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Clinical Trial Results:
A phase III randomized, single-blind, controlled study to demonstrate the non-inferiority of co-administration of GSK Biologicals’ 10-valent pneumococcal conjugate vaccine with Pediacel™ versus co-administration with Infanrix hexa™, when administered to infants as a three-dose primary vaccination course during the first six months of life and as a booster dose at 11-13 months of age.

Summary
EudraCT number	2007-004002-26
Trial protocol	NL
Global end of trial date	01 Dec 2010

Results information
Results version number	v2
This version publication date	12 Mar 2016
First version publication date	19 Jun 2015
Other versions	v1 , v3
Version creation reason	New data added to full data set Data for secondary endpoints have been added.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

110142, 111053

ISRCTN number

US NCT number

NCT00652951

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

Rue de l’Institut 89, Rixensart, Belgium, B-1330

Public contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

12 Dec 2011

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 May 2009

Global end of trial reached?

Yes

Global end of trial date

01 Dec 2010

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that GSK Biologicals’ 10 valent pneumococcal conjugate vaccine when co-administered with DTPa-IPV-Hib (Pediacel) (10Pn-PDC group) is non-inferior to co-administration with DTPa-HBV-IPV/Hib (Infanrix hexa) (10Pn-Hexa group), in terms of immune response to the 10 pneumococcal vaccine serotypes and to protein D, when administered as a three-dose primary vaccination course. Criteria for non-inferiority: For each of the 10 pneumococcal vaccine serotypes and protein D, non-inferiority will be demonstrated if the upper limit of the 2-sided 95% CI of the GMC ratio between groups (10Pn-Hexa group over 10Pn-PDC group), is lower than 2.

Protection of trial subjects

All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available in case of a rare anaphylactic reaction. Vaccines/products were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Also, all Intramuscular injections were administered into the anterolateral region of the thigh or into the deltoid. The buttock was not used for administration of vaccines because of the potential risk of injury to the sciatic nerve and the risk of decreased immunogenicity because of inadvertent subcutaneous injection or injection into deep fat tissue. For all intramuscular injections, the needle was selected long enough to reach the muscle mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve underling nerves and blood vessels or bone. Vaccinators were familiar with the anatomy of the area into which they are injecting vaccine. When appropriate, an individual decision on needle size and site of injection was made for each person on the basis of age, and the size of the muscle. Subjects were followed-up for 31 days after the last vaccination/product administration for adverse events following vaccination. Subjects were also followed during the entire study period for serious adverse events (SAEs).

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 780

Worldwide total number of subjects

780

EEA total number of subjects

780

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

780

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study included a Primary (PRI) Phase, up to Month 3, followed by a Booster (BST) Phase, up to Month 9.

Screening details

At screening the following was performed: informed consent was obtained and signed from subjects’ parents/guardians, check for inclusion/exclusion criteria and contraindications/precautions was performed as regards to vaccination, and medical history of subjects was collected. Subjects’ pre-vaccination body temperature was evaluated.

Period 1 title

Primary Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Yes

10Pn+DTPa-HBV-IPV/Hib Group

Arm description

Subjects received 3 doses of 10Pn-PD-DiT (or GSK1024850A) vaccine co-administered with DTPa-HBV-IPV/Hib vaccine (Infanrix hexa by GSK Biologicals) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (10Pn-PD-DiT) or left (DTPa-HBV-IPV/Hib) thigh or deltoid.

Arm type

Experimental

Investigational medicinal product name

Synflorix

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn-PD-DiT, 10Pn, GSK1024850A

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Infanrix hexa

Investigational medicinal product code

DTPa-HBV-IPV/Hib

Other name

DTPa-HBV-IPV/Hib

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

10Pn+DTPa-IPV-Hib Group

Arm description

Subjects received 3 doses of 10Pn-PD-DiT (or GSK1024850A) vaccine co-administered with DTPa-IPV-Hib vaccine (Pediacel by Sanofi Pasteur MSD) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (10Pn-PD-DiT) or left (DTPa-IPV/Hib) thigh or deltoid.

Arm type

Experimental

Investigational medicinal product name

Synflorix

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn-PD-DiT, 10Pn, GSK1024850A

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Pediacel

Investigational medicinal product code

DTPa-IPV-Hib

Other name

DTPa-IPV-Hib

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

7Pn+DTPa-IPV-Hib Group

Arm description

Subjects received 3 doses of 7Pn vaccine (or Prevenar by Pfizer [formerly Wyeth Lederle Vaccines S.A.]) co-administered with DTPa-IPV-Hib vaccine(Pediacel by Sanofi Pasteur MSD) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (7Pn) or left (DTPa-IPV-Hib; DTPa-HBV-IPV/Hib) thigh or deltoid.

Arm type

Experimental

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

7Pn

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Pediacel

Investigational medicinal product code

DTPa-IPV-Hib

Other name

DTPa-IPV-Hib

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

Number of subjects in period 1	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Started	260	260	260
Completed	260	260	260

Period 2 title

Booster Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Yes

10Pn+DTPa-HBV-IPV/Hib Group

Arm description

Arm type

Experimental

Investigational medicinal product name

Synflorix

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn-PD-DiT, 10Pn, GSK1024850A

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Infanrix hexa

Investigational medicinal product code

DTPa-HBV-IPV/Hib

Other name

DTPa-HBV-IPV/Hib

Pharmaceutical forms

Powder and solvent for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

10Pn+DTPa-IPV-Hib Group

Arm description

Arm type

Experimental

Investigational medicinal product name

Synflorix

Investigational medicinal product code

10Pn-PD-DiT

Other name

10Pn-PD-DiT, 10Pn, GSK1024850A

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Pediacel

Investigational medicinal product code

DTPa-IPV-Hib

Other name

DTPa-IPV-Hib

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

7Pn+DTPa-IPV-Hib Group

Arm description

Subjects received 3 doses of 7Pn vaccine (or Prevenar by Pfizer [formerly Wyeth Lederle Vaccines S.A.]) co-administered with DTPa-IPV-Hib vaccine(Pediacel by Sanofi Pasteur MSD) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (10Pn; 7Pn) or left (DTPa-IPV-Hib; DTPa-HBV-IPV/Hib) thigh or deltoid.

Arm type

Experimental

Investigational medicinal product name

Prevenar

Investigational medicinal product code

Other name

7Pn

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the right thigh or deltoid.

Investigational medicinal product name

Pediacel

Investigational medicinal product code

DTPa-IPV-Hib

Other name

DTPa-IPV-Hib

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses at 2, 3 and 4 months of age (Study Months 0, 1, 2) followed by a booster dose between 11 and 13 months of age (Study Month 9). Vaccine was administered in the left thigh or deltoid.

Number of subjects in period 2 ^[1]	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Started	257	259	258
Completed	256	258	258
Not completed	1	1	0
Adverse event, non-fatal	-	1	-
Not specified	1	-	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 6 subjects did not join the study for the BST phase, 3 subjects from the 10Pn+DTPa-HBV-IPV/Hib Group, 1 subject from the 10Pn+DTPa-IPV-Hib Group and 2 subjects from the 7Pn+DTPa-IPV-Hib Group.

Baseline characteristics

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Reporting group title

10Pn+DTPa-HBV-IPV/Hib Group

Reporting group description

Reporting group title

10Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group title

7Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group	Total
Number of subjects	260	260	260	780
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	7.4 ( 1.2 )	7.6 ( 1.29 )	7.6 ( 1.26 )	-
Gender categorical
Units: Subjects
Female	118	130	136	384
Male	142	130	124	396

End points

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Reporting group title

10Pn+DTPa-HBV-IPV/Hib Group

Reporting group description

Reporting group title

10Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group title

7Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group title

10Pn+DTPa-HBV-IPV/Hib Group

Reporting group description

Reporting group title

10Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group title

7Pn+DTPa-IPV-Hib Group

Reporting group description

Subjects received 3 doses of 7Pn vaccine (or Prevenar by Pfizer [formerly Wyeth Lederle Vaccines S.A.]) co-administered with DTPa-IPV-Hib vaccine(Pediacel by Sanofi Pasteur MSD) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (10Pn; 7Pn) or left (DTPa-IPV-Hib; DTPa-HBV-IPV/Hib) thigh or deltoid.

Primary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) - Primary vaccination.

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End point title

Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) - Primary vaccination.

End point description

Anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations (Anti-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) were measured by 22F-inhibition Enzyme-Linked ImmunSorbent Assay (ELISA) Assay; calculated, expressed as geometric mean concentrations (GMCs) and tabulated. The seropositivity cut-off for the assay was >= 0.05 microgram per millilitre (microg/mL).

End point type

Primary

End point timeframe

At Month 3, aka one month after the administration of the third dose of pneumococcal conjugate vaccine

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	194	189	192
Units: microg/mL
geometric mean (confidence interval 95%)
Anti-1 (N=181;178;178)	1.17 (1.02 to 1.33)	1.31 (1.16 to 1.48)	0.03 (0.03 to 0.03)
Anti-4 (N=192;185;191)	1.61 (1.41 to 1.84)	1.59 (1.38 to 1.83)	2.44 (2.19 to 2.73)
Anti-5 (N=187;181;178)	2.11 (1.88 to 2.37)	2.16 (1.92 to 2.43)	0.03 (0.03 to 0.03)
Anti-6B (N=177;174;180)	0.33 (0.26 to 0.4)	0.35 (0.28 to 0.43)	0.41 (0.34 to 0.51)
Anti-7F (N=192;187;183)	1.7 (1.52 to 1.9)	1.77 (1.57 to 1.99)	0.04 (0.03 to 0.04)
Anti-9V (N=185;186;187)	1.4 (1.2 to 1.63)	1.47 (1.29 to 1.68)	2.14 (1.91 to 2.4)
Anti-14 (N=192;187;192)	3.38 (2.99 to 3.81)	3.33 (2.93 to 3.78)	3.64 (3.24 to 4.1)
Anti-18C (N=194;189;191)	1.73 (1.45 to 2.05)	1.07 (0.92 to 1.25)	2.1 (1.83 to 2.4)
Anti-19F (N=189;183;189)	2.07 (1.73 to 2.48)	1.96 (1.64 to 2.34)	3.04 (2.71 to 3.42)
Anti-23F (N=179;175;184)	0.5 (0.41 to 0.6)	0.54 (0.44 to 0.66)	1.24 (1.04 to 1.47)

Immune response non-inferiority - serotype 1

Statistical analysis description

The 2-sided 95% CI of the geometric mean concentration (GMC) ratio between the 10Pn+DTPa-HBV-IPV/Hib and 10Pn+DTPa-IPV-Hib groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), at one month after Dose 3 of pneumococcal vaccine, was computed for each of the 10 pneumococcal vaccine serotypes and protein D. This statistical method concerns pneumococcal vaccine serotype 1.

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

GMC ratio

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.07

Notes
[1] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 4

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.23

Notes
[2] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 5

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

GMC ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.15

Notes
[3] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 6B

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

GMC ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.26

Notes
[4] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 7F

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMC ratio

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.13

Immune response non-inferiority - serotype 9V

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

Parameter type

GMC ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.16

Notes
[5] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 14

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

GMC ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.21

Notes
[6] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 18C

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

Method

Regression, Cox

Parameter type

GMC ratio

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

1.28

upper limit

2.03

Notes
[7] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 19F

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

Parameter type

GMC ratio

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.36

Notes
[8] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Immune response non-inferiority - serotype 23F

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

Parameter type

GMC ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.23

Notes
[9] - The non-inferiority objective was reached if the upper limit of the 2-sided 95% CI of the GMC ratio for between groups (10Pn+DTPa-HBV-IPV/Hib Group over 10Pn+DTPa-IPV-Hib Group), was lower than 2, for each of the 10 pneumococcal serotypes and protein D.

Primary: Antibody concentration against protein D (PD) - Primary vaccination.

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End point title

Antibody concentration against protein D (PD) - Primary vaccination.

End point description

Anti-PD antibody concentrations were calculated, expressed as geometric mean concentrations (GMCs) and tabulated. The seropositivity cut-off for the assay was >= 100 Enzyme-Linked ImmunoSobent Assay (ELISA) units per millilitre (EL.U/mL).

End point type

Primary

End point timeframe

At Month 3, aka one month after the administration of the third dose of pneumococcal conjugate vaccine

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	195	189	182
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PD	1580 (1409.5 to 1771.1)	1743 (1560.2 to 1947.2)	69.7 (63 to 77.1)

Immune response non-inferiority - protein D

Statistical analysis description

Comparison groups

10Pn+DTPa-HBV-IPV/Hib Group v 10Pn+DTPa-IPV-Hib Group

Number of subjects included in analysis

384

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMC ratio

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.06

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Primary vaccination.

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End point title

Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	194	189	192
Units: Subjects
Anti-1 (N=181;178;178)	174	176	5
Anti-4 (N=192;185;191)	188	180	189
Anti-5 (N=187;181;178)	187	179	0
Anti-6B (N=177;174;180)	122	113	124
Anti-7F (N=192;187;183)	190	186	11
Anti-9V (N=185;186;187)	176	181	184
Anti-14 (N=192;187;192)	191	187	192
Anti-18C (N=194;189;191)	183	178	187
Anti-19F (N=189;183;189)	180	174	189
Anti-23F (N=179;175;184)	134	133	171

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Primary vaccination.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	139	135	132
Units: Titers
geometric mean (confidence interval 95%)
Opsono-1 (N=132;126;125)	20.7 (15.6 to 27.6)	20.8 (15.8 to 27.4)	4.7 (4.1 to 5.2)
Opsono-4 (N=133;132;129)	592.9 (475.9 to 738.7)	600.4 (492.2 to 732.3)	838.4 (718.7 to 978.2)
Opsono-5 (N=138;134;132)	54.8 (44 to 68.4)	60.1 (48.2 to 74.8)	4.2 (3.9 to 4.6)
Opsono-6B (N=129;130;123)	261.3 (176 to 388)	296.4 (198 to 443.7)	633 (419 to 956.4)
Opsono-7F (N=130;127;114)	2063.3 (1691.7 to 2516.6)	2136.1 (1707.9 to 2671.5)	18.4 (12.1 to 28)
Opsono-9V (N=132;129;125)	863.6 (687.6 to 1084.7)	1277.7 (1053.3 to 1550.1)	1194 (1009.5 to 1412.1)
Opsono-14 (N=134;135;127)	990.4 (820.6 to 1195.5)	1086.4 (899.6 to 1311.9)	1373.3 (1040.4 to 1812.7)
Opsono-18C (N=133;129;129)	122.6 (89.4 to 168.2)	84.2 (60.9 to 116.5)	213.6 (163.6 to 278.8)
Opsono-19F (N=137;133;130)	133 (98.1 to 180.2)	143.8 (108.6 to 190.3)	39.2 (30.6 to 50.4)
Opsono-23F (N=139;133;130)	847.4 (626.5 to 1146.3)	1089 (800.2 to 1482)	3703.4 (3119.4 to 4396.8)

No statistical analyses for this end point

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Primary vaccination.

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End point title

Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >=0.05 µg/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	185	177	183
Units: Subjects
Anti-6A (N=185;176;183)	58	51	41
Anti-19A (N=180;177;180	56	50	40

No statistical analyses for this end point

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Primary vaccination.

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End point title

Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >=0.05 µg/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	185	177	183
Units: µg/mL
geometric mean (confidence interval 65%)
Anti-6A (N=185;176;183)	0.1 (0.08 to 0.12)	0.1 (0.09 to 0.12)	0.08 (0.06 to 0.09)
Anti-19A (N=180;177;180)	0.1 (0.09 to 0.13)	0.09 (0.08 to 0.11)	0.08 (0.07 to 0.1)

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Primary vaccination.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	135	129	130
Units: Titres
geometric mean (confidence interval 95%)
Opsono-6A (N=128;120;121)	23.2 (16.1 to 33.6)	25.4 (17.1 to 37.8)	33 (21.4 to 50.8)
Opsono-19A (N=135;129;130)	9 (6.9 to 11.7)	8 (6.3 to 10.2)	4.9 (4.4 to 5.4)

No statistical analyses for this end point

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Primary vaccination.

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End point title

Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Primary vaccination.

End point description

A seroprotected subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.1 IU/mL

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	187	180	189
Units: IU/mL
geometric mean (confidence interval 95%)
Anti-diphteria (N=185;176;187)	1.475 (1.307 to 1.664)	1.078 (0.939 to 1.237)	1.077 (0.949 to 1.222)
Anti-tetanus (N=187;180;189)	2.873 (2.622 to 3.147)	1.702 (1.528 to 1.897)	0.934 (0.837 to 1.043)

No statistical analyses for this end point

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Primary vaccination.

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End point title

Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Primary vaccination.

End point description

A seroprotected subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.15 µg/mL and >= 1.0 µg/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	189	179	188
Units: µg/mL
geometric mean (confidence interval 95%)
Anti-PRP (N=189;179;188)	2.139 (1.766 to 2.59)	4.796 (3.829 to 6.007)	2.219 (1.724 to 2.857)

No statistical analyses for this end point

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Primary vaccination.

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End point title

Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Primary vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >=5 EL.U/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	187	180	188
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT (N=187;180;188)	42.7 (39.1 to 46.6)	36.4 (33.4 to 39.8)	40.1 (37 to 43.6)
Anti-FHA (N=183;172;183)	145.6 (130.4 to 162.5)	100.8 (89.6 to 113.5)	100.5 (89.9 to 112.4)
Anti-PRN (N=187;180;188)	97.6 (86.8 to 109.7)	40.1 (34.8 to 46.1)	45.1 (39.3 to 51.7)

No statistical analyses for this end point

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Primary vaccination.

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End point title

Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Primary vaccination.

End point description

A seroprotected subject was a subject whose antibody ChemiLuminescence ImmunoAssay (CLIA) concentration was greater than or equal to the cut-off value >=10 mIU/mL. Note: investigations on the quality of some serology assays revealed that the anti-HBs ELISA overestimated concentration between 10-100 mIU/mL while values > 100 mIU/mL were confirmed valid. Therefore, all available samples at one month post-dose III and one month post-dose IV timepoints for which the anti-HBs antibody concentration was between 10-100 mIU/mL by in-house ELISA, were retested by the commercial assay Centaur™, an FDA-approved and CE-marked CLIA with a cut-off defining seropositivity of 6.2 mIU/mL. Anti-HBs seroprotection was redefined as in-house ELISA concentration > 100 mIU/mL or CLIA concentration > 10 mIU/mL.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	111	112	113
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HBs (N=111;112;113)	356.9 (279.4 to 455.8)	14 (11.6 to 16.9)	11.5 (9.8 to 13.5)

No statistical analyses for this end point

Secondary: Anti-polio types 1, 2 and 3 titers - Primary vaccination.

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End point title

Anti-polio types 1, 2 and 3 titers - Primary vaccination.

End point description

A seroprotected subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8.

End point type

Secondary

End point timeframe

One month after the administration of the third vaccine dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	156	150	149
Units: Titers
geometric mean (confidence interval 95%)
Anti-polio 1 (N=155;150;149)	27.2 (21.7 to 34.1)	16 (13 to 19.7)	18.1 (14.8 to 22.1)
Anti-polio 2 (N=156;149;149)	37.1 (29.1 to 47.4)	29 (23 to 36.6)	23.2 (18.5 to 29.1)
Anti-polio 3 (N=156;148;149)	47.3 (35.8 to 62.4)	34.2 (27 to 43.4)	26.7 (21.5 to 33)

No statistical analyses for this end point

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Booster vaccination.

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End point title

Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	190	198	202
Units: Subjects
Anti-1, PRE(N=178;185;198)	84	92	6
Anti-4, PRE (N=174;181;194)	136	147	148
Anti-5, PRE (N=181;181;198)	142	152	3
Anti-6B, PRE (N=175;180;192)	117	127	62
Anti-7F, PRE(N=176;181;195)	165	164	5
Anti-9V, PRE(N=180;180;196)	168	168	176
Anti-14, PRE (N=183;184;199)	170	172	190
Anti-18C, PRE (N=179;181;194)	152	143	151
Anti-19F, PRE(N=172;177;197)	149	157	109
Anti-23F, PRE (N=180;182;196)	123	140	108
Anti-1, POST(N=187;196;199)	187	195	7
Anti-4, POST (N=187;194;198)	187	194	198
Anti-5, POST (N=186;191;195)	185	191	4
Anti-6B, POST (N=186;193;199)	176	181	192
Anti-7F, POST (N=189;198;199)	189	198	8
Anti-9V, POST (N=188;197;202)	188	197	202
Anti-14, POST (N=190;198;201)	190	197	198
Anti-18C, POST (N=189;197;200)	188	196	200
Anti-19F, POST(N=183;194;196)	180	191	196
Anti-23F, POST (N=185;194;199)	179	190	194

No statistical analyses for this end point

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - Booster vaccination.

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End point title

Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	190	198	202
Units: μg/mL
geometric mean (confidence interval 95%)
Anti-1, PRE(N=178;185;198)	0.2 (0.17 to 0.22)	0.22 (0.19 to 0.26)	0.03 (0.03 to 0.04)
Anti-4, PRE (N=174;181;194)	0.39 (0.34 to 0.46)	0.43 (0.37 to 0.5)	0.38 (0.34 to 0.43)
Anti-5, PRE (N=181;181;198)	0.41 (0.36 to 0.47)	0.42 (0.37 to 0.48)	0.03 (0.03 to 0.04)
Anti-6B, PRE (N=175;180;192)	0.3 (0.25 to 0.36)	0.32 (0.27 to 0.38)	0.13 (0.11 to 0.16)
Anti-7F, PRE(N=176;181;195)	0.6 (0.54 to 0.68)	0.62 (0.55 to 0.71)	0.03 (0.03 to 0.03)
Anti-9V, PRE(N=180;180;196)	0.68 (0.6 to 0.78)	0.76 (0.66 to 0.89)	0.55 (0.49 to 0.62)
Anti-14, PRE (N=183;184;199)	1.06 (0.9 to 1.26)	1.14 (0.95 to 1.36)	1.55 (1.35 to 1.79)
Anti-18C, PRE (N=179;181;194)	0.58 (0.49 to 0.68)	0.43 (0.36 to 0.5)	0.4 (0.35 to 0.45)
Anti-19F, PRE(N=172;177;197)	0.79 (0.64 to 0.99)	0.9 (0.73 to 1.11)	0.31 (0.25 to 0.37)
Anti-23F, PRE (N=180;182;196)	0.33 (0.27 to 0.39)	0.38 (0.32 to 0.46)	0.26 (0.22 to 0.3)
Anti-1, POST(N=187;196;199)	2.16 (1.89 to 2.46)	2.5 (2.19 to 2.86)	0.03 (0.03 to 0.04)
Anti-4, POST (N=187;194;198)	3.04 (2.7 to 3.42)	3.29 (2.89 to 3.73)	4.01 (3.53 to 4.56)
Anti-5, POST (N=186;191;195)	3.27 (2.9 to 3.7)	3.27 (2.9 to 3.68)	0.04 (0.03 to 0.04)
Anti-6B, POST (N=186;193;199)	1.45 (1.23 to 1.71)	1.41 (1.19 to 1.67)	2.52 (2.15 to 2.96)
Anti-7F, POST (N=189;198;199)	3.79 (3.4 to 4.23)	4.06 (3.63 to 4.54)	0.03 (0.03 to 0.04)
Anti-9V, POST (N=188;197;202)	3.96 (3.58 to 4.39)	4.23 (3.78 to 4.74)	6.05 (5.38 to 6.8)
Anti-14, POST (N=190;198;201)	4.59 (4.06 to 5.19)	4.95 (4.38 to 5.6)	7.31 (6.37 to 8.39)
Anti-18C, POST (N=189;197;200)	6.36 (5.56 to 7.27)	4.63 (4.09 to 5.25)	5.08 (4.47 to 5.78)
Anti-19F, POST(N=183;194;196)	5.45 (4.72 to 6.3)	5.8 (5.04 to 6.68)	2.4 (2.14 to 2.7)
Anti-23F, POST (N=185;194;199)	2.32 (1.98 to 2.71)	2.6 (2.24 to 3.02)	5.32 (4.49 to 6.31)

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Booster vaccination.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	156	154	168
Units: Titers
geometric mean (confidence interval 95%)
Opsono-1, PRE (N=149;152;168)	5.5 (4.7 to 6.4)	5.6 (4.7 to 6.7)	5 (4.4 to 5.8)
Opsono-4, PRE (N=145;150;164)	11.3 (8.6 to 14.9)	15.3 (11.3 to 20.6)	12.3 (9.3 to 16.2)
Opsono-5, PRE (N=148;151;166)	7.2 (6.1 to 8.5)	7 (6 to 8.1)	4.3 (4 to 4.6)
Opsono-6B, PRE (N=141;138;153)	52 (34.8 to 77.7)	96.7 (63.1 to 148)	27.4 (18.6 to 40.3)
Opsono-7F, PRE (N=146;150;146)	818.9 (642.2 to 1044.3)	754.3 (598.4 to 950.8)	138.1 (91.2 to 209.2)
Opsono-9V, PRE (N=143;147;159)	267.2 (212.7 to 335.8)	338.7 (264.8 to 433.2)	149.5 (112.4 to 198.9)
Opsono-14, PRE (N=143;144;161)	117.3 (82.9 to 165.9)	142.5 (101.3 to 200.4)	156 (114.5 to 212.5)
Opsono-18C, PRE (N=139;148;162)	8.2 (6.2 to 10.8)	6.8 (5.3 to 8.5)	7 (5.7 to 8.7)
Opsono-19F, PRE (N=149;149;167)	13.8 (10.6 to 18.1)	15.4 (11.8 to 20.2)	7.8 (6.2 to 9.9)
Opsono-23F, PRE (N=143;143;162)	314.1 (198.6 to 496.7)	350.4 (229.8 to 534.2)	338.9 (219.9 to 522.3)
Opsono-1, POST (N=156;154;164)	208.8 (160.6 to 271.7)	221.4 (165.1 to 297)	4.6 (4.2 to 5.1)
Opsono-4, POST (N=155;152;164)	1046.8 (865.8 to 1265.7)	1121.6 (909.4 to 1383.3)	2335.8 (1946.3 to 2803.3)
Opsono-5, POST (N=152;151;164)	149.3 (119.2 to 187)	132.4 (103.8 to 168.9)	4.1 (4 to 4.3)
Opsono-6B, POST (N=153;149;160)	681.4 (514.6 to 902.1)	763.3 (581.9 to 1001.3)	1807.5 (1408 to 2320.3)
Opsono-7F, POST (N=154;152;153)	3936.5 (3413.2 to 4540)	3976 (3390.2 to 4663.1)	129.1 (85.9 to 193.9)
Opsono-9V, POST (N=153;151;163)	2512.9 (2213.1 to 2853.2)	2257.6 (1974.3 to 2581.5)	3889.5 (3260.1 to 4640.2)
Opsono-14, POST (N=154;154;164)	1534.2 (1290.9 to 1823.3)	1896.3 (1591.3 to 2259.7)	1867.9 (1540.5 to 2265.1)
Opsono-18C, POST (N=153;152;159)	720.7 (597.5 to 869.4)	385.9 (303.5 to 490.8)	660.4 (520.9 to 837.3)
Opsono-19F, POST (N=153;149;164)	435.7 (336.3 to 564.5)	475.4 (377.8 to 598.1)	123.2 (95.9 to 158.2)
Opsono-23F, POST (N=152;154;164)	2895.4 (2276.1 to 3683.1)	2895.3 (2419.3 to 3465)	12418.7 (10171.8 to 15161.9)

No statistical analyses for this end point

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Booster vaccination.

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End point title

Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	187	196	201
Units: Subjects
Anti-6A, PRE (N=181;185;193)	50	56	28
Anti-19A, PRE (N=182;184;199)	61	63	29
Anti-6A, POST (N=187;196;201)	135	142	160
Anti-19A, POST (N=187;195;200)	130	139	97

No statistical analyses for this end point

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Booster vaccination.

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End point title

Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	187	196	201
Units: μg/mL
geometric mean (confidence interval 95%)
Anti-6A, PRE (N=181;185;193)	0.1 (0.09 to 0.12)	0.11 (0.09 to 0.13)	0.06 (0.05 to 0.07)
Anti-19A, PRE (N=182;184;199)	0.12 (0.1 to 0.15)	0.12 (0.09 to 0.14)	0.06 (0.05 to 0.07)
Anti-6A, POST (N=187;196;201)	0.45 (0.36 to 0.55)	0.49 (0.4 to 0.61)	0.71 (0.58 to 0.88)
Anti-19A, POST (N=187;195;200)	0.5 (0.39 to 0.63)	0.52 (0.41 to 0.66)	0.21 (0.17 to 0.25)

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Booster vaccination.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	151	148	167
Units: Titers
geometric mean (confidence interval 95%)
Opsono-6A, PRE (N=128;135;151)	23.3 (15.7 to 34.6)	30.7 (20.8 to 45.2)	15.5 (11.1 to 21.6)
Opsono-19A, PRE (N=148;148;167)	5.7 (4.6 to 7)	5.5 (4.6 to 6.5)	5.5 (4.6 to 6.5)
Opsono-6A, POST (N=145;142;160)	143.3 (99.1 to 207.3)	197.1 (138 to 281.3)	493.3 (357.1 to 681.6)
Opsono-19A, POST (N=151;148;162)	34.9 (24.8 to 49.2)	24.6 (17.7 to 34.3)	7.7 (6.2 to 9.5)

No statistical analyses for this end point

Secondary: Concentrations of antibodies against protein D (Anti-PD) - Booster vaccination.

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End point title

Concentrations of antibodies against protein D (Anti-PD) - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 100 EL.U/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	189	198	201
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PD, PRE (N=182;189;195)	421 (370.3 to 478.5)	520.5 (455.8 to 594.3)	80.8 (73.1 to 89.4)
Anti-PD, POST (N=189;198;201)	1715 (1510.3 to 1947.5)	1936.8 (1710.5 to 2193.2)	84.1 (76 to 93.1)

No statistical analyses for this end point

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Booster vaccination.

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End point title

Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Booster vaccination.

End point description

A seroprotected subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.1 IU/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	186	194	197
Units: IU/mL
geometric mean (confidence interval 95%)
Anti-diphteria, PRE (N=175;179;192)	0.235 (0.205 to 0.27)	0.232 (0.203 to 0.264)	0.266 (0.235 to 0.301)
Anti-tetanus, PRE (N=175;180;193)	0.728 (0.656 to 0.809)	0.536 (0.477 to 0.603)	0.232 (0.202 to 0.267)
Anti-diphteria, POST (N=186;194;197)	4.061 (3.601 to 4.58)	3.226 (2.866 to 3.632)	4.882 (4.425 to 5.386)
Anti-tetanus, POST (N=186;194;197)	8.628 (7.867 to 9.462)	5.989 (5.461 to 6.568)	3.248 (2.859 to 3.69)

No statistical analyses for this end point

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Booster vaccination.

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End point title

Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Booster vaccination.

End point description

A seroprotected subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.15 µg/mL and >= 1.0 µg/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	184	192	197
Units: μg/mL
geometric mean (confidence interval 95%)
Anti-PRP, PRE (N=174;179;193)	0.475 (0.386 to 0.585)	0.855 (0.682 to 1.072)	0.371 (0.298 to 0.461)
Anti-PRP, POST (N=184;192;197)	19.331 (16.144 to 23.147)	39.383 (32.617 to 47.551)	23.676 (18.944 to 29.591)

No statistical analyses for this end point

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Booster vaccination.

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End point title

Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Booster vaccination.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >=5 EL.U/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	186	194	197
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT, PRE (N=174;176;189)	7.4 (6.6 to 8.4)	6 (5.4 to 6.7)	6.6 (5.9 to 7.3)
Anti-FHA, PRE (N=175;179;191)	34 (29.4 to 39.4)	35.3 (30.8 to 40.6)	34.7 (30.1 to 39.9)
Anti-PRN, PRE (N=175;179;192)	14.1 (12.3 to 16.2)	6.8 (5.9 to 7.9)	8.6 (7.4 to 10)
Anti-PT, POST (N=186;194;196)	53.5 (48.3 to 59.2)	47.4 (42.9 to 52.5)	54.8 (48.9 to 61.4)
Anti-FHA, POST (N=184;192;194)	343.5 (308 to 383.1)	135.7 (121.2 to 151.9)	140 (123.2 to 159.1)
Anti-PRN, POST (N=186;193;197)	281.7 (247.2 to 321)	97.8 (85.4 to 112)	106.4 (91.5 to 123.8)

No statistical analyses for this end point

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Booster vaccination.

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End point title

Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Booster vaccination.

End point description

A seroprotected subject was a subject whose antibody ChemiLuminescence ImmunoAssay (CLIA) concentration was greater than or equal to the cut-off value >= 10 mIU/mL. Note: investigations on the quality of some serology assays revealed that the anti-HBs ELISA overestimated concentration between 10-100 mIU/mL while values > 100 mIU/mL were confirmed valid. Therefore, all available samples at one month post-dose III and one month post-dose IV timepoints for which the anti-HBs antibody concentration was between 10-100 mIU/mL by in-house ELISA, were retested by the commercial assay Centaur™, an FDA-approved and CE-marked CLIA with a cut-off defining seropositivity of 6.2 mIU/mL. Anti-HBs seroprotection was redefined as in-house ELISA concentration > 100 mIU/mL or CLIA concentration > 10 mIU/mL.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	125	124	135
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HBs, PRE (121;124;135)	142.1 (113.4 to 178.1)	9.9 (8.8 to 11.2)	9.9 (8.8 to 11.2)
Anti-HBs, POST (125;123;135)	1981 (1552 to 2528.7)	8.6 (7.6 to 9.9)	8.5 (7.6 to 9.5)

No statistical analyses for this end point

Secondary: Anti-polio types 1, 2 and 3 titers - Booster vaccination.

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End point title

Anti-polio types 1, 2 and 3 titers - Booster vaccination.

End point description

A seroprotected subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8.

End point type

Secondary

End point timeframe

Prior (PRE) to and one month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	167	173	182
Units: Titers
geometric mean (confidence interval 95%)
Anti-polio 1, PRE (N=156;166;182)	8.3 (7 to 10)	7.3 (6.3 to 8.4)	7 (6.1 to 8)
Anti-polio 2, PRE (N=156;164;182)	13.4 (10.8 to 16.6)	10.6 (8.8 to 12.7)	10.4 (8.9 to 12.2)
Anti-polio 3, PRE (N=156;166;180)	11.3 (9.3 to 13.9)	9 (7.5 to 10.7)	8.7 (7.4 to 10.3)
Anti-polio 1, POST (N=166;173;170)	370.7 (289.8 to 474.2)	177.5 (135.8 to 231.9)	221.2 (171.5 to 285.3)
Anti-polio 2, POST (N=167;173;169)	710.8 (588 to 859.3)	338.8 (272.7 to 420.8)	481.4 (391 to 592.7)
Anti-polio 3, POST (N=167;172;170)	631.5 (495.7 to 804.4)	311.9 (240.4 to 404.6)	348.3 (263.6 to 460.2)

No statistical analyses for this end point

Secondary: Number of subjects with booster vaccine response against pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) antibodies - Booster vaccination.

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End point title

Number of subjects with booster vaccine response against pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) antibodies - Booster vaccination.

End point description

A booster responder to PT/FHA/PRN was defined as a subject with antibodies concentration >=5 EL.U/mL against PT/FHA/PRN in subjects who were initially seronegative for anti-PT/FHA/PRN antibodies (i.e., subjects with anti-PT/FHA/PRN antibody concentrations < 5 EL.U/mL), or antibody concentration >= 2 fold the pre-vaccination antibody concentration in subjects who were initially seropositive (i.e., subjects with anti-PT/FHA/PRN antibody concentrations >=5 EL.U/mL).

End point type

Secondary

End point timeframe

One month after (POST) the administration of the booster dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	135	143	150
Units: Subjects
Anti-PT, S- seronegative (N=40;48;48)	40	47	48
Anti-PT, S+ seropositive (N=99;95;105)	95	94	98
Anti-FHA, S- seronegative (N=4;1;2)	4	1	2
Anti-FHA, S+ seropositive (N=135;143;150)	128	119	125
Anti-PRN, S- seronegative (N=18;56;53)	18	56	51
Anti-PRN, S+ seropositive (N=122;89;102)	122	88	101

No statistical analyses for this end point

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - 12 months after booster dose.

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End point title

Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	166	169	177
Units: Subjects
Anti-1, M12 (N=163;166;173)	106	108	6
Anti-4, M12 (N=163;167;173)	101	102	130
Anti-5, M12 (N=163;163;170)	129	129	10
Anti-6B, M12 (N=162;164;173)	94	96	133
Anti-7F, M12 (N=163;165;170)	157	157	15
Anti-9V, M12 (N=165;168;173)	155	157	160
Anti-14, M12 (N=166;169;177)	149	156	173
Anti-18C, M12 (N=164;167;174)	160	155	161
Anti-19F, M12 (N=164;165;171)	158	158	134
Anti-23F, M12(N=162;166;172)	123	126	153

No statistical analyses for this end point

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - 12 months after booster dose.

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End point title

Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	166	169	177
Units: μg/mL
geometric mean (confidence interval 95%)
Anti-1, M12 (N=163;166;173)	0.3 (0.26 to 0.35)	0.32 (0.28 to 0.38)	0.04 (0.03 to 0.04)
Anti-4, M12 (N=163;167;173)	0.25 (0.22 to 0.29)	0.29 (0.25 to 0.34)	0.36 (0.32 to 0.42)
Anti-5, M12 (N=163;163;170)	0.45 (0.39 to 0.53)	0.47 (0.39 to 0.55)	0.05 (0.04 to 0.05)
Anti-6B, M12 (N=162;164;173)	0.3 (0.25 to 0.36)	0.32 (0.26 to 0.4)	0.46 (0.38 to 0.56)
Anti-7F, M12 (N=163;165;170)	0.72 (0.63 to 0.81)	0.73 (0.64 to 0.84)	0.04 (0.03 to 0.05)
Anti-9V, M12 (N=165;168;173)	0.74 (0.63 to 0.88)	0.78 (0.66 to 0.91)	0.81 (0.7 to 0.94)
Anti-14, M12 (N=166;169;177)	0.73 (0.62 to 0.86)	0.85 (0.73 to 0.99)	1.28 (1.1 to 1.48)
Anti-18C, M12 (N=164;167;174)	1.03 (0.89 to 1.19)	0.64 (0.56 to 0.74)	0.66 (0.59 to 0.75)
Anti-19F, M12 (N=164;165;171)	1.48 (1.22 to 1.8)	1.46 (1.2 to 1.78)	0.76 (0.59 to 0.98)
Anti-23F, M12(N=162;166;172)	0.51 (0.41 to 0.63)	0.52 (0.42 to 0.63)	1.01 (0.83 to 1.24)

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - 12 months after booster dose.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8.

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	159	152	165
Units: Titers
geometric mean (confidence interval 95%)
Opsono-1, M12 (N=159;150;162)	10.9 (8.5 to 14.1)	9.9 (7.8 to 12.5)	4.3 (3.9 to 4.7)
Opsono-4, M12 (N=154;147;160)	12 (9.1 to 15.9)	15.5 (11 to 21.7)	45.2 (30.8 to 66.5)
Opsono-5, M12 (N=159;152;165)	12.9 (10.4 to 16)	13.7 (11 to 17.1)	4.1 (3.9 to 4.3)
Opsono-6B, M12 (N=139;137;152)	77.7 (48.8 to 123.8)	137.6 (83.5 to 226.6)	220 (145.4 to 332.8)
Opsono-7F, M12 (N=142;136;143)	1982.9 (1568.8 to 2506.2)	2205.6 (1833.4 to 2653.4)	738.1 (549.8 to 990.7)
Opsono-9V, M12 (N=143;135;147)	465.9 (324.2 to 669.5)	470 (325.8 to 677.9)	476.2 (317.8 to 713.5)
Opsono-14, M12 (N=128;121;149)	93.1 (60 to 144.4)	151.6 (97.7 to 235.4)	238.7 (163.5 to 348.6)
Opsono-18C, M12 (N=135;133;151)	21.6 (15.2 to 30.6)	12.5 (8.9 to 17.6)	15.3 (10.9 to 21.3)
Opsono-19F, M12 (N=148;150;162)	31.1 (22.6 to 42.8)	32.9 (23.8 to 45.4)	15.1 (11 to 20.6)
Opsono-23F, M12 (N=146;140;161)	366.5 (218.3 to 615.3)	706.1 (443.5 to 1124.3)	3879.8 (2774.4 to 5425.5)

No statistical analyses for this end point

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - 12 months after booster dose.

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End point title

Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	165	166	176
Units: Subjects
Anti-6A, M12 (N=163;166;174)	54	57	92
Anti-19A, M12 (N=165;166;176)	120	97	80

No statistical analyses for this end point

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - 12 months after booster dose.

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End point title

Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 0.05 µg/mL.

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	165	166	176
Units: μg/mL
geometric mean (confidence interval 95%)
Anti-6A, M12 (N=163;166;174)	0.14 (0.12 to 0.17)	0.15 (0.12 to 0.19)	0.22 (0.18 to 0.27)
Anti-19A, M12 (N=165;166; 176)	0.43 (0.35 to 0.53)	0.29 (0.23 to 0.36)	0.21 (0.16 to 0.27)

No statistical analyses for this end point

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - 12 months after booster dose.

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End point title

Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody titers were greater than or equal to the cut-off value >= 8

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	150	146	158
Units: Titers
geometric mean (confidence interval 95%)
Opsono-6A, M12 (N=126;129;148)	21.6 (14.1 to 33.1)	24.8 (15.5 to 39.5)	56.5 (36.4 to 87.7)
Opsono-19A, M12 (N=150;146;158)	12.6 (9.5 to 16.7)	9.1 (7 to 11.9)	9.6 (7.1 to 12.9)

No statistical analyses for this end point

Secondary: Concentrations of antibodies against protein D (Anti-PD) - 12 months after booster dose.

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End point title

Concentrations of antibodies against protein D (Anti-PD) - 12 months after booster dose.

End point description

A seropositive subject was a subject whose antibody concentration was greater than or equal to the cut-off value >= 100 EL.U/mL

End point type

Secondary

End point timeframe

12 months after the administration of the booster dose (at 23-25 months of age, M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	168	170	178
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PD, M12 (N=168;170;178)	332 (287.1 to 384)	423 (359.9 to 497.1)	81.4 (73.1 to 90.6)

No statistical analyses for this end point

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Primary vaccination.

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End point title

Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Primary vaccination.

End point description

Positive cultures of H. influenza* (HI) and S. pneumonia (SP) identified in the nasopharynx one month after the third dose of primary vaccination. *Data presented only include results from samples confirmed as positive for H. influenzae / Non-typeable H. influenzae after differentiation from H. haemolyticus by Polymerase Chain Reaction (PCR) assay

End point type

Secondary

End point timeframe

One month after the third dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	259	259
Units: Subjects
Any SP (N=260;259;259)	102	109	100
Any HI (N=259;258;258)	94	91	85

No statistical analyses for this end point

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Booster vaccination.

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End point title

Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Booster vaccination.

End point description

Positive cultures of H. influenza* (HI) and S. pneumonia (SP) identified in the nasopharynx at each swab time point: pre-booster vaccination (11-13 months of age), M3 (14-16 months of age), M7 (18-20 months of age) and M12 (23-25 months of age). *Data presented only include results from samples confirmed as positive for H. influenzae / Non-typeable H. influenzae after differentiation from H. haemolyticus by Polymerase Chain Reaction (PCR) assay

End point type

Secondary

End point timeframe

Prior to the booster dose (PRE), at 14-16 months of age (3 months after the booster dose - M3), at 18-20 months of age (7 months after the booster dose – M7) and at 23-25 months of age (12 months after the booster dose – M12)

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	256	259	258
Units: Subjects
Any SP, PRE (N=255;259;258)	115	134	119
Any SP, M3 (N=256;258;257)	121	131	126
Any SP, M7 (N=256;258;258)	151	135	148
Any SP, M12 (N=255;257;257)	154	139	131
Any HI, PRE (N=254;258;256)	152	155	144
Any HI, M3 (N=256;258;257)	159	160	165
Any HI, M7 (N=252;258;256)	185	169	162
Any HI, M12 (N=254;255;254)	192	192	177

No statistical analyses for this end point

Secondary: Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Primary vaccination.

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End point title

Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Primary vaccination.

End point description

Positive cultures of S. pneumonia (SP) identified in the nasopharynx one month after the third dose of primary vaccination.

End point type

Secondary

End point timeframe

One month after the third dose

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	259	259
Units: Subjects
S. pneumoniae, VS (N=260;259;259)	18	25	21
S. pneumoniae, CRS (N=260;259;259)	25	32	20
S. pneumoniae, OS (N=260;259;259)	45	40	51

No statistical analyses for this end point

Secondary: Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Booster vaccination.

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End point title

Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Booster vaccination.

End point description

Positive cultures of S. pneumonia (SP) identified in the nasopharynx at each swab time point: pre-booster vaccination (11-13 months of age), M3 (14-16 months of age), M7 (18-20 months of age) and M12 (23-25 months of age).

End point type

Secondary

End point timeframe

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	256	259	258
Units: Subjects
S. pneumoniae, VS PRE (N=255;259;257)	16	20	18
S. pneumoniae, VS M3 (N=256;258;257)	11	18	13
S. pneumoniae, VS M7 (N=256;258;258)	15	12	12
S. pneumoniae, VS M12 (N=255;257;257)	8	8	8
S. pneumoniae, CRS PRE (N=255;259;257)	15	30	25
S. pneumoniae, CRS M3 (N=256;258;257)	25	26	27
S. pneumoniae, CRS M7 (N=256;258;258)	33	33	31
S. pneumoniae, CRS M12 (N=255;257;257)	28	13	25
S. pneumoniae, OS PRE (N=255;259;257)	69	61	60
S. pneumoniae, OS M3 (N=256;258;257)	74	69	70
S. pneumoniae, OS M7 (N=256;258;258)	86	67	89
S. pneumoniae, OS M12 (N=255;257;257)	97	81	80

No statistical analyses for this end point

Secondary: Number of subjects with acquisition of new Streptococcus pneumoniae and Haemophilus Influenzae strains identified in nasopharyngeal swabs

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End point title

Number of subjects with acquisition of new Streptococcus pneumoniae and Haemophilus Influenzae strains identified in nasopharyngeal swabs

End point description

Acquisition of new H. influenza* (HI) and S. pneumonia (SP) strains, identified in the nasopharynx at each swab time point: pre-booster vaccination (11-13 months of age), M3 (14-16 months of age), M7 (18-20 months of age) and M12 (23-25 months of age). *Data presented only include results from samples confirmed as positive for H. influenzae / Non-typeable H. influenzae after differentiation from H. haemolyticus by Polymerase Chain Reaction (PCR) assay

End point type

Secondary

End point timeframe

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	256	259	258
Units: Subjects
Any SP, PRE (N=255;259;258)	103	114	107
Any SP, M3 (N=256;258;257)	86	95	90
Any SP, M7 (N=256;258;258)	128	105	125
Any SP, M12 (N=255;257;257)	132	113	110
Any HI, PRE (N=254;258;256)	88	84	83
Any HI, M3 (N=256;258;257)	47	48	58
Any HI, M7 (N=252;258;256)	71	55	64
Any HI, M12 (N=254;255;254)	73	75	71

No statistical analyses for this end point

Secondary: Number of subjects with acquisition of new Streptococcus pneumoniae vaccine serotypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) identified in nasopharyngeal swabs

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End point title

Number of subjects with acquisition of new Streptococcus pneumoniae vaccine serotypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) identified in nasopharyngeal swabs

End point description

Acquisition of new S. pneumonia (SP) strains, identified in the nasopharynx at each swab time point: pre-booster vaccination (11-13 months of age), M3 (14-16 months of age), M7 (18-20 months of age) and M12 (23-25 months of age).

End point type

Secondary

End point timeframe

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	256	259	258
Units: Subjects
S. pneumoniae, VS PRE (N=255;259;257)	14	11	15
S. pneumoniae, VS M3 (N=256;258;257)	8	9	8
S. pneumoniae, VS M7 (N=256;258;258)	13	7	9
S. pneumoniae, VS M12 (N=255;257;257)	4	7	6
S. pneumoniae, CRS PRE (N=255;259;257)	13	26	20
S. pneumoniae, CRS M3 (N=256;258;257)	19	15	20
S. pneumoniae, CRS M7 (N=256;258;258)	27	25	24
S. pneumoniae, CRS M12 (N=255;257;257)	22	8	18
S. pneumoniae, OS PRE (N=255;259;257)	64	55	57
S. pneumoniae, OS M3 (N=256;258;257)	52	59	52
S. pneumoniae, OS M7 (N=256;258;258)	74	55	77
S. pneumoniae, OS M12 (N=255;257;257)	87	69	69

No statistical analyses for this end point

Secondary: Number of subjects with solicited local symptoms - Primary vaccination

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End point title

Number of subjects with solicited local symptoms - Primary vaccination

End point description

Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any occurrence of the specified symptom regardless of intensity. Grade 3 pain was defined as cried when limb was moved/spontaneously painful. Grade 3 redness/swelling was defined as redness/swelling > 30 millimetres from injection site.

End point type

Secondary

End point timeframe

Within 4 days (Day 0 - Day 3) post-primary vaccination across the 3 doses.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	260	260
Units: Subjects
Any Pain, PRI (N=260;260;260)	205	193	178
Grade 3 Pain, PRI (N=260;260;260)	42	40	29
Any Redness, PRI (N=260;260;260)	197	193	184
Grade 3 Redness, PRI (N=260;260;260)	12	26	19
Any Swelling, PRI (N=260;260;260)	205	199	179
Grade 3 Swelling, PRI (N=260;260;260)	18	29	24

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms - Primary vaccination

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End point title

Number of subjects with solicited general symptoms - Primary vaccination

End point description

Solicited general symptoms assessed include drowsiness, fever (defined as rectal temperature ≥ 38.0°C), irritability, and loss of appetite. Grade 3 drowsiness was defined as drowsiness which prevented normal everyday activities. Grade 3 fever was defined as fever (rectal temperature) above (>) 40.0 degree Celsius (°C). Grade 3 irritability was defined as crying that could not be comforted/preventing normal activity. Grade 3 loss of appetite was defined as the subject not eating at all. “Any” is defined as incidence of the specified symptom regardless of intensity.

End point type

Secondary

End point timeframe

Within 4 days (Day 0 - Day 3) post-primary vaccination across the 3 doses.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	260	260
Units: Subjects
Any Drowsiness, PRI (N=260; 260;260)	231	220	215
Grade 3 Drowsiness, PRI (N=260; 260;260)	14	13	7
Any Temperature, PRI (N=260; 260;260)	153	124	110
Grade 3 Temperature, PRI (N=260; 260;260)	0	0	0
Any Irritability, PRI (N=260; 260;260)	241	230	235
Grade 3 Irritability, PRI (N=260; 260;260)	42	37	16
Any Loss of appetite, PRI (N=260; 260;260)	155	145	153
Grade 3 Loss of appetite, PRI (N=260; 260;260)	4	4	1

No statistical analyses for this end point

Secondary: Number of subjects with unsolicited adverse events (AEs) - Primary vaccination.

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End point title

Number of subjects with unsolicited adverse events (AEs) - Primary vaccination.

End point description

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. “Any” is defined an incidence of an unsolicited AE regardless of intensity or relationship to study vaccination.

End point type

Secondary

End point timeframe

Within 31 days (Day 0 - Day 30) after each primary vaccination.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	260	260
Units: Subjects
Subject(s) with AE(s), PRI	181	177	185

No statistical analyses for this end point

Secondary: Number of subjects with serious adverse events (SAEs)

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End point title

Number of subjects with serious adverse events (SAEs)

End point description

SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.

End point type

Secondary

End point timeframe

Throughout the entire study period

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	260	260	260
Units: Subjects
Subject(s) with SAE(s)	35	26	35

No statistical analyses for this end point

Secondary: Number of subjects with solicited local symptoms -Booster vaccination

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End point title

Number of subjects with solicited local symptoms -Booster vaccination

End point description

End point type

Secondary

End point timeframe

Within 4 days (Day 0 - Day 3) after the booster vaccination.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	257	258	258
Units: Subjects
Any Pain, BST (N=257;258; 258)	174	161	145
Grade 3 Pain, BST (N=257;258; 258)	21	21	7
Any Redness, BST (N=257;258; 258)	175	144	180
Grade 3 Redness, BST (N=257;258; 258)	22	10	10
Any Swelling, BST (N=257;258; 258)	185	146	160
Grade 3 Swelling, BST (N=257;258; 258)	27	15	11

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms - Booster vaccination.

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End point title

Number of subjects with solicited general symptoms - Booster vaccination.

End point description

End point type

Secondary

End point timeframe

Within 4 days (Day 0 - Day 3) after booster vaccination.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	256	258	258
Units: Subjects
Any Drowsiness, BST (N=256; 258;258)	131	118	128
Grade 3 Drowsiness, BST (N=256; 258;258)	6	5	3
Any Temperature, BST (N=256; 258;258)	100	100	103
Grade 3 Temperature, BST (N=256; 258;258)	1	2	1
Any Irritability, BST (N=256; 258;258)	167	161	166
Grade 3 Irritability, BST (N=256; 258;258)	11	8	1
Any Loss of appetite, BST (N=256; 258;258)	93	83	111
Grade 3 Loss of appetite, BST dose (N=256; 258;258	5	0	2

No statistical analyses for this end point

Secondary: Number of subjects with unsolicited adverse events (AEs) - Booster vaccination.

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End point title

Number of subjects with unsolicited adverse events (AEs) - Booster vaccination.

End point description

End point type

Secondary

End point timeframe

Within 31 days (Day 0 - Day 30) after booster vaccination.

End point values	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Number of subjects analysed	257	259	258
Units: Subjects
Subject(s) with AE(s), BST	106	105	105

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited & Unsolicited AEs: During the 4-and 31-days period(s) post primary (PRI) or booster (BST) vaccinations, respectively; SAEs: from study start to study end

Adverse event reporting additional description

The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

10Pn+DTPa-HBV-IPV/Hib Group

Reporting group description

Reporting group title

10Pn+DTPa-IPV-Hib Group

Reporting group description

Reporting group title

7Pn+DTPa-IPV-Hib Group

Reporting group description

Subjects received 3 doses of 7Pn vaccine (or Prevenar by Pfizer [formerly Wyeth Lederle Vaccines S.A.]) co-administered with DTPa-IPV-Hib vaccine(Pediacel by Sanofi Pasteur MSD) at 2, 3 and 4 months of age (Study Months 0, 1, 2) and received a booster dose of each vaccine between 11 and 13 months of age (Study Month 9). All vaccines were administered intramuscularly in the right (10Pn; 7Pn) or left (DTPa-IPV-Hib; DTPa-HBV-IPV/Hib) thigh or deltoid.

Serious adverse events	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 260 (13.46%)	26 / 260 (10.00%)	35 / 260 (13.46%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	3 / 260 (1.15%)	2 / 260 (0.77%)	2 / 260 (0.77%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Greenstick fracture
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Poisoning
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Velo-cardio-facial syndrome
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Adhesion
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 260 (0.38%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenitis
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Coeliac disease
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal stenosis
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 260 (0.00%)	2 / 260 (0.77%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apparent life threatening event
subjects affected / exposed	2 / 260 (0.77%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	2 / 260 (0.77%)	1 / 260 (0.38%)	4 / 260 (1.54%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchiolitis
subjects affected / exposed	3 / 260 (1.15%)	1 / 260 (0.38%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterovirus infection
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	8 / 260 (3.08%)	4 / 260 (1.54%)	5 / 260 (1.92%)
occurrences causally related to treatment / all	0 / 8	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	1 / 260 (0.38%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	1 / 260 (0.38%)	2 / 260 (0.77%)	2 / 260 (0.77%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	3 / 260 (1.15%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 260 (0.38%)	2 / 260 (0.77%)	3 / 260 (1.15%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia primary atypical
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	3 / 260 (1.15%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	5 / 260 (1.92%)	2 / 260 (0.77%)	5 / 260 (1.92%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	1 / 260 (0.38%)	0 / 260 (0.00%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 260 (0.38%)	1 / 260 (0.38%)	4 / 260 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 260 (0.00%)	2 / 260 (0.77%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 260 (0.00%)	0 / 260 (0.00%)	1 / 260 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Feeding disorder neonatal
subjects affected / exposed	0 / 260 (0.00%)	1 / 260 (0.38%)	0 / 260 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	10Pn+DTPa-HBV-IPV/Hib Group	10Pn+DTPa-IPV-Hib Group	7Pn+DTPa-IPV-Hib Group
Total subjects affected by non serious adverse events
subjects affected / exposed	241 / 260 (92.69%)	230 / 260 (88.46%)	235 / 260 (90.38%)
General disorders and administration site conditions
Pyrexia - BST
subjects affected / exposed ^[1]	16 / 257 (6.23%)	13 / 259 (5.02%)	21 / 258 (8.14%)
occurrences all number	16	13	21
Pain - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	205 / 260 (78.85%)	193 / 260 (74.23%)	178 / 260 (68.46%)
occurrences all number	205	193	178
Redness - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	197 / 260 (75.77%)	193 / 260 (74.23%)	184 / 260 (70.77%)
occurrences all number	197	193	184
Swelling - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	205 / 260 (78.85%)	199 / 260 (76.54%)	179 / 260 (68.85%)
occurrences all number	205	199	179
Pain - BST
alternative assessment type: Systematic
subjects affected / exposed ^[2]	174 / 257 (67.70%)	161 / 258 (62.40%)	145 / 258 (56.20%)
occurrences all number	174	161	145
Redness – BST
alternative assessment type: Systematic
subjects affected / exposed ^[3]	175 / 257 (68.09%)	144 / 258 (55.81%)	180 / 258 (69.77%)
occurrences all number	175	144	180
Swelling - BST
alternative assessment type: Systematic
subjects affected / exposed ^[4]	185 / 257 (71.98%)	146 / 258 (56.59%)	160 / 258 (62.02%)
occurrences all number	185	146	160
Drowsiness - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	231 / 260 (88.85%)	220 / 260 (84.62%)	215 / 260 (82.69%)
occurrences all number	231	220	215
Rectal Temperature >=38.0°C - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	153 / 260 (58.85%)	124 / 260 (47.69%)	110 / 260 (42.31%)
occurrences all number	153	124	110
Irritability - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	241 / 260 (92.69%)	230 / 260 (88.46%)	235 / 260 (90.38%)
occurrences all number	241	230	235
Loss of appetite - PRI
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
subjects affected / exposed	155 / 260 (59.62%)	145 / 260 (55.77%)	153 / 260 (58.85%)
occurrences all number	155	145	153
Drowsiness – BST
alternative assessment type: Systematic
subjects affected / exposed ^[5]	131 / 256 (51.17%)	118 / 258 (45.74%)	128 / 258 (49.61%)
occurrences all number	131	118	128
Rectal Temperature >=38.0°C – BST
alternative assessment type: Systematic
subjects affected / exposed ^[6]	100 / 256 (39.06%)	100 / 258 (38.76%)	103 / 258 (39.92%)
occurrences all number	100	100	103
Irritability – BST
alternative assessment type: Systematic
subjects affected / exposed ^[7]	167 / 256 (65.23%)	161 / 258 (62.40%)	166 / 258 (64.34%)
occurrences all number	167	161	166
Loss of appetite - BST
alternative assessment type: Systematic
subjects affected / exposed ^[8]	93 / 256 (36.33%)	83 / 258 (32.17%)	111 / 258 (43.02%)
occurrences all number	93	83	111
Gastrointestinal disorders
Diarrhoea - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	15 / 260 (5.77%)	14 / 260 (5.38%)	12 / 260 (4.62%)
occurrences all number	15	14	12
Vomiting - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	11 / 260 (4.23%)	13 / 260 (5.00%)	0 / 260 (0.00%)
occurrences all number	11	13	0
Respiratory, thoracic and mediastinal disorders
Wheezing - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	15 / 260 (5.77%)	7 / 260 (2.69%)	10 / 260 (3.85%)
occurrences all number	15	7	10
Skin and subcutaneous tissue disorders
Eczema - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	24 / 260 (9.23%)	15 / 260 (5.77%)	18 / 260 (6.92%)
occurrences all number	24	15	18
Infections and infestations
Upper respiratory tract infection - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	99 / 260 (38.08%)	108 / 260 (41.54%)	111 / 260 (42.69%)
occurrences all number	99	108	111
Gastroenteritis - PRI
alternative dictionary used: MedDRA 12.1
subjects affected / exposed	16 / 260 (6.15%)	13 / 260 (5.00%)	13 / 260 (5.00%)
occurrences all number	16	13	13
Viral infection - BST
subjects affected / exposed ^[9]	5 / 257 (1.95%)	17 / 259 (6.56%)	5 / 258 (1.94%)
occurrences all number	5	17	5
Upper respiratory tract infection - BST
subjects affected / exposed ^[10]	27 / 257 (10.51%)	32 / 259 (12.36%)	34 / 258 (13.18%)
occurrences all number	27	32	34

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this specified phase was performed solely on subjects with available results.

More information

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Were there any global substantial amendments to the protocol? Yes

22 Nov 2007

A first amendment was made to the protocol in response to comments from the Dutch Authorities to clarify that this study was a single-centre study.

30 Jan 2008

On request of the Dutch Authorities, a second amendment to the protocol was made. Changes concerned the study design: 1) Before vaccination at Visit 1 no blood sample was to be collected; 2) The priority ranking for testing of opsonophagocytic activity (OPA) activity against the 10 pneumococcal vaccine serotypes in case of insufficient blood sample volume was changed; 3) Testing of OPA activity against the 10 pneumococcal vaccine serotypes was to be done for all subjects i.e. all subjects for which the amount of remaining/available serum is sufficient; 4) The sample size was increased.

14 Aug 2008

Changes concerned the study design: 1) To collect information about factors that could potentially influence nasopharyngeal carriage of Streptococcus (S.). pneumoniae and Haemophilus (H.) influenzae, it was planned that the subjects’ parents/ guardian(s) would be asked some questions at Visits 4, 5, 7, 8 and 9; 2) The recruitment period was changed to 9 months.

22 Mar 2010

The following changes were introduced: 1) Due to the H1N1 influenza pandemic, the children were offered H1N1 influenza vaccine as part of a national pandemic prevention plan. Thus, the age range for the booster vaccination visit and subsequent visits was extended; 2) Further details on microbiological testing were included; 3) A second Interim Analysis was added to evaluate carriage (at 3 timepoints) using classical methods for bacterial identification / typing, additional microbiological techniques for H. influenzae/H. haemolyticus discrimination and quantitative molecular techniques for H. influenzae carriage; 4) The back-up contact details for reporting SAEs were updated.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) - Primary vaccination.

Primary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) - Primary vaccination.

Primary: Antibody concentration against protein D (PD) - Primary vaccination.

Primary: Antibody concentration against protein D (PD) - Primary vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Primary vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Primary vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Primary vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Primary vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Primary vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Primary vaccination.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Primary vaccination.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Primary vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Primary vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Primary vaccination.

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Primary vaccination.

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Primary vaccination.

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Primary vaccination.

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Primary vaccination.

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Primary vaccination.

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Primary vaccination.

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Primary vaccination.

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Primary vaccination.

Secondary: Anti-polio types 1, 2 and 3 titers - Primary vaccination.

Secondary: Anti-polio types 1, 2 and 3 titers - Primary vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Booster vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - Booster vaccination.

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - Booster vaccination.

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - Booster vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Booster vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - Booster vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Booster vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - Booster vaccination.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Booster vaccination.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - Booster vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Booster vaccination.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - Booster vaccination.

Secondary: Concentrations of antibodies against protein D (Anti-PD) - Booster vaccination.

Secondary: Concentrations of antibodies against protein D (Anti-PD) - Booster vaccination.

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Booster vaccination.

Secondary: Concentrations of antibodies against diphtheria and tetanus toxoids (anti-D and T) - Booster vaccination.

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Booster vaccination.

Secondary: Anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations - Booster vaccination.

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Booster vaccination.

Secondary: Anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations - Booster vaccination.

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Booster vaccination.

Secondary: Anti-hepatitis B surface antigen (anti-HBs) antibody concentrations - Booster vaccination.

Secondary: Anti-polio types 1, 2 and 3 titers - Booster vaccination.

Secondary: Anti-polio types 1, 2 and 3 titers - Booster vaccination.

Secondary: Number of subjects with booster vaccine response against pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) antibodies - Booster vaccination.

Secondary: Number of subjects with booster vaccine response against pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) antibodies - Booster vaccination.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - 12 months after booster dose.

Secondary: Number of subjects with antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) ≥ 0.2 μg/mL - 12 months after booster dose.

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - 12 months after booster dose.

Secondary: Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) - 12 months after booster dose.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - 12 months after booster dose.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F - 12 months after booster dose.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - 12 months after booster dose.

Secondary: Number of subjects with antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) ≥ 0.2 μg/mL - 12 months after booster dose.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - 12 months after booster dose.

Secondary: Antibody concentrations against pneumococcal cross-reactive serotypes 6A and 19A (Anti-6A and 19A) - 12 months after booster dose.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - 12 months after booster dose.

Secondary: Opsonophagocytic activity (OPA) titers against pneumococcal cross-reactive serotypes 6A and 19A - 12 months after booster dose.

Secondary: Concentrations of antibodies against protein D (Anti-PD) - 12 months after booster dose.

Secondary: Concentrations of antibodies against protein D (Anti-PD) - 12 months after booster dose.

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Primary vaccination.

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Primary vaccination.

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Booster vaccination.

Secondary: Number of subjects with positive cultures of Haemophilus Influenzae and/or Streptococcus Pneumoniae in the Nasopharynx - Booster vaccination.

Secondary: Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Primary vaccination.

Secondary: Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Primary vaccination.

Secondary: Number of subjects with positive cultures of Streptococcus Pneumoniae vaccine seroptypes (VS), cross-reactive serotypes (CRS) or other serotypes (OS) in the Nasopharynx - Booster vaccination.