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Clinical Trial Results:
Phase III randomized, open, controlled study to evaluate the immune response to the hepatitis B antigen of the RTS,S/AS01E candidate vaccine, when administered as primary vaccination integrated into an EPI regimen to infants living in sub-Saharan Africa.

Summary
EudraCT number	2011-001508-37
Trial protocol	Outside EU/EEA
Global end of trial date	09 Feb 2017

Results information
Results version number	v2(current)
This version publication date	27 Dec 2019
First version publication date	17 Aug 2017
Other versions	v1
Version creation reason	New data added to full data set New available data added to the full data set.

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

113681

ISRCTN number

US NCT number

NCT01345240

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

26 Apr 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

To demonstrate in terms of antibody (ab) response to the HBs antigen, the non-inferiority (noninf) of RTS,S/AS01E (RTSS) to a primary vaccination regimen of a licensed hepatitis B vaccine (Engerix-B) integrated into an expanded program on immunization (EPI) regimen.

Protection of trial subjects

The vaccinees were observed closely for at least 60 minutes following the administration of all vaccines used in the study, with appropriate medical treatment readily available in case of an anaphylactic reaction.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Nov 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

51 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ghana: 197

Country: Number of subjects enrolled

Burkina Faso: 508

Worldwide total number of subjects

705

EEA total number of subjects

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)

705

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

Screening details

The study was conducted in 4 phases, a Primary Vaccination Phase (up to Month (M) 3), a Safety Follow-Up Phase (M3-8), a First Immunogenicity Follow-Up (FU) Phase (M8-26), and a Second Immunogenicity FU Phase (M26 to study end at M51).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RTS,S Regimen A Group

Arm description

This group results from the pooling of the RTS,S Regimen A Lot 1, RTS,S Regimen A Lot 2 and RTS,S Regimen A Lot 3 groups. Subjects, healthy male and female infants aged between 8 and 12 weeks inclusive at the time of first vaccination, received 3 doses of RTS,S vaccine, Lot 1, 2 or 3, co-administered with Infanrix-Hib, Polio Sabin and Synflorix, at Weeks 0, 4 and 8, and 2 doses of Rotarix vaccine, at Weeks 6 and 10. In addition, subjects also received one dose of vaccine against yellow fever and against measles, at Week 32, and one booster dose of Infanrix-Hib and Synflorix, at Month 16, and one booster dose of Engerix B vaccine, at Month 50. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Arm type

Experimental

Investigational medicinal product name

Candidate Plasmodium falciparum malaria vaccine

Investigational medicinal product code

RTS,S/AS02D

Other name

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh

Investigational medicinal product name

Engerix-B Junior

Investigational medicinal product code

HBV Paediatric 10

Other name

Engerix-B

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Infanrix-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the deltoid.

Investigational medicinal product name

Polio Sabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3-dose orally

Investigational medicinal product name

Synflorix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Rotarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2-dose orally

Investigational medicinal product name

Measles and yellow fever vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

1-dose intramuscular injection in the deltoid

RTS,S Regimen B Group

Arm description

This group results from the pooling of the RTS,S Regimen B Lot 1, RTS,S Regimen B Lot 2 and RTS,S Regimen B Lot 3 groups. Subjects, healthy male and female infants aged between 8 and 12 weeks inclusive at the time of first vaccination, received 3 doses of RTS,S vaccine, Lot 1, 2 or 3, co-administered with Infanrix-Hib and Polio Sabin, at Weeks 0, 4 and 8, 2 doses of Rotarix, at Weeks 4 and 8, and 3 doses of Synflorix at Weeks 2, 6 and 10. In addition, subjects also received one dose of vaccine against yellow fever and against measles, at Week 32, and one booster dose of Infanrix-Hib and Synflorix, at Month 16, and one booster dose of Engerix B vaccine, at Month 50. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Arm type

Experimental

Investigational medicinal product name

Candidate Plasmodium falciparum malaria vaccine

Investigational medicinal product code

RTS,S/AS02D

Other name

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh

Investigational medicinal product name

Engerix-B Junior

Investigational medicinal product code

HBV Paediatric 10

Other name

Engerix-B

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Infanrix-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the deltoid.

Investigational medicinal product name

Polio Sabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3-dose orally

Investigational medicinal product name

Synflorix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Rotarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2-dose orally

Investigational medicinal product name

Measles and yellow fever vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

1-dose intramuscular injection in the deltoid

RTS,S Regimen C Group

Arm description

This group results from the pooling of the RTS,S Regimen C Lot 1, RTS,S Regimen C Lot 2 and RTS,S Regimen C Lot 3 groups. Subjects, healthy male and female infants aged between 8 and 12 weeks inclusive at the time of first vaccination, received 3 doses of RTS,S vaccine, Lot 1, 2 or 3, co-administered with Infanrix-Hib and Polio Sabin, at Weeks 0, 4 and 8, 2 doses of Rotarix, at Weeks 6 and 10, and 3 doses of Synflorix at Weeks 2, 6 and 10. In addition, subjects also received one dose of vaccine against yellow fever and against measles, at Week 32, and one booster dose of Infanrix-Hib and Synflorix, at Month 16, and one booster dose of Engerix B vaccine, at Month 50. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Arm type

Experimental

Investigational medicinal product name

Candidate Plasmodium falciparum malaria vaccine

Investigational medicinal product code

RTS,S/AS02D

Other name

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh

Investigational medicinal product name

Engerix-B Junior

Investigational medicinal product code

HBV Paediatric 10

Other name

Engerix-B

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Infanrix-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the deltoid.

Investigational medicinal product name

Polio Sabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3-dose orally

Investigational medicinal product name

Synflorix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Rotarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2-dose orally

Investigational medicinal product name

Measles and yellow fever vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

1-dose intramuscular injection in the deltoid

Engerix B Regimen A Group

Arm description

Subjects, healthy male and female infants between 8 and 12 weeks of age inclusive at the time of first vaccination, received the Engerix-B Vaccination Regimen A. This regimen included 3 doses of Engerix B co-administered with Infanrix-Hib, Polio Sabin and Synflorix at Weeks 0, 4 and 8, and 2 doses of Rotarix, at Weeks 6 and 10. Additionally, subjects also received one dose of vaccine against yellow fever and against measles, at Week 32, and one booster dose of Infanrix-Hib and Synflorix, at Month 16, and one booster dose of Engerix B vaccine, at Month 50. Engerix B was administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Arm type

Active comparator

Investigational medicinal product name

Engerix-B Junior

Investigational medicinal product code

HBV Paediatric 10

Other name

Engerix-B

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Infanrix-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the deltoid.

Investigational medicinal product name

Polio Sabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3-dose orally

Investigational medicinal product name

Synflorix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Rotarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2-dose orally

Investigational medicinal product name

Measles and yellow fever vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

1-dose intramuscular injection in the deltoid

Engerix B Regimen B Group

Arm description

Subjects, healthy male and female infants between 8 and 12 weeks of age inclusive at the time of first vaccination, received the Engerix-B Vaccination Regimen B. This regimen included 3 doses of Engerix B co-administered with Infanrix-Hib and Polio Sabin, at Weeks 0, 4 and 8, 2 doses of Rotarix vaccine, at Weeks 4 and 8, and 3 doses of Synflorix at Weeks 2, 6 and 10. Additionally, subjects also received one dose of vaccine against yellow fever and against measles, at Week 32, and one booster dose of Infanrix-Hib and Synflorix, at Month 16, and one booster dose of Engerix B vaccine, at Month 50. Engerix B was administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Arm type

Active comparator

Investigational medicinal product name

Engerix-B Junior

Investigational medicinal product code

HBV Paediatric 10

Other name

Engerix-B

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Infanrix-Hib

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the deltoid.

Investigational medicinal product name

Polio Sabin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3-dose orally

Investigational medicinal product name

Synflorix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3-dose intramuscular injection in the thigh.

Investigational medicinal product name

Rotarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2-dose orally

Investigational medicinal product name

Measles and yellow fever vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

1-dose intramuscular injection in the deltoid

Number of subjects in period 1	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Started	142	142	141	141	139
Completed	131	128	123	132	129
Not completed	11	14	18	9	10
Adverse event, non-fatal	3	5	4	2	1
Lost to follow-up	8	9	14	7	9

Baseline characteristics

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Reporting group title

RTS,S Regimen A Group

Reporting group description

Reporting group title

RTS,S Regimen B Group

Reporting group description

Reporting group title

RTS,S Regimen C Group

Reporting group description

Reporting group title

Engerix B Regimen A Group

Reporting group description

Reporting group title

Engerix B Regimen B Group

Reporting group description

Reporting group values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group	Total
Number of subjects	142	142	141	141	139	705
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	142	142	141	141	139	705
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	8.4 ± 0.83	8.3 ± 0.62	8.3 ± 0.69	8.3 ± 0.74	8.3 ± 0.74	-
Gender categorical
Units: Subjects
Female	59	69	67	81	63	339
Male	83	73	74	60	76	366
Race/Ethnicity, Customized
Units: Subjects
African Heritage/African American	142	142	141	141	139	705

Subject analysis set title

RTS,S Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in any of its formulations, Lot 1, 2 or 3, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regimen received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

Engerix B Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the Engerix B Regimen A and Engerix B Regimen B groups who were administered Engerix B as a 3-dose primary vaccination course, at Weeks 0, 4 and 8, followed by a booster dose, at Month 50. Subjects in this group were also administered, according to varied schedules, depending on the vaccination regimen they were allocated too in their respective group, doses Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix and of vaccines against yellow fever and against measles. Engerix B was administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

RTS,S Lot 1 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 1 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regiment received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

RTS,S Lot 2 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 2 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regiment received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

RTS,S Lot 3 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 3 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regimen received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis sets values	RTS,S Group	Engerix B Group	RTS,S Lot 1 Group	RTS,S Lot 2 Group	RTS,S Lot 3 Group
Number of subjects	425	280	141	142	142
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	425	280	141	142	142
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 0
Gender categorical
Units: Subjects
Female	195	144	59	66	70
Male	230	136	82	76	72
Race/Ethnicity, Customized
Units: Subjects
African Heritage/African American	425	280	141	142	142

End points

Top of page

Reporting group title

RTS,S Regimen A Group

Reporting group description

Reporting group title

RTS,S Regimen B Group

Reporting group description

Reporting group title

RTS,S Regimen C Group

Reporting group description

Reporting group title

Engerix B Regimen A Group

Reporting group description

Reporting group title

Engerix B Regimen B Group

Reporting group description

Subject analysis set title

RTS,S Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Engerix B Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

RTS,S Lot 1 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 1 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regiment received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

RTS,S Lot 2 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 2 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regiment received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Subject analysis set title

RTS,S Lot 3 Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects in this group were subjects from the RTS,S Regimen A, RTS,S Regimen B, and RTS,S Regimen C groups who were administered a 3-dose primary vaccination course of the RTS,S vaccine in its Lot 3 formulation only, at Weeks 0, 4 and 8. Subjects in this group were also administered, according to varied schedules depending on the RTS,S vaccination regimen received, doses of Infanrix-Hib, Polio Sabin, Rotarix, Synflorix, Rotarix, Engerix B and vaccines against yellow fever and against measles. The RTS,S vaccine and Engerix B were administered intramuscularly (IM) in the left anterolateral thigh, Infanrix-Hib IM in the right deltoid, Synflorix IM in the right anterolateral thigh, and Rotarix and Polio Sabin orally. The measles and yellow fever vaccines were administered IM in the deltoid.

Primary: Anti-Hepatitis B (HBs) antibody concentrations RTS,S Group and Engerix B Group

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End point title

Anti-Hepatitis B (HBs) antibody concentrations RTS,S Group and Engerix B Group ^[1]

End point description

Concentrations, by enzyme-linked immunosorbent assay (ELISA), were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 10 mIU/mL. A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis, with study groups pooled by primary vaccine administered (RTS,S vs Engerix-B).

End point type

Primary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B™

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This outcome was descriptive; hence no statistical analyses were required.

End point values	RTS,S Group	Engerix B Group
Number of subjects analysed	397	253
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	6412.7 (5732.9 to 7173)	377.4 (310.6 to 458.7)

No statistical analyses for this end point

Primary: Anti-Hepatitis B (HBs) antibody concentrations for all study Groups

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End point title

Anti-Hepatitis B (HBs) antibody concentrations for all study Groups ^[2]

End point description

Concentrations, by enzyme-linked immunosorbent assay (ELISA), were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 10 mIU/mL. A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis, for each RTS,S Regimen A, B, C and each Engerix B Regimen A and B study groups.

End point type

Primary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This outcome was descriptive; hence no statistical analyses were required.

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	140	123	134	135	118
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	5467.6 (4493.8 to 6652.5)	6989.9 (5747.5 to 8501)	6998.7 (5779.1 to 8475.7)	334.4 (253.4 to 441.4)	433.4 (329.5 to 570.1)

No statistical analyses for this end point

Primary: Percentage of seroprotected subjects against Anti-Hepatitis B (HBs) antigen

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End point title

Percentage of seroprotected subjects against Anti-Hepatitis B (HBs) antigen

End point description

A seroprotected subject was defined as a subject with anti-HBs antibody titers greater than or equal to (>=) the cutoff of 10 mili-international units per mililiter (mIU/mL). A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis, with study groups pooled by primary vaccine administered (RTS,S vs Engerix -B).

End point type

Primary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Group	Engerix B Group
Number of subjects analysed	397	253
Units: Percentage of subjects
number (confidence interval 95%)	100 (99.1 to 100)	96 (92.9 to 98.1)

Anti-HBs: difference in seroprotection rate

Statistical analysis description

Non-inferiority of the immune response to the hepatitis B antigen induced by RTS,S/AS01E vaccine versus a licensed hepatitis B vaccine.

Comparison groups

RTS,S Group v Engerix B Group

Number of subjects included in analysis

650

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

ANOVA

Parameter type

Difference in percent seroprotection

Point estimate

-3.95

Confidence interval

level

95%

sides

2-sided

lower limit

-7.12

upper limit

-2.16

Notes
[3] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the difference in percent seroprotection below 5% between recipients of licensed hepatitis B vaccine (Engerix-B) and recipients of RTS,S/AS01E vaccine.

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 3

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End point title

Anti-Hepatitis B (HBs) antibody concentrations at Month 3

End point description

Concentrations, by enzyme-linked immunosorbent assay (ELISA), were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 10 mIU/mL. A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis. Results presented are for the study groups receiving the RTS,S vaccine, pooled by vaccine lot, that is, for the RTS,S Lot 1, RTS,S Lot 2, and RTS,S Lot 3 groups, as defined below.

End point type

Secondary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Lot 1 Group	RTS,S Lot 2 Group	RTS,S Lot 3 Group
Number of subjects analysed	132	134	131
Units: mIU/mL
geometric mean (confidence interval 95%)
mIU/mL	6214.3 (5115.6 to 7548.9)	6826.1 (5569.4 to 8366.3)	6209.2 (5144.2 to 7494.8)

Anti-HBs: lot1-to-lot2 consistency

Statistical analysis description

To demonstrate the lot-to-lot consistency in terms of anti-HBs immunogenicity between three commercial lots of the RTS,S/AS01E candidate malaria vaccine.

Comparison groups

RTS,S Lot 2 Group v RTS,S Lot 1 Group

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

equivalence ^[4]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.2

Notes
[4] - Criteria for consistency: one month post Dose 3 of RTS,S/AS01E, the two-sided 95% confidence interval (CI) of the geometric mean concentration (GMC) ratio between all pairs of lots are within [0.5, 2].

Anti-HBs: lot1-to-lot3 consistency

Statistical analysis description

To demonstrate the lot-to-lot consistency in terms of anti-HBs immunogenicity between three commercial lots of the RTS,S/AS01E candidate malaria vaccine.

Comparison groups

RTS,S Lot 1 Group v RTS,S Lot 3 Group

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

equivalence ^[5]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.32

Notes
[5] - Criteria for consistency: one month post Dose 3 of RTS,S/AS01E, the two-sided 95% confidence interval (CI) of the geometric mean concentration (GMC) ratio between all pairs of lots are within [0.5, 2].

Anti-HBs: lot2-to-lot3 consistency

Statistical analysis description

To demonstrate the lot-to-lot consistency in terms of anti-HBs immunogenicity between three commercial lots of the RTS,S/AS01E candidate malaria vaccine.

Comparison groups

RTS,S Lot 2 Group v RTS,S Lot 3 Group

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

equivalence ^[6]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.45

Notes
[6] - Criteria for consistency: one month post Dose 3 of RTS,S/AS01E, the two-sided 95% confidence interval (CI) of the geometric mean concentration (GMC) ratio between all pairs of lots are within [0.5, 2].

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 14 and 26

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End point title

Anti-Hepatitis B (HBs) antibody concentrations at Month 14 and 26

End point description

Concentrations, by enzyme-linked immunosorbent assay (ELISA), were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 10 mIU/mL. A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis. Results presented are for each RTS,S Regimen A, B & C, and for each Engerix B Regimen A & B study groups.

End point type

Secondary

End point timeframe

At Months 14 and 26, aka at 12 and 24 months post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	133	118	129	127	114
Units: mIU/mL
geometric mean (confidence interval 95%)
Anti-HBs – At Month 14	1530.1 (1259.4 to 1859.1)	2430.9 (1975.7 to 2991.0)	2189.1 (1840.3 to 2603.9)	119.5 (91 to 157)	137.5 (103.3 to 183.2)
Anti-HBs – At Month 26	1092.6 (867.4 to 1376.3)	1896.0 (1487.2 to 2417.3)	1849.8 (1478.9 to 2313.6)	68.8 (50.7 to 93.3)	71 (51.6 to 97.8)

No statistical analyses for this end point

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti-HBs RF1) at Month 3

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End point title

Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti-HBs RF1) at Month 3

End point description

Anti-HBs RF1 antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and presented as geometric mean concentrations (GMCs) expressed in ELISA units per milliliter (EL.U/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 33 EL.U/mL. The table shows results for each RTS,S Regimen A, B & C, and for each Engerix B Regimen A & B study groups.

End point type

Secondary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	141	123	135	135	117
Units: EL.U/mL
geometric mean (confidence interval 95%)
EL.U/mL	268.7 (226.8 to 318.3)	327.1 (272.2 to 393.1)	335.5 (283.2 to 397.5)	25.5 (22.8 to 28.7)	28.7 (24.6 to 33.4)

No statistical analyses for this end point

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 3

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End point title

Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 3

End point description

End point type

Secondary

End point timeframe

At Month 3, aka at one month post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	141	123	136	135	118
Units: EL.U/mL
geometric mean (confidence interval 95%)
EL.U/mL	142.2 (116.4 to 173.7)	188.5 (156.5 to 227)	205.5 (167.3 to 252.5)	0.3 (0.3 to 0.3)	0.3 (0.3 to 0.4)

No statistical analyses for this end point

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 14

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End point title

Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 14

End point description

Anti-CS antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and presented as geometric mean concentrations (GMCs) expressed in ELISA units per milliliter (EL.U/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 0.5 EL.U/mL. The table shows results for each RTS,S Regimen A, B & C, and for each Engerix B Regimen A & B study groups. No anti-CS results are available for the time point 24 months post Dose 3 (Month 26) because the quantity of serum available for the anti-CS assay was insufficient for many samples.

End point type

Secondary

End point timeframe

At Month 14, aka at 12 months post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	91	82	96	85	76
Units: EL.U/mL
geometric mean (confidence interval 95%)
EL.U/mL	5.7 (4.2 to 7.7)	6.8 (5.0 to 9.4)	7.5 (5.3 to 10.6)	0.3 (0.3 to 0.3)	0.3 (0.3 to 0.4)

No statistical analyses for this end point

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 3

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End point title

Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 3 ^[7]

End point description

Antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA), and expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (μg/mL). The pneumococcal vaccine serotypes assessed were the serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay, by GSK assay, was greater than or equal to (>=) 0.2 μg/mL. This corresponds to the standard ELISA value of 0.35 μg/mL. This outcome concerns the subjects who received the RTS,S or Engerix-B vaccine co-administered with Synflorix. Results presented are for the study groups pooled by co-administration, that is, for the RTS,S Regimen A and Engerix-B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 3, aka at one month post Dose 3 of Synflorix

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	141	135
Units: µg/mL
geometric mean (confidence interval 95%)
ANTI-1	3.1 (2.8 to 3.6)	3.6 (3.1 to 4.2)
ANTI-4	3.5 (3.0 to 4.0)	4.2 (3.5 to 4.9)
ANTI-5	5.1 (4.5 to 5.8)	6.5 (5.6 to 7.4)
ANTI-6B	1.1 (0.8 to 1.3)	1.2 (1.0 to 1.6)
ANTI-7F	4.4 (3.9 to 4.9)	4.9 (4.3 to 5.7)
ANTI-9V	2.8 (2.4 to 3.3)	3.7 (3.3 to 4.2)
ANTI-14	5.8 (5.0 to 6.7)	5.7 (4.7 to 7.0)
ANTI-18C	3.4 (2.8 to 4.1)	6.2 (5.1 to 7.5)
ANTI-19F	4.2 (3.4 to 5.2)	5.1 (4.1 to 6.4)
ANTI-23F	1.3 (1.1 to 1.6)	1.5 (1.1 to 1.9)

Antibody against pneumococcal serotype 1 response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 1 responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.39

Notes
[8] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 4 response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 4 responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

Engerix B Regimen A Group v RTS,S Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.48

Notes
[9] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 5 response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 5 responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

1.52

Notes
[10] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 6B response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 6B responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.65

Notes
[11] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for Nothing selected the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 7F response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 7F responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.33

Notes
[12] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 9V response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 9V responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

1.63

Notes
[13] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype 14 response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 14 responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.27

Notes
[14] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype18C response

Statistical analysis description

To demonstrate the non-inferiority of antibody against 18C responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.81

Confidence interval

level

95%

sides

2-sided

lower limit

1.38

upper limit

2.38

Notes
[15] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype19F response

Statistical analysis description

To demonstrate the non-inferiority of antibody against serotype 19F responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.65

Notes
[16] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Antibody against pneumococcal serotype23F response

Statistical analysis description

To demonstrate the non-inferiority of antibody against 23F responses to the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Regimen A Group v Engerix B Regimen A Group

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.55

Notes
[17] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers (measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate vaccine when co-administered with versus without RTS,S/AS01E.

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 17

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End point title

Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 17 ^[18]

End point description

Antibody concentrations were measured by GSK assay, and expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (μg/mL). The pneumococcal vaccine serotypes assessed were the serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. The cut-off of the assay, by GSK assay, was greater than or equal to (>=) 0.2 μg/mL. This corresponds to the standard ELISA value of 0.35 μg/mL. This outcome concerns the subjects who received the RTS,S or Engerix -B vaccine co-administered with Synflorix. Results presented are for the study groups pooled by co-administration, that is, for the RTS,S Regimen A and Engerix -B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 17, aka one month post the Month 16 booster dose of Synflorix

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	133	126
Units: μg/mL
geometric mean (confidence interval 95%)
ANTI-1	4.5 (3.8 to 5.4)	5.4 (4.5 to 6.4)
ANTI-4	6.1 (5.1 to 7.2)	6.8 (5.7 to 8.0)
ANTI-5	6.5 (5.5 to 7.8)	7.6 (6.4 to 9.1)
ANTI-6B	4.7 (4.0 to 5.5)	4.1 (3.5 to 4.9)
ANTI-7F	7.1 (6.2 to 8.2)	7.2 (6.3 to 8.2)
ANTI-9V	6.0 (5.1 to 7.1)	5.7 (4.9 to 6.6)
ANTI-14	9.0 (7.6 to 10.7)	9.0 (7.4 to 10.8)
ANTI-18C	13.7 (11.5 to 16.3)	14.5 (12.3 to 17.2)
ANTI-19F	6.0 (4.9 to 7.4)	7.2 (5.8 to 8.8)
ANTI-23F	4.1 (3.4 to 5.1)	3.9 (3.2 to 4.8)

No statistical analyses for this end point

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 3

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End point title

Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 3 ^[19]

End point description

The pneumococcal vaccine serotypes assessed were the serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Streptococcus pneumoniae opsonophagocytic activity was presented as the dilution of serum (opsonic titer) able to sustain 50 % killing of live pneumococci under the assay conditions, expressed as geometric mean titers (GMTs). The cut-off of the assay was an opsonic dilution >= 8. This outcome concerns the subjects who received the RTS,S or Engerix-B vaccine co-administered with Synflorix. Results presented are for the study groups pooled by coadministration, that is, for the RTS,S Regimen A and Engerix-B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 3, aka at one month (1M) post Dose 3 of Synflorix

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	133	124
Units: Titer
geometric mean (confidence interval 95%)
ANTI-1	48.9 (34.6 to 68.9)	65 (45 to 93.7)
ANTI-4	768.3 (617.6 to 955.8)	810.9 (676.5 to 972)
ANTI-5	77.6 (61.9 to 97.3)	93.8 (73.6 to 119.6)
ANTI-6B	444.4 (295 to 669.5)	389.3 (250.1 to 606.1)
ANTI-7F	3774 (3232.7 to 4405.8)	3947.4 (3338.3 to 4667.7)
ANTI-9V	1257.7 (977.3 to 1618.7)	1469.3 (1180.4 to 1828.8)
ANTI-14	1426.3 (1136 to 1790.9)	1269 (965.1 to 1668.6)
ANTI-18C	192.6 (139.2 to 266.4)	249.7 (185 to 337)
ANTI-19F	159.3 (109.9 to 231)	228.8 (160.4 to 326.3)
ANTI-23F	760.9 (476.3 to 1215.5)	735.6 (456.3 to 1185.9)

No statistical analyses for this end point

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 17

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End point title

Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 17 ^[20]

End point description

The pneumococcal vaccine serotypes assessed were the serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Streptococcus pneumoniae opsonophagocytic activity was presented as the dilution of serum (opsonic titer) able to sustain 50 % killing of live pneumococci under the assay conditions, expressed as geometric mean titers (GMTs). The cut-off of the assay was an opsonic dilution >= 8. This outcome concerns the subjects who received the RTS,S or Engerix -B vaccine co-administered with Synflorix . Results presented are for the study groups pooled by coadministration, that is, for the RTS,S Regimen A and Engerix -B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 17, aka one month post the Month 16 booster dose of Synflorix

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	130	121
Units: Titer
geometric mean (confidence interval 95%)
Opsono-1	649.9 (464.7 to 908.9)	840.1 (603.4 to 1169.7)
Opsono-4	2347.1 (1847.4 to 2982)	2527.8 (2064.1 to 3095.7)
Opsono-5	324.2 (244.1 to 430.5)	392.8 (291.3 to 529.6)
Opsono-6B	955.3 (761.4 to 1198.6)	828.2 (652.7 to 1050.9)
Opsono-7F	9167.3 (7979.2 to 10532.3)	7794.6 (6577.6 to 9236.8)
Opsono-9V	3035.3 (2523.3 to 3651.3)	3164.6 (2669.8 to 3751.1)
Opsono-14	1975.7 (1565.8 to 2493)	1865 (1463.9 to 2375.9)
Opsono-18C	1694.1 (1188.6 to 2414.7)	1548.7 (1096.3 to 2188)
Opsono-19F	344.5 (223 to 532.3)	469.7 (320 to 689.4)
Opsono-23F	3199.8 (2543.7 to 4025.1)	3198.1 (2526.5 to 4048.4)

No statistical analyses for this end point

Secondary: Anti-protein D (PD) antibody concentrations at Month 3

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End point title

Anti-protein D (PD) antibody concentrations at Month 3 ^[21]

End point description

Anti-PD antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs), in ELISA units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off value of greater than or equal to 100 EL.U/mL. This outcome concerns the subjects who received the RTS,S or Engerix-B vaccine co-administered with Synflorix. Results presented are for the study groups pooled by co-administration, that is, for the RTS,S Regimen A and Engerix-B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 3, aka at one month post Dose 3 of Synflorix

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	141	134
Units: EL.U/mL
geometric mean (confidence interval 95%)
EL.U/mL	2435.3 (2204.3 to 2690.6)	2956.7 (2647.5 to 3302.1)

No statistical analyses for this end point

Secondary: Anti-protein D (PD) antibody concentrations at Month 17

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End point title

Anti-protein D (PD) antibody concentrations at Month 17 ^[22]

End point description

Anti-PD antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs), in ELISA units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off value of greater than or equal to 100 EL.U/mL. This outcome concerns the subjects who received the RTS,S or Engerix -B vaccine co-administered with Synflorix. Results presented are for the study groups pooled by co-administration, that is, for the RTS,S Regimen A and Engerix -B Regimen A groups.

End point type

Secondary

End point timeframe

At Month 17, aka one month post the Month 16 booster dose of Synflorix

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen A Group	Engerix B Regimen A Group
Number of subjects analysed	133	126
Units: EL.U/mL
geometric mean (confidence interval 95%)
EL.U/mL	2648.3 (2194.2 to 3196.4)	2819.1 (2391.1 to 3323.7)

No statistical analyses for this end point

Secondary: Concentrations of antibodies against acellular B-pertussis (BPT) at Day 0 and at Month 3

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End point title

Concentrations of antibodies against acellular B-pertussis (BPT) at Day 0 and at Month 3

End point description

The antibodies against BPT assessed were against pertussis toxoid (anti-PT), against filamentous haemagglutinin (anti-FHA), and against pertactin (anti-PRN). Concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs), in ELISA units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off value of greater than or equal to (>=) 5 EL.U/mL. The table shows results for study groups pooled by primary vaccine administered (RTS,S vs Engerix -B).

End point type

Secondary

End point timeframe

At Day 0 and at Month 3 (one month post Dose 3 of Infanrix-Hib)

End point values	RTS,S Group	Engerix B Group
Number of subjects analysed	401	253
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-PT – At Day 0	3.8 (3.6 to 4.1)	4.3 (3.9 to 4.8)
Anti-PT – At Month 3	105.9 (99.2 to 113.1)	114.2 (104.8 to 124.5)
Anti-FHA – At Day 0	13.9 (12.7 to 15.2)	15.7 (14.1 to 17.5)
Anti-FHA – At Month 3	271.1 (252.8 to 290.8)	292.9 (268.9 to 319.1)
Anti-PRN – At Day 0	3.2 (3 to 3.4)	3.2 (3 to 3.5)
Anti-PRN – At Month 3	164.1 (153.6 to 175.3)	179.7 (164.4 to 196.5)

Anti-PT response

Statistical analysis description

To demonstrate the non-inferiority of antibody response to the acellular B pertussis antigen, pertussis toxoid, (PT) of the DTPa/Hib vaccine when co-administered with RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Group v Engerix B Group

Number of subjects included in analysis

654

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[23]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.2

Notes
[23] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of anti-PT, anti-FHA, anti-PRN antibody concentrations, is below a limit of 2 for the DTPa/Hib vaccine when co-administered with versus without RTS,S/AS01E.

Anti-FHA response

Statistical analysis description

To demonstrate the non-inferiority of antibody response to the acellular B pertussis antigen, filamentous haemagglutinin (FHA), of the DTPa/Hib vaccine when co-administered with RTS,S/AS01E as part of an EPI regimen.

Comparison groups

Engerix B Group v RTS,S Group

Number of subjects included in analysis

654

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[24]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.21

Notes
[24] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of anti-PT, anti-FHA, anti-PRN antibody concentrations, is below a limit of 2 for the DTPa/Hib vaccine when co-administered with versus without RTS,S/AS01E.

Anti-PRN response

Statistical analysis description

To demonstrate the non-inferiority of antibody response to the acellular B pertussis antigen, pertactin (anti-PRN), of the DTPa/Hib vaccine when co-administered with RTS,S/AS01E as part of an EPI regimen.

Comparison groups

RTS,S Group v Engerix B Group

Number of subjects included in analysis

654

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.22

Notes
[25] - Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the GMC ratios of anti-PT, anti-FHA, anti-PRN antibody concentrations, is below a limit of 2 for the DTPa/Hib vaccine when co-administered with versus without RTS,S/AS01E.

Secondary: Anti-Rotavirus (anti-RV) antibody concentrations

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End point title

Anti-Rotavirus (anti-RV) antibody concentrations ^[26]

End point description

Anti-Rotavirus (anti-RV) antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA)and expre ssed as geometric mean concentrations (GMCs). The cut-off of the assay was the seropositive cut-off value of greater than or equal to (>=) 20 units per milliliter (U/mL). This outcome measure was assessed in subjects who were administered Rotarix as part of an EPI regimen, with and without RTS,S vaccine co-administration. This outcome concerns the subjects who received the RTS,S or Engerix-B vaccine co-administered with Rotarix. Results presented are for the study groups pooled by RTS,S or Engerix-B vaccine co-administration, that is, for the RTS,S Regimen B and Engerix-B Regimen B groups.

End point type

Secondary

End point timeframe

At Month 3, aka one month post Dose 2 of Rotarix

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results in this study were tabulated by the study groups pooled by co-administration. Hence for each related endpoint, they are presented for only the respective groups in the baseline period, while the results for multiple endpoints account for all baseline groups.

End point values	RTS,S Regimen B Group	Engerix B Regimen B Group
Number of subjects analysed	120	116
Units: U/mL
geometric mean (confidence interval 95%)
U/mL	24.9 (19.3 to 32)	27.6 (20.8 to 36.5)

Anti-RV response

Statistical analysis description

To demonstrate the non-inferiority of antibody response to the rotavirus vaccine when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.

Comparison groups

Engerix B Regimen B Group v RTS,S Regimen B Group

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

Method

ANOVA

Parameter type

GMC ratio

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.61

Notes
[27] - Criteria for non-inferiority: one month post Dose 2, upper limit (UL) of the 2-sided 95% confidence interval (CI) on the geometric mean concentrations (GMC) ratios of rotavirus antibodies (IgA) concentrations is below 2 for the rotavirus vaccine when coadministered with versus without RTS,S/AS01E.

Secondary: Number of subjects with solicited local symptoms

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End point title

Number of subjects with solicited local symptoms

End point description

Assessed solicited local symptoms were pain, redness and swelling at the site of injection. All solicited local symptoms assessed were considered by the investigator as causally related to the study vaccination. Analysis for this outcome was performed solely for the 7-days follow-up periods following the primary vaccination with RTS,S vaccine or Engerix-B (at Day 0, and Months 1 and 2). Data presented are those for any occurrence of the assessed solicited local symptoms, that is, the occurrences of these symptoms regardless of their intensity grade.

End point type

Secondary

End point timeframe

Within the 7-day follow-up period (Days 0-6) after administration of Dose (D) 1, 2 and 3, respectively, with RTS,S or Engerix-B vaccine

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Pain - Post D1	41	28	31	29	15
Pain – Post D2	30	14	21	24	9
Pain – Post D3	14	10	14	18	7
Redness – Post D1	1	0	2	5	1
Redness – Post D2	5	1	2	3	0
Redness – Post D3	3	0	1	3	0
Swelling – Post D1	5	2	6	10	4
Swelling – Post D2	8	3	4	9	4
Swelling – Post D3	7	2	6	11	3

No statistical analyses for this end point

Secondary: Number of subjects with solicited general symptoms

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End point title

Number of subjects with solicited general symptoms

End point description

Assessed solicited general symptoms were fever, irritability/fussiness, drowsiness, and loss of appetite. Fever was defined as axillary temperature higher than (>) 37.5 degrees Celsius (°C). Analysis for this outcome was performed solely for the 7-days follow-up periods following the primary vaccination with RTS,S vaccine or Engerix-B (at Day 0, and Months 1 and 2). Data presented are those for any occurrence of the assessed solicited general symptoms, that is, the occurrences of these symptoms regardless of their intensity grade or relationship to vaccination.

End point type

Secondary

End point timeframe

Within the 7-day follow-up period (Days 0-6) after administration of Dose (D) 1, 2 and 3, respectively, with RTS,S or Engerix-B vaccine

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Fever – D1	44	20	16	23	13
Fever – D2	30	14	18	20	5
Fever – D3	38	20	26	16	12
Irritability – D1	15	11	11	9	5
Irritability – D2	13	7	12	10	0
Irritability – D3	5	3	10	6	1
Drowsiness – D1	2	1	3	3	0
Drowsiness – D2	5	1	1	3	0
Drowsiness – D3	3	0	2	1	0
Loss of appetite – D1	4	1	2	4	0
Loss of appetite – D2	3	1	1	3	0
Loss of appetite – D3	2	0	1	1	1

No statistical analyses for this end point

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 8

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End point title

Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 8

End point description

A potential immune mediated disorder (pIMD) was defined as an event about which concerns arose that vaccination may have interfered with immunological self-tolerance of the subjects. IMDs assessed included among others neuroinflammatory disorders (such as optic neuritis, multiple sclerosis, or encephalitis), musculoskeletal disorders (such as cutaneous lupus, rheumatoid arthritis, juvenile arthritis, or psoriatic arthropathy), gastrointestinal disorders (ulcerative colitis and ulcerative proctitis, celiac disease), metabolic diseases (such as autoimmune thyroiditis, or diabetes Mellitus Type 1, Addison’s disease), skin disorders (such as psoriasis or vitiligo), and other disorders such as vasculitis, pernicious anemia, or, sarcoidosis.

End point type

Secondary

End point timeframe

From Day 0 to Month 8

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Subject	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 26

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End point title

Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 26

End point description

End point type

Secondary

End point timeframe

From study start at Day 0 to Month 26

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Subject	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with unsolicited adverse events (AEs)

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End point title

Number of subjects with unsolicited adverse events (AEs)

End point description

An unsolicited AE was defined as an untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.

End point type

Secondary

End point timeframe

Within the 30-day follow-up periods (Days 0-29) after vaccination with RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Subject	121	115	120	120	105

No statistical analyses for this end point

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) within the 30-day follow-up periods (Days 0-29)

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End point title

Number of subjects with any and fatal serious adverse events (SAEs) within the 30-day follow-up periods (Days 0-29)

End point description

A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in death, was lifethreatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or a reported adverse event of specific interest such as seizures occurring within a 30-day period of vaccination, immune-mediated disorders, and specific autoimmune diseases. A fatal SAE was defined as a SAE resulting in the death of the study subject.

End point type

Secondary

End point timeframe

Within the 30-day follow-up periods (Days 0-29) after vaccination with RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Subject with SAE(s)	1	3	3	1	3
Subjects with fatal SAE(s)	1	0	1	0	0

No statistical analyses for this end point

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 8

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End point title

Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 8

End point description

A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or a reported adverse event of specific interest such as seizures occurring within a 30-day period of vaccination, immune-mediated disorders, and specific autoimmune diseases. A fatal SAE was defined as a SAE resulting in the death of the study subject.

End point type

Secondary

End point timeframe

From Day 0 to Month 8

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Subjects with SAE(s)	1	7	7	3	5
Subjects with fatal SAE(s)	1	2	2	0	0

No statistical analyses for this end point

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 26

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End point title

Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 26

End point description

End point type

Secondary

End point timeframe

From Day 0 to Month 26

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Any SAEs - At Month 26	1	8	7	6	6
Fatal SAEs - At Month 26	1	3	2	2	1

No statistical analyses for this end point

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 38, 50 and 51

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End point title

Anti-Hepatitis B (HBs) antibody concentrations at Month 38, 50 and 51

End point description

Concentrations, by enzyme-linked immunosorbent assay (ELISA), were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 10 mIU/mL. A decrease in the specificity of the anti-HBs ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete retesting/reanalysis. Results presented are for each RTS,S Regimen A, B & C, and for each Engerix B Regimen A & B study groups.

End point type

Secondary

End point timeframe

At Months 38, 50 and 51, aka 36 and 48 months post Dose 3 of RTS,S vaccine or Engerix-B and one month post the Month 50 booster dose of Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	131	111	122	127	106
Units: mIU/mL
geometric mean (confidence interval 95%)
Month 38	706.8 (548.0 to 911.6)	1081.7 (845.3 to 1384.2)	977.4 (786.7 to 1214.3)	39.0 (29.0 to 52.4)	41.2 (29.8 to 57.0)
Month 50	499.4 (382.2 to 652.6)	765.3 (590.5 to 992.0)	807.3 (649.6 to 1003.4)	29.2 (22.0 to 38.7)	32.9 (23.9 to 45.4)
Month 51	32345.9 (24758.5 to 42258.4)	54977.1 (43579.1 to 69356.4)	59630.0 (48606.1 to 73154.0)	8995.0 (5935.8 to 13631.0)	9578.9 (6374.2 to 14395.0)

No statistical analyses for this end point

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti- HBs RF1) at Month 51

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End point title

Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti- HBs RF1) at Month 51

End point description

End point type

Secondary

End point timeframe

At Month 51, aka one month post the Month 50 booster dose of Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	124	104	113	107	95
Units: EL.U/mL
geometric mean (confidence interval 95%)	307.8 (239.0 to 396.4)	471.6 (372.5 to 597.1)	514.5 (415.3 to 637.5)	120.5 (86.6 to 167.6)	127.9 (94.5 to 173.1)

No statistical analyses for this end point

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 38 and 50

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End point title

Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 38 and 50

End point description

Anti-CS antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and geometric mean concentrations (GMCs) expressed in ELISA units per milliliter (EL.U/mL). The assay cut-off was the seropositivity cut-off value of greater than or equal to (>=) 1.9 EL.U/mL. The table shows results for each RTS,S Regimen A, B & C, and for each Engerix B Regimen A & B study groups.

End point type

Secondary

End point timeframe

At Months 38 and 50, aka 36 and 48 months post Dose 3 of RTS,S vaccine or Engerix-B

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	131	111	122	127	107
Units: EL.U/mL
geometric mean (confidence interval 95%)
Month 38	2.6 (2.2 to 3.1)	2.8 (2.3 to 3.4)	3.5 (2.9 to 4.2)	1.0 (1.0 to 1.1)	1.0 (1.0 to 1.0)
Month 50	2.3 (2.0 to 2.7)	2.4 (2.0 to 2.8)	2.7 (2.3 to 3.2)	1.1 (1.0 to 1.1)	1.1 (1.0 to 1.3)

No statistical analyses for this end point

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 up to Study End (Month 51)

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End point title

Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 up to Study End (Month 51)

End point description

End point type

Secondary

End point timeframe

From Day 0 up to Study End (Month 51)

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with any, fatal and related serious adverse events (SAEs) from Day 0 up to Study End (Month 51)

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End point title

Number of subjects with any, fatal and related serious adverse events (SAEs) from Day 0 up to Study End (Month 51)

End point description

End point type

Secondary

End point timeframe

From Day 0 up to Study End (Month 51)

End point values	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Number of subjects analysed	142	142	141	141	139
Units: Subject
Any SAEs	3	10	9	6	6
Fatal SAEs	3	5	4	2	1
Related SAEs	0	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited local, general symptoms and unsolicited AEs: within the 30-day periods after primary co-administration vaccination. SAEs: during the entire study period (Month 0 to Month 51).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

RTS,S Regimen A Group

Reporting group description

Reporting group title

RTS,S Regimen B Group

Reporting group description

Reporting group title

RTS,S Regimen C Group

Reporting group description

Reporting group title

Engerix B Regimen A Group

Reporting group description

Reporting group title

Engerix B Regimen B Group

Reporting group description

Serious adverse events	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 142 (2.11%)	10 / 142 (7.04%)	9 / 141 (6.38%)	6 / 141 (4.26%)	6 / 139 (4.32%)
number of deaths (all causes)	3	5	4	2	1
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Accident
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Glucose-6-phosphate dehydrogenase deficiency
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	1 / 141 (0.71%)	3 / 141 (2.13%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1
Intravascular haemolysis
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	2 / 141 (1.42%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Malaria
subjects affected / exposed	1 / 142 (0.70%)	2 / 142 (1.41%)	2 / 141 (1.42%)	2 / 141 (1.42%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
Endocarditis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 142 (0.70%)	2 / 142 (1.41%)	2 / 141 (1.42%)	2 / 141 (1.42%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
Trichomoniasis intestinal
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Meningitis bacterial
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Meningitis streptococcal
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Salmonella sepsis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
Metabolism and nutrition disorders
Failure to thrive
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	RTS,S Regimen A Group	RTS,S Regimen B Group	RTS,S Regimen C Group	Engerix B Regimen A Group	Engerix B Regimen B Group
Total subjects affected by non serious adverse events
subjects affected / exposed	135 / 142 (95.07%)	129 / 142 (90.85%)	132 / 141 (93.62%)	135 / 141 (95.74%)	119 / 139 (85.61%)
General disorders and administration site conditions
Pain
subjects affected / exposed	55 / 142 (38.73%)	40 / 142 (28.17%)	47 / 141 (33.33%)	48 / 141 (34.04%)	25 / 139 (17.99%)
occurrences all number	85	52	66	71	32
Swelling
subjects affected / exposed	17 / 142 (11.97%)	7 / 142 (4.93%)	14 / 141 (9.93%)	23 / 141 (16.31%)	10 / 139 (7.19%)
occurrences all number	20	7	16	30	11
Pyrexia
alternative assessment type: Non-systematic
subjects affected / exposed	81 / 142 (57.04%)	49 / 142 (34.51%)	50 / 141 (35.46%)	55 / 141 (39.01%)	34 / 139 (24.46%)
occurrences all number	116	56	66	65	37
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	2 / 139 (1.44%)
occurrences all number	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Allergic bronchitis
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	1	0	0	1	0
Cough
subjects affected / exposed	0 / 142 (0.00%)	2 / 142 (1.41%)	2 / 141 (1.42%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	2	2	0	0
Psychiatric disorders
Irritability
subjects affected / exposed	28 / 142 (19.72%)	18 / 142 (12.68%)	27 / 141 (19.15%)	19 / 141 (13.48%)	5 / 139 (3.60%)
occurrences all number	33	21	33	25	6
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	0	1
Contusion
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	1	0	0	0
Foreign body in eye
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	1	0	0	0
Wound
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	1	0	1
Congenital, familial and genetic disorders
Respiratory tract malformation
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Somnolence
subjects affected / exposed	8 / 142 (5.63%)	2 / 142 (1.41%)	5 / 141 (3.55%)	5 / 141 (3.55%)	0 / 139 (0.00%)
occurrences all number	10	2	6	7	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	1 / 141 (0.71%)	2 / 141 (1.42%)	2 / 139 (1.44%)
occurrences all number	2	0	1	2	2
Iron deficiency anaemia
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Ear and labyrinth disorders
Excessive cerumen production
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	1	1	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	1 / 141 (0.71%)	2 / 141 (1.42%)	2 / 139 (1.44%)
occurrences all number	1	1	1	2	2
Anal fissure
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	2 / 141 (1.42%)	1 / 139 (0.72%)
occurrences all number	1	0	0	2	1
Diarrhoea
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	1 / 141 (0.71%)	2 / 141 (1.42%)	0 / 139 (0.00%)
occurrences all number	1	1	1	2	0
Enteritis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	1	0	0	1	0
Mouth ulceration
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	0	1	0
Stomatitis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Erythema
alternative assessment type: Non-systematic
subjects affected / exposed	19 / 142 (13.38%)	8 / 142 (5.63%)	20 / 141 (14.18%)	12 / 141 (8.51%)	6 / 139 (4.32%)
occurrences all number	19	8	20	13	6
Dermatitis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	1 / 139 (0.72%)
occurrences all number	0	1	1	1	1
Dermatitis allergic
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	0	1	0
Dermatitis atopic
subjects affected / exposed	0 / 142 (0.00%)	3 / 142 (2.11%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	3	0	1	0
Dermatitis diaper
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	0 / 141 (0.00%)	2 / 141 (1.42%)	1 / 139 (0.72%)
occurrences all number	1	1	0	2	1
Dermatosis
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	3 / 141 (2.13%)	4 / 141 (2.84%)	1 / 139 (0.72%)
occurrences all number	1	1	3	4	1
Eczema
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	1	0	0
Prurigo
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	4 / 141 (2.84%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	1	0	4	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	0	1
Infections and infestations
Conjunctivitis
alternative assessment type: Non-systematic
subjects affected / exposed	8 / 142 (5.63%)	10 / 142 (7.04%)	11 / 141 (7.80%)	9 / 141 (6.38%)	7 / 139 (5.04%)
occurrences all number	8	10	12	10	7
Malaria
alternative assessment type: Non-systematic
subjects affected / exposed	44 / 142 (30.99%)	44 / 142 (30.99%)	39 / 141 (27.66%)	49 / 141 (34.75%)	44 / 139 (31.65%)
occurrences all number	50	54	46	52	53
Gastroenteritis
alternative assessment type: Non-systematic
subjects affected / exposed	42 / 142 (29.58%)	47 / 142 (33.10%)	51 / 141 (36.17%)	43 / 141 (30.50%)	38 / 139 (27.34%)
occurrences all number	55	58	71	57	47
Rhinitis
alternative assessment type: Non-systematic
subjects affected / exposed	32 / 142 (22.54%)	35 / 142 (24.65%)	33 / 141 (23.40%)	31 / 141 (21.99%)	31 / 139 (22.30%)
occurrences all number	37	41	41	36	36
Bronchitis
alternative assessment type: Non-systematic
subjects affected / exposed	36 / 142 (25.35%)	33 / 142 (23.24%)	28 / 141 (19.86%)	28 / 141 (19.86%)	29 / 139 (20.86%)
occurrences all number	47	35	35	31	37
Pharyngitis
alternative assessment type: Non-systematic
subjects affected / exposed	23 / 142 (16.20%)	13 / 142 (9.15%)	15 / 141 (10.64%)	15 / 141 (10.64%)	17 / 139 (12.23%)
occurrences all number	24	15	19	18	18
Otitis media
alternative assessment type: Non-systematic
subjects affected / exposed	11 / 142 (7.75%)	12 / 142 (8.45%)	6 / 141 (4.26%)	15 / 141 (10.64%)	10 / 139 (7.19%)
occurrences all number	11	13	6	19	11
Upper respiratory tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	16 / 142 (11.27%)	8 / 142 (5.63%)	12 / 141 (8.51%)	8 / 141 (5.67%)	7 / 139 (5.04%)
occurrences all number	18	9	15	9	10
Respiratory tract infection
alternative assessment type: Non-systematic
subjects affected / exposed	10 / 142 (7.04%)	14 / 142 (9.86%)	15 / 141 (10.64%)	12 / 141 (8.51%)	10 / 139 (7.19%)
occurrences all number	10	16	18	13	11
Fungal skin infection
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 142 (0.70%)	7 / 142 (4.93%)	6 / 141 (4.26%)	12 / 141 (8.51%)	4 / 139 (2.88%)
occurrences all number	1	7	6	12	4
Bronchiolitis
alternative assessment type: Non-systematic
subjects affected / exposed	8 / 142 (5.63%)	5 / 142 (3.52%)	5 / 141 (3.55%)	4 / 141 (2.84%)	4 / 139 (2.88%)
occurrences all number	9	5	5	4	4
Pneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	5 / 142 (3.52%)	14 / 142 (9.86%)	4 / 141 (2.84%)	11 / 141 (7.80%)	2 / 139 (1.44%)
occurrences all number	5	15	4	11	2
Abscess
subjects affected / exposed	2 / 142 (1.41%)	0 / 142 (0.00%)	1 / 141 (0.71%)	2 / 141 (1.42%)	0 / 139 (0.00%)
occurrences all number	2	0	1	2	0
Acarodermatitis
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Anal fungal infection
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	0	1	0
Bullous impetigo
subjects affected / exposed	3 / 142 (2.11%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	3	0	0	0	0
Candida infection
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	2 / 141 (1.42%)	0 / 139 (0.00%)
occurrences all number	0	0	1	2	0
Conjunctivitis bacterial
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	1 / 141 (0.71%)	2 / 141 (1.42%)	0 / 139 (0.00%)
occurrences all number	1	0	1	2	0
Dysentery
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	1	1	2	0
Ear infection
subjects affected / exposed	2 / 142 (1.41%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	2	0	0	1	0
Folliculitis
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Fungal infection
subjects affected / exposed	3 / 142 (2.11%)	3 / 142 (2.11%)	5 / 141 (3.55%)	3 / 141 (2.13%)	4 / 139 (2.88%)
occurrences all number	3	3	5	3	4
Furuncle
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	2 / 141 (1.42%)	2 / 139 (1.44%)
occurrences all number	0	1	0	2	2
Gastrointestinal candidiasis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	1	1	0
Impetigo
subjects affected / exposed	3 / 142 (2.11%)	1 / 142 (0.70%)	0 / 141 (0.00%)	2 / 141 (1.42%)	4 / 139 (2.88%)
occurrences all number	3	1	0	2	4
Laryngitis
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	2 / 141 (1.42%)	0 / 141 (0.00%)	3 / 139 (2.16%)
occurrences all number	1	0	2	0	3
Oral candidiasis
subjects affected / exposed	5 / 142 (3.52%)	3 / 142 (2.11%)	3 / 141 (2.13%)	4 / 141 (2.84%)	1 / 139 (0.72%)
occurrences all number	5	3	3	4	1
Oral herpes
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Otitis externa
subjects affected / exposed	4 / 142 (2.82%)	3 / 142 (2.11%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	4	3	1	1	0
Otitis media acute
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	1	0	0	1	0
Parasitic gastroenteritis
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	1	0	0	0
Pyoderma
subjects affected / exposed	5 / 142 (3.52%)	7 / 142 (4.93%)	5 / 141 (3.55%)	6 / 141 (4.26%)	3 / 139 (2.16%)
occurrences all number	7	7	5	7	3
Rash pustular
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	0	0	0	0	1
Skin bacterial infection
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	1 / 141 (0.71%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	1	1	1	1	0
Staphylococcal infection
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	0 / 141 (0.00%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	0	0	1	0
Staphylococcal skin infection
subjects affected / exposed	1 / 142 (0.70%)	0 / 142 (0.00%)	0 / 141 (0.00%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	1	0	0	0	0
Tinea infection
subjects affected / exposed	0 / 142 (0.00%)	2 / 142 (1.41%)	2 / 141 (1.42%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	2	2	1	0
Urinary tract infection
subjects affected / exposed	0 / 142 (0.00%)	1 / 142 (0.70%)	3 / 141 (2.13%)	1 / 141 (0.71%)	0 / 139 (0.00%)
occurrences all number	0	1	3	1	0
Viral infection
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	0 / 141 (0.00%)	1 / 141 (0.71%)	1 / 139 (0.72%)
occurrences all number	1	1	0	1	1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	1 / 141 (0.71%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	1	1	1	0	1
Visceral larva migrans
subjects affected / exposed	0 / 142 (0.00%)	0 / 142 (0.00%)	1 / 141 (0.71%)	0 / 141 (0.00%)	0 / 139 (0.00%)
occurrences all number	0	0	1	0	0
Wound infection
subjects affected / exposed	1 / 142 (0.70%)	1 / 142 (0.70%)	0 / 141 (0.00%)	0 / 141 (0.00%)	1 / 139 (0.72%)
occurrences all number	1	1	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	7 / 142 (4.93%)	2 / 142 (1.41%)	4 / 141 (2.84%)	5 / 141 (3.55%)	1 / 139 (0.72%)
occurrences all number	9	2	4	8	1

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Were there any global substantial amendments to the protocol? No

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

Clinical Trial Results: Phase III randomized, open, controlled study to evaluate the immune response to the hepatitis B antigen of the RTS,S/AS01E candidate vaccine, when administered as primary vaccination integrated into an EPI regimen to infants living in sub-Saharan Africa.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Anti-Hepatitis B (HBs) antibody concentrations RTS,S Group and Engerix B Group

Primary: Anti-Hepatitis B (HBs) antibody concentrations RTS,S Group and Engerix B Group

Primary: Anti-Hepatitis B (HBs) antibody concentrations for all study Groups

Primary: Anti-Hepatitis B (HBs) antibody concentrations for all study Groups

Primary: Percentage of seroprotected subjects against Anti-Hepatitis B (HBs) antigen

Primary: Percentage of seroprotected subjects against Anti-Hepatitis B (HBs) antigen

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 3

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 3

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 14 and 26

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 14 and 26

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti-HBs RF1) at Month 3

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti-HBs RF1) at Month 3

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 3

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 3

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 14

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 14

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 3

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 3

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 17

Secondary: Pneumococcal antibody concentrations against Synflorix pneumococcal vaccine serotypes at Month 17

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 3

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 3

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 17

Secondary: Titers for opsonophagocytic activity against Synflorix pneumococcal vaccine serotypes at Month 17

Secondary: Anti-protein D (PD) antibody concentrations at Month 3

Secondary: Anti-protein D (PD) antibody concentrations at Month 3

Secondary: Anti-protein D (PD) antibody concentrations at Month 17

Secondary: Anti-protein D (PD) antibody concentrations at Month 17

Secondary: Concentrations of antibodies against acellular B-pertussis (BPT) at Day 0 and at Month 3

Secondary: Concentrations of antibodies against acellular B-pertussis (BPT) at Day 0 and at Month 3

Secondary: Anti-Rotavirus (anti-RV) antibody concentrations

Secondary: Anti-Rotavirus (anti-RV) antibody concentrations

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited local symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with solicited general symptoms

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 8

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 8

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 26

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 to Month 26

Secondary: Number of subjects with unsolicited adverse events (AEs)

Secondary: Number of subjects with unsolicited adverse events (AEs)

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) within the 30-day follow-up periods (Days 0-29)

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) within the 30-day follow-up periods (Days 0-29)

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 8

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 8

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 26

Secondary: Number of subjects with any and fatal serious adverse events (SAEs) from Day 0 to Month 26

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 38, 50 and 51

Secondary: Anti-Hepatitis B (HBs) antibody concentrations at Month 38, 50 and 51

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti- HBs RF1) at Month 51

Secondary: Concentrations of antibodies to the Hepatitis B RF1 surface antigen (anti- HBs RF1) at Month 51

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 38 and 50

Secondary: Anti-circumsporozoite protein (anti-CS) antibody concentrations at Month 38 and 50

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 up to Study End (Month 51)

Secondary: Number of subjects with potential immune mediated disorders (pIMDs) from Day 0 up to Study End (Month 51)

Secondary: Number of subjects with any, fatal and related serious adverse events (SAEs) from Day 0 up to Study End (Month 51)

Secondary: Number of subjects with any, fatal and related serious adverse events (SAEs) from Day 0 up to Study End (Month 51)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase III randomized, open, controlled study to evaluate the immune response to the hepatitis B antigen of the RTS,S/AS01E candidate vaccine, when administered as primary vaccination integrated into an EPI regimen to infants living in sub-Saharan Africa.