Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa

Full Te ms & Condi ions o access and use can be ound a h p://www. and online.com/ac ion/jou nalIn o ma ion?jou nalCode=kh i20 Download by: [Tampe e Uni e si y] Da e: 07 Augus 2017, A : 22:46 Human Vaccines & Immuno he apeu ics ISSN: 2164-5515 (P in ) 2164-554X (Online) Jou nal homepage: h p://www. and online.com/loi/kh i20 Immunogenici y and sa e y o p ima y and boos e accina ion wi h 2 in es iga ional o mula ions o diph he ia, e anus and Haemophilus in luenzae ype b an igens in a hexa alen DTPa-HBV-IPV/Hib combina ion accine in compa ison wi h he licensed In an ix hexa Timo Vesika i, Luis Ri e a, Tiina Ko honen, Ani a Ahonen, B igi e Cheu a , Ma jan Heza eh, Winnie Janssens & Na cisa Mesa os To ci e his a icle: Timo Vesika i, Luis Ri e a, Tiina Ko honen, Ani a Ahonen, B igi e Cheu a , Ma jan Heza eh, Winnie Janssens & Na cisa Mesa os (2017) Immunogenici y and sa e y o p ima y and boos e accina ion wi h 2 in es iga ional o mula ions o diph he ia, e anus and Haemophilus in luenzae ype b an igens in a hexa alen DTPa-HBV-IPV/Hib combina ion accine in compa ison wi h he licensed In an ix hexa, Human Vaccines & Immuno he apeu ics, 13:7, 1505-1515, DOI: 10.1080/21645515.2017.1294294 To link o his a icle: h p://dx.doi.o g/10.1080/21645515.2017.1294294 © 2017 The Au ho (s). Published wi h license by Taylo & F ancis© Timo Vesika i, Luis Ri e a, Tiina Ko honen, Ani a Ahonen, B igi e Cheu a , Ma jan Heza eh, Winnie Janssens, and Na cisa Mesa os Published online: 24 Ma 2017. Submi you a icle o his jou nal A icle iews: 453 View ela ed a icles View C ossma k da a RESEARCH PAPER Immunogenici y and sa e y o p ima y and boos e accina ion wi h 2 in es iga ional o mula ions o diph he ia, e anus and Haemophilus influenzae ype b an igens in a hexa alen DTPa-HBV-IPV/Hib combina ion accine in compa ison wi h he licensed In an ix hexa Timo Vesika i a , y , Luis Ri e a b , y , Tiina Ko honen c , Ani a Ahonen d , B igi e Cheu a e , Ma jan Heza eh , Winnie Janssens g , and Na cisa Mesa os g a Vaccine Resea ch Cen e , Uni e si y o Tampe e, Tampe e, Finland; b Hospi al Ma e nidad Nues a Se~ no a de la Al ag acia San o Domingo, San o Domingo, Dominican Republic; c Uni e si y o Tampe e, Tampe e Vaccine Resea ch Clinic, Tampe e, Finland; d Vaccine Resea ch Cen e , Uni e si y o Tampe e, J€ a enp€ a€ a Vaccine Clinic, J€ a enp€ a€ a, Finland; e GSK, Wa e, Belgium; Chil e n In e na ional c/o GSK, Wa e, Belgium; g GSK, Wa e, Belgium ARTICLE HISTORY Recei ed 15 Decembe 2016 Re ised 2 Feb ua y 2017 Accep ed 8 Feb ua y 2017 ABSTRACT Sa e y and immunogenici y o 2 in es iga ional o mula ions o diph he ia, e anus and Haemophilus influenzae ype b an igens o he combined diph he ia- e anus-acellula pe ussis-hepa i is B-inac i a ed poliomyeli is-Hib accine (DTPa-HBV-IPV/Hib) we e e alua ed in a P ima y (NCT01248884) and a Boos e accina ion (NCT01453998) s udy. In he P ima y s udy, 721 heal hy in an s ( andomized1:1:1) ecei ed3doseso DTPa-HBV-IPV/Hib o mula ion A (D A T A Pa-HBV-IPV/Hib), o B (D B T B Pa-HBV-IPV/Hib) o he licensed DTPa-HBV-IPV/Hib accine (In an ix hexa, GSK; con ol g oup) a 2, 3, 4 mon hs o age. In an s we e planned o ecei e a boos e dose a 12–15 mon hs o age wi h he same o mula ion ecei ed in he P ima y s udy; howe e , ollowing high incidence o e e associa ed wi h he in es iga ional o mula ions in he P ima y s udy, he Boos e s udy p o ocol was amended and all in an s ye o ecei e a boos e dose (N D385) ecei ed he licensed accine. In he P ima y s udy, non-in e io i y o 3-dose accina ion wi h in es iga ional o mula ions compa ed wi h he licensed accine was no demons a ed due o an i-pe ac in ailing o mee he non-in e io i y c i e ion. Pos -p ima y accina ion, mos in an s had se op o ec i e le els o an i-diph he ia (100% o in an s), an i- e anus an igens (100%), agains hepa i is B (97.5% ac oss g oups), poly ibosyl- ibi ol- phospha e (88.0%) and polio i us ypes 1–3(90.5%). Se oposi i i y a es o each pe ussis an igen we e 100% in all g oups. Highe incidence o e e (>38C) was epo ed in in an s ecei ing he in es iga ional o mula ions (P ima y s udy: 75.0% [A] and 72.1% [B] s 58.8% [con ol]; Boos e s udy, be o e amendmen : 49.4% and 46.6% s 37.4%, espec i ely). The de elopmen o he in es iga ional o mula ions was no u he pu sued. KEYWORDS acellula pe ussis; DTPa- HBV-IPV/Hib; diph he ia; hepa i is B; Haemophilus influenzae ype b; immunogenici y; in an s; polio i us; sa e y; e anus In oduc ion Combining mul iple an igens in o a single accine has se e al po en ial ad an ages including simplified adminis a ion, highe accine co e age, educ ion in accina ion cos s and numbe o isi s, and minimized isk o adminis a ion e o s and missed doses. 1,2 A combined hexa alen diph he ia (D), e anus (T), acellula pe ussis (Pa), hepa i is B (HBV), inac i a ed poliomyeli is (IPV), and Haemophilus influenzae ype b (Hib) accine (DTPa-HBV-IPV/Hib; In an ix hexa,GSK)wasfi s au ho- ized o use in 2000. 3 DTPa-HBV-IPV/Hib is indica ed o p i- ma y accina ion as a 2- o 3-dose p ima y accina ion cou se in in an s, ollowed by a boos e accina ion wi h an in e al o a leas 6 mon hs be ween he las dose o p ima y accina ion and he boos e dose. The cu en ly licensed o mula ion o DTPa-HBV-IPV/ Hib con ains D and T an igens om No a is Vaccines and Diagnos ics, while he o he an igens a e manu ac u ed in- house. In esponse o an inc easing demand o DTPa- based accines and o inc ease supply flexibili y, al e na i e o mula ions o diph he ia and e anus an igens o use in DTPa combina ion accines ha e been de eloped and es ed in p e-clinical se ings and we e p oposed o p og ess in clinical e alua ion. The his o ical manu ac u ing acili ies could po en ially no be able o ace he inc easing equi e- men s o DTPa combina ion accines. Inc easing he manu ac u ing capabili y would o e come his ising demand and help con olling he whole manu ac u ing p o- cess. Two DTPa-HBV-IPV/Hib o mula ions con aining new diph he ia and e anus an igens (D A T A Pa-HBV-IPV/ CONTACT Timo Vesika i imo. esika i@u a.fiVaccine Resea ch Cen e , Uni e si y o Tampe e, Bioka u 10, FI-33014 Tampe e, Finland. y Au ho s wi h equal con ibu ion. © 2017 Timo Vesika i, Luis Ri e a, Tiina Ko honen, Ani a Ahonen, B igi e Cheu a , Ma jan Heza eh, Winnie Janssens, and Na cisa Mesa os. Published wi h license by Taylo & F ancis. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/3.0/), which pe mi s un es ic ed use, dis ibu- ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. The mo al igh s o he named au ho (s) ha e been asse ed. HUMAN VACCINES & IMMUNOTHERAPEUTICS 2017, VOL. 13, NO. 7, 1505–1515 h ps://doi.o g/10.1080/21645515.2017.1294294 Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 Hib and D B T B Pa-HBV-IPV/Hib, o mula ions A and B, espec i ely), de oxified and adso bed on aluminum hyd ox- ide used as an adju an ollowing 2 di e en p ocesses (A and B), we e chosen o clinical de elopmen . Addi ionally, in bo h in es iga ional o mula ions, he Hib an igen was conjuga ed o he in es iga ional e anus oxoid (TT). We aimed o e alua e he immunogenici y and sa e y o he 2 new o mula ions adminis e ed as a p ima y 3-dose acci- na ion o in an s a 2, 3 and 4 mon hs o age (P ima y ac- cina ion s udy) and as a boos e dose a 12–15 mon hs o age (Boos e s udy). All in an s we e co-adminis e ed wi h a 13- alen pneumococcal conjuga e accine (PCV13; P e e- na 13TM,Pfize Inc.). The licensed o mula ion o DTPa- HBV-IPV/Hib accine was used as a benchma k o in es i- ga e non-in e io i y o he immune esponse o all accine an igens. Resul s S udy pa icipan s In he P ima y s udy, a o al o 721 in an s, 456 in an s om Finland and 265 in an s om Dominican Republic, we e en olled and included in he o al accina ed coho (TVC) (240 ecei ed o mula ion A [g oup A], 242 ecei ed o mula- ion B [g oup B] and 239 ecei ed he licensed accine [con ol g oup]); o hose, 651 (215 in g oup A, 217 in g oup B and 219 in he con ol g oup) we e included in he acco ding- o-p o o- col (ATP) coho o immunogenici y (ATP-I) (Fig. 1). Sc een ailu es we e no eco ded o he p ima y s udy. In o al, 657 in an s (409 om Finland and 248 om Dominican Republic) we e en olled in he Boos e s udy. The emaining 64 sc eened pa icipan s we e no en olled in he s udy due o wi hd awal o consen (31), non- P ima y TVC N=240 Boos e TVC p e*: N=85; pos *: N=131 En olled (N=721) G oup B G oup A Con ol 2 Wi hd awn: Consen wi hd awal (1); Dea h (1) Comple ed N=238 25 Excluded: Adminis a ion o accine(s) o bidden in he p o ocol (3); S udy accine dose no adminis e ed acco ding o p o ocol (1); Non-compliance wi h accina ion schedule (11); Non-compliance wi h blood sampling schedule (2); Essen ial se ological da a missing (8) ATP coho o immunogenici y N=215 P ima y TVC N=242 P ima y TVC N=239 3 Wi hd awn: Consen wi hd awal (3) Comple ed N=239 1 Wi hd awn: Consen wi hd awal (1) Comple ed N=238 25 Excluded: Adminis a ion o accine(s) o bidden in he p o ocol (1); Adminis a ion o any medica ion o bidden by he p o ocol (1); Non-compliance wi h accina ion schedule (9); Non-compliance wi h blood sampling schedule (2); Essen ial se ological da a missing (12) ATP coho o immunogenici y N=217 20 Excluded: Adminis a ion o accine(s) o bidden in he p o ocol (2); Non-compliance wi h accina ion schedule (8); Non-compliance wi h blood sampling schedule (6); Essen ial se ological da a missing (4) ATP coho o immunogenici y N=219 Boos e TVC p e*: N=88; pos *: N=130 Boos e TVC p e*: N=99; pos *: N=124 4 Excluded p e: Vaccine empe a u e de ia ion (1); P o ocol iola ion (2); Non-compliance wi h blood sampling schedule (1) 8 Excluded pos : P o ocol iola ion (5); Non- compliance wi h blood sampling schedule (2); Essen ial se ological da a missing (1) Boos e ATP immunogenici y coho p e*: N=81; pos *: N=123 6 Excluded p e: Adminis a ion o accine(s) o bidden in he p o ocol (1); P o ocol iola ion (2); Non-compliance wi h blood sampling schedule (1); Essen ial se ological da a missing (2) 8 Excluded pos : P o ocol iola ion (4); Non- compliance wi h blood sampling schedule (2); Essen ial se ological da a missing (2) Boos e ATP immunogenici y coho p e*: N=82; pos *: N=122 9 Excluded p e: Adminis a ion o accine(s) o bidden in he p o ocol (2); P o ocol iola ion (3); Non-compliance wi h blood sampling schedule (1); Essen ial se ological da a missing (3) 6 Excluded pos : Adminis a ion o accine(s) o bidden in he p o ocol (1); S udy accine dose no adminis e ed acco ding o p o ocol (1); P o ocol iola ion (4); Boos e ATP immunogenici y coho p e*: N=90; pos *: N=118 P ima y accina ion s udy Boos e accina ion s udy 0 Wi hd awn p e 1 Wi hd awn pos : Consen wi hd awal Comple ed p e*: N=85; pos *: N=130 0 Wi hd awn p e & pos Comple ed p e*: N=88; pos *: N=130 0 Wi hd awn p e & pos Comple ed p e*: N=99; pos *: N=124 Figu e 1. Flow o pa icipan s in he P ima y and Boos e accina ion s udies. N, numbe o pa icipan s, TVC, o al accina ed coho ; ATP, acco ding o p o ocol; g oup A/ g oup B, in an s who ecei ed he new o mula ions A o B o DTPa-HBV-IPV/Hib CPCV13 as a p ima y accina ion a 2, 3, 4 mon hs o age and a boos e dose wi h he same accine a 12–15 mon hs o age (a e p o ocol amendmen , bo h g oups ecei ed he licensed DTPa-HBV-IPV/Hib and PCV13 as boos e ); Con ol, in an s who ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 as a p ima y accina ion a 2, 3, 4 mon hs o age and a boos e dose a 12–15 mon hs o age; p e  , be o e p o ocol amendmen ; pos  , a e p o ocol amendmen . 1506 T. VESIKARI ET AL. Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 eligibili y (14), los o ollow up (8), mo ing om he s udy a ea (7) o non-willingness o blood sampling (1). One in an had died (se ious ad e se e en [SAE] desc ibed in Sa e y –P ima y s udy sec ion)and2didno pa icipa e because o an ad e se e en (AE; acu e disease a en olmen and oo e y hema). Ini ially, 85, 88 and 99 in an s we e en olled in g oups A, B and con ol, espec i ely, o ecei e a boos e o he o mula ion as in he p ima y s udy; o hese, 81 (g oup A), 82 (g oup B) and 90 (con ol g oup) we e included in he ATP-I. Following a high incidence o e e obse ed in in an s who ecei ed he in es iga ional o mula ions in he P ima y s udy (see Sa e y sec ion o he Resul s), he s udy p o ocol was amended and all in an s (N D385) who we e s ill o ecei e he boos e dose, ecei ed he licensed o mula ion as boos e . A e he p o- ocol amendmen , 131, 130 and 124 in an s we e included in g oups A, B and con ol, espec i ely; o hese, 123 (g oup A), 122 (g oup B) and 118 (con ol g oup) we e included in ATP-I (Table 1). Immunogenici y P ima y s udy The non-in e io i y o he immunogenici y o he in es iga- ional DTPa-HBV-IPV/Hib o mula ions compa ed wi h he licensed accine was assessed in e ms o se op o ec ion a es o diph he ia and e anus an igens, hepa i is B su ace an igens (HBsAg), and poly ibosyl- ibi ol-phospha e an igens (PRP, a polysaccha ide componen o Haemophilus influenzae bac e- ium capsule associa ed wi h i ulence), and in e ms o an i- body geome ic mean concen a ions (GMCs) o pe ussis an igens one mon h a e he hi d accine dose. The non-in e- io i y o he in es iga ional D A T A Pa-HBV-IPV/Hib and D B T B Pa-HBV-IPV/Hib o mula ions o he licensed accine was no demons a ed as he uppe limi s (ULs) o he 97.5% confidence in e als (CIs) o an i-pe ac in (PRN) GMC a io (con ol g oup/in es iga ional o mula ion) exceeded he p e- defined limi o 1.5 o bo h o mula ions (A: 1.54 and B: 1.84); o no e, he non-in e io i y c i e ia we e me o all o he an i- gens (Table 2). One mon h pos -dose 3, se op o ec i e/se oposi i e concen- a ions o an ibodies agains diph he ia, e anus and all pe us- sis an igens we e obse ed in all in an s in he 3 g oups, and a leas 97.5% o in an s in all g oups had se op o ec i e le els o an i-HBs an ibodies, a leas 88.0% o in an s had an i-PRP an ibody concen a ions 0.15 mg/mL, and a leas 97.4%, 90.5% and 97.9% o in an s had se op o ec i e i e s o an ibod- ies agains polio i us ypes 1, 2 and 3 ac oss he 3 g oups, espec i ely (Table 3). Se oposi i i y a es o each pe ussis an igen we e 100% in all g oups. Vaccine esponse o PT, FHA and PRN was moun ed in a leas 97.1%, 96.9% and 91.0% o in an s, espec i ely (Table 4). Boos e s udy The pe cen age o in an s wi h an i-D, an i-T, an i-HBs, an i-PRP and an i-polio i us ypes 1–3 an ibody concen a- ions abo e he se op o ec i e cu -o s one mon h a e boos e accina ion was a leas 97.3% be o e he p o ocol amendmen , and a leas 98.3% a e he amendmen . Wi h espec o pe ussis, highe GMCs we e obse ed when he licensed accine was adminis e ed in he p ima y phase (Table 3). Table 1. Summa y o demog aphic cha ac e is ics ( o al accina ed coho s). TVC G oup A (N D240) G oup B (N D242) Con ol g oup (N D239) P ima y s udy Age a dose 1 (we) Mean 9.7 9.8 9.7 Range (min–max) 8–12 8–12 8–12 Female/male, % 49.6/50.4 57.0/43.0 41.4/58.6 Ances y, n (%) Whi e Caucasian 144 (60.0) 148 (61.2) 140 (58.6) O he 96 (40.0) 94 (38.8) 99 (41.4) Boos e s udy (Be o e p o ocol amendmen ) G oup A (N D85) G oup B (N D88) Con ol g oup (N D99) Age a boos e dose (mo) Mean 12.9 13.0 13.0 Range (min–max) 12–15 12–15 12–15 Female/male, % 55.3/44.7 55.7/44.3 38.4/61.6 Ances y, n (%) Whi e Caucasian 79 (92.9) 83 (94.3) 91 (91.9) O he 6 (7.1) 5 (5.7) 8 (8.1) Boos e s udy (A e p o ocol amendmen ) G oup A (N D131) G oup B (N D130) Con ol g oup (N D124) Age a boos e dose (mo) Mean 14.1 13.9 14.0 Range (min-–max) 12–16 12–15 12–15 Female/male, % 46.6/53.4 58.5/41.5 42.7/57.3 Ances y, n (%) Whi e Caucasian 49 (37.4) 46 (35.4) 39 (31.5) O he 82 (62.6) 84 (64.6) 85 (68.5) N, numbe o pa icipan s; n (%), numbe (pe cen age) o pa icipan s in a gi en ca ego y; TVC, o al accina ed coho ; we, weeks; mo, mon hs; min, minimum; max, max- imum. In he P ima y and Boos e s udies (be o e p o ocol amendmen ) g oups A and B ecei ed he in es iga ional o mula ions A and B o DTPa-HBV-IPV/Hib CPCV13 a 2, 3 and 4 mon hs o age and as a boos e dose a 12–15 mon hs o age; he con ol g oup ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 accines a 12–15 mon hs o age. A e p o ocol amendmen o he Boos e s udy, all 3 g oups ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 accines. HUMAN VACCINES & IMMUNOTHERAPEUTICS 1507 Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 Sa e y P ima y s udy Injec ion si e pain was he mos equen ly epo ed soli- ci ed local symp om in he 3 g oups, epo ed in 79.2%, 70.4% and 65.1% o in an s in g oups A, B and con ol, espec i ely; he mos common g ade 3 solici ed local symp- om was swelling, epo ed in 15.4% o in an s in g oup A, 15.0% o in an s in g oup B, and 16.4% o in an s in he con ol g oup (Fig. 2A). I i abili y was he mos common solici ed gene al symp- om in all 3 g oups (g oup A: 82.1%, g oup B: 85.4%, con- ol: 80.3%), and was also he mos common g ade 3 symp om (g oup A: 14.2%, g oup B: 17.1%, con ol: 10.5%) (Fig. 2B). The incidence o e e epo ed in in an s who ecei ed he in es iga ional o mula ions appea ed highe compa ed wi h con ol (g oup A: 75.0%, g oup B: 72.1%, con ol: 58.8%). The incidence o e e was in majo i y con- side ed by he in es iga o s o be ela ed o accina ion and causally ela ed e e incidence was 74.6% in g oup A, 70.0% in g oup B and 58.0% in he con ol g oup. G ade 3 e e (>39.0C axilla y empe a u e) was epo ed o 1.7% o in an s in g oup A and he con ol g oup, and o 2.1% o in an s in g oup B (Fig. 2B). Du ing he 31-day pos - accina ion pe iod, a leas one unsolici ed ad e se e en was epo ed o 63.8%, 68.2%, and 66.5% o in an s in g oups A, B, and con ol, espec i ely; g ade 3 unsolici ed AEs we e epo ed o 7.1%, 8.7% and 6.7% o in an s and unsolici ed AEs wi h a causal ela ionship o acci- na ion, o 21.7%, 21.1% and 23.0% o in an s in hese g oups, espec i ely. Twen y-one SAEs we e epo ed o 18 in an s (9, 5, and 4 in an s in g oups A, B and con ol, espec i ely). Du ing he en i e s udy pe iod, one a al SAE was epo ed in he Domini- can Republic in g oup A 17 d pos -dose 1, he eason being asphyxia and in e s i ial lung disease. None o he SAEs we e conside ed by he in es iga o o be po en ially ela ed o accina ion. Boos e s udy Be o e p o ocol amendmen The mos common solici ed local symp om was injec ion si e pain, epo ed o 65.9%, 76.1% and 63.6% o in an s in g oups A, B, and con ol, espec i ely; he mos common g ade 3 soli- ci ed local symp om was swelling, epo ed in 20.0% o in an s in g oup A, 11.4% o in an s in g oup B, and 19.2% o in an s in he con ol g oup (Fig. 2A). The incidence o solici ed gene al symp oms anged om 49.4%–81.2% in g oup A, om 46.6%–83.0% in g oup B, and om 37.4%–74.7% in he con ol g oup. I i abili y was he mos common solici ed gene al symp om in all 3 g oups (g oup A: 81.2%, g oup B: 83.0%, con ol: 74.7%), and was also he mos common g ade 3 symp om (g oup A: 5.9%, g oup B: 4.5%, con ol: 2.0%) (Fig. 2B). The incidence o e e appea ed highe in g oups A (49.4%) and B (46.6%) compa ed o con ol (37.4%); g ade 3 e e (>39.0Caxil- la y empe a u e) was no epo ed (Fig. 2B). The incidence o e e was in majo i y conside ed by he in es iga o s o be ela ed o accina ion and causally ela ed incidence was 49.4% in g oup A, 45.5% in g oup B and 36.4% in he con- ol g oup. The incidence o unsolici ed AEs epo ed up o day 31 ol- lowing accina ion was simila in in an s who ecei ed he in es iga ional o mula ions o he licensed accine as boos e (g oup A: 49.4%, g oup B: 44.3%, con ol: 50.5%). No SAEs we e epo ed be o e p o ocol amendmen . A e p o ocol amendmen The mos common solici ed local symp om in all g oups was injec ion si e pain (58.0% in g oup A, 50.8% in g oup B and 51.6% in con ol g oup). The mos common g ade 3 solici ed local symp oms we e edness (g oup A: 6.1%, g oup B: 6.2%, con ol: 6.5%) and swelling (g oup A: 6.1%, g oup B: 7.7%, con- ol: 4.8%). The mos common gene al symp om in all g oups was i i- abili y epo ed in 50.4%, 44.6% and 50.0% o in an s om Table 2. G oup di e ences in se op o ec ion/se oposi i i y a es and adjus ed GMC a io one mon h pos -dose 3 in he P ima y accina ion s udy (ATP coho o immunogenici y). Con ol G oup A Di e ence in pe cen age (con ol g oup minus g oup A) G oup B Di e ence in pe cen age (con ol g oup minus g oup B) An ibody n (%) n (%) % (97.5% CI) n (%) % (97.5% CI) An i-D (0.1 IU/mL) 219 (100) 214 (100) 0.00 (¡2.25–2.30) 217 (100) 0.00 (¡2.25–2.27) An i-T (0.1 IU/mL) 219 (100) 214 (100) 0.00 (¡2.25–2.30) 217 (100) 0.00 (¡2.25–2.27) An i- HBs 10 mIU/mL, in-house ELISA 205 (98.1) 197 (97.5) 0.56 (¡3.27–4.63) 203 (99.0) ¡0.94 (¡4.57–2.36) 10 mIU/mL, CLIA adjus ed 203 (97.1) 197 (97.5) ¡0.40 (¡4.62–3.80) 201 (98.0) ¡0.92 (¡5.07–3.02) An i-PRP (0.15 mg/mL) 193 (88.5) 197 (92.1) ¡3.52 (¡10.19–3.00) 190 (88.0) 0.57 (¡6.53–7.70) Adjus ed GMC Adjus ed GMC a io (con ol g oup/g oup A) Adjus ed GMC Adjus ed GMC a io (con ol g oup/g oup B) Pe ussis an igens Con ol G oup A Value (97.5% CI) G oup B Value (97.5% C) An i-PT (EU/mL) 73.9 58.5 1.26 (1.11–1.44) 59.0 1.25 (1.10–1.43) An i-FHA (EU/mL) 207.6 193.0 1.08 (0.94–1.23) 166.6 1.25 (1.09–1.42) An i-PRN (EU/mL) 105.6 79.5 1.33 (1.14–1.54) 66.7 1.58 (1.37–1.84) ATP, acco ding- o-p o ocol; n (%), numbe (pe cen age) o pa icipan s wi h an ibody concen a ion abo e he specified cu -o ; CI, confidence in e al; D, diph he ia; T, e anus; PRP, poly ibosyl- ibi ol phospha e; HBs, hepa i is B; PT, pe ussis oxoid; FHA, filamen ous hemagglu inin; PRN, pe ac in; CLIA, ChemiLuminescence ImmunoAs- say; ELISA, enzyme-linked immunoso ben assay; EU/ml, ELISA uni s pe millili e ; IU/ml, in e na ional uni s pe millili e . Adjus ed GMC a io, geome ic mean an ibody concen a ion adjus ed o baseline concen a ion. In he P ima y s udy, g oups A and B ecei ed he in es iga ional o mula ions A and B o DTPa-HBV-IPV/Hib CPCV13 a 2, 3 and 4 mon hs o age; con ol g oup ecei ed he licensed DTPa-HBV-IPV/HibCPCV13 accine a 2, 3 and 4 mon hs o age. 1508 T. VESIKARI ET AL. Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 Table 3. Se op o ec ion/se oposi i i y a es and GMCs/GMTs be o e and one mon h pos -dose 3 in he P ima y and Boos e accina ion s udies (ATP-I coho s). P ima y Vaccina ion Boos e Vaccina ion be o e amendmen Boos e Vaccina ion a e amendmen An ibody G oups Time poin %SP 95% CI GMC/GMT 95% CI %SP 95% CI GMC/GMT 95% CI %SP 95% CI GMC/GMT 95% CI An i-D A P e 77.0 70.5–82.6 0.292 0.247–0.347 96.3 89.6–99.2 0.357 0.305–0.419 87.0 79.7–92.4 0.247 0.213–0.287 (0.1 IU/mL) Pos 100 98.3–100 1.499 1.367–1.644 100 95.5–100 5.652 4.985–6.408 100 97.0–100 6.327 5.698–7.025 B P e 78.6 72.4–83.9 0.281 0.238–0.332 97.6 91.5–99.7 0.445 0.381–0.520 94.2 88.4–97.6 0.278 0.244–0.317 Pos 100 98.3–100 1.704 1.564–1.856 100 95.6–100 5.494 4.891–6.171 100 97.0–100 5.452 4.956–5.998 Con ol P e 75.8 69.5–81.4 0.290 0.245–0.343 94.4 87.4–98.2 0.401 0.343–0.468 88.9 81.7–93.9 0.304 0.258–0.360 Pos 100 98.3–100 1.839 1.686–2.005 100 96.0–100 6.772 5.897–7.777 100 96.9–100 7.192 6.419–8.059 An i-T A P e 98.5 95.7–99.7 0.936 0.832–1.053 93.8 86.2–98.0 0.358 0.301–0.427 94.3 88.6–97.7 0.364 0.313–0.422 (0.1 IU/mL) Pos 100 98.3–100 1.761 1.624–1.910 100 95.5–100 5.015 4.341–5.794 100 97.0–100 5.986 5.204–6.885 B P e 98.1 95.2–99.5 0.920 0.822–1.029 95.1 88.0–98.7 0.362 0.306–0.428 94.2 88.4–97.6 0.332 0.289–0.380 Pos 100 98.3–100 1.726 1.597–1.865 100 95.6–100 5.034 4.366–5.803 100 97.0–100 5.316 4.716–5.992 Con ol P e 99.1 96.6–99.9 0.907 0.812–1.013 95.5 88.9–98.8 0.394 0.337–0.459 94.9 89.2–98.1 0.331 0.285–0.383 Pos 100 98.3–100 1.947 1.818–2.085 100 96.0–100 5.571 4.869–6.374 100 96.9–100 5.993 5.222–6.878 An i-PRP A P e 50.6 39.3–61.9 0.173 0.138–0.216 74.8 66.2–82.2 0.328 0.262–0.409 (0.15 mg/mL) Pos 92.1 87.6–95.3 0.951 0.793–1.142 100 95.5–100 12.765 9.300–17.520 99.2 95.6–100 21.462 16.65–27.664 B P e 54.9 43.5–65.9 0.175 0.142–0.216 64.5 55.2–73 0.288 0.227–0.365 Pos 88.0 82.9–92.0 0.730 0.606–0.880 100 95.6–100 15.904 11.723–21.576 100 97.0–100 15.903 12.132–20.848 Con ol P e 58.4 47.5–68.8 0.236 0.182–0.307 69.2 60.0–77.4 0.334 0.254–0.439 Pos 88.5 83.5–92.4 1.082 0.884–1.324 100 96–100 17.099 12.966–22.55 99.2 95.4–100 17.429 13.429–22.620 An i-PT A P e 16.6 11.7–22.5 3.3 3.0–3.6 85.0 75.3–92.0 10.5 8.8–12.6 77.2 68.8–84.3 8.3 7.2–9.7 (5 EU/mL) Pos 100 98.3–100 57.7 52.9–62.9 100 95.4–100 76.1 66.1–87.6 100 96.9–100 92.4 80.6–106 B P e 18.1 13.1–24 3.4 3.1–3.7 81.3 71.0–89.1 9.5 7.9–11.4 77.7 69.2–84.8 7.9 6.8–9.1 Pos 100 98.3–100 57.5 53.1–62.4 100 95.5–100 74.3 62.6–88.1 100 97.0–100 93.6 83.1–105.5 Con ol P e 14.8 10.3–20.3 3.1 2.9–3.4 89.7 81.3–95.2 12.7 10.8–15.0 82.9 74.8–89.2 9.9 8.5–11.5 Pos 100 98.3–100 73.2 67.7–79.2 100 95.9–100 96.0 83.5–110.3 100 96.9–100 132.6 114.9–153.0 An i-FHA A P e 80.6 74.4–85.9 10.6 9.3–12.2 100 95.5–100 41.7 35.4–49.2 99.2 95.6–100 37.6 32.5–43.4 (5 EU/mL) Pos 100 98.3–100 192.4 175–211.4 100 95.5–100 393.7 346.4–447.6 100 97.0–100 467.3 417.3–523.3 B P e 76.7 70.4–82.2 9.7 8.5–11.1 98.8 93.4–100 36.9 31.5–43.3 99.2 95.4–100 34.0 28.7–40.4 Pos 100 98.3–100 165.5 151.5–180.7 100 95.6–100 372.4 332.7–416.7 100 97.0–100 446.2 402.3–494.9 Con ol P e 75.0 68.5–80.7 9.1 8.0–10.4 100 95.9–100 47.1 40.3–55.1 100 96.9–100 45.7 38.8–53.9 Pos 100 98.3–100 210.6 194.1–228.6 100 96.0–100 423.0 368.1–485.9 100 96.9–100 582.9 517.1–657.1 An i-PRN A P e 42.0 35.1–49.2 5.1 4.5–5.9 84.0 74.1–91.2 12.8 10.4–15.7 79.7 71.5–86.4 11.6 9.7–13.9 (5 EU/mL) Pos 100 98.3–100 76.6 68.1–86.3 100 95.5–100 213.0 178.1–254.7 100 97.0–100 253.2 216.9–295.6 B P e 42.4 35.6–49.4 4.9 4.3–5.5 85.2 75.6–92.1 10.8 8.9–13.1 76.0 67.4–83.3 9.7 8.1–11.7 Pos 100 98.3–100 65.7 58.9–73.3 100 95.5–100 180.0 154.2–210.1 100 97.0–100 181.0 154.8–211.7 Con ol P e 36.2 29.7–43.1 4.9 4.3–5.7 93.3 85.9–97.5 18.2 15.0–22.1 89.7 82.8–94.6 15.6 13.0–18.7 Pos 100 98.3–100 106.6 96.6–117.8 100 95.9–100 372.9 309.3–449.5 100 96.9–100 401.1 342.2–470.0 An i-HBs A P e 91.9 83.2–97.0 130.3 91.2–186.0 90.0 83.2–94.7 94.9 72.2–124.8 (10 mIU/mL) Pos 97.5 94.3–99.2 639.5 523.6–781.2 98.7 93.1–100 2233.3 1479.7–3370.8 98.4 94.2–99.8 2229.3 1625.5–3057.5 B P e 93.7 85.8–97.9 124.4 89.5–173.0 84.0 76.2–90.1 61.8 45.7–83.5 Pos 99.0 96.5–99.9 602.6 492.1–737.9 98.7 93.1–100 2026.3 1389.4–2955.2 98.3 93.9–99.8 1729.8 1240.6–2411.9 Con ol P e 92.9 85.1–97.3 166.4 112.8–245.5 92.2 85.7–96.4 125.9 94.6–167.7 Pos 98.1 95.2–99.5 799.0 662.2–964.0 100 95.7–100 2685.7 1868.8–3859.7 99.1 95.3–100 3711.4 2729.7–5046.1 An i-polio i us ype 1 (8ED 50 ) A P e 63.9 56.7–70.7 13.5 11.5–16.0 72.5 60.4–82.5 18.2 13.7–24.1 89.6 82.2–94.7 53.5 39.6–72.4 Pos 97.4 94.1–99.2 110.0 88.6–136.5 98.7 93.0–100 572.9 435.5–753.6 100 96.7–100 1121.0 904.2–1389.8 B P e 67.0 60.1–73.4 13.3 11.4–15.5 73.0 61.4–82.6 17.8 13.5–23.5 86.7 78.6–92.5 50.7 37.2–69.2 Pos 97.5 94.2–99.2 94.6 77.2–116.0 100 95.0–100 558.3 422–738.8 100 96.6–100 1099.6 905.2–1335.8 Con ol P e 58.4 51.3–65.3 13.2 11.1–15.8 78.9 67.6–87.7 22.4 16.8–29.9 92.9 86.0–97.1 70.8 52.4–95.8 (Con inued on nex page) HUMAN VACCINES & IMMUNOTHERAPEUTICS 1509 Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 Table 3. (Con inued ) P ima y Vaccina ion Boos e Vaccina ion be o e amendmen Boos e Vaccina ion a e amendmen An ibody G oups Time poin %SP 95% CI GMC/GMT 95% CI %SP 95% CI GMC/GMT 95% CI %SP 95% CI GMC/GMT 95% CI Pos 97.5 94.4–99.2 143.8 117.7–175.7 100 95.8–100 902.1 698.4–1165.0 99.0 94.7–100 1386.2 1091.8–1760.0 An i-polio i us ype 2 (8ED 50 ) A P e 67.0 59.6–73.9 16.0 13.3–19.3 55.1 42.6–67.1 12.7 9.5–16.9 86.7 77.9–92.9 76.6 50.3–116.7 Pos 90.5 85.4–94.3 72.0 57.3–90.4 100 94.2–100 629.7 452.6–876.1 100 96.2–100 1485.3 1182.4–1865.8 B P e 71.9 64.8–78.2 18.4 15.2–22.2 61.1 48.9–72.4 17.1 12.3–23.8 87.1 78.5–93.2 55.0 38.2–79.3 Pos 94.8 90.6–97.5 68.5 55.3–84.9 98.4 91.2–100 668.7 489.9–912.7 99.0 94.4–100 1215.6 973.8–1517.4 Con ol P e 70.4 63.3–76.8 18.8 15.5–22.8 63.8 51.3–75.0 16.6 12.0–22.8 87.1 78.0–93.4 82.7 55.6–122.9 Pos 93.4 89.0–96.4 81.0 65.1–101.0 100 95.3–100 1184.9 901.1–1558.1 100 95.8–100 1537.2 1191.0–1984.1 An i-polio i us ype 3 (8ED 50 ) A P e 51.8 44.5–59.0 13.0 10.7–15.8 69.9 58.0–80.1 24.7 17.1–35.8 88.9 81.4–¡4.1 67.8 47.3–97.2 Pos 97.9 94.8–99.4 179.4 141.2–227.9 100 94.4–100 1147.5 846.2–1556.0 100 96.8–100 1851.2 1473.2–2326.1 B P e 51.2 44.2–58.2 12.5 10.4–15.0 58.9 46.8–70.3 16.8 12.0–23.5 90.8 83.8–95.5 73.8 52.2–104.2 Pos 97.9 94.8–99.4 159.6 126.9–200.8 100 94.3–100 614.0 453.9–830.6 100 96.5–100 1960.4 1574.0–2441.5 Con ol P e 53.2 46.1–60.2 12.6 10.5–15.1 76.3 65.4–85.1 26.6 19.2–36.9 87.5 79.6–93.2 93.9 64.4–136.8 Pos 98.9 96.2–99.9 221.7 176.1–279.2 97.3 90.5–99.7 1120.7 793.0–1583.9 100 96.3–100 2376.4 1874.2–3013.2 ATP-I, acco ding- o-p o ocol (coho o ) immunogenici y; %SP, pe cen age o se op o ec ed/se oposi i e in an s; GMC/GMT, geome ic mean an ibody concen a ion/ i e ; 95% CI, 95% confidence in e al; P e, p e-p ima y/boos e accina ion; Pos , pos -dose 3/boos e accina ion; D, diph he ia; T, e anus; PRP, poly ibosyl- ibi ol phospha e; PT, pe ussis oxoid; FHA, filamen ous hemagglu inin; PRN, pe ac in, HBs, hepa i is B; EU/ml, ELISA uni s pe millili e ; IU/ml, in e na ional uni s pe millili e ; ED 50 , median e ec i e dose. In he P ima y and Boos e s udies (be o e p o ocol amendmen ), g oups A and B ecei ed he in es iga ional o mula ions A and B o DTPa-HBV-IPV/Hib CPCV13 a 2, 3 and 4 mon hs o age and as a boos e dose a 12–15 mon hs o age; he con ol g oup ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 accines a 12–15 mon hs o age. A e p o ocol amendmen o he Boos e s udy, all 3 g oups ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 accines. All samples wi h an i- HBs an ibody concen a ions be ween 10–100 mIU/mL a one mon h a e he p ima y accina ion by he in-house ELISA (conside ed o e es ima ed), we e e es ed wi h he comme cial ChemiLuminescence ImmunoAssay (CLIA) wi h a cu -o defining se oposi i i y o 6.2 mIU/mL. An i-HBs se op o ec ion was edefined as in-house ELISA concen a ion abo e 100 mIU/mL (conside ed alid) o CLIA concen a ion abo e 10 mIU/mL. CLIA was also used o he Boos e s udy. 1510 T. VESIKARI ET AL. Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 g oup A, g oup B and con ol, espec i ely, and was also he mos common g ade 3 gene al symp om (g oup A: 4.6%, g oup B: 1.5%, con ol: 1.6%). The incidence o e e was always conside ed by he in es iga o s o be ela ed o accina ion and appea ed simi- la in all g oups (g oup A: 44.3%, g oup B: 38.5%, con ol: 41.9%, espec i ely); g ade 3 e e was no epo ed (Fig. 2B). Th ee SAEs we e epo ed a e he amendmen , 2 cases o pneumonia and a case o dehyd a ion (all in g oup B); none we e conside ed by he in es iga o o be ela ed o accina ion and all eco e ed be o e he s udy end. Table 4. Vaccine esponse a e o an i-PT, an i-FHA and an i-PRN an ibodies one mon h pos -p ima y accina ion (ATP coho o immunogenici y). % Vaccine esponse (95% CI) An ibody G oup A (N D181) G oup B (N D194) Con ol (N D198) An i-PT 98.0 (94.9–99.4) 97.1 (93.9–98.9) 99.0 (96.6–99.9) An i-FHA 96.9 (93.5–98.9) 97.6 (94.5–99.2) 98.1 (95.1–99.5) An i-PRN 91.0 (86.1–94.6) 93.3 (89.0–96.3) 94.3 (90.2–97.0) ATP, acco ding- o-p o ocol; %, pe cen age o in an s wi h accine esponse; CI, confidence in e al; PT, pe ussis oxoid; FHA, filamen ous hemagglu inin; PRN, pe ac in; N, minimum numbe o in an s wi h a ailable esul s. G oups A and B ecei ed he in es iga ional o mula ions A and B o DTPa-HBV-IPV/Hib CPCV13 a 2, 3 and 4 mon hs o age. Con ol g oup ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 accines a 2, 3 and 4 mon hs o age. Vaccine esponse was defined as a pos -dose 3 an ibody concen a ion 5 ELISA uni s/mL (EU/mL) o ini ially se onega i e in an s, o an an ibody concen a ion 1- old he p e- accina ion an ibody concen a ion o ini ially se oposi i e in an s. In an s wi h an ibody concen a ion <5 EU/mL be o e accina ion we e conside ed se onega i e; in an s wi h an ibody concen a ion 5 EU/mL be o e accina ion we e conside ed se oposi i e. Figu e 2. Incidence o solici ed local (A) and gene al symp oms (B) in P ima y (day 0–7) and Boos e s udy (day 0–4) ( o al accina ed coho s). G oup A/G oup B, in an s who ecei ed he new o mula ions A o B o DTPa-HBV-IPV/Hib CPCV13 as a p ima y accina ion a 2, 3, 4 mon hs o age and a boos e dose wi h he same accine a 12–15 mon hs o age (a e p o ocol amendmen , bo h g oups ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 as boos e ); Con ol, in an s who ecei ed he licensed DTPa-HBV-IPV/Hib CPCV13 as a p ima y accina ion a 2, 3, 4 mon hs o age and a boos e dose a 12–15 mon hs o age; P i, p ima y accina ion; P e, boos e accina- ion be o e p o ocol amendmen ; Pos , boos e accina ion a e p o ocol amendmen . The e o ba s indica e 95% confidence in e als. HUMAN VACCINES & IMMUNOTHERAPEUTICS 1511 Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017 Discussion The immunogenici y o he in es iga ional DTPa-HBV-IPV/ Hib o mula ions adminis e ed o in an s as a 3-dose p ima y accina ion was in e io o he licensed DTPa-HBV-IPV/Hib accine and he eac ogenici y was highe . In he P ima y accina ion s udy epo ed in his manusc ip , he incidence o e e ollowing 3 doses o he in es iga ional DTPa-HBV-IPV/Hib o mula ions was much highe (g oup A: 75.0%, g oup B: 72.1%), and was likely ei he due o he new o - mula ions o he diph he ia and e anus an igens o o he PRP ha was conjuga ed o he in es iga ional e anus an igen. Ne e heless, he incidence o g ade 3 e e epo ed o he in es iga ional ac- cine o mula ion pos -p ima y accina ionwaslow(1.7%–2.1% ac oss he g oups), simila o p e iously epo ed o he in es iga- ional DTaP5-IPV-Hib-HepB o mula ion (2%). 4 Al oge he , he esul s o he P ima y and Boos e accina- ion s udies p esen ed in his manusc ip indica e ha he DTPa-HBV-IPV/Hib accine o mula ions con aining in es i- ga ional diph he ia and e anus an igens a e associa ed wi h a lowe immunogenici y and a highe eac ogenici y compa ed o he licensed DTPa-HBV-IPV/Hib accine. The incidence o SAEs was low, consis en wi h he esul s o p e ious s udies wi h he DTPa-HBV-IPV/Hib accine. 5,6 This finding empha- sizes he need o ca y ou head- o-head compa isons o any new composi ions o hexa alen accine. This expe ience sug- ges s ha he o mula ion o a hexa alen accine is sensi i e o changes in he accine componen s and new expe imen al combina ions may be less immunogenic han he licensed In an ix hexa. In he ligh o waning immuni y ollowing accina ion wi h acellula pe ussis accines, he need o a new gene a ion o pe us- sis accines is ecognized. Al e na i e o mula ions migh be imp o ed wi h he addi ion o mo e o imp o ed an igens o he mul icomponen accines, emo al o an igens o adju an imp o emen , o use o DNA o a enua ed, li e bac e ial accines. 7 The s udies had he ollowing s eng hs: (1) en olmen om di e en se ings (Finland and Dominican Republic) allowed assessing whe he he obse ed e ec s we e coun y specific; (2) he sho accina ion schedule p o ided a wo s case sce- na io o assessing se op o ec ion by he di e en accine o - mula ions; (3) he d op-ou a e was easonably low o his ype o s udy as app oxima ely 85% o he in an s comple ed bo h p ima y and boos e s udies. Ano he ad an age o he s udy design was he a ailabili y o blood samples p e- accina- ion, allowing an i-pe ussis geome ic mean i e (GMT) g oup compa isons while accoun ing o he p e- accina ion immunogenici y. Po en ial limi a ions o he s udies include he ac ha in e en ial analysis linked o he p ima y objec i e in he Boos e s udy could no be pe o med due o ailu e o he p i- ma y non-in e io i y objec i e in he P ima y accina ion s udy and due o he p o ocol amendmen . As he in es iga ional o mula ions o he DTPa-HBV-IPV/ Hib ailed o demons a e non-in e io i y o he accine immu- nogenici y o he licensed o mula ion, and because o a highe incidence o e e associa ed wi h he in es iga ional o mula- ions compa ed o he licensed accine, he de elopmen o he in es iga ional o mula ions was no u he pu sued. Pa ien s and Me hods S udy design The P ima y accina ion s udy was a phase I/II double-blind, andomized, mul icen e s udy conduc ed in 2 cen e s in he Dominican Republic and 14 cen e s in Finland be ween Decembe 2010 and Janua y 2012. Heal hy in an s we e an- domized (1:1:1) o ecei e 3 doses o 2 in es iga ional DTPa- HBV-IPV/Hib o mula ions (A o B; g oup A and B, espec- i ely) o he licensed DTPa-HBV-IPV/Hib o mula ion (con- ol g oup) a 2, 3, 4 mon hs o age; in addi ion, all in an s ecei ed concomi an injec ions o PCV13. In an s who ecei ed 3 doses o ei he o mula ion o DTPa-HBV-IPV/Hib accine (A, B o con ol [licensed ac- cine]) in he P ima y s udy we e in i ed o pa icipa e in a ollow-up, phase II, andomized, double-blind Boos e ac- cina ion s udy (Oc obe 2011–No embe 2012) o e alua e he esponse o he boos e accina ion wi h DTPa-HBV- IPV/Hib ecei ed be ween 12 and 15 mon hs o age. In an s pa icipa ing in he Boos e s udy e ained he g oup alloca- ion o which hey we e andomized in he P ima y s udy. In addi ion, all in an s ecei ed a concomi an boos e dose o PCV13. Ini ially, in an s ecei ed a boos e dose wi h he same ac- cine o mula ions as in he P ima y s udy; ollowing a p o ocol amendmen (see Resul s sec ion), in an s in all 3 g oups ecei ed he licensed DTPa-HBV-IPV/Hib o mula ion as boos e dose. The double-blinding ega ding he accine ecei ed du ing he P ima y s udy was main ained un il he end o he Boos e s udy. W i en in o med consen was ob ained o each in an om he pa en o he legally accep able ep esen a i e (LAR). The s udy was conduc ed acco ding o he Decla a ion o Helsinki, Good Clinical P ac ice, In e na ional Con e ence on Ha moni- sa ion (ICH) Ha monised T ipa i e Guideline o clinical in es iga ion o medicinal p oduc s in he pedia ic popula ion (ICH E11), and he Finnish and Dominican laws and egula- ions. The s udy p o ocol, he amendmen s, he in o med con- sen , and all documen s equi ing p e-app o al we e e iewed and app o ed by an Ins i u ional Re iew Boa d o an Indepen- den E hics Commi ee. The s udies a e egis e ed a www.clinical ials.go (NCT01248884 and NCT01453998). A summa y o each s udy p o ocol is a ailable a h p://www.gsk-clinicals udy egis e . com (GSK s udy ID: 113948 and 114843). S udy objec i es P ima y accina ion s udy The p ima y objec i e o he s udy was o demons a e non- in e io i y o a leas one o he 2 in es iga ional DTPa-HBV- IPV/Hib o mula ions compa ed wi h he licensed o mula ion in e ms o se op o ec ion a es o diph he ia, e anus, HBsAg and PRP an igens, and in e ms o an ibody GMCs o pe ussis an igens one mon h a e he hi d dose. The seconda y objec i es included he assessmen o he immune esponse o he s udy accines in e ms o : se op o ec- ion/se oposi i i y and an ibody concen a ions o i e s, one mon h a e he hi d dose; immunological s a us owa d 1512 T. VESIKARI ET AL. Downloaded by [Tampe e Uni e si y] a 22:46 07 Augus 2017