
MenACWY-TT accine o he oddle popula ion [9], and
when co-adminis e ed wi h he DTaP-IPV-HB-PRP-T accine
In an ix
Ò
-hexa [18].
The immunogenici y assessmen used o he MenACWY-TT
accine ( abbi SBA) was consis en wi h ha gene ally used o
his ype o accine (including Nimen ix) [9,18–20]. Fu he mo e,
he use o MenC accine in he p ima y se ies schedule did no p e-
clude he use o MenACWY-TT o co-adminis a ion wi h a DTaP-
IPV-HB-Hib boos e dose pos -boos e , and esponse a es/
an ibody GMTs we e high o all MenACWY an igens whe he
MenC-TT accine was used in he p ima y se ies schedule o no .
P io eceip o MenC-TT accine in he cu en s udy led o a
highe GMT o MenC an igen, as p e iously documen ed [21].
An ibody pe sis ence a 12 mon hs o age agains he DTaP-IPV-
HB-PRP-T accine an igens was simila be ween p ima y se ies
g oups excep o highe an i-T an ibody le el in subjec s who
had ecei ed bo h TT-con aining accines (DTaP-IPV-HB-PRP-T
and MenC). A 12 mon hs o age, a high p opo ion o subjec s
e ained an ibody le els associa ed wi h sho - e m p o ec ion
ha a e consis en wi h hose p e iously obse ed a e a 2, 3
and 4 mon hs p iming [17] and equal o o highe han hose
obse ed in a simila popula ion ecei ing wo-dose p iming a 3
and 5 mon hs o age [22]. This inding suppo s he adminis a ion
o a boos e dose, as con i med by he subsequen obus pos -
boos e esponse in all boos e g oups.
The co-adminis a ion o he hexa alen DTaP-IPV-HB-PRP-T
accine and o he MenACWY-TT conjuga e accine esul ed in
highe eac ogenici y o many sys emic signs. The equency
o injec ion si e ad e se eac ions epo ed in his p esen s udy
o he MenACWY-TT accine was consis en wi h clinical ials
da a epo ed in he Nimen ix summa y o p oduc cha ac e is-
ics [9].
Table 4
Summa y o pos - accina ion an ibody le els (A) and geome ic means o an ibody i es (B) o MenACWY-TT accine an igens (PPS).
G oup A
Hexa alen co-adminis e ed wi h MenACWY (N = 87)
G oup C
MenACWY alone (N = 94)
A. Pos - accina ion an ibody le els
Componen Endpoin (1/dil) M
*
n (%) 95% CI M
*
n (%) 95% CI
An i-MenA 8 87 87 (100.0) 95.8; 100.0 94 94 (100.0) 96.2; 100.0
An i-MenC 8 All subjec s 87 86 (98.9) 93.8; 100.0 94 90 (95.7) 89.5; 98.8
Subjec s who ecei ed he MenC accine in
p ima y se ies pa
y
43 43 (100.0) 91.8; 100.0 47 46 (97.9) 88.7; 99.9
Subjec s who did no ecei e any MenC
accine in p ima y se ies pa
à
44 43 (97.7) 88.0; 99.9 47 44 (93.6) 82.5; 98.7
128 All subjec s 87 85 (97.7) 91.9; 99.7 94 85 (90.4) 82.6; 95.5
Subjec s who ecei ed he MenC accine in
p ima y se ies pa
y
43 43 (100.0) 91.8; 100.0 47 46 (97.9) 88.7; 99.9
Subjec s who did no ecei e any MenC
accine in p ima y se ies pa
à
44 42 (95.5) 84.5; 99.4 47 39 (83.0) 69.2; 92.4
An i-MenW 8 87 87 (100.0) 95.8; 100.0 94 93 (98.9) 94.2; 100.0
An i-MenY 8 87 87 (100.0) 95.8; 100.0 94 94 (100.0) 96.2; 100.0
B. Pos -boos e GMTs
Componen M Geome ic mean
(GMT)
95% CI M Geome ic mean
(GMT)
95% CI
An i-MenA 87 4096.00 3335.98;
5029.17
94 5302.07 4249.49;
6615.38
An i-MenC
All subjec s 87 693.03 524.15;
916.33
94 620.20 425.53;
903.94
Subjec s who ecei ed he MenC accine in p ima y se ies pa
y
43 1262.73 901.11;
1769.46
47 1617.53 1083.22;
2415.39
Subjec s who did no ecei e any MenC accine in p ima y se ies pa
à
44 385.59 264.11;
562.93
47 237.80 141.85;
398.66
An i-MenW 87 2148.28 1650.66;
2795.91
94 2555.07 1930.58;
3381.58
An i-MenY 87 1952.40 1538.58;
2477.53
94 2003.19 1592.49;
2519.81
Abb e ia ions: CI, con idence in e al; GMT, geome ic mean i e; MenACWY, meningococcal se og oups A, C, W and Y; PPS, pe -p o ocol se ; TT, e anus oxoid.
*
M: numbe o subjec s wi h a ailable da a.
y
Subjec s om G oup 1 in p ima y se ies: hexa alen accine co-adminis e ed wi h MenC accine.
à
Subjec s om G oup 2 in p ima y se ies: hexa alen accine wi hou MenC accine.
T. Vesika i e al. / Vaccine 36 (2018) 8019–8027 8025
5. Conclusions
Co-adminis a ion o DTaP-IPV-HB-PRP-T accine wi h
MenACWY-TT accine did no a ec he immune esponse o
ei he accine. P io eceip o MenC-TT conjuga e accine du ing
in ancy did no p eclude he use o a MenACWY-TT accine o
boos e accina ion and esul ed in highe esponses o MenC a e
boos e .
The immunogenici y and sa e y indings o his s udy suppo
he concomi an adminis a ion o he DTaP-IPV-HB-PRP-T accine
wi h a MenACWY-TT conjuga e accine when gi en om
12 mon hs o age, bu a highe sys emic eac ion a e a e con-
comi an accina ion should be no ed.
Acknowledgemen s
The au ho s ake ull esponsibili y o he con en o his con i-
bu ion and hank G aham Join o Syne com L d, Maccles ield, UK
(suppo ed by Sano i Pas eu ) o p epa ing he manusc ip d a s.
The au ho s would like o hank he pa icipa ing amilies, as
well as he in es iga o s and hei s udy-si e pe sonnel, o hei
con ibu ion o he s udy: Ani a Ahonen, Aino Fo s én, Tiina
Haapaniemi, Tiina Ka ppa, Sa u Kokko, Tiina Ko honen, Pia-Ma ia
Lage s om-Ti i, Ilkka Seppä and Iina Volanen. They would also
like o hank: Xa ie Co nen and A melle Ma ais (Sano i Pas eu
MSD) o hei con ibu ion o he conduc o he s udy; TFS In e -
na ional AB o aking cha ge o he moni o ing o he s udy; Emilia
Jo dano , Emmanuel Fe oldi and Emmanuel Vido (Sano i Pas eu )
o hei con ibu ion o he manusc ip e iew; Helen Findlow and
Xilian Bai (Vaccine E alua ion Uni , Public Heal h Labo a o y,
Manches e ) o meningococcal an ibody es ing; Monique B own
and he GCI eam (Sano i Pas eu , Global Clinical Immunology pla -
o m, Swi wa e , PA, USA) o p o iding immunogenici y da a o
he hexa alen accine an igens.
Disclosu es/con lic o in e es s a emen
Timo Vesika i was lead in es iga o suppo ed by esea ch
g an s. Ray Bo ow pe o med he MenACWY assays suppo ed
by esea ch g an s. Xa ie Da Cos a was an employee o Sano i Pas-
eu a he ime he s udy was conduc ed and holds company s ock
and/o s ock op ions. Flo ence Boisna d, Cécile Eymin, S ephen
Lockha and S éphane Thomas we e all Sano i Pas eu MSD
employees a he ime he s udy was conduc ed.
Table 5
Sa e y o e iew om app oxima ely 12 o 13 mon hs o age (sa e y analysis se ).
G oup A DTaP-IPV-HB-PRP-T
co-adminis e ed wi h
MenACWY (N = 103)
G oup B DTaP-IPV-HB-PRP-T
alone (N = 105)
G oup C MenACWY-TT alone
(N = 103)
Pe iod/pa icipan s wi h a leas one o he ollowing: n (%) 95% CI
(pa icipan s)
*
n (%) 95% CI
(pa icipan s)
*
n (%) 95% CI
(pa icipan s)
*
AE wi hin 30 days a e any injec ion a app oxima ely 12 mon hs
o age
97
(94.2)
87.8; 97.8 97
(92.4)
85.5; 96.7 90
(87.4)
79.4; 93.1
Immedia e unsolici ed AE 1 (1.0) <0.1; 5.3 1 (1.0) <0.1; 5.2 0 –
Solici ed eac ions wi hin 7 days a e boos e accina ion 96
(93.2)
86.5; 97.2 96
(91.4)
84.4; 96.0 80
(77.7)
68.4; 85.3
G ade 3 solici ed eac ion 14
(13.6)
7.6; 21.8 11
(10.5)
5.3; 18.0 5 (4.9) 1.6; 11.0
Solici ed injec ion si e eac ion 71
(68.9)
59.1; 77.7 63
(60.0)
50.0; 69.4 33
(32.0)
23.2; 42.0
G ade 3 ISR 11
(10.7)
5.5; 18.3 5 (4.8) 1.6; 10.8 1 (1.0) <0.1; 5.3
A e Hexa alen accine 68
(66.0)
56.0; 75.1 63
(60.0)
50.0; 69.4 NA –
G ade 3 ISR 10 (9.7) 4.8; 17.1 5 (4.8) 1.6; 10.8 NA –
A e MenACWY accine 49
(47.6)
37.6; 57.6 NA – 33
(32.0)
23.2; 42.0
G ade 3 ISR 1 (1.0) <0.1; 5.3 NA – 1 (1.0) <0.1; 5.3
Solici ed sys emic eac ion 91
(88.3)
80.5; 93.8 90
(85.7)
77.5; 91.8 75
(72.8)
63.2; 81.1
G ade 3 solici ed sys emic eac ion 5 (4.9) 1.6; 11.0 6 (5.7) 2.1; 12.0 4 (3.9) 1.1; 9.6
Unsolici ed non-se ious sys emic AE 53
(51.5)
41.4; 61.4 50
(47.6)
37.8; 57.6 60
(58.3)
48.1; 67.9
Unsolici ed non-se ious sys emic AR 5 (4.9) 1.6; 11.0 4 (3.8) 1.0; 9.5 1 (1.0) <0.1; 5.3
AE leading o s udy discon inua ion 0 – 0 – 0 –
SAE 1 (1.0) <0.1; 5.3 0 – 1 (1.0) <0.1; 5.3
SAR 0– 0– 0–
Dea h 0 – 0 – 0 –
AESI/SAE om app oxima ely 12–13 mon hs o age 97
(94.2)
87.8; 97.8 97
(92.4)
85.5; 96.7 90
(87.4)
79.4; 93.1
AESI 0 – 0 – 1 (1.0) <0.1; 5.3
SAEs 1 (1.0) <0.1; 5.3 1 (1.0)
y
<0.1; 5.2 1 (1.0) <0.1; 5.3
Rela ed o Hexyon 0 – 0 – 0 –
Dea h 0 – 0 – 0 –
Abb e ia ions: AE, ad e se e en ; AESI, ad e se e en o special in e es ; aP, acellula pe ussis; AR, ad e se eac ion; CI, con idence in e al; D, diph he ia; HB, hepa i is B;
IPV, inac i a ed polio i us; ISR, injec ion si e eac ions; MenACWY, meningococcal se og oups A, C, W and Y; NA, no applicable; PRP, Haemophilus in luenzae ype b capsula
poly ibosyl- ibi ol-phospha e; SAE, se ious ad e se e en ; SAR, se ious ad e se eac ion; T, e anus; TT, e anus oxoid.
*
Two-sided 95% CIs o he pe cen age o pa icipan s p esen ing he speci ied e en a leas once we e calcula ed using he exac binomial me hod.
y
This e en occu ed 64 days a e accina ion a app oxima ely 12 mon hs o age ( isi 5); consequen ly, he isi a 13 mon hs o age was delayed and pe o med 85 days
a e isi 5.
8026 T. Vesika i e al. / Vaccine 36 (2018) 8019–8027
Con ibu ions
TV con ibu ed o he p o ocol e iew, pa icipan s’ en olmen ,
pa icipan s’ da a collec ion/acquisi ion, and da a in e p e a ion.
RB and XDC con ibu ed o he labo a o y analysis and da a in e -
p e a ion. FB, ST and SL con ibu ed o he s udy design and de el-
opmen , and da a analysis and in e p e a ion. CE con ibu ed o he
w i ing o he manusc ip d a s. All au ho s c i ically e iewed
and e ised he manusc ip d a s, and app o ed he inal e sion
o he manusc ip . All au ho s ake esponsibili y o he in eg i y
o he da a and accu acy o he da a analysis. All au ho s we e
in ol ed in he decision o submi he manusc ip o Vaccine o
publica ion.
Role o he unding sou ce
Sano i Pas eu MSD, Lyon, F ance p o ided inancial suppo o
he conduc o he esea ch and p epa a ion o he a icle and was
in ol ed in he s udy design, in he collec ion, analysis and in e -
p e a ion o da a, and in he w i ing o he ial epo .
Appendix A. Supplemen a y ma e ial
Supplemen a y da a o his a icle can be ound online a
h ps://doi.o g/10.1016/j. accine.2018.10.100.
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