Combined paediatric vaccines for national

immunization programmes

Francis E. André

Vice-President and senior Medical Director

GlaxoSmithKline, Rixensart, Belgium

Current shifts in pediatric immunization

Replacement of DTPw by DTPa

Introduction of universal hepatitis B vaccination

Introduction of universal Hib vaccination

Switch from OPV to IPV

SB DTPa-based pediatric combinationsSB DTPa-based pediatric combinations

DTP : Diphtheria/ Tetanus/ PT, FHA, PertactinHBV : Recombinant HBsAgIPV : Inactivated enhanced-potency polio vaccineHib : Lyophilized PRP-T conjugate

DTPa - HBV

DTPa

DTPa - IPV

DTPa - HBV - IPV

DTPa / Hib

DTPa - HBV / Hib

DTPa - IPV / Hib

DTPa - HBV - IPV / Hib

SB DTPa-based pediatric combinationsSB DTPa-based pediatric combinations

DTP : Diphtheria/ Tetanus/ PT, FHA, PertactinHBV : Recombinant HBsAgIPV : Inactivated enhanced-potency polio vaccineHib : Lyophilized PRP-T conjugate

DTPa - HBV

DTPa

DTPa - IPV

DTPa - HBV - IPV Infanrix penta

DTPa / Hib

DTPa - HBV / Hib

DTPa - IPV / Hib

DTPa - HBV - IPV / Hib Infanrix hexa

Infanrix penta

DTPa components

D: 25 Lf PT: 25 mcg

T: 10 Lf FHA: 25 mcg PRN: 8 mcg

Hepatitis B component

HBsAg: 10 mcg

Polio components

Polio 1: 40 DUPolio 2: 8 DUPolio 3: 32 DU

Excipients: Alum salts as adjuvant2-Phenoxyethanol as antiseptic

Infanrix penta and Infanrix hexa

DTPa components

D: 25 Lf PT: 25 mcg

T: 10 Lf FHA: 25 mcg PRN: 8 mcg

Hepatitis B component

HBsAg: 10 mcg

Polio components

Polio 1: 40 DUPolio 2: 8 DUPolio 3: 32 DU

Excipients: Alum salts as adjuvant2-Phenoxyethanol as antiseptic

Hib component

PRP: 10 mcg

conjugated to TT

Potentially deleterious interactions between vaccine components

Possible adverse consequences

• Reduced immunogenicity

• Increased reactogenicity

• Shortened shelf life

• Complicated manufacture

Antigens

Preservative(s)Adjuvant(s)

Contaminants

pH

Stabilizer(s) Excipient(s)

Infanrix penta and Infanrix hexa:Key objectives of clinical development

Demonstration of

safety and acceptable reactogenicity

immunogenicity in various schedules

persistence of antibodies up to the booster dose

protective efficacy of each vaccine component

lot-to-lot consistency

Infanrix penta and Infanrix hexa:Integrated clinical trial programme

Common inclusion and exclusion criteria

Common reactogenicity assessment

Common serological assays

Randomized controlled trials: predefined statistical criteria to demonstrate non-inferiority vs. licensed vaccines

Infanrix penta: primary immunization trialsStudy Country PI Schedule

(months)No. of infants receiving

Infanrix penta (ATP analysis)001 Turkey Kanra 3, 4, 5 20002 Finland Mertsola 2, 4, 6 30004 Canada Scheifele 2, 4, 6 50005 Belgium Blancke 3, 4, 5 563008 Belgium Lebacq 3, 4, 5 195011 Germany Zepp 3, 4, 5 4,696012 Lithuania Usonis 3, 4½, 6 549015 USA Ward 2, 4, 6 200016 Germany Zepp 3, 4, 5 182017 France Bégué 2, 3, 4 29019 Estonia Lutsar 3, 4½, 6 60023 Germany Schmitt 3, 4, 5 179025 France Cohen 2, 3, 4 159030 Moldavia Gylca 1½, 2½, 3½* 160044 USA Edwards 2, 4, 6 477

TOTAL : 7,549

* a dose of HBV was given at birth

Infanrix hexa: primary immunization trials

Study Country PI Schedule(months)

No. of infants receivingInfanrix hexa (ATP analysis)

001 USA Blatter 2, 4, 6 134

003 USA Blatter 2, 4, 6* 525 )

023 Germany Schmitt 3, 4, 5 179

025 France Cohen 2, 3, 4 166

027 USA Black 2, 4, 6 1076

031 Slovakia Avdicova 3, 5, 11 155

036 Australia Nolan 2, 4, 6 182

039 Germany Zepp 3, 4, 5 1581

040 Philippines Montellano 1½, 2½, 3½* 144

048 Germany Heininger 3, 4, 5 555

037 Germany Zepp 3, 4, 5 49

TOTAL : 4746

* one study group received a dose of HBV at birth

Infanrix penta + Hib vs. separate administration of antigens: study design

DTPa-HepB-IPV + Hib

DTPa-HepB-IPV + Hib DTPa-HepB + Hib + OPV

DTPa-HepB + IPV + Hib

DTPa + HepB + Hib + OPV

Group 2 mo 4 mo 6 mo

IPV

Combined

IPV-OPV

Separate(OPV)

All groups N = 100 enrolledStudy 015: Ward, USA

Immunogenicity of D, T and HBsAg

0

20

40

60

80

100

Anti-D Anti-T Anti-HBs

%

Ser

op

rote

ctio

n

GMTs: 1.3 0.8 3.7 2.3 1661 805

Combined (N=89-90) Separate (N=77-78)

anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 015: Ward, USA

Immunogenicity of PT, FHA and PRN%

V

acci

ne

Res

po

nse

0

20

40

60

80

100

Anti-PT Anti-FHA Anti-PRN

GMTs: 97 47 119 153 150 109

Combined (N=91) Separate (N=77-78)

anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 015: Ward, USA

Immunogenicity of Polio types 1, 2, and 3

0

20

40

60

80

100

Anti-Polio 1 Anti-Polio 2 Anti-Polio 3

%

Ser

op

rote

ctio

n

Combined (N=86) Separate OPV (N=73)

GMTs: 415 819 514 1262 1729 453

Study 015: Ward, USA

Immunogenicity of Polio types 1, 2, and 3

0

20

40

60

80

100

Anti-Polio 1 Anti-Polio 2 Anti-Polio 3

%

Ser

op

rote

ctio

n

Combined (N=86) Separate IPV (N=77)

GMTs: 415 213 514 329 1729 432

Study 015: Ward, USA

Study 015 - Local Reactions

Group 1 = Combined

DTPa-HepB-IPV

2 injections

Hib

Group 4 = Separate + OPV

DTPa

HepB

Hib

3 injections

OPV o o o

Dose 1 Dose 2 Dose 3

DTPa-HepB-IPV Any 17.0 17.7 20.0

(group 1) > 20 mm 2.0 1.0 0.0

DTPa Any 14.3 10.3 14.3

(group 4) > 20 mm 0.0 0.0 0.0

4-day follow-up period

Study 015: Incidence (%) of redness by dose

(N = 84 - 100 per dose)

Dose 1 Dose 2 Dose 3

DTPa-HepB-IPV Any 11.0 15.6 14.7

(group 1) > 20 mm 2.0 2.1 2.1

DTPa Any 7.1 10.3 10.7

(group 4) > 20 mm 1.0 1.1 0.0

4-day follow-up period

Study 015: Incidence (%) of swelling by dose

(N = 84 - 100 per dose)

Study 015: Incidence (%) of pain by dose

Dose 1 Dose 2 Dose 3

DTPa-HepB-IPV Any 35.0 26.0 22.1

(group 1) Grade 3 2.0 0.0 0.0

DTPa Any 33.7 19.5 21.4

(group 4) Grade 3 4.1 0.0 0.0

4-day follow-up period (N = 84 - 100 per dose)

Study 015: Incidence (%) of solicited general symptoms per subject

4-day follow-up period over the full vaccination course

DTPa-HepB-IPV + Hib DTPa+HepB+Hib+OPV

General Symptom % 95%CI % 95%CI

Diarrhea 26.0 (17.7 –35.7) 28.6 (19.9 – 38.6)

Fussiness 82.0 (73.1 – 89.0) 85.7 (77.2 – 92.0)

Loss of appetite 38.0 (28.5 – 48.3) 38.8 (29.1 – 49.2)

Sleeping less than usual 42.0 (32.2 – 52.3) 42.9 (32.9 – 53.3)

Sleeping more than usual 64.0 (53.8 – 73.4) 60.2 (49.8 – 70.0)

Unusual crying 6.0 (2.2 – 12.6) 6.1 (2.3 – 12.9)

Vomiting 13.0 (7.1 – 21.2) 16.3 (9.6 – 25.2)

Fever > 38°C/100.4°F 41.0 (31.3 – 51.3) 29.6 (20.8 – 39.7)

4-day follow-up period over the full vaccination course

DTPa-HepB-IPV + Hib DTPa+HepB+Hib+OPV

General Symptom % 95%CI % 95%CI

Diarrhea 2.0 (0.2 – 7.0) 1.0 (0.0 – 5.6)

Fussiness 7.0 (2.9 – 13.9) 11.2 (5.7 – 19.2)

Loss of appetite 1.0 (0.0 – 5.4) 2.0 (0.2 – 7.2)

Sleeping less than usual 1.0 (0.0 – 5.4) 4.1 (1.1 – 10.1)

Sleeping more than usual 1.0 (0.0 – 5.4) 2.0 (0.2 – 7.2)

Unusual crying 0.0 (0.0 – 3.6) 0.0 (0.0 – 3.7)

Vomiting 1.0 (1.0 – 0.0) 2.0 (0.2 – 7.2)

Fever > 39.5°C/103.2°F 3.0 (0.6 – 8.5) 2.0 (0.2 – 7.2)

Study 015: Incidence (%) of “grade 3” solicited general symptoms per subject

Infanrix hexa vs. separate administration of antigens (standard of care)

Group N Vaccine(s) # injections

Combined 134 DTPa-HBV-IPV/Hib 1

Separate 134 DTPa + HBV + Hib + OPV 3

Open, randomized, multicenter

Schedule: 2, 4, 6 months

Study 001: Blatter, USA

Immunogenicity of D, T and HBsAg

0

20

40

60

80

100

Anti-D Anti-T Anti-HBs

%

Ser

op

rote

ctio

n

Combined (N=134) Separate (N=134)

GMTs: 1.43 1.01 1.98 1.49 1240 934

anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 001, Blatter, USA

Immunogenicity of PT, FHA, and PRN%

V

acci

ne

Res

po

nse

0

20

40

60

80

100

Anti-PT Anti-FHA Anti-PRN

Combined (N=134) Separate (N=134)

GMTs: 67.4 41.8 288 303 168 137

anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 001: Blatter, USA

Immunogenicity of Polio types 1, 2, and 3

0

20

40

60

80

100

Anti-Polio 1 Anti-Polio 2 Anti-Polio 3

%

Ser

op

rote

ctio

n

Combined (N=134) Separate (N=134)

GMTs: 495 1278 507 1350 1275 368

Study 001: Blatter, USA

Immunogenicity of Hib: anti-PRP antibodies

100 % 96.9 %

%

Ser

op

rote

ctio

n

91.8 %84.0 %

Combined (N=134) Separate (N=134)

GMCs: 2.65 5.52

Study 001: Blatter, USA

0

20

40

60

80

100

> 0.15 mcg/ml > 1.0 mcg/ml

Study 001: reactogenicityStudy 001: reactogenicity

Pain

Grade 3

Redness

> 20 mm

Swelling

> 20 mm

Fever

> 39.5 °C

% s

ub

ject

s re

po

rtin

g t

he

sym

pto

m(r

egar

dle

ss o

f in

ject

ion

sit

e)

DTPa-HBV-IPV/Hib (N=134)

DTPa + HBV + Hib + OPV (N=134)

Reactogenicity of Infanrix hexa Reactogenicity of Infanrix hexa vsvs. whole-cell pertussis - . whole-cell pertussis - containing combinationcontaining combination

DTPa-HBV-IPV/Hib (N =166)

DTPw-IPV/Hib (Pentacoq TM) + HBV (Engerix TM) (N =82)

% s

ubje

cts

repo

rtin

g th

e sy

mpt

om(r

egar

dles

s of

inje

ctio

n si

te)

Pain

Grade 3

Redness

> 20 mm

Swelling

> 20 mm

Fever

> 39.5 °C

Study 025: Cohen, France, schedule 2-3-4

Infanrix hexa: seroprotection rates for antigens with established surrogate markers of protection(all studies, all schedules)

Antibody Definition of minimalseroprotective titre

% of subjects withseroprotective titres

anti-D 0.1 IU/ml* 98.5

anti-T 0.1 IU/ml* 99.2

anti-HBs 10 mIU/ml 98.5

anti-polio 1 1 : 8 99.2

anti-polio 2 1 : 8 94.5

anti-polio 3 1 : 8 98.8

* by ELISA

Infanrix hexa: D, T, Pa, HepB, IPV

Non-inferiority of Infanrix hexa post-primary vaccination as compared to licensed vaccines

– DTPa-IPV/Hib

– DTPw-IPV/Hib

– Separate administration of DTPa, HepB, Hib and OPV

Similar distribution of antibody titres (Reverse Cumulative Distribution Curves - RCCs)

DTPa-HBV-IPV/Hib

Anti-PT antibody titres following administration of Anti-PT antibody titres following administration of DTPa-HBV-IPV/Hib and of DTPa (Infanrix™) vaccineDTPa-HBV-IPV/Hib and of DTPa (Infanrix™) vaccine

RCCs generated for lots that induced the highest (*) and lowest (**) antibody response

Household contact study* Household contact study ** DTPa-HBV-IPV/Hib

Per

cen

tag

e o

f su

bjec

ts

Anti-PT antibody titre (EU/ml)

Study 048, PI: Heininger, Germany, schedule 3-4-5

Hib immunogenicity

Anti-PRP antibody titres are lower when Hib

vaccines are combined with DTPa-based

vaccines as compared to the separate injection

of the vaccines

Lancet 1999, 354: 2063-68

Infanrix hexa: Hib

In all clinical trials, regardless of vaccination schedule, 96 % of subjects achieved concentrations 0.15 µg/ml

Non-inferiority of Infanrix hexa as compared to licensed DTPa-IPV/Hib vaccine

Identical functional capacity of anti-PRP antibodies induced by Infanrix hexa and by licensed Hib vaccines

Effective induction of immune memory

Proven field effectiveness of DTPa/Hib andDTPa-IPV/Hib under conditions of routine use

• Subjects primed with 3 doses of Infanrix hexa(study 039)

• Randomised at 12-18 months to 3 booster groups

N

• DTPa-IPV/Hib 163• DTPa-IPV/Hib + HepB168• Infanrix hexa 544

Infanrix hexa as a 4th dose: reactogenicity

Study 058: Zepp, Germany

Incidence of solicited symptomsfollowing 3 different boosters

0

10

20

30

40

50

60

Redness Swelling Pain Fever > 38.0°C

DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168)Infanrix hexa (N=544)

% o

f su

bje

cts

wit

h a

sy

mp

tom

Incidence of solicited symptomsfollowing 3 different boosters

0

10

20

30

40

50

60

Redness Swelling Pain Fever

0

10

20

30

40

50

60

Redness Swelling Pain Fever

DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168)Infanrix hexa (N=544)

= Grade 3; fever > 39.5°C

% o

f su

bje

cts

wit

h a

sy

mp

tom

0

10

20

30

40

50

60

% o

f su

bje

cts

wit

h a

sym

pto

m

Irritability Sleepiness Loss of appetite

DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168) Infanrix hexa (N=544)

Incidence of solicited symptomsfollowing 3 different boosters

In all clinical trials,no cases reported of

Hypotonic hyporesponsiveness

Encephalopathy

AnaphylaxisInfanrix penta: 23 439 doses

Infanrix hexa: 15 920 doses

Infanrix penta and Infanrix hexa: conclusions

Protective efficacy not affected by combination of antigens

Tolerability of primary and booster doses in line with that

of other licensed vaccines

Reduced number of injections

Make room for new (pneumococcal, meningococcal) vaccines

Add value to current standard of medical care