Safety and Immunogenicity of GSK Meningococcal Group B Vaccine and 13-valent Pneumococcal Vaccine Administered Concomitantly With Routine Infant Vaccines to Healthy Infants
Phase: PHASE3
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89, 
1330 Rixensart, Belgium 
Primary Study vaccine 
(and number) 
• 
GlaxoSmithKline (GSK) Biologicals’ meningococcal 
group-B vaccine Bexsero (GSK3536829A). 
• 
Pfizer’s pneumococcal polysaccharide conjugate 
vaccine (13-valent, adsorbed, Prevnar13). 
• 
Pfizer’s pneumococcal polysaccharide conjugate 
vaccine (20-valent, adsorbed, Prevnar20). 
Other Study 
vaccines/products 
• 
GSK Biologicals’ diphtheria and tetanus toxoids and 
acellular pertussis adsorbed, hepatitis B 
(recombinant) and inactivated poliovirus vaccine 
(Pediarix, GSK217744). 
• 
GSK Biologicals’ oral live attenuated human 
rotavirus (HRV) vaccine (Rotarix, GSK444563). 
• 
GSK Biologicals’ Haemophilus influenzae type b 
(Hib) conjugate vaccine (Hiberix, GSK208108). 
• 
Merck’s measles, mumps and rubella (MMR) virus 
live vaccine (M-M-R II). 
• 
Merck’s varicella virus live vaccine (Varivax).  
• 
Saline placebo. 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN-023 [V72_57]) 
Investigational New 
Drug (IND) number 
IND-011561 
EudraCT number 
2016-003268-37 
Date of protocol 
Final Version 1: 16 December 2014 
Date of protocol 
amendment 
Amendment 1 Final: 02 August 2016 
Amendment 2 Final: 11 December 2017 
Amendment 3 Final: 25 April 2018 
Amendment 4 Final: 02 November 2018 
Amendment 5 Final: 10 April 2020 
Amendment 6 Final: 9 December 2021 
Amendment 7 Final: 24 October 2022 
Amendment 8 Final: 19 Dec 2023 
Title 
Safety and Immunogenicity of GSK Meningococcal 
Group B Vaccine and 13-valent Pneumococcal Vaccine 
administered Concomitantly with Routine Infant Vaccines 
to Healthy Infants  

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Detailed Title 
A Phase IIIB, Observer-Blind, Randomized, Placebo-
Controlled, Multi-Center Study to Assess the Safety and 
Immunogenicity of GSK Meningococcal Group B 
Vaccine and 13-valent Pneumococcal Vaccine when 
Administered Concomitantly with Routine Vaccines to 
Healthy Infants 
GSK Biologicals’ Protocol DS for Legacy Novartis programs v 1.0 
© 2014-2023 GSK group of companies or its licensor. 

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Protocol Amendment 8 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
205239 (MENB REC 2ND GEN-023 [V72_57]) 
IND number 
IND-011561.  
EudraCT number 
2016-003268-37  
Date of protocol amendment 
Amendment 8 Final: 19 Dec 2023 
Detailed Title  
A Phase IIIB, Observer-Blind, Randomized, Placebo-
Controlled, Multi-Center Study to Assess the Safety 
and Immunogenicity of GSK Meningococcal Group 
B Vaccine and 13-valent Pneumococcal Vaccine 
when Administered Concomitantly with Routine 
Vaccines to Healthy Infants  
Sponsor signatory 
Alessandro Ble,  
Director, Associate Clinical Project Lead  
 
 
Signature 
 
 
 
Date 
 
 
 
Note: Not applicable if an alternative signature process (e.g. electronic signature or 
email approval) is used to get the sponsor approval. 

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Protocol Amendment 8 Rationale 
Amendment number: 
Amendment 8 
Rationale/background for changes:  
The purpose of the amendment 8 is to align the protocol with the recent update of 
CDC’s ACIP for the US NIP (National Immunization Program). According to 
this ACIP update, the 20-valent pneumococcal conjugate vaccine (PCV20) is 
listed as one of the recommended vaccines for the immunization of 
pneumococcal disease in children in U.S while PCV13 is no longer 
recommended for full series of pneumococcal vaccination. Children who 
received 3 PCV13 doses before 12 months but have not received their 
fourth booster dose, have now the option to receive PCV20 or PCV13. Therefore, 
to incorporate the current ACIP recommendations, subjects who have not reached 
their visit 5 at the time when this protocol amendment becomes effective have the 
option to receive either PCV13 or PCV20 based on the investigator judgment 
and/or parent’s preference. 
Amended text is indicated in bold italics in the body of the protocol. 

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Protocol Amendment 8 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical 
trial agreement and with any other study conduct procedures and/or study 
conduct documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and 
all applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed 
about the GSK Biologicals’ study vaccine and other study-related duties and 
functions as described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if 
required by local regulations, obtain the laboratory’s current certification or 
Quality Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite 
or elsewhere without the approval of GSK Biologicals and the express written 
informed consent of the subject and/or the subject’s legally acceptable 
representative.  
• 
To perform no other biological assays on the clinical samples except those 
described in the protocol or its amendment(s).  
• 
To co-operate with a representative of GSK Biologicals in the monitoring 
process of the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the 
sponsor to obtain and supply, as necessary, details about the investigator’s 
ownership interest in the sponsor or the investigational vaccines, and more 
generally about his/her financial ties with the sponsor. GSK Biologicals will use 
and disclose the information solely for the purpose of complying with regulatory 
requirements. 
Hence I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and 
dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during 
the course of the study and for one year following completion of the study.  
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 

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eTrack study number and 
Abbreviated Title 
205239 (MENB REC 2ND GEN-023 [V72_57]) 
IND number  
IND-011561  
EudraCT number 
2016-003268-37  
Date of protocol amendment 
Amendment 8 Final: 19 Dec 2023 
Detailed Title 
A Phase IIIB, Observer-Blind, Randomized, Placebo-
Controlled, Multi-Center Study to Assess the Safety 
and Immunogenicity of GSK Meningococcal Group 
B Vaccine and 13-valent Pneumococcal Vaccine 
when Administered Concomitantly with Routine 
Vaccines to Healthy Infants.  
Investigator name 
 
 
 
 
 
Signature 
 
 
 
Date 
 

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SPONSOR INFORMATION 
1. Sponsor 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330, Rixensart, Belgium 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 7.3.2. 
5. GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding 
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 7.3.2.  

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SYNOPSIS 
Detailed Title 
A Phase IIIB, Observer-Blind, Randomized, Placebo-
Controlled, Multi-Center Study to Assess the Safety and 
Immunogenicity of GSK Meningococcal Group B Vaccine and 
13-valent Pneumococcal Vaccine when Administered 
Concomitantly with Routine Vaccines to Healthy Infants  
Indication 
Active immunization against invasive disease caused 
by Neisseria meningitidis serogroup B strains. Although the 
meningococcal group B vaccine was developed for individuals 
aged 2 months and older, the actual age range for which this 
recommendation extends varies depending on the approval from 
different health authorities. In the US, the current indication is 
for individuals 10 through 25 years of age. 
Rationale for the 
study and study 
design  
• 
Rationale for the study 
As part of the US Food and Drug Administration’s approval of a 
biologics license application for GSK meningococcal group B 
vaccine (rMenB+OMV NZ, Bexsero), the present study V72_57 
(205239) is a required pediatric study under the Pediatric 
Research Equity Act to evaluate the safety and immunogenicity 
of Bexsero in North American infants 6 weeks through 12 
months of age. 
Previous clinical studies conducted in Europe and other 
countries worldwide have shown that rMenB+OMV NZ 
demonstrated a robust immune response in all age groups 
against indicator test strains, H44/76 (fHbp), 5/99 (NadA), 
NZ98/254 (PorA P1.4) and M10713 (NHBA) and that the 
concomitant administration of rMenB+OMV NZ does not 
clinically interfere with response to the vaccine antigens present 
in routinely administered infant vaccines: diphtheria, tetanus, 
acellular pertussis, Haemophilus influenzae type b, inactivated 
poliomyelitis, hepatitis B, measles, mumps, rubella, varicella 
and 7-valent pneumococcal conjugate vaccine. However, no 
data on the concomitant use of rMenB+OMV NZ with PCV13 
and routine infant vaccines in North American infants is 
currently available. 
The 3 strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA 
P1.4) in addition to M13520 (NHBA) strain are considered by 
the CBER to better evaluate the protective response of the 
vaccine. 
The purpose of this study therefore is to assess the immune 
response against those strains and the safety of rMenB+OMV 
NZ vaccine when administered concomitantly with the PCV13 
and other US Advisory Committee on Immunization Practices 

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(ACIP) recommended RIV. The study will also assess the safety 
and the immunogenicity of the PCV13 vaccine when 
concomitantly administered with rMenB+OMV NZ vaccine and 
RIV, compared to PCV13 administered with a placebo and RIV. 
In addition, the safety and immunogenicity of RIV (Pediarix, 
Hiberix, Rotarix, M-M-R II, Varivax) will be assessed following 
their concomitant administration with rMenB+OMV NZ and/or 
PCV13. 
• 
Rationale for the study design 
The parallel group study design was selected to allow an 
assessment of the immune responses and safety of the 
rMenB+OMV NZ and PCV13 vaccines when co-administered, 
along with other RIV.  
• 
Rationale for the use of placebo 
For this study, a placebo (saline solution) will be administered 
concomitantly with the PCV13 vaccine to subjects in group 
Placebo+PCV. As all other vaccines recommended for this age 
group have been included as study vaccines, a placebo is the 
only available option to minimize possible introduction of 
reporting bias in collecting information about AEs and to ensure 
the same number of vaccinations are administered to subjects 
assigned to either of the 2 study groups.  
• 
Rationale for the use of non-study vaccine 
In order to ease the disruption to the standard infant vaccine 
schedule caused by participating to the study, all subjects will 
also receive the following standardized non-study vaccines at 13 
months of age (Visit 6): 
• 
Diphtheria, tetanus toxoids and acellular pertussis adsorbed 
vaccine (DTaP, Infanrix). 
• 
Haemophilus influenzae type b Conjugate Vaccine (Hib, 
Hiberix). 
Study design 
• 
Experimental design: Phase IIIB, observer-blind, 
randomized, placebo-controlled, multi-centric, study with 2 
parallel groups. 
• 
Duration of the study: 
− 
Epoch 001 Primary starting at Visit 1 (Day 1) and 
ending at Visit 5 (Day 301). 
− 
Epoch 002: Secondary starting at Visit 5 (Day 301) and 
ending at Visit 6 (Day 331). 

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− 
Epoch 003: Safety follow-up period starting at Visit 6 
(Day 331) and ending at Visit 7 (Day 481 or Day 661). 
For subjects who have not yet reached the 6-month 
safety follow-up after the last dose at the time protocol 
amendment 7 takes effect, Visit 7 will take place on 
Day 481. 
• 
Primary completion date (PCD): Visit 7 (Day 481 or 
Day 661).  
• 
End of Study (EoS): Date of the last testing/reading 
released of the Human Biological Samples (HBS), related 
to primary and secondary endpoints. Study completion 
must be achieved no later than 8 months after LSLV. 
• 
Study groups: 
− 
Group MenB+PCV: rMenB+OMV NZ given 
concomitantly with PCV13 at 2, 4, 6, and 12 months of 
age. Either PCV13 or PCV20 is allowed to be given at 
12 months of age (Visit 5) for subjects who have not 
reached Visit 5 at the time this protocol amendment 8 
becomes effective. Subjects will also receive routine 
infant vaccines (DTPa-HBV-IPV, HRV, Hib, MMR, 
VV) at applicable timepoints.  
− 
Group Placebo+PCV: Placebo and PCV13 at 2, 4, 6, 
and 12 months of age. Either PCV13 or PCV20 is 
allowed to be given at 12 months of age (Visit 5) for 
subjects who have not reached Visit 5 at the time this 
protocol amendment 8 becomes effective. Subjects 
will also receive routine infant vaccines (DTPa-HBV-
IPV, HRV, Hib, MMR, VV) at applicable timepoints.  
Objectives 
Endpoints 
Primary Safety 
• 
To assess the safety and tolerability of 
rMenB+OMV NZ, PCV13 and other RIV when 
administered concomitantly to healthy infants at 
2, 4, 6 and 12 months of age, throughout the 
study duration. 
• 
The percentages of subjects with solicited local 
Adverse events (AEs) (administration site 
event) and systemic AEs during the 7 days 
(including the day of vaccination) after the 1st, the 
2nd, the 3rd and the 4th vaccination (Visits 1, 2, 3 
and 5). 
• 
The percentages of subjects with solicited 
systemic AEs of parotid/salivary gland swelling, 
fever and rash during the 30 days (including the 
day of vaccination) after the 4th vaccination (Visit 
5). 
• 
The percentages of subjects with all unsolicited 
AEs (including serious adverse events [SAEs], 
AEs leading to withdrawal, adverse event of 
special interest [AESIs], and medically attended 
AEs) during 30 days (including the day of 

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vaccination) after the 1st, the 2nd, the 3rd and the 
4th vaccination (Visits 1, 2, 3 and 5). 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs from study Day 1 (Visit 1) until 
study end (6 months or 12 months after last study 
vaccination, Visit 7¥). 
Co-Primary Immunogenicity 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4 and 6 months of age, at 
one month after the 3rd vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ at one month after the 3rd vaccination 
will be demonstrated if the adjusted lower confidence 
limit for the percentage of subjects achieving serum 
bactericidal assay using human complement (hSBA) 
titers ≥ Lower Limit of Quantitation (LLOQ) is ≥ 60% for 
the N. meningitidis serogroup B test strains M14459, 
96217, NZ98/254, M13520 (individually); and is ≥ 50% 
for all strains combined (composite endpoint). 
• 
At 1 month after the 3rd vaccination (Day 151): 
- 
the percentages of subjects with hSBA 
titers ≥LLOQ; for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
- 
the percentages of subjects with hSBA 
titers ≥LLOQ for all strains combined 
(composite endpoint). 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4, 6 and 12 months of age, at 
one month after the 4th vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ will be demonstrated if the adjusted 
lower confidence limit for the percentage of subjects 
with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) is ≥75% for the 
individual N. meningitidis serogroup B test strains and 
is ≥65% for all strains combined (composite endpoint). 
• 
At 1 month after the 4th vaccination (Day 331): 
- 
the percentages of subjects with hSBA 
titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) for 
each of the test strains. 
- 
the percentages of subjects with hSBA 
titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) for all 
strains combined (composite endpoint). 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4 and 6 months of age, compared to PCV13 
without rMenB+OMV NZ, at one month after the 
3rd vaccination. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the adjusted lower confidence 
limit for the between-group ratio of 
electrochemiluminescence (ECL) assay GMCs is >0.5 
for each of the 13 PCV13 antigens. 
• 
At 1 month after the 3rd vaccination (Day 151): 
- 
the ECL GMCs for each of the 13 PCV13 
antigens. 
Secondary Immunogenicity 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4, 6 and 12 months of age, compared to 
PCV13 and other RIV alone, at one month after 
the 4th vaccination. 
• 
At one month after the 4th vaccination (Day 331): 
− 
The ECL GMCs for each of the 13 PCV13 
antigens. 

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Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of 2-sided 95% CI 
for the between-group-ratio of ECL assay GMCs is >0.5 
for each of the 13 PCV13 antigens. 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
at 2, 4, 6 and 12 months of age compared to 
PCV13 and other RIV alone, at both one month 
after the 3rd and the 4th vaccinations. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of the 2-sided 
95% CI for the group differences in percentage of 
subjects with IgG ≥ 0.35 µg/mL is >-10% for each of 
the 13 PCV13 antigens at one month after both 3rd and 
4th vaccination. 
• 
At 1 month after the 3rd (Day 151) and the 4th 
vaccination (Day 331): 
− 
Percentages of subjects with serum 
pneumococcal anti-capsular 
polysaccharide IgG ≥0.35 μg/mL for each 
of the 13 PCV13 antigens. 
• 
To demonstrate the immunological non-inferiority 
of DTaP-HBV-IPV and Hib vaccines when 
administered concomitantly with rMenB+OMV NZ 
and PCV13 to healthy infants at 2, 4, and 6 
months compared to DTaP-HBV-IPV and Hib 
vaccines concomitantly administered with PCV13 
without rMenB+OMV NZ, in terms of D, T, PT, 
FHA, PRN, Hep B and Hib, at one month after 
the 3rd vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI for 
the between-group differences is greater than the pre-
specified margin† for each antigen at one month after 
3rd vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
GMCs against the 3 pertussis antigens 
(Pertussis toxin [PT], pertactin [PRN], 
filamentous hemagglutinin [FHA]). 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥10 mIU/mL. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations 
≥0.1 IU/mL. 
− 
Percentages of subjects with anti-PRP 
concentration ≥0.15 µg/mL and ≥1 µg/mL. 
• 
To demonstrate the immunological non-inferiority 
of MMR and VV vaccines when administered 
concomitantly with rMenB+OMV NZ and PCV13 
to healthy subjects at 12 months compared to 
MMR and VV vaccines concomitantly 
administered with PCV13, without rMenB+OMV 
NZ, at one month after vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI for 
the between-group ratio of GMCs is >0.67 at one 
month after the MMR and VV vaccinations. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
GMCs against measles, mumps, rubella 
and VZV antigens. 
• 
To evaluate the immune response to 
rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4, 6 and 12 months of age, at 
one month after the 3rd vaccination, at 6 months 
after the 3rd vaccination (immediately before the 
4th vaccination), and at one month after the 4th 
vaccination against the M14459, 96217, 
NZ98/254 and M13520 test strains. 
• 
At 1 month after the 3rd vaccination (Day 151) 
− 
the percentages of subjects with hSBA 
titers ≥5, ≥8 and ≥16 for each of the 
M14459, 96217, NZ98/254 and M13520 
test strains. 
− 
the hSBA geometric mean titers (GMTs) 
against each strain. 
• 
At 6 months after the 3rd vaccination (Day 301, 
immediately before the 4th vaccination): 

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− 
the percentages of subjects with hSBA 
titers ≥LLOQ for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
− 
the percentages of subjects with hSBA 
titers ≥5 and ≥8 for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
− 
the hSBA GMTs against each strain. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
the percentages of subjects with hSBA 
titers ≥LLOQ for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
− 
the percentages of subjects with hSBA 
titers ≥5 for each of the M14459, 96217, 
NZ98/254 and M13520 test strains. 
− 
the hSBA GMTs and geometric mean ratios 
(GMRs) over pre-4th vaccination against 
each strain. 
− 
the percentages of subjects with 4-fold rise* 
in hSBA titers (from pre-4th vaccination) for 
each of the M14459, 96217, NZ98/254 and 
M13520 test strains. 
• 
To evaluate immune responses to routine infant 
vaccines DTaP-HBV-IPV, Hib, MMR and VV 
vaccines when administered concomitantly with 
rMenB+OMV NZ and PCV13 to healthy infants at 
2, 4, 6 and 12 months of age, at one month after 
the 3rd vaccination, at 1 month after the 4th 
vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥100 mIU/mL. 
− 
Anti-HBsAg GMCs. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations ≥1 IU/mL. 
− 
Anti-diphtheria and anti-tetanus antibody 
GMCs. 
− 
Percentage of subjects with anti-polio type 
1, 2 and 3 neutralization antibody titers ≥8. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
Seroresponse, defined as post-vaccination 
anti-VZV virus, anti-measles virus, anti-
mumps virus and anti-rubella virus antibody 
concentration^ ≥ a protective threshold 
among subjects who were seronegative 
(antibody concentration <assay cut-off) 
before vaccination. 
^ A suitable ELISA assay for analysis of anti-VZV, anti-
measles virus, anti-mumps virus and anti-rubella virus 
antibody concentrations is yet to be selected and/or 
developed. 
* A 4-fold rise in hSBA titers is defined as 
- if pre-vaccination titer <Limit of Detection (LOD), then a post-vaccination titer ≥ 4 times the LOD or ≥ LLOQ, 
whichever is greater; 
- if pre-vaccination titer is ≥LOD but <LLOQ, then a post-vaccination titer ≥4 times the LLOQ;  
- if pre-vaccination titer is ≥LLOQ, then a post-vaccination titer ≥4 times the pre-vaccination titer, 

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where pre-vaccination titer=pre-4th dose titers (Day 301) 
† The endpoints and thresholds used for evaluation of the non-inferiority criteria for DTaP-HBV-IPV and Hib vaccines 
can be found in Table 21 and the thresholds and endpoint for evaluating the non-inferiority criteria for MMR and VV 
vaccines can be found in Table 22. 
¥ Visit 7 will occur either on Day 481 (for subjects who have not yet reached the 6-month follow-up after the last dose 
at the time protocol amendment 7 takes effect) or on Day 661 (for all other subjects). 
Note 1: To control the risk of erroneously concluding, a hierarchical procedure will be used for the multiple 
confirmatory study objectives, with the possibility to conclude on the study success based on the results of 
the co-primary objectives alone (refer to Section 9.5.3 for details). 
Note 2: In the context of this study, the following are considered as RIVs at different visits: 
Visit 1 and Visit 2: DTPa-HBV-IPV, HRV, Hib; 
Visit 3: DTPa-HBV-IPV, Hib; 
Visit 5: MMR and VV. 
Synopsis Table 1 
Study groups and epochs foreseen in the study  
Study Groups 
Number of 
subjects 
Age (Min – Max) 
Epochs 
Epoch 001  
Epoch 002 
Epoch 003 
MenB+PCV 
800 
6 weeks – 12 weeks 
x  
x  
x  
Placebo+PCV 
400 
6 weeks – 12 weeks 
x  
x 
x  
Synopsis Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Vaccine name 
Study Groups 
MenB+PCV  
Placebo+PCV  
Bexsero  
rMenB+OMV NZ 
X 
- 
Prevnar13 
PCV13* 
X 
X 
Prevnar20 
PCV20* 
X 
X 
Placebo 
NaCl 
- 
X 
Pediarix  
DTPa-HBV-IPV  
X 
X 
Rotarix 
HRV 
X 
X 
Hiberix  
Hib 
X 
X 
M-M-R II 
MMR  
X 
X 
Varivax  
VV 
X 
X 
Note: Subjects in both groups will receive a fourth dose of Hib vaccine (Hiberix) and a single dose of DTPa vaccine 
(Infanrix) as non-study vaccines at Visit 6. 
* Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
 
• 
Control: placebo control. 
• 
Vaccination schedule: Visit 1 (Day 1), Visit 2 (Day 61) 
Visit 3 (Day 121), Visit 5 (Day 301). 
 
• 
Treatment allocation: Subjects to be randomized in a 2:1 
ratio at Visit 1 (Day 1) to Group MenB+PCV and Group 
Placebo+PCV, respectively. 
• 
Blinding: observer-blind study.  

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Synopsis Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch 002  
observer-blind 
Epoch 003  
observer-blind 
 
• 
Sampling schedule: The sampling schedule for both 
study groups is the same. Three blood samples of 
approximately 5 mL each are to be taken at: 
− 
Visit 4 (Day 151), i.e., 30 (-9 to +30) days after the 
3rd vaccination. 
− 
Visit 5 (Day 301), i.e., 180 (-7 to +91) days after the 
3rd vaccination (pre-4th vaccination). 
− 
Visit 6 (Day 331), i.e., 30 (-9 to +30) days after the 
4th vaccination. 
• 
Type of study: self-contained. 
• 
Data collection: electronic case report form (eCRF). 
Solicited symptoms will be collected using a subject 
electronic Diary (eDiary).  
Number of subjects  
Target enrolment is 1200 subjects who will be randomly 
assigned to the 2 study groups in a 2:1 ratio. 

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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION .................................................................................................... 34 
1.1. 
Background ................................................................................................ 34 
1.2. 
Rationale for the study and study design .................................................... 36 
1.2.1. 
Rationale for the study ................................................................. 36 
1.2.2. 
Rationale for the study design ...................................................... 37 
1.2.3. 
Rationale for the use of placebo .................................................. 37 
1.2.4. 
Rationale for the use of non-study vaccines ................................. 37 
1.3. 
Benefit : Risk Assessment .......................................................................... 37 
1.3.1. 
Risk Assessment ......................................................................... 38 
Allergic reactions (including anaphylactic reactions) are listed in the 
Bexsero US PI. ........................................................................................... 38 
1.3.2. 
Benefit Assessment ..................................................................... 44 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 44 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................... 45 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 49 
4. 
STUDY COHORT ................................................................................................... 52 
4.1. 
Number of subjects/centers ........................................................................ 52 
4.2. 
Inclusion criteria for enrolment .................................................................... 52 
4.3. 
Exclusion criteria for enrolment ................................................................... 52 
5. 
CONDUCT OF THE STUDY .................................................................................. 54 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 54 
5.1.1. 
Responsibilities of the Investigator ............................................... 56 
5.1.2. 
Protocol Amendments.................................................................. 57 
5.2. 
Subject identification and randomization ..................................................... 57 
5.2.1. 
Subject identification .................................................................... 57 
5.2.2. 
Randomization of treatment ......................................................... 57 
5.2.2.1. 
Randomization of supplies .......................................... 57 
5.2.2.2. 
Treatment allocation to the subject ............................. 57 
5.2.2.2.1. 
Study group and treatment 
number allocation ................................... 57 
5.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 58 
5.2.3. 
Allocation of subjects to assay subsets ........................................ 59 
5.3. 
Method of blinding ...................................................................................... 59 
5.4. 
General study aspects ................................................................................ 60 
5.5. 
Outline of study procedures ........................................................................ 60 
5.6. 
Detailed description of study procedures .................................................... 65 
5.6.1. 
Data collected from subjects ........................................................ 65 
5.6.2. 
Pre-vaccination procedures (Visit 1) ............................................ 66 
5.6.3. 
Informed consent ......................................................................... 67 
5.6.4. 
Check inclusion and exclusion criteria ......................................... 67 
5.6.5. 
Collect demographic data ............................................................ 67 
5.6.6. 
Medical history ............................................................................. 67 

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5.6.7. 
Physical examination ................................................................... 68 
5.6.8. 
Check contraindications, warnings and precautions to 
vaccination ................................................................................... 68 
5.6.9. 
Assess pre-vaccination body temperature ................................... 68 
5.6.10. 
Study group and treatment number allocation .............................. 68 
5.6.11. 
Sampling...................................................................................... 68 
5.6.11.1. Blood sampling for immune response 
assessments .............................................................. 69 
5.6.12. 
Study vaccines administration ...................................................... 69 
5.6.13. 
Post-vaccination procedures ........................................................ 70 
5.6.14. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions .................................................... 71 
5.6.14.1. Follow-up safety clinic visit ......................................... 71 
5.6.15. 
Study procedures during special circumstances .......................... 72 
5.6.16. 
Recording of AEs, SAEs and AESIs ............................................ 72 
5.6.16.1. Subject Diary .............................................................. 72 
5.6.16.1.1. Subject diary alerts ................................. 74 
5.6.16.2. Safety follow-up calls .................................................. 74 
5.6.17. 
Study conclusion .......................................................................... 75 
5.7. 
Biological sample handling and analysis ..................................................... 76 
5.7.1. 
Use of specified study materials .................................................. 77 
5.7.2. 
Biological samples ....................................................................... 78 
5.7.3. 
Laboratory assays ....................................................................... 78 
5.7.4. 
Biological samples evaluation ...................................................... 81 
5.7.4.1. 
Immunological read-outs ............................................ 81 
5.7.5. 
Immunological correlates of protection ......................................... 83 
6. 
STUDY VACCINES AND ADMINISTRATION ........................................................ 84 
6.1. 
Description of study vaccines ...................................................................... 84 
6.1.1. 
Study vaccines ............................................................................ 84 
6.1.2. 
Non-study vaccines ..................................................................... 87 
6.2. 
Storage and handling of study and non-study vaccines .............................. 88 
6.3. 
Dosage and administration of study vaccines ............................................. 90 
6.4. 
Replacement of unusable vaccine doses .................................................... 92 
6.5. 
Contraindications to subsequent vaccination .............................................. 92 
6.6. 
Warnings and precautions .......................................................................... 93 
6.7. 
Concomitant medications/products and concomitant vaccinations .............. 93 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 93 
6.7.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 94 
6.8. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 95 
7. 
SAFETY ................................................................................................................. 95 
7.1. 
Safety definitions ........................................................................................ 95 
7.1.1. 
Definition of an adverse event ...................................................... 95 
7.1.2. 
Definition of a serious adverse event ........................................... 96 
7.1.3. 
Solicited adverse events .............................................................. 97 
7.1.3.1. 
Solicited local adverse events (administration 
site event) ................................................................... 97 
7.1.3.2. 
Solicited systemic adverse events .............................. 97 

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7.1.3.3. 
Other solicited adverse events ................................... 98 
7.1.4. 
Unsolicited Adverse Events ......................................................... 98 
7.1.5. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 99 
7.1.6. 
Adverse events of special interest................................................ 99 
7.1.6.1. 
Febrile seizures .......................................................... 99 
7.1.6.2. 
Arthritis ..................................................................... 100 
7.1.6.3. 
Potential immune-mediated diseases ....................... 100 
7.2. 
Detecting and recording adverse events and serious adverse 
events ....................................................................................................... 102 
7.2.1. 
Time period for detecting and recording adverse events 
and serious adverse events ....................................................... 102 
7.2.2. 
Post-Study adverse events and serious adverse events ............ 106 
7.2.3. 
Evaluation of adverse events and serious adverse events ......... 106 
7.2.3.1. 
Active questioning to detect adverse events 
and serious adverse events ...................................... 106 
7.2.3.2. 
Assessment of adverse events ................................. 106 
7.2.3.2.1. 
Assessment of intensity ........................ 106 
7.2.3.2.2. 
Assessment of causality ....................... 108 
7.2.3.3. 
Assessment of outcomes.......................................... 109 
7.2.3.4. 
Medically attended visits ........................................... 109 
7.2.4. 
Recording of AEs related to COVID-19 ...................................... 110 
7.2.4.1. 
WHO Case Definition ............................................... 110 
7.3. 
Reporting of serious adverse events and other events.............................. 111 
7.3.1. 
Prompt reporting of serious adverse events and other 
events to GSK Biologicals .......................................................... 111 
7.3.2. 
Contact information for reporting serious adverse events 
and AESIs .................................................................................. 111 
7.3.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................. 112 
7.3.3.1. 
Back-up system in case the electronic 
reporting system does not work ................................ 112 
7.3.4. 
Reporting of AESIs to GSK Biologicals ...................................... 112 
7.3.5. 
Updating of SAE and AESI information after removal of 
write access to the subject’s eCRF ............................................ 113 
7.3.6. 
Regulatory reporting requirements for serious adverse 
events ........................................................................................ 113 
7.4. 
Follow-up of adverse events and serious adverse events ......................... 113 
7.4.1. 
Follow-up of adverse events and serious adverse events .......... 113 
7.4.1.1. 
Follow-up during the study ........................................ 113 
7.4.1.2. 
Follow-up after the subject is discharged from 
the study ................................................................... 114 
7.5. 
Treatment of adverse events .................................................................... 114 
7.6. 
Unblinding ................................................................................................. 114 
7.7. 
Emergency unblinding .............................................................................. 114 
7.8. 
Subject card .............................................................................................. 115 
7.9. 
Medical device deficiencies ...................................................................... 115 
7.9.1. 
Detection, follow-up and prompt reporting of medical 
device deficiency ....................................................................... 115 
7.9.2. 
Regulatory reporting of medical device deficiency when 
used as combination product ..................................................... 116 

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8. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................... 116 
8.1. 
Subject completion ................................................................................... 116 
8.2. 
Subject withdrawal .................................................................................... 116 
8.2.1. 
Subject withdrawal from the study ............................................. 116 
8.2.2. 
Subject withdrawal from study vaccine(s) .................................. 119 
8.3. 
Screen and baseline failures ..................................................................... 119 
9. 
STATISTICAL METHODS .................................................................................... 119 
9.1. 
Determination of sample size .................................................................... 119 
9.2. 
Analysis Sets ............................................................................................ 124 
9.2.1. 
Enrolled Set ............................................................................... 124 
9.2.2. 
Exposed Set .............................................................................. 125 
9.2.3. 
Safety Sets ................................................................................ 125 
9.2.3.1. 
Solicited Safety Set (solicited local and 
systemic adverse events and other solicited 
adverse events) ........................................................ 125 
9.2.3.2. 
Unsolicited Safety Set (unsolicited adverse 
events) ..................................................................... 125 
9.2.4. 
Full Analysis Set (FAS) for Immunogenicity ............................... 125 
9.2.5. 
Per Protocol (PP) Set for Immunogenicity .................................. 125 
9.2.6. 
Other Analysis Sets ................................................................... 126 
9.2.7. 
Subgroups ................................................................................. 126 
9.3. 
Derived and transformed data ................................................................... 126 
9.4. 
Analysis of demographics ......................................................................... 127 
9.5. 
Analysis of immunogenicity ....................................................................... 127 
9.5.1. 
Within groups assessment ......................................................... 128 
9.5.2. 
Between groups assessment ..................................................... 128 
9.5.3. 
Analysis of Primary Immunogenicity Objectives ......................... 129 
9.5.3.1. 
Statistical Hypotheses .............................................. 129 
9.5.3.2. 
Statistical Methods ................................................... 130 
9.5.4. 
Analysis of Secondary Immunogenicity Objectives .................... 132 
9.5.4.1. 
Statistical Methods ................................................... 132 
9.6. 
Analysis of safety ...................................................................................... 133 
9.6.1. 
Within groups assessment ......................................................... 133 
9.6.1.1. 
Analysis of Solicited Adverse events ........................ 133 
9.6.1.2. 
Analysis of Unsolicited Adverse Events .................... 134 
9.6.2. 
Between groups assessment ..................................................... 134 
9.7. 
Interpretation of analyses .......................................................................... 135 
9.8. 
Conduct of analyses ................................................................................. 135 
9.8.1. 
Sequence of analyses................................................................ 135 
9.8.2. 
Statistical considerations for interim analyses ............................ 135 
10. ADMINISTRATIVE MATTERS ............................................................................. 135 
10.1. 
Electronic Case Report Form instructions ................................................. 135 
10.2. 
Subject Diary ............................................................................................ 136 
10.3. 
Study Monitoring by GSK Biologicals ........................................................ 137 
10.4. 
Record retention ....................................................................................... 137 
10.5. 
Quality assurance ..................................................................................... 138 
10.6. 
Definition of medical device AE, adverse device effect (ADE), 
serious adverse device effect (SADE) and unanticipated SADE 
(USADE) ................................................................................................... 138 

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10.6.1. 
Definition of medical device AE and adverse device effect 
(ADE) ......................................................................................... 138 
10.6.2. 
Definition of medical device SAE, SADE and USADE ................ 139 
10.6.3. 
Recording and reporting of medical device AE, ADEs, 
SADEs and USADE ................................................................... 139 
10.7. 
Posting of information on publicly available clinical trial registers and 
publication policy ...................................................................................... 140 
10.8. 
Provision of study results to investigators ................................................. 140 
10.9. 
Data Sharing ............................................................................................. 141 
11. COUNTRY SPECIFIC REQUIREMENTS ............................................................. 141 
12. REFERENCES ..................................................................................................... 142 

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LIST OF TABLES 
PAGE 
Table 1 
Study Groups and Epochs Foreseen in the Study .................................. 50 
Table 2 
Study Groups and Treatment Foreseen in the Study .............................. 50 
Table 3 
Overview of the Study Design: Blood Draws and Study vaccines ........... 51 
Table 4 
Blinding of Study Epochs ....................................................................... 51 
Table 5 
List of Study Procedures ........................................................................ 61 
Table 6 
Intervals Between Study Visits ............................................................... 65 
Table 7 
Humoral Immunity (Antibody determination) ........................................... 78 
Table 8 
Immunological Read-outs ....................................................................... 81 
Table 9 
Immunogenicity Subsets ........................................................................ 82 
Table 10 
Study Vaccines ...................................................................................... 85 
Table 11 
Dosage and Administration .................................................................... 91 
Table 12 
List of Potential Immune-Mediated Diseases ........................................ 100 
Table 13 
Reporting Periods for Collecting Safety Information ............................. 104 
Table 14 
Grading of Solicited Local Adverse Events (Administration Site 
Event) for All Subjects .......................................................................... 107 
Table 15 
Grading of Solicited Systemic Adverse Events for All Subjects ............ 107 
Table 16 
Timeframes for submitting serious adverse event and other 
events reports to GSK Biologicals ........................................................ 111 
Table 17 
Power to Show Non-Inferiority PCV13 Co-Primary Objective and 
Sufficiency rMenB+OMV NZ Co-Primary Objectives ............................ 120 
Table 18 
Two-sided 80% Upper Confidence Limit of Standard Deviations .......... 122 
Table 19 
GMTs at One Month Post 3rd Dose and GMRs at One Month 
Post 4th rMenB+OMV NZ Vaccination .................................................. 123 
Table 20 
Limits of Detection and Lower Limits of Quantitation for 
rMenB+OMV NZ strains ....................................................................... 123 
Table 21 
Non-inferiority to Each Individual Antigen (excluding polio 
antigens) in Pediarix and Hiberix, at One Month After 3rd Dose 
of rMenB+OMV NZ............................................................................... 124 

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Table 22 
Non-inferiority to Each Individual Antigen in MMR II and Varivax, 
at One Month After 4th Dose of rMenB+OMV NZ ................................. 124 
Table 23 
GSK Biologicals’ Laboratories .............................................................. 147 
Table 24 
Overview of the Study Design: Blood Draws and Study vaccines ......... 231 

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LIST OF FIGURES 
PAGE 
Figure 1 
Overview of Study Design – V72_57 ...................................................... 49 
Figure 2 
Testing Strategy for Three Families with Corresponding α 
Propagation .......................................................................................... 131 
 

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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ..................................................................... 144 
APPENDIX B CLINICAL LABORATORIES ................................................................ 147 
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 148 
 

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LIST OF ABBREVIATIONS 
ACIP:  
Advisory Committee on Immunization Practices  
ADEM: 
Acute disseminated encephalomyelitis 
AE: 
Adverse Event 
AESI: 
Adverse Event of Special Interest 
ANOVA: 
Analysis of Variance 
CBER:  
Center for Biologics Evaluation and Research  
CDC: 
Centers for Disease Control 
CFS  
Chronic fatigue syndrome  
CI: 
Confidence Interval 
CLIA: 
ChemiLuminescence ImmunoAssay 
CLS: 
Clinical Laboratory Sciences 
COVID-19 
Coronavirus Disease 2019 
CRO: 
Contract Research Organization 
DTPa-HBV-IPV: 
Diphtheria, Tetanus, acellular Pertussis, Haemophilus influenzae 
type b, inactivated Poliovirus combined vaccine 
ECDC: 
European Center for Disease Prevention and Control 
ECL: 
Electrochemiluminescence 
eCRF: 
electronic Case Report Form 
EoS: 
End of Study 
FAS: 
Full Analysis Set 
FDA: 
Food and Drug Administration, United States of America 
FHA: 
Filamentous hemagglutinin 
fHbp: 
Factor H binding protein 
GBS: 
Guillain-Barre Syndrome  
GCP: 
Good Clinical Practice 
GDS: 
Global Data Sheet 
GMC: 
Geometric Mean Concentration 
GMR: 
Geometric Mean Ratio 
GMT: 
Geometric Mean Titer 
GSK: 
GlaxoSmithKline 
HBV: 
Hepatitis B (recombinant)vaccine 
HBS: 
Human Biological Samples  
Hib: 
Haemophilus influenzae type b conjugate vaccine 
HIPAA: 
Health Insurance Portability and Accountability Act 
HRV: 
Human rotavirus vaccine (2-dose regimen) 
hSBA: 
Human Serum Bactericidal Assay 
IB: 
Investigator Brochure 
iPSP 
initial Pediatric Study Plan  
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonization 
ID: 
Identification (Subject ID), Intradermal  
IEC: 
Independent Ethics Committee 
IM: 
Intramuscular 

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IMD: 
Invasive meningococcal disease 
IMP: 
Investigational Medicinal Product 
IND: 
Investigational New Drug 
IPV: 
Inactivated poliovirus vaccine 
IRB: 
Institutional Review Board 
IU: 
International Unit 
JIA: 
Juvenile Idiopathic Arthritis 
LAR: 
Legally Acceptable Representative 
LLOQ: 
Lower Limit of Quantitation 
LOD: 
Lower Limit of Detection 
LSLV: 
Last Subject Last Visit 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mL: 
Milliliter 
MMR: 
Measles, Mumps, Rubella vaccine 
NadA: 
Neisseria adhesin A  
NHBA: 
Neisserial Heparin Binding Antigen  
NIMP: 
Non-investigational medicinal product 
OMV: 
Outer Membrane Vesicles 
PCD: 
Primary Completion Date 
PCV13: 
13-valent Pneumococcal Conjugate Vaccine 
PCV20: 
20-valent Pneumococcal Conjugate Vaccine 
pIMD: 
Potential Immune-Mediated Disease 
PorA: 
Porin Protein A 
PPS: 
Per Protocol Set 
PRN: 
Pertactin 
PT: 
Pertussis toxin 
RIV: 
Routine Infant Vaccines  
rMenB+ 
OMV NZ: 
Recombinant Meningococcal B with Outer Membrane Vesicle 
derived from Neisseria meningitidis serogroup B strain NZ98/254 
(New Zealand strain) Vaccine 
SAE: 
Serious Adverse Event 
SBIR: 
Source Database for Internet Randomization 
SD: 
Standard Deviation 
SDA: 
Source Documentation Agreement Form 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SMQ 
Standard MedDRA Query 
SOC: 
System Organ Class 
SPM: 
Study Procedures Manual 
SRT: 
Safety Review Team 
VV: 
Varicella vaccine 
WHO: 
World Health Organization 

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GLOSSARY OF TERMS 
Adverse Event of Special 
Interest:  
Adverse events of special interest (AESIs): are 
predefined (serious or non-serious) adverse events of 
scientific and medical concern specific to the product or 
program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be 
appropriate, because such an event might warrant further 
investigation in order to characterize and understand it. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered 
related to the medicinal product.  
An adverse event (AE) can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal 
product. For marketed medicinal products, this also 
includes failure to produce expected benefits (i.e. lack of 
efficacy), abuse or misuse. 
Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
trial, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. In an observer-blind study, the subject and the site 
and sponsor personnel involved in the clinical evaluation 
of the subjects are blinded while other study personnel 
may be aware of the treatment assignment (see Section 
5.2.3 for details on observer-blinded studies). 
Child in care: 
A child who has been placed under the control or 
protection of an agency, organization, institution or 
entity by the courts, the government or a government 
body, acting in accordance with powers conferred on 
them by law or regulation. The definition of a child in 
care can include a child cared for by foster parents or 
living in a care home or institution, provided that the 
arrangement falls within the definition above. The 
definition of a child in care does not include a child who 
is adopted or has an appointed legal guardian. 

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Co-administered 
(concomitant) products 
A product given to clinical trial participants as 
required in the protocol as part of their standard care 
for a condition which is not the indication for which 
the IMP is being tested and is therefore not part of the 
objective of the study. 
Combination product: 
Combination product comprises any combination of  
− 
drug  
− 
device  
− 
biological product  
Each drug, device and biological product included 
in a combination product is a constituent part. 
Comparator 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study:  
(Synonym of End of Trial) 
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).  
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV. 
Enrolled: 
All screened subjects who provide informed consent and 
provide demographic and/or baseline screening 
assessments and are randomized and have received a 
Subject ID, regardless of the subject’s treatment status in 
the study. 

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Epoch: 
An epoch is a set of consecutive time points or a single 
time point from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data 
collected at the time points included in an epoch must be 
sufficient to fulfill the purpose of the epoch. 
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety. 
Immunological correlate 
of protection: 
The defined immune response above which there is a 
high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the 
infectious agent. 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorised form, 
or when used for an unauthorised indication, or when 
used to gain further information about the authorised 
form. 
Legally acceptable 
representative: 
(The terms legal 
representative or legally 
authorized representative 
are used in some settings) 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject’s participation in the clinical trial. 
Medically attended 
adverse events: 
Symptoms or illnesses requiring hospitalization, or 
emergency room visit, or tele visit or visit to/by a health 
care provider.  
Medical device deficiency: 
 
A device deficiency is an inadequacy of a medical 
device with respect to its identity, quality, durability, 
reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors and information 
supplied by the manufacturer. 

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Non-study Vaccine: 
A vaccine which will be given to subjects during the 
study, but does not have associated study objectives. 
Non-study vaccines are Non-Investigational Medicinal 
Products (NIMPs). 
Observer-blind: 
The subject, site and Sponsor personnel involved in the 
evaluation of the subjects are blinded while other study 
personnel (unblinded staff) may be aware of the 
treatment allocation. 
Placebo 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Potential Immune-
Mediated Disease: 
Potential immune-mediated diseases (pIMDs) are a 
subset of AEs that include autoimmune diseases and 
other inflammatory and/or neurologic disorders of 
interest which may or may not have an autoimmune 
aetiology. 
Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated. 
Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.  
Protocol amendment: 
The International Conference on Harmonization (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of 
subjects, scope of the investigation, study design, or 
scientific integrity of the study. 
Protocol violation 
(deviation): 
A protocol deviation is any change, divergence, or 
departure from the study design or procedures of a study 
protocol. In general, subjects associated with protocol 
deviations may remain in the study unless continuation 
in the study jeopardizes the subject’s health, safety, or 
rights. 
Qualified health care 
professional: 
Any licensed or certified health care professional who is 
permitted by institutional policy to perform protocol 
required procedures, and who is identified within the 
Study Staff Signature Log.  

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Randomization: 
Process of random attribution of treatment/schedule to 
subjects in order to reduce bias of selection. 
Routine infant vaccines: 
Certain routine infant vaccines that are part of the 
recommended schedule. In the context of this study, the 
following are considered as RIVs, based on the 
recommended infant childhood vaccination schedule by 
the Advisory Committee on Immunization Practices 
(ACIP) and on the different study visits: 
• 
Visit 1 and Visit 2: DTPa-HBV-IPV, HRV, Hib. 
• 
Visit 3: DTPa-HBV-IPV, Hib. 
• 
Visit 5: MMR, VV. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Site Monitor: 
An individual assigned by the sponsor who is 
responsible for assuring proper conduct of clinical 
studies at one or more investigational sites. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period. 
Study vaccine/product: 
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/ product /placebo as a 
reference or administered concomitantly, in a clinical 
trial that evaluates the use of an investigational 
vaccine/product. Study vaccines are Investigational 
Medicinal Products (IMPs). 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient 
of the vaccines or as a control. 
Subset  
(Synonym of 
Immunosubset): 
Selection of blood samples among all blood sample 
collected at given time point(s) for testing by specific 
assay 
Treatment number: 
A unique number identifying a treatment to a subject, 
according to treatment allocation. 

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Treatment: 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
Unblinded site staff: 
Study personnel aware of the subject treatment 
allocation, delegated for administering study vaccines to 
subjects but not involved in the safety or 
immunogenicity evaluation of the subjects. 
All study vaccines will be administered only by 
unblinded personnel who are qualified to perform that 
function under applicable laws and regulations for the 
specific study site. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 

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TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the protocol (including the synopsis), the names of the vaccines will 
be written without the superscript symbol ™ or ® and in italics. 
Trademarks of the GSK group of companies 
 
Generic description 
Bexsero  
 
Meningococcal group B vaccine (rDNA, component, 
adsorbed) 
Hiberix  
 
Haemophilus influenzae type b (Hib) conjugate vaccine 
(tetanus toxoid, conjugate) 
Infanrix 
 
Diphtheria, Tetanus Toxoids and Acellular Pertussis 
Adsorbed Vaccine 
Pediarix 
 
Diphtheria, Tetanus Toxoids and Acellular Pertussis 
Adsorbed, Hepatitis B and Inactivated Poliovirus Vaccine 
Rotarix 
 
Rotavirus vaccine, live, oral 
 
Trademarks not owned by the GSK group of 
companies 
 
Generic description 
M-M-R II (Merck & Co., Inc.) 
 
Measles, Mumps and Rubella Virus Vaccine Live 
Prevnar 13 (Wyeth Pharmaceuticals Inc./Pfizer 
Inc.) 
 
Pneumococcal polysaccharide conjugate vaccine (13-
valent, adsorbed) 
Prevnar 20 (Wyeth Pharmaceuticals Inc./Pfizer 
Inc.) 
 
Pneumococcal polysaccharide conjugate vaccine 
(20-valent, adsorbed) 
Varivax (Merck & Co., Inc.) 
 
Varicella Virus Vaccine Live 

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1. 
INTRODUCTION 
1.1. 
Background 
Invasive meningococcal disease occurs when the normally asymptomatically carried 
bacterium Neisseria meningitidis enters the bloodstream, multiplies and causes sepsis. If 
the bacteria cross the blood–brain barrier, meningitis occurs [Khatami, 2010]. 
Invasive meningococcal disease occurs worldwide. Although incidence varies in different 
regions of the world, infants, children and adolescents are the most vulnerable to 
developing invasive disease. Symptoms of the disease occur rapidly and often result in 
severe outcomes within a few hours; otherwise healthy individuals can be permanently 
disabled or disfigured or die of the disease. Despite the availability of medical treatment 
and effective antibiotics for invasive meningococcal disease, approximately 9% of 
European patients die, with case-fatality rates generally increasing with age [ECDC, 2016]. 
In the United States (US), the overall case-fatality ratio remains at 10%–15%, and 11%–
19% of survivors have long-term sequelae [Cohn, 2013]. 
No reliable estimates of the global burden of disease are currently available as case 
definitions differ and surveillance data from many regions are incomplete [WHO, 2011]. 
The overall incidence of confirmed invasive meningococcal diseases (IMDs) in European 
countries in 2012 ranged from 0.11 to 1.77 cases per 100,000 populations [ECDC, 2016]. 
In the US, the incidence was 0.18 cases per 100 000 population in 2014 [Adams, 2016]. 
Currently, 13 serogroups of pathogenic N. meningitidis [Harrison, 2013] are known to 
exist; however, virtually all meningococcal meningitis and septicemia are caused by only 
six serogroups: (i.e. A, B, C, W, Y and X). The introduction of conjugate serogroup C 
meningococcal vaccines has dramatically changed the epidemiology of the disease in 
industrialized nations, showing potential for broader control with A, C, Y and W 
conjugates, and leaving serogroup B as the predominant cause of disease. Development of 
vaccines for prevention of serogroup B disease in industrialized nations and serogroup A 
conjugate vaccines for Africa could lead to global control of meningococcal disease 
[Khatami, 2010].  
For the US, the 2015 Centers for Disease Control (CDC) data indicate a total of 370 cases 
and 60 deaths attributable to meningococcal disease, with the majority of these caused by 
serogroup B, C and Y infections [Cohn, 2013; CDC, 2015a]. In Europe, the incidence of 
disease due to serogroup B is particularly high in Ireland, the United Kingdom (UK), 
Denmark and Spain. These same countries had early introduction of Meningococcal 
serogroup C vaccination after high incidences of serogroup C infections in the late 1990s 
[ECDC, 2016]. 
In Europe, the majority of disease occurs in infants under 1 year of age, followed by 
children from 1 through 5 years of life. A second peak occurs in adolescents 15 to 19 
years of age. In the US, incidence of meningococcal disease peaks in three age groups: 
infants and children aged <5 years, adolescents and young adults aged 16 through 21 
years, and adults aged ≥65 years. Approximately 60% of disease in the first year of life is 
caused by serogroup B [Cohn, 2013]. 

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Capsular polysaccharide vaccines have been used successfully in preventing disease and 
limiting epidemics and outbreaks caused by meningococcal serogroups A, C, W and Y. 
However the capsular polysaccharide of meningococcal serogroup B is poorly 
immunogenic in humans, possibly due to similarities in serogroup B carbohydrate 
moieties to carbohydrates widely distributed in the human body. As a result, research has 
focused on proteins in the outer membrane of meningococci as potential antigens for 
candidate vaccines. Serogroup B vaccines based on protein-containing outer membrane 
vesicles (OMV) have been safe and effective in controlling epidemic disease caused by 
strains homologous to the vaccine strain in Cuba, Brazil, Chile, Norway, and New 
Zealand. The use of these OMV vaccines to combat serogroup B meningococcal disease 
has been limited, however, due to the strain-specific nature of the protection and the lack 
of consistent efficacy in young children.  
The knowledge gained during vaccine development for the Norwegian (MenBvac) and 
New Zealand (MeNZB) epidemics, together with the identification of the N. meningitidis 
serogroup B genome sequence, was used to develop GSK serogroup B meningococcal 
vaccine (rMenB+OMV NZ). The availability of the bacterial genome sequence allowed 
identification of conserved surface-exposed outer membrane proteins of serogroup B 
strains that were targets for bactericidal antibodies [Pizza, 2000]. 
The current vaccine formulation (referred to as rMenB+OMV NZ, i.e., GSK recombinant 
Meningococcal B vaccine with the OMV derived from New Zealand strain) is based on 
three proteins: i) factor H binding protein (fHbp), ii) Neisseria adhesin A (NadA) and iii) 
Neisserial Heparin Binding Antigen (NHBA) or 287. The fHbp protein has been 
combined with the accessory protein GNA2091 (936), and the 287 protein has been 
combined with GNA1030 (953), to create two fusion proteins. In addition the vaccine 
also contains OMV derived from the New Zealand epidemic strain. 
On 23 January 2015, the US Food and Drug Administration (FDA) approved a biologics 
licence application for GSK meningococcal group B vaccine according to the regulations 
for accelerated approval; the vaccine was approved for use in individuals 10 through 25 
years of age. As part of the approval, the present study V72_57 (205239) meets the 
requirement for a pediatric study under the Pediatric Research Equity Act to evaluate the 
safety and immunogenicity of GSK meningococcal group B vaccine in North American 
infants 6 weeks through 12 months of age for the prevention of invasive group B 
meningococcal disease. 
Previous data from clinical studies conducted largely in Europe and Latin America in 
several age groups showed that rMenB+OMV NZ is generally well tolerated and 
immunogenic. These studies formed the basis of the marketing authorizations in the 
European Union (EU), Canada and Australia and other countries in individuals over 2 
months of age.  
The rMenB+OMV vaccine has shown to generate robust antibody responses in pediatric 
populations, even when administered concomitantly with other routine infant vaccines. 
Concomitant administration of rMenB+OMV NZ was shown not to interfere with the 
immune response to the following vaccine antigens, either as monovalent or as 
combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae 

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type b, inactivated poliomyelitis, hepatitis B, measles, mumps, rubella, varicella and 7-
valent pneumococcal conjugate vaccine. Overall, data from these studies demonstrated 
that the immune responses of the co-administered routine vaccines were unaffected by 
concomitant administration of rMenB+OMV NZ, based on non-inferior antibody 
response rates to the routine vaccines given alone. 
The use of rMenB+OMV NZ in infants was associated with frequent reports of 
reactogenicity and especially of local reactions, although most were of mild or moderate 
severity and transient. Consistent with the extensive safety data collected in the 
vaccination campaigns with other OMV-based vaccines, increased rates of fever were 
associated with rMenB+OMV NZ vaccination in the infant population, especially when 
given concomitantly with routine vaccines. As the fever resolved soon after vaccination 
and these higher rates were not associated with an increase in medically attended adverse 
events (AEs) or an increase in febrile seizure risk, these data overall supported giving 
rMenB+OMV NZ either concomitantly with or without routine pediatric vaccines. 
Additionally, the use of prophylactic acetaminophen (paracetamol) given at the time of 
vaccination and/or closely thereafter has shown to decrease fever and reactogenicity in 
infants, without interfering with the antibody response to rMenB+OMV NZ, nor to the 
concomitantly administered routine vaccines (DTPa-HBV-IPV/Hib and PCV7) [Prymula, 
2014]. 
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of rMenB+OMV NZ 
(Bexsero). 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study  
As part of the US FDA’s approval of a biologics license application for GSK 
meningococcal group B vaccine (rMenB+OMV NZ, Bexsero), a pediatric study under the 
Pediatric Research Equity Act was required to evaluate the safety and immunogenicity of 
GSK meningococcal group B vaccine, Bexsero in North American infants 6 weeks 
through 12 months of age. 
Previous clinical studies conducted in Europe and other countries worldwide have shown 
that rMenB+OMV NZ demonstrated a robust immune response in all age groups against 
strains H44/76 (fHbp), 5/99 (NadA), NZ98/254 (PorA P1.4) and M10713 (NHBA) and 
that the concomitant administration of rMenB+OMV NZ did not interfere with response 
to the vaccine antigens present in routinely administered infant vaccines. However, no 
data on the concomitant use of rMenB+OMV NZ with PCV13 and routine infant 
vaccines in North American infants is currently available.  
The 3 strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4) in addition to 
M13520 (NHBA) strain are considered by the Center for Biologics Evaluation and 
Research (CBER) to better evaluate the protective response of the vaccine. 

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The purpose of this study therefore is to assess the immune responses against those 
strains and the safety of the rMenB+OMV NZ vaccine when administered concomitantly 
with the 13-valent pneumococcal conjugate vaccine (PCV13) and with other US 
Advisory Committee on Immunization Practices (ACIP) recommended routine infant 
vaccines (RIV). The study will also assess the safety and the immunogenicity of the 
PCV13 vaccine when concomitantly administered with rMenB+OMV NZ and RIV, 
compared to PCV13 administered with a placebo and RIV. In addition, the safety and 
immunogenicity of RIV (Pediarix, Hiberix, Rotarix, M-M-R II, Varivax) will be assessed 
following administration with rMenB+OMV NZ and/or PCV13. 
1.2.2. 
Rationale for the study design 
The parallel group study design was selected to allow an assessment of the immune 
responses and safety of the rMenB+OMV NZ and PCV13 vaccines when co-
administered, along with other RIV. 
1.2.3. 
Rationale for the use of placebo  
For this study, a placebo (saline solution) will be administered concomitantly with the 
PCV13 vaccine to subjects in Group Placebo+PCV. As all other vaccines recommended 
for this age group have been included as study vaccines, a placebo is the only available 
option to minimize possible introduction of reporting bias in collecting information about 
AEs and to ensure the same number of vaccinations are administered to subjects assigned 
to either of the 2 study groups.  
1.2.4. 
Rationale for the use of non-study vaccines 
In order to ease the disruption to the standard infant vaccine schedule caused by 
participating to the study, GSK will provide all subjects the following standardized non-
study vaccines at 13 months of age (Visit 6): 
• 
Diphtheria, tetanus toxoids and acellular pertussis adsorbed vaccine (DTPa, Infanrix) 
• 
Haemophilus influenzae type b Conjugate vaccine (Hib, Hiberix). 
1.3. 
Benefit : Risk Assessment 
Please refer to the Prescribing Information [BEXSERO; 2023] for information regarding 
the summary potential risks and benefits of Bexsero.  
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:  

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1.3.1. 
Risk Assessment 
Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
IMP: Bexsero 
Important identified risk: 
Fever 
Fever may occur following vaccination. 
Fever is listed in the Bexsero US Product 
Information (PI). 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and the eCRF (see 
Section 6.7.1). 
Important potential risks : 
Guillain-Barre 
Syndrome (GBS) 
 
GBS has been observed with other 
vaccines. No cases have been observed 
during the Bexsero clinical development 
program. 
The potential risk of events of possible 
autoimmune aetiology that might occur 
is mentioned in the Informed Consent 
Form (ICF). GBS will be monitored 
through the potential immune-mediated 
diseases (pIMDs) collection. 
Important potential risk:  
Acute disseminated 
encephalomyelitis 
(ADEM) 
ADEM has been observed with other 
vaccines. No cases have been reported 
during the Bexsero clinical development 
program.  
The potential risk of events of possible 
autoimmune aetiology that might occur 
is mentioned in the ICF. ADEM will be 
monitored through the pIMDs collection. 
Important potential risk: 
Anaphylaxis and 
anaphylactic shock 
No cases of anaphylaxis related to Bexsero 
have been reported in the Bexsero clinical 
development program. However, one 
related case of anaphylaxis within 30 
minutes post-vaccination was reported in a 
third party expanded access program 
(V72_70TP). 
Allergic reactions (including anaphylactic 
reactions) are listed in the Bexsero US PI. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis 
(see Section 5.6.12). 
Important potential risk: 
Vasculitis/Kawasaki 
Disease (KD) 
There were some cases of suspected KD 
reported in subjects receiving Bexsero in 
four clinical studies, all recovered 
completely. The occurrence of the cases in 
Bexsero studies is consistent with the 
known epidemiology of KD in terms of 
geographic and temporal clustering, and 
seasonal variation. As the exposure in 
clinical trial of subject was limited 
considering the incidence of the disease, 
KD is considered as a potential risk. 
The potential risk of events of possible 
autoimmune aetiology that might occur 
is mentioned in the ICF. KD and 
vasculitis will be monitored through the 
pIMDs collection. 
Important potential risk: 
Seizure including 
Febrile Seizure 
Cases of seizure, including febrile seizure, 
have been reported during the Bexsero 
clinical development program and from the 
post-marketing experience. Seizures 
(including febrile seizures) are listed (see 
US PI). 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1. Seizures will 
be monitored through the adverse event 
of special interest (AESI) collection. 

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important potential risk: 
Arthritis 
Attenuated live virus vaccines (rubella) 
were reported to be associated with joint-
related diseases [Tingle, 1986]. Among 
inactivated vaccines, different 
manifestations of arthritis following hepatitis 
B vaccination (psoriatic arthritis, reactive 
arthritis, etc.) were described [IOM, 2011]; 
however no association with meningococcal 
vaccines has been reported in the literature. 
One clinical case of juvenile idiopathic 
arthritis (JIA) possibly related to 
rMenB+OMV NZ and 6 spontaneous 
reports considered to have a possible 
causal relationship have been observed. 
Arthritis will be monitored through the 
AESI collection. 
IMP: Prevnar13* and Prevnar20* 
Hypersensitivity and 
anaphylaxis 
Hypersensitivity including anaphylaxis to 
one or several components of the vaccine 
can rarely occur. 
Hypersensitivity reaction including face 
oedema, dyspnea, bronchospasm is listed 
in the clinical trial section of Prevnar13 US 
PI as well as anaphylactic /anaphylactoid 
reaction including shock is a listed adverse 
reaction from the post-marketing 
experience. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). The 
subjects will be observed closely for at 
least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12).  
Seizures (including 
febrile seizures) 
The febrile convulsion is a risk for the infant 
and toddler groups. Seizures (including 
febrile seizures) are listed adverse 
reactions in the clinical trial section of 
Prevnar13 US PI. 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1. Seizure will 
be monitored through the AESI 
collection.  
Fever 
Fever may occur following vaccination. 
Fever is listed in the Prevnar13 and 
Prevnar20 US PI. 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination e study (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and in the eCRF (see 
Section 6.7.1). 
Erythema multiforme 
Erythema multiforme is listed in the post-
marketing section of the Prevnar13 US PI. 
No specific mitigation in this study: SAE 
collection is part of the study protocol. 
IMP: Pediarix 
Important identified risk: 
Hypersensitivity 
People may develop allergic reactions to 
any type of vaccine and/or its components. 
Hypersensitivity reactions to vaccines highly 
vary in severity, ranging from mild to 
potentially life-threatening hypersensitivity 
reactions. Severe allergic reactions to 
vaccines are rare but tend to occur within 
hours after vaccination. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12). 

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important identified risk: 
Temperature of ≥ 40.0° 
C 
In rare occasion, hyperpyrexia above 
40.0°C may occur after vaccination, 
particularly associated with booster 
vaccination. 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and in the eCRF (see 
Section 6.7.1).  
Important identified 
risk: Hypotonic-
hyporesponsive 
episode (HHE) 
HHE occurs more commonly in early 
childhood after primary vaccination and 
particularly after the first dose of vaccine. 
Most HHE events have been associated 
with whole cell pertussis-containing 
vaccines (36-250 episodes per 100,000 
doses). A much lower rate of HHE has been 
observed following vaccination with 
acellular pertussis vaccine (4-140 episodes 
per 100,000 doses). 
Collapse or shock-like state (hypotonic-
hyporesponsive episode) within 48 
hours of vaccination is a 
contraindication to further administration 
of Pediarix (see US PI). 
Important identified risk: 
Apnoea in infants born 
prematurely 
Apnoea of prematurity is due to immaturity 
of the neurological and respiratory system 
in premature infants. The risk appears to be 
related to the degree of prematurity of the 
infant. 
Only subjects born full-term (i.e. after a 
gestation period of ≥ 38 weeks) will be 
enrolled (see Section 4.2). 
Important identified risk: 
Convulsions with or 
without fever, 
occurring within 3 days 
Seizures occurring soon after immunization 
are mostly triggered by fever induced by the 
vaccine or are not vaccine related. Febrile 
convulsions usually occur in individuals 
aged between 3 months and 6 years with a 
peak incidence at 18 months. 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1. Seizure will 
be monitored through the AESI 
collection.  
Important potential risk: 
Encephalopathy 
Reports of encephalopathy were received 
with previous whole cell pertussis vaccines. 
Encephalopathy (e.g., coma, decreased 
level of consciousness, prolonged 
seizures) within 7 days of administration 
of a previous dose of a pertussis -
containing vaccine that is not 
attributable to another identifiable cause 
is a contraindication to administration of 
any pertussis-containing vaccine, 
including Pediarix (see US PI). 
IMP: Hiberix 
Important identified risk: 
Apnoea in premature 
infants 
 
No case observed in the Hiberix clinical 
development programme. The risk is listed 
in the US PI. The apnoea is due to the 
immaturity of the neurological and 
respiratory systems in premature infants 
and appears to be related to the degree of 
prematurity. The mechanism by which 
immunization may result in apnoea in 
premature infants remains unknown. 
Only subjects born full-term (i.e. after a 
gestation period of ≥ 38 weeks) will be 
enrolled (see Section 4.2). 

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important identified risk: 
Allergic reactions 
(including anaphylactic 
and anaphylactoid 
reactions) 
No case of anaphylaxis was observed in the 
Hiberix clinical development programme. 
The risk is listed in the US PI. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12).  
Important identified risk: 
Angioedema 
See allergic reactions above 
See allergic reactions above 
Important identified risk: 
Hypotonic-
Hyporesponsive 
Episodes (HHE) 
No case observed in the Hiberix clinical 
development programme. The risk is listed 
in the post-marketing section of the core 
safety information. The mechanism by 
which immunization may result in HHE 
remains unknown; however, most reported 
episodes followed the administration of a 
pertussis-containing vaccine and have been 
associated with whole-cell vaccines more 
often than acellular. 
HHE is unpredictable and although it 
may be frightening for 
parents/caregivers, it usually resolves 
spontaneously without any intervention 
being required or any sequelae. 
No specific mitigation in this study: SAE 
collection is part of the study protocol 
(see Section 5.6.15). 
Important identified risk: 
Convulsion (with or 
without fever) 
Cases of convulsion, including febrile 
convulsion, have been reported during the 
Hiberix clinical development program, and 
also from post-marketing experience. 
Convulsions (including febrile convulsions) 
are listed in the US PI. 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1. Seizure will 
be monitored through the AESI 
collection. 
IMP: Rotarix 
Important identified risk: 
Intussusception (IS) 
Following administration of a previously 
licensed oral live rhesus rotavirus-based 
vaccine, an increased risk of 
intussusception was observed. In a 
postmarketing, observational study 
conducted in Mexico, cases of 
intussusception were observed in temporal 
association within 31 days following the first 
dose of Rotarix, with a clustering of cases in 
the first 7 days. Other postmarketing 
observational studies conducted in Brazil 
and Australia also suggest an increased 
risk of intussusception within the first 7 days 
following the second dose of Rotarix. 
Intussusception (including death) is listed 
(see US PI). 
Infants with a history of uncorrected 
congenital malformation of the 
gastrointestinal tract (such as Meckel’s 
diverticulum) that would predispose the 
infant for intussusception or with a 
history of intussusception should not 
receive Rotarix (see US PI). 
Important identified risk: 
Hematochezia 
Hematochezia has been observed during 
the post-marketing experience with Rotarix 
and it is listed in the US PI. 
No specific mitigation in this study: SAE 
collection is part of the study protocol. 
Important identified risk: 
Gastroenteritis with 
vaccine viral shedding 
in infants with Severe 
Combined 
Immunodeficiency 
(SCID) 
Cases of SCID has been reported during 
the post-marketing experience with Rotarix. 
This risk is listed (see US PI). 
Subjects with SCID will be excluded 
from participating in this study (see 
Section 4.3). 

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important potential risk: 
Kawasaki Disease (KD) 
Based on signal observed for RotaTeq 
vaccine. KD is listed in the US PI. 
The potential risk of events of possible 
autoimmune aetiology that might occur 
is mentioned in the ICF. KD will be 
monitored through the pIMDs collection. 
IMP: M-M-R II 
Important identified risk: 
Exposure to 
immunocompromized 
individuals 
In severely immunocompromized 
individuals who have been inadvertently 
vaccinated with measles-containing 
vaccine; measles inclusion body 
encephalitis, pneumonitis, and fatal 
outcome as a direct consequence of 
disseminated measles vaccine virus 
infection have been reported. In this 
population, disseminated mumps and 
rubella vaccine virus infection have also 
been reported (see M-M-R II US PI). 
Abnormal function of the immune 
system including immunodeficiency is 
an exclusion criterion in this study (see 
Section 4.3). 
Important potential risk: 
Hypersensitivity 
including Anaphylaxis 
Hypersensitivity including anaphylaxis to 
one or several components of the vaccine 
can rarely occur. Anaphylaxis and 
anaphylactoid reactions are listed in the M-
M-R II US PI. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12). 
Important potential risk: 
Thrombocytopenia 
The risk of an exacerbation of 
thrombocytopenia following vaccination and 
the risk to develop thrombocytopenia with 
repeat doses in individuals who 
experienced thrombocytopenia with the first 
dose constitute a warning in the M-M-R II 
US PI. Moreover, thrombocytopenia is an 
adverse reaction listed in the US PI.  
Thrombocytopenia will be monitored 
through the SAE collection (see Section 
5.6.15). 
Important potential risk: 
Fever 
Fever may occur following vaccination. 
Fever is listed in the M-M-R II US PI. 
 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and in the eCRF (see 
Section 6.7.1). 
IMP: Varivax 
Important identified risk: 
Hypersensitivity 
reactions 
Hypersensitivity to one or several 
components of the vaccine can rarely 
occur. Anaphylaxis (including anaphylactic 
shock) and related phenomena such as 
angioneurotic edema, 
facial edema, and peripheral edema are 
listed (see Varivax US PI). 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12). 

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important identified risk: 
Exposure to 
immunocompromized 
individuals 
Varivax is a live, attenuated varicella-zoster 
vaccine (VZV) and may cause an extensive 
vaccine-associated rash or disseminated 
disease in individuals who are 
immunosuppressed or immunodeficient 
(see US PI). 
Abnormal function of the immune 
system including immunodeficiency is 
an exclusion criterion in this study (see 
Section 4.3). 
Important identified risk: 
Vaccine Virus 
Transmission 
Post-marketing experience suggests that 
transmission of vaccine virus may occur 
rarely between healthy vaccinees who 
develop a varicella-like rash and healthy 
susceptible contacts. 
Vaccinees should attempt to avoid 
whenever possible close association 
with susceptible high-risk individuals 
(e.g. immunocompromized individuals) 
for up to 6 weeks following vaccination 
with Varivax (see US PI). 
Non-IMP: Infanrix 
Important identified risk: 
Hypersensitivity 
People may develop allergic reactions to 
any type of vaccine and/or its components. 
Hypersensitivity reactions to vaccines highly 
vary in severity, ranging from mild to 
potentially life-threatening hypersensitivity 
reactions. Severe allergic reactions to 
vaccines are rare but tend to occur within 
hours after vaccination. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). The 
subjects will be observed closely for at 
least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12). 
Important identified risk: 
Temperature of ≥ 40.0° 
C 
In rare occasion, hyperpyrexia above 
40.0°C may occur after vaccination, 
particularly associated with booster 
vaccination. 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and in the eCRF (see 
Section 6.7.1). 
Important identified 
risk: Hypotonic-
hyporesponsive 
episode (HHE) 
HHE occurs more commonly in early 
childhood after primary vaccination and 
particularly after the first dose of vaccine. 
Most HHE events have been associated 
with whole cell pertussis-containing 
vaccines (36-250 episodes per 100,000 
doses). A much lower rate of HHE has been 
observed following vaccination with 
acellular pertussis vaccine (4-140 episodes 
per 100,000 doses). 
Collapse or shock-like state (hypotonic-
hyporesponsive episode) within 48 
hours of vaccination is a 
contraindication to further administration 
of Infanrix (see US PI). 
Important identified risk: 
Apnoea in infants born 
prematurely 
Apnoea of prematurity is due to immaturity 
of the neurological and respiratory system 
in premature infants. The risk appears to be 
related to the degree of prematurity of the 
infant. 
Only subjects born full-term (i.e. after a 
gestation period of ≥ 38 weeks) will be 
enrolled (see Section 4.2). 
Important identified risk: 
Convulsions with or 
without fever, 
occurring within 3 days 
Seizures occurring soon after immunization 
are mostly triggered by fever induced by the 
vaccine or are not vaccine related. Febrile 
convulsions usually occur in individuals 
aged between 3 months and 6 years with a 
peak incidence at 18 months. 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1 Seizure will 
be monitored through the AESI 
collection.  

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Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important potential risk: 
Encephalopathy 
Reports of encephalopathy were received 
with previous whole cell pertussis vaccines. 
Encephalopathy (e.g., coma, decreased 
level of consciousness, prolonged 
seizures) within 7 days of administration 
of a previous dose of a pertussis -
containing vaccine that is not 
attributable to another identifiable cause 
is a contraindication to administration of 
any pertussis-containing vaccine, 
including Infanrix (see US PI). 
Study procedures 
Risk of blood sampling 
Blood sampling is associated with a risk of 
local reactions and infection after or during 
venipuncture. 
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available. The 
potential risk of experiencing mild local 
pain, bruising, irritation or redness at the 
site where blood was taken, is 
mentioned in the ICF. The amount of 
blood to be taken for sampling is within 
the allowed range for this age and will 
not be harmful to the health of the 
subject. 
* information derived from the publicly available data. 
Note 1: According to the label, events from clinical trials and post marketing experience of Prevnar and 
Prevnar 13 are applicable also to Prevnar 20. 
1.3.2. 
Benefit Assessment 
Benefits considerations include: 
• 
Receiving GSK’s meningococcal vaccine (rMenB+OMV NZ, Bexsero) during study 
duration may protect against meningococcal B disease. Bexsero is currently licensed 
in the US for use in individuals 10 through 25 years of age. 
• 
Receiving Prevnar 13 during the study may prevent occurrence of pneumococcal 
pneumonia and invasive disease caused by 13 Streptococcus pneumoniae strains (1, 
3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). For subjects who received 
PCV20 at visit 5, PCV20 may prevent occurrence of pneumococcal pneumonia 
and invasive disease caused by 20 Streptococcus pneumoniae strains (1, 3, 4, 5, 
6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F). 
• 
Receiving ACIP recommended vaccines (Pediarix, Rotarix, Hiberix, M-M-R II, 
Varivax, Infanrix) may protect against the diseases for which these vaccines are 
indicated for. Medical evaluations/assessments associated with this study (i.e. 
physical examination). 
1.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks in association with the rMenB+OMV NZ, PCV13 
(or PCV20 ), DTPa-HBV-IPV, HRV, Hib, MMR and VV vaccines are justified by the 
potential benefits (prevention) that may be afforded to subject(s) receiving these 
vaccines. 

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2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Safety 
• 
To assess the safety and tolerability of 
rMenB+OMV NZ, PCV13 and other RIV when 
administered concomitantly to healthy infants at 
2, 4, 6 and 12 months of age, throughout the 
study duration. 
• 
The percentages of subjects with solicited local 
Adverse events (AEs) (administration site event) 
and systemic AEs during the 7 days (including the 
day of vaccination) after the 1st, the 2nd, the 3rd and 
the 4th vaccination (Visits 1, 2, 3 and 5). 
• 
The percentages of subjects with solicited systemic 
AEs of parotid/salivary gland swelling, fever and 
rash during the 30 days (including the day of 
vaccination) after the 4th vaccination (Visit 5). 
• 
The percentages of subjects with all unsolicited 
AEs (including SAEs, AEs leading to withdrawal, 
AESIs, and medically attended AEs) during 30 days 
(including the day of vaccination) after the 1st, the 
2nd, the 3rd and the 4th vaccination (Visits 1, 2, 3 
and 5). 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs from study Day 1 (Visit 1) until study 
end (6 months or 12 months after last study 
vaccination, Visit 7¥). 
Co-Primary Immunogenicity 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4 and 6 months of age, at 
one month after the 3rd vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ at one month after the 3rd 
vaccination will be demonstrated if the adjusted lower 
confidence limit for the percentage of subjects 
achieving serum bactericidal assay using human 
complement (hSBA) titers ≥ Lower Limit of 
Quantitation (LLOQ) is ≥ 60% for the N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254, 
M13520 (individually); and is ≥ 50% for all strains 
combined (composite endpoint). 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ; for each of the M14459, 96217, 
NZ98/254 and M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for all strains combined (composite 
endpoint). 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4, 6 and 12 months of age, 
at one month after the 4th vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ will be demonstrated if the adjusted 
lower confidence limit for the percentage of subjects 
with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) is ≥75% for the 
individual N. meningitidis serogroup B test strains and 
is ≥65% for all strains combined (composite endpoint). 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
the percentages of subjects with hSBA titers 
≥ 8 (for strains M14459, NZ98/254, M13520) 
and ≥16 (for strain 96217) for each of the test 
strains. 
− 
the percentages of subjects with hSBA titers 
≥ 8 (for strains M14459, NZ98/254, M13520) 
and ≥16 (for strain 96217) for all strains 
combined (composite endpoint). 

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Objectives 
Endpoints 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4 and 6 months of age, compared to PCV13 
without rMenB+OMV NZ, at one month after the 
3rd vaccination. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the adjusted lower confidence 
limit for the between-group ratio of 
electrochemiluminescence (ECL) assay GMCs is >0.5 
for each of the 13 PCV13 antigens. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
the ECL GMCs for each of the 13 PCV13 
antigens. 
Secondary Immunogenicity 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4, 6 and 12 months of age, compared to 
PCV13 and other RIV alone, at one month after 
the 4th vaccination. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of 2-sided 95% 
CI for the between-group-ratio of ECL assay GMCs is 
>0.5 for each of the 13 PCV13 antigens. 
• 
At one month after the 4th vaccination (Day 331): 
− 
The ECL GMCs for each of the 13 PCV13 
antigens. 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
at 2, 4, 6 and 12 months of age compared to 
PCV13 and other RIV alone, at both one month 
after the 3rd and the 4th vaccinations. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of the 2-sided 
95% CI for the group differences in percentage of 
subjects with IgG ≥ 0.35 µg/mL is >-10% for each of 
the 13 PCV13 antigens at one month after both 3rd and 
4th vaccination. 
• 
At 1 month after the 3rd (Day 151) and the 4th 
vaccination (Day 331): 
− 
Percentages of subjects with serum 
pneumococcal anti-capsular polysaccharide 
IgG ≥0.35 μg/mL for each of the 13 PCV13 
antigens. 
• 
To demonstrate the immunological non-inferiority 
of DTaP-HBV-IPV and Hib vaccines when 
administered concomitantly with rMenB+OMV 
NZ and PCV13 to healthy infants at 2, 4, and 6 
months compared to DTaP-HBV-IPV and Hib 
vaccines concomitantly administered with PCV13 
without rMenB+OMV NZ, in terms of D, T, PT, 
FHA, PRN, Hep B and Hib, at one month after 
the 3rd vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI 
for the between-group differences is greater than the 
pre-specified margin† for each antigen at one month 
after 3rd vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
GMCs against the 3 pertussis antigens 
(Pertussis toxin [PT], pertactin [PRN], 
filamentous hemagglutinin [FHA]). 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥10 mIU/mL. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations ≥0.1 IU/mL. 
− 
Percentages of subjects with anti-PRP 
concentration ≥0.15 µg/mL and ≥1 µg/mL. 
• 
To demonstrate the immunological non-inferiority 
of MMR and VV vaccines when administered 
concomitantly with rMenB+OMV NZ and PCV13 
to healthy subjects at 12 months compared to 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
GMCs against measles, mumps, rubella and 
VZV antigens. 

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Objectives 
Endpoints 
MMR and VV vaccines concomitantly 
administered with PCV13, without rMenB+OMV 
NZ, at one month after vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI 
for the between-group ratio of GMCs is >0.67 at one 
month after the MMR and VV vaccinations. 
• 
To evaluate the immune response to 
rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4, 6 and 12 months of age, 
at one month after the 3rd vaccination, at 6 
months after the 3rd vaccination (immediately 
before the 4th vaccination), and at one month 
after the 4th vaccination against the M14459, 
96217, NZ98/254 and M13520 test strains. 
• 
At 1 month after the 3rd vaccination (Day 151) 
− 
the percentages of subjects with hSBA titers 
≥5, ≥8 and ≥16 for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
− 
the hSBA geometric mean titers (GMTs) 
against each strain. 
• 
At 6 months after the 3rd vaccination (Day 301, 
immediately before the 4th vaccination): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for each of the M14459, 96217, 
NZ98/254 and M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥5 and ≥8 for each of the M14459, 96217, 
NZ98/254 and M13520 test strains. 
− 
the hSBA GMTs against each strain. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for each of the M14459, 96217, 
NZ98/254 and M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥5 for each of the M14459, 96217, NZ98/254 
and M13520 test strains. 
− 
the hSBA GMTs and geometric mean ratios 
(GMRs) over pre-4th vaccination against 
each strain. 
− 
the percentages of subjects with 4-fold rise* 
in hSBA titers (from pre-4th vaccination) for 
each of the M14459, 96217, NZ98/254 and 
M13520 test strains. 
• 
To evaluate immune responses to routine infant 
vaccines DTaP-HBV-IPV, Hib, MMR and VV 
vaccines when administered concomitantly with 
rMenB+OMV NZ and PCV13 to healthy infants at 
2, 4, 6 and 12 months of age, at one month after 
the 3rd vaccination, at 1 month after the 4th 
vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥100 mIU/mL. 
− 
Anti-HBsAg GMCs. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations ≥1 IU/mL. 
− 
Anti-diphtheria and anti-tetanus antibody 
GMCs. 

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Objectives 
Endpoints 
− 
Percentage of subjects with anti-polio type 1, 
2 and 3 neutralization antibody titers ≥8. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
Seroresponse, defined as post-vaccination 
anti-VZV virus, anti-measles virus, anti-
mumps virus and anti-rubella virus antibody 
concentration^ ≥ a protective threshold 
among subjects who were seronegative 
(antibody concentration <assay cut-off) 
before vaccination. 
^ A suitable ELISA assay for analysis of anti-VZV, anti-
measles virus, anti-mumps virus and anti-rubella virus 
antibody concentrations is yet to be selected and/or 
developed. 
* A 4-fold rise in hSBA titers is defined as 
- if pre-vaccination titer <Limit of Detection (LOD), then a post-vaccination titer ≥ 4 times the LOD or ≥ LLOQ, 
whichever is greater; 
- if pre-vaccination titer is ≥LOD but <LLOQ, then a post-vaccination titer ≥4 times the LLOQ;  
- if pre-vaccination titer is ≥LLOQ, then a post-vaccination titer ≥4 times the pre-vaccination titer, 
where pre-vaccination titer=pre-4th dose titers (Day 301) 
† The endpoints and thresholds used for evaluation of the non-inferiority criteria for DTaP-HBV-IPV and Hib vaccines 
can be found in Table 21 and the thresholds and endpoint for evaluating the non-inferiority criteria for MMR and VV 
vaccines can be found in Table 22. 
¥ Visit 7 will occur either on Day 481 (for subjects who have not yet reached the 6-month follow-up after the last dose 
at the time protocol amendment 7 takes effect) or on Day 661 (for all other subjects). 
Note 1: To control the risk of erroneously concluding, a hierarchical procedure will be used for the multiple confirmatory 
study objectives, with the possibility to conclude on the study success based on the results of the co-primary objectives 
alone (refer to Section 9.5.3 for details). 
Note 2: In the context of this study, the following are considered as RIVs at different visits: 
Visit 1 and Visit 2: DTPa-HBV-IPV, HRV, Hib; 
Visit 3: DTPa-HBV-IPV, Hib; 
Visit 5: MMR and VV. 
 

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3. 
STUDY DESIGN OVERVIEW 
Figure 1 
Overview of Study Design – V72_57 
 
D: day; Vacc: vaccination, FU: follow-up call, RIV: routine infant vaccines (Visit 1 and Visit 2: DTPa-HBV-IPV, HRV, 
Hib; Visit 3: DTPa-HBV-IPV, Hib; Visit 5: MMR, VV) 
Refer to Section 7.2.4 for study procedures to be considered during special circumstances. 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 5.5), are essential 
and required for study conduct. Refer to Section 7.2.4 for study procedures to be 
considered during special circumstances. 
• 
Experimental design: Phase IIIB , observer-blind, randomized, placebo-controlled, 
multi-centric study with 2 parallel groups. 
• 
Duration of the study: 
− 
Epoch 001 Primary starting at Visit 1 (Day 1) and ending at Visit 5 (Day 301). 
− 
Epoch 002: Secondary starting at Visit 5 (Day 301) and ending at Visit 6 (Day 
331). 
− 
Epoch 003: Safety follow-up period starting at Visit 6 (Day 331) and ending at 
Visit 7 (Day 481 or Day 661). For subjects who have not yet reached the 6-
month safety follow-up after the last dose at the time protocol amendment 7 
takes effect, Visit 7 will take place on Day 481. 
• 
Primary completion Date (PCD): Visit 7 (Day 481 or Day 661).  
Refer to glossary of terms for the definition of PCD. 

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• 
End of Study (EoS): Date of the last testing/reading released of the Human 
Biological Samples (HBS) related to primary and secondary endpoints. Study 
completion must be achieved no later than 8 months after LSLV. 
Refer to glossary of terms for the definition of EoS. 
• 
Study groups: 
− 
Group MenB+PCV: rMenB+OMV NZ vaccine given concomitantly with 
PCV13 at 2, 4, 6, and 12 months of age. Either PCV13 or PCV20 is allowed to 
be given at 12 months of age (Visit 5) for subjects who have not reached Visit 
5 at the time this protocol amendment becomes effective. Subjects should also 
receive routine infant vaccines (DtaP-HBV-IPV, HRV, Hib, MMR, VV) at 
applicable timepoints. 
− 
Group Placebo+PCV: PCV 13 vaccine given concomitantly with Placebo at 2, 4, 
6 and 12 months of age. Either PCV13 or PCV20 is allowed to be given at 12 
months of age (Visit 5) for subjects who have not reached Visit 5 at the time 
this protocol amendment becomes effective. Subjects should also receive 
routine infant vaccines (DtaP-HBV-IPV, HRV, Hib, MMR, VV) at applicable 
timepoints. 
Table 1 
Study Groups and Epochs Foreseen in the Study  
Study Groups 
Number of 
subjects 
Age (Min – Max)  
Epochs 
Epoch 001  
Epoch 002  
Epoch 003 
MenB+PCV 
800 
6 weeks – 12 weeks 
x 
x 
x  
Placebo+PCV 
400 
6 weeks – 12 weeks 
x 
x 
x  
Table 2 
Study Groups and Treatment Foreseen in the Study 
Treatment name 
Vaccine name 
Study Groups 
MenB+PCV  
Placebo+PCV  
Bexsero  
rMenB+OMV NZ 
X 
- 
Prevnar13 
PCV13* 
X 
X 
Prevnar 20 
PCV20* 
X 
X 
Placebo 
NaCl 
- 
X 
Pediarix  
DTPa-HBV-IPV  
X 
X 
Rotarix 
HRV 
X 
X 
Hiberix  
Hib 
X 
X 
M-M-R II 
MMR  
X 
X 
Varivax  
VV 
X 
X 
Note: Subjects in both groups will receive a fourth dose of Hib vaccine (Hiberix) and a single dose of DTPa vaccine 
(Infanrix) as non-study vaccines at Visit 6. 
* Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 

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Table 3 
Overview of the Study Design: Blood Draws and Study vaccines  
Clinic Visits 
(Study Day) 
Visit 1 
(Day 1) 
Visit 2 
(Day 61) 
Visit 3 
(Day 
121) 
Visit 4 
(Day 
151) 
Visit 5 
(Day 301) 
Visit 6 
(Day 
331) 
Months of Age (MoA) 
~2 MoA1 
4 MoA 
6 MoA 
7 MoA 
12 MoA 
13 MoA3 
Study Vaccines 
Group MenB+PCV 
N=800 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
Blood 
Draw2 
Blood Draw2 
rMenB+ 
OMV NZ 
PCV134 
Blood 
Draw2, 3 
Group 
Placebo+PCV 
N=400 
Placebo 
PCV13 
Placebo 
PCV13 
Placebo 
PCV13  
Blood Draw2 
Placebo 
PCV134 
Routine Study 
Vaccines 
Both groups 
N=1200 
DTPa-
HBV-IPV 
HRV 
Hib 
DTPa-HBV-IPV 
HRV 
Hib 
DTPa-
HBV-
IPV 
Hib 
 
MMR 
VV 
 
MOA, months of age. 
1 Age at enrollment can be between 6 weeks to 12 weeks of age.  
2 Blood draw to be performed prior to any vaccination (study or non-study).  
3 Subjects in both groups will receive a fourth dose of Hib vaccine (Hiberix) and a single dose of DTPa vaccine 
(Infanrix) at 13 months of age, i.e. Visit 6 at Day 331. No immunogenicity or safety assessments will be performed 
following these Visit 6 vaccinations. 
4 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
Note: Study visits do not include safety follow-up calls. Although not conducted face-to-face, safety calls are intended 
for safety data collection. For details, refer to Table 5. 
• 
Control: placebo control. 
• 
Vaccination schedule: Visit 1 (Day 1), Visit 2 (Day 61) Visit 3 (Day 121), Visit 5 
(Day 301). 
• 
Treatment allocation: Subjects to be randomized in a 2:1 ratio at Visit 1 (Day 1) to 
Groups MenB+PCV and Group Placebo+PCV, respectively. 
Refer to Section 5.2 for a detailed description of the randomization method. 
• 
Blinding: observer-blind study. 
Table 4 
Blinding of Study Epochs 
Study Epochs 
Blinding 
Epoch 001  
Observer-blind 
Epoch 002  
Observer-blind  
Epoch 003  
Observer-blind 
• 
Sampling schedule: The sampling schedule for both study groups is the same. Three 
blood samples of approximately 5 mL each are to be taken at: 
− 
Visit 4 (Day 151), i.e., 30 (-9 to +30) days after the 3rd vaccination. 
− 
Visit 5 (Day 301), i.e., 180 (-7 to 91)days after the 3rd vaccination (pre-4th 
vaccination). 

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− 
Visit 6 (Day 331), i.e., 30 (-9 to +30) days after the 4th vaccination. 
• 
Type of study: self-contained. 
• 
Data collection: Standardized Electronic Case Report Form (eCRF). Solicited 
symptoms will be collected using a subject Diary (electronic Diary [eDiary]). 
4. 
STUDY COHORT 
4.1. 
Number of subjects/centers  
A total of 1200 healthy subjects, 42 through 84 days of age (i.e. 6 through 12 weeks) will 
be enrolled in a 2:1 ratio. A detailed description of the criteria used in the determination 
of the sample size is provided in Section 9.1. The enrolment rate will be monitored using 
a study-specific central Randomization System on Internet (SBIR). The randomization 
algorithm will use a minimization procedure accounting for center.  
For the analysis of the immune responses to the RIVs, subjects in each of the two study 
groups will be randomly assigned to different immunogenicity subsets. Further details are 
found in Section 5.2.3 and Section 5.7.  
4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects’ parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the 
opinion of the investigator, can and will comply, with the requirements of the 
protocol (e.g. completion of the eDiary, return for follow-up visits). 
• 
Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to 
performing any study specific procedure.  
• 
A male or female between, and including, 42 and 84 days of age (i.e., 6 through 12 
weeks) at the time of the first vaccination. 
• 
Healthy subjects as established by medical history and clinical examination before 
entering into the study. 
• 
Born full-term (i.e. after a gestation period of 38 weeks). 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 

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The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
• 
Child in care 
Please refer to the glossary of terms for the definition of child in care. 
Each subject must not have: 
• 
Progressive, unstable or uncontrolled clinical conditions. 
• 
Hypersensitivity, including allergy to any component of vaccines, medicinal product 
or medical equipment whose use is foreseen in this study. 
• 
Hypersensitivity to latex. 
• 
Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
• 
Abnormal function of the immune system resulting from: 
− 
Clinical conditions. 
− 
Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days from birth. 
− 
Administration of antineoplastic and immunomodulating agents or radiotherapy 
for any duration from birth. 
− 
autoimmune disorders (including, but not limited to: blood, endocrine, hepatic, 
muscular, nervous system or skin autoimmune disorders; lupus erythematosus 
and associated conditions; rheumatoid arthritis and associated conditions; 
scleroderma and associated disorders) or immunodeficiency syndromes 
(including, but not limited to: acquired immunodeficiency syndromes and 
primary immunodeficiency syndromes). 
• 
Received immunoglobulins or any blood products from birth. 
• 
Received an investigational or non-registered medicinal product from birth. 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study. 
• 
Neuroinflammatory disorders (including but not limited to: demyelinating disorders, 
encephalitis or myelitis of any origin), congenital and peripartum neurological 
conditions, encephalopathies, seizures (including all subtypes such as: absence 
seizures, generalized tonic-clonic seizures, partial complex seizures, partial simple 
seizures or febrile convulsions). 
• 
Congenital or peripartum disorders resulting in a chronic condition (including but not 
limited to: chromosomal abnormalities, cerebral palsy, metabolism or synthesis 
disorders, cardiac disorders). 
• 
Study personnel as an immediate family or household member. 
• 
Current or previous, confirmed or suspected disease caused by N. meningitidis 

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• 
Household contact with and/or intimate exposure from birth to an individual with 
laboratory confirmed N. meningitidis and/or Streptococcus pneumoniae infection or 
colonization.  
• 
Previous administration of meningococcal B or pneumococcal vaccine at any time 
prior to informed consent. 
• 
Received a dose of DTPa-HBV-IPV , HRV, MMR, VV and/or Hib at any time prior 
to informed consent. Receipt of one dose of HBV up to 4 weeks prior to informed 
consent is allowed. 
• 
Serious chronic illness. 
• 
Uncorrected congenital malformation (such as Meckel’s diverticulum) of the 
gastrointestinal tract that would predispose for Intussusception (IS). 
Prior to receipt of each study vaccination, subjects must be evaluated to confirm that they 
are eligible for subsequent vaccination. If subjects meet any of the original exclusion 
criteria listed above (with the exception of the criterion regarding previous administration 
of meningococcal B, pneumococcal or any of the other RIV vaccines), they should not 
receive additional study vaccinations. Similarly, certain events may lead to a delay in 
vaccination (see Section 6.5) or blood sampling (see Section 5.6.11.1). Eligibility to each 
study vaccination should be documented in the source documents. 
5. 
CONDUCT OF THE STUDY 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki.  
The study has been designed and will be conducted in accordance with the ICH 
Harmonized Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines. 
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject’s parent(s)/LAR(s) informed consent. 
• 
Investigator reporting requirements as stated in the protocol. 

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GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.  
Properly constituted IRB/EC is defined in ICH Guideline for GCP E6 (R2), Section 3 
[ICH, 2018].  
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s), as appropriate, prior to participation in the study.  
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.  
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. A copy of the approved version must be provided to the 
GSK monitor after IRB/EC approval. 
This review and approval will be documented and stored with other study documents. 
The investigator or designee must fully inform the subject’s parent(s)/LAR(s) of all 
pertinent aspects of the study. A copy of the written informed consent will be given to the 
subjects’ parent(s)/LAR(s) or the designee. The subject/designee must be allowed ample 
time to ask about the details of the study and to make a decision as to whether or not to 
participate in the study. The subject’s parent(s)/LAR(s) must sign the consent form 
indicating their agreement to participate in the study before any study-related procedures 
are conducted. The informed consent process may be conducted up to 5 days prior to 
vaccination on Day 1. If the subject’s parent(s)/ legal guardian(s) is unable to read and 
write, a witness must be present during the informed consent discussion and at the time of 
informed consent signature. 
Potential subjects’ parent(s)/LAR(s) or the designee must be informed that their 
participation is voluntary. They will be required to physically or digitally sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, HIPAA requirements, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 

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5.1.1. 
Responsibilities of the Investigator  
Prior to study start and at any time the protocol is amended during study conduct, the 
investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to 
GSK monitors, auditors, GSK Clinical Quality Assurance representatives, designated 
agents of GSK, IRBs/Ecs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform GSK 
immediately that this request has been made. 
In addition to what is stated in the Investigator Agreement, the investigator is also 
responsible for the following: 
• 
Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
• 
Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
• 
Demonstrating sufficient time and staffing to properly conduct and complete the 
study within the agreed study period. 
• 
Ensuring that qualified trained health care professionals (see glossary of terms) are 
responsible for all study-related medical decisions and for ensuring appropriate 
medical care of subjects experiencing any adverse event related to the study. 
• 
If permission to do so is given by the subject’s parent(s)/LAR(s), ensuring that the 
subject’s primary healthcare provider is informed of the subject’s participation in the 
study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favorable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted within 10 working days: 
1. to the IRB/IEC for review and approval/favorable opinion, 
2. to the Sponsor for agreement and, if required, 
3. to the regulatory authority(ies). 

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5.1.2. 
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be 
conducted and no effect on subject safety (e.g., change of telephone number(s), logistical 
changes). Protocol amendments must be approved by GSK, health authorities where 
required, and the IRB/EC. 
5.2. 
Subject identification and randomization  
5.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center. The Subject ID will be documented in the 
Screening and Enrolment log. The eligibility of the subject will be determined based on 
the inclusion and exclusion criteria listed in Section 4 and evaluated during this screening 
procedure. The Subject ID will be the subject’s unique identification number for all 
eCRFs and associated study documentation that will be used for duration of the study. 
5.2.2. 
Randomization of treatment 
5.2.2.1. 
Randomization of supplies 
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial Excellence (MATEX), a program developed for use in SAS (Cary, NC, USA) 
by GSK (Rixensart, Belgium). 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-center study and to thus reduce the overall 
study recruitment period, an over-randomization of supplies will be prepared. Further 
details are provided in the Study Procedures Manual (SPM). 
5.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose for Bexsero and placebo vaccines. 
Treatment allocation will be by components for all other products. 
5.2.2.2.1. Study group and treatment number allocation  
The target will be to enroll approximately 1200 eligible subjects who will be randomly 
assigned to 2 study groups in a 2:1 ratio. 

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Allocation of the subject to a study group at the investigator site will be performed using 
the Source Data Base for Internet Randomization system (SBIR). The randomization 
algorithm will use a minimization procedure accounting for center.  
After obtaining the signed and dated ICF from the subject’s parent/ LAR and having 
checked the eligibility of the subject, the site staff will access SBIR. Upon providing the 
subject identification number, the randomization system will determine the study group 
and will provide the treatment number to be used for each dose. 
Subjects will be randomized in the SBIR system to one of the two groups in a 2:1 ratio to 
receive: 
• 
Group MenB+PCV: rMenB+OMV NZ given concomitantly with PCV13 at 2, 4, 6 
and 12 months of age, along with other RIV. Either PCV13 or PCV20 is allowed to 
be given at 12 months of age (Visit 5) for subjects who have not reached Visit 5 at 
the time this protocol amendment becomes effective. 
• 
Group Placebo+PCV: PCV13 and Placebo given concomitantly at 2, 4, 6 and 12 
months of age, along with other RIV. Either PCV13 or PCV20 is allowed to be 
given at 12 months of age (Visit 5) for subjects who have not reached Visit 5 at the 
time this protocol amendment becomes effective. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
Note: In case of supplies shortage for the next assigned vaccine according to the 
randomization schedule at the clinical site, the SBIR system will use the forced 
randomization procedure in order to continue to enroll and vaccinate subjects. The 
system moves seamlessly to the next treatment in the minimization algorithm arm for 
which the vaccine supplies are available. The site will not be aware of the forced 
randomization event. 
5.2.2.2.2. Treatment number allocation for subsequent doses 
For each dose subsequent to the first dose, the study staff will access SBIR, provide the 
subject identification number, and the system will provide a treatment number consistent 
with the allocated study group. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 

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5.2.3. 
Allocation of subjects to assay subsets  
For the analysis of the immune responses to the RIV antigens, subjects in each of the 2 
study groups will be randomly assigned to different immunogenicity subsets. The 
assignment of the immunogenicity subsets will be performed by a second randomization, 
whereas the first randomization will be performed at the enrolment to assign subjects to 
Group MenB+PCV or Group Placebo+PCV. 
Group MenB+PCV: All 800 subjects will be randomly assigned into one of the 3 
immunogenicity subsets: 
• 
Subset A1: 400 subjects  
• 
Subset A2: 200 subjects  
• 
Subset A3: 200 subjects 
Group Placebo+PCV: A total of 400 subjects will be randomly assigned into 2 
immunogenicity subsets: 
• 
Subset B1: 200 subjects 
• 
Subset B2: 200 subjects 
The different subsets against which the different antigens will be tested are described in 
Table 9. Testing of diphtheria, tetanus, pertussis, polio, HepB and Hib antigens will be 
performed at Visit 4 (post-3rd vaccination). Testing of MMR and VV will be done at Visit 
5 (pre-4th vaccination) and Visit 6 (post-4th vaccination). In addition, subjects from subset 
B1 (200 subjects) will also be tested against the 4 serogroup B strains at all 3 timepoints 
in order to maintain the observer-blindness of the study during the blood sample testing. 
5.3. 
Method of blinding  
This trial is designed as an observer-blind study.  
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccines recipient and those responsible for the 
evaluation of any study endpoint (e.g. safety and reactogenicity) will all be unaware of 
which vaccine was administered. To do so, vaccine preparation and administration will 
be done by authorized medical personnel who will not participate in any of the study 
clinical evaluation assays or procedures.  
Each study site is responsible for having a blinding plan. To work in an observer-blind 
manner, vaccine preparation and administration will be done by authorized medical 
personnel who will not participate in any of the study clinical evaluation assays or 
procedures. See the glossary of terms for definition of unblinded study staff. Two teams 
of study personnel will hence be set up: 
• 
A team of unblinded personnel (responsible for the preparation and the 
administration of the vaccines).  

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• 
A team of blinded personnel (responsible for the clinical evaluation of the subjects 
including blood sampling). 
Refer to the SPM for guidance on vaccine preparation and administration while 
maintaining the blind. The serological data, which would lead to the unblinding of the 
study groups, will not be available during the course of the study to any investigator or 
any person involved in the clinical conduct of the study (including data cleaning). 
The laboratory in charge of the laboratory testing will be blinded to the treatment as well 
as to the subject number. In addition, a different subject code will be used for each 
timepoint tested. This subject coding will prevent the laboratory from linking the 
consecutive visits to a specific subject. 
The serological data, which would lead to the unblinding of the study groups, will not be 
available during the course of the study to any investigator or any person involved in the 
clinical conduct of the study (including data cleaning). 
5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
The staff participating in this study conducted as multicenter trial will be trained in a 
uniform fashion and sites will be monitored to ensure consistency in study execution 
across all centers.  
No Data Monitoring Committee will be convened for this trial. 
5.5. 
Outline of study procedures 
An outline of the different study procedures to be performed are listed in Table 5.  
 

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Table 5 
List of Study Procedures 
Age (approximate) 
~2 
moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 
1 SFC 1 SFC 2 Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 
1 
Day 
16 
Day 
31 
Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-vaccination 1  
0 
15 
days 
post-
vacc 
1 
30 
days 
post-
vacc 
1 
60 
days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 -3/+3 
-
31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
Sampling timepoints 
 
 
 
 
 
 
 
 
Post-
vacc 
3 
 
 
Pre-
vacc 
4 
 
Post-
vacc 
4 
 
 
 
- 
 
 
- 
Informed consent 3  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion 
criteria  
● 
 
 
O  
 
 
O  
 
 
 
 
 O  
 
 
 
 
 
 
 
 
 
Medical history  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History directed physical 
examination  
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom directed physical 
examination  
 
 
 
O 
 
 
O 
 
O 
 
 
O 
 
O 
 
 
 
O 
 
 
O 
Check contraindications and 
warnings and precautions to 
vaccination  
O 
 
 
O 
 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
 
 
Pre-vaccination body 
temperature  
● 
 
 
● 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Study group and/or treatment 
number allocation  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Age (approximate) 
~2 
moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 
1 SFC 1 SFC 2 Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 
1 
Day 
16 
Day 
31 
Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-vaccination 1  
0 
15 
days 
post-
vacc 
1 
30 
days 
post-
vacc 
1 
60 
days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 -3/+3 
-
31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
Sampling timepoints 
 
 
 
 
 
 
 
 
Post-
vacc 
3 
 
 
Pre-
vacc 
4 
 
Post-
vacc 
4 
 
 
 
- 
 
 
- 
Treatment number allocation for 
subsequent doses  
 
 
 
● 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Vaccines administration 4  
● 
 
 
● 
 
 
● 
 
 
 
 
●13 
 
● 5  
 
 
 
 
 
 
 
Blood sampling (5 mL) 6  
 
 
 
 
 
 
 
 
● 
 
 
●  
 
● 
 
 
 
 
 
 
 
Record any concomitant 
medications/vaccinations 
administered for treatment of an 
AE  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Training of eDiary and 
distribution  
● 
 
 
O 
 
 
O 
 
 
 
 
●  
 
 
 
 
 
 
 
 
 
Review of eDiary  
 
 
 
O 
 
 
O 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
Return of eDiary  
 
 
 
 
 
 
 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
30 Minutes post-injection 
assessment (including body 
temperature measurement) 
● 
 
 
● 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 

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Age (approximate) 
~2 
moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 
1 SFC 1 SFC 2 Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 
1 
Day 
16 
Day 
31 
Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-vaccination 1  
0 
15 
days 
post-
vacc 
1 
30 
days 
post-
vacc 
1 
60 
days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 -3/+3 
-
31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
Sampling timepoints 
 
 
 
 
 
 
 
 
Post-
vacc 
3 
 
 
Pre-
vacc 
4 
 
Post-
vacc 
4 
 
 
 
- 
 
 
- 
Recording of solicited local 
(administration site) and 
systemic AEs (Days 1–7 post 
vaccination) in eDiary 9  
O 
 
 
O 
 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
 
 
Recording of selected solicited 
systemic AEs of parotid/salivary 
gland swelling, fever and rash 
(Days 1–30 post vaccination) in 
eDiary  
 
 
 
 
 
 
 
 
 
 
 
O 
O 
O 
 
 
 
 
 
 
 
Recording of all unsolicited AEs 
within 30 days post-
vaccination12  
● 
● 
● 
● 
●  
●  
● 
● 
● 
 
 
● 
● 
● 
 
 
 
 
 
 
 
Recording of SAEs, medically 
attended AEs, AEs leading to 
withdrawal and AESIs 7, 12  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study Conclusion 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
AE: adverse event, Moa: months of age, Pre-vacc: pre-vaccination, Post-vacc: post-vaccination, SFC: safety follow-up call, SAE: serious adverse event. 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 

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○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
Note: Procedures to be performed prior to any vaccination.  
Although not conducted face-to-face, safety follow-up calls are intended for safety data collection and considered equivalent to clinic study visits.  
The double line after Visit 6 at Day 331 indicates the potential interim analysis time period. 
1. Days post injection are included to keep track of the days intercurring between vaccinations, they do not indicate ‘Study Day’.  
2. All visits and visit windows should be planned using the day of last vaccination as the reference point.  
3. Confirm consent form(s) signed prior to any procedures. Pre-vaccination clinic visit can occur within 5 days prior to up to the time of the vaccination Clinic Visit on Day 1 (inclusive). 
Procedures performed include obtaining informed consent from subject’s parent(s)/legal guardian(s), screening, enrolment and randomization.  
4. Subjects will receive study and concomitant vaccinations according to the study group they are randomized. See Section 6 for further details. 
5. Administration of non-IMP vaccines DTPa and fourth dose of Hib to all subjects at 13 months of age (Visit 6 Day 331). See Section 6.1.2 for further details. 
6. Blood sampling at all timepoints should be done prior to administration of any study or non-study vaccines.  
7. Includes recording of all SAEs related to study participation, or to a concurrent GSK medication/vaccine.  
8. Subjects who terminate the study early are recommended to complete certain study-related procedures. See Section 5.6.15 for further details.  
9. Solicited AEs that are ongoing after the 7-day reporting period will continue to be recorded in the eDiary until resolution or day 30, whichever occurs first. 
10 For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol amendment 7 takes effect, Visit 7 will occur on Day 481. 
11. Visit 7 may be a telephone contact during special circumstances. Refer to Section 5.6.15 for study procedures to be considered during special circumstances.  
12.COVID-19 infection related AEs and SAEs should be recorded in a separate eCRF. 
13 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached Visit 5 at the time the protocol amendment 8 becomes 
effective. 
 

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The investigator should arrange study visits within the interval described in Table 6. 
Table 6 
Intervals Between Study Visits 
Interval 
Optimal length of interval 
Allowed interval1, 2 
Visit 1 →Visit 2 
60 days 
29 days – 81 days  
Visit 2 → Visit 3  
60 days  
29 days – 81 days 
Visit 3 →Visit 4 
30 days  
21 days – 60 days 
Visit 3 → Visit 5  
180 days  
173 days – 201 days  
Visit 5 → Visit 6  
30 days  
21 days – 60 days  
Visit 5 → Visit 7 (Study termination)3 
180 days 
173 days – 201 days 
Visit 5→ Visit 7 (Study termination) 
360 days 
353 days – 381 days 
1The investigator should arrange study visits within this interval as subjects may not be eligible for inclusion in the PPS 
cohorts if they make the study visit outside this interval. All visits and windows should be planned using the day of last 
vaccination as the reference point 
2The allowed interval have been modified in keeping with ACIP guidelines to facilitate the safe scheduling of study 
visits during the COVID-19 pandemic situation. 
3 For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol 
amendment 7 takes effect, Visit 7 will occur on Day 481. 
Refer to Table 6 for intervals between study visits that determine subjects’ eligibility for 
inclusion in the per-protocol analysis. 
5.6. 
Detailed description of study procedures 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. An 
outline is provided in Table 5. An overview of the data collected during the course of the 
study is given in Section 5.6.1. 
During special circumstances, exemplified by the COVID-19 pandemic, certain study 
procedures may be adapted to protect the subject and promote data integrity. Refer to 
Section 5.6.15 for further details. 
5.6.1. 
Data collected from subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
• 
Demographic information 
• 
Medical history 
• 
Vaccination history 
• 
Prior and concomitant medication, as defined in Section 6.7. 
• 
Pre-vaccination body temperature 
• 
30 minutes post-vaccination immediate reactions: signs or symptoms of anaphylaxis, 
allergic phenomena (such as rashes, itching, or other allergic manifestations). 
Solicited Local (administration site) and systemic data (including e.g., use of 
medication to treat or prevent fever and/or pain, body temperature measurement). 

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• 
Adverse Events (AEs): 
− 
Post-vaccination solicited local (administration site) and systemic AEs 
(including related information such as use of medication to treat or prevent 
fever), collected at home by subjects’ parent(s)/LAR(s), and recorded on Subject 
eDiary for 7 days following each vaccination visit (including the day of 
vaccination) or until they resolve or Day 30 (whichever occurs first). Specific 
systemic AEs (parotid/salivary gland swelling, fever and rash) will be collected 
for 30 days (including the day of vaccination) following the MMR and VV 
vaccinations at Visit 5. 
− 
Unsolicited AEs occurring within 30 days after each vaccination will be 
collected by interviewing the subject’s parent(s)/legal guardian(s) and by review 
of available medical records at the next visit.  
− 
SAEs will be collected from study Day 1 until study end, inclusive. 
− 
Medically attended AEs (including any medical visit) will be collected from 
study Day 1 until study end, inclusive. 
− 
AEs leading to premature withdrawal from the study will be collected from 
study Day 1 until study end, inclusive. 
− 
AESIs (pIMDs, seizures, and arthritis) will be collected from study Day 1 until 
study end, inclusive. 
All data collected must only be identified using the GSK Subject ID, as described in 
Section 5.2.  
5.6.2. 
Pre-vaccination procedures (Visit 1) 
A pre-vaccination clinic visit may occur within 5 days prior and up to the time of the 
vaccination Visit 1 on Day 1 (inclusive). The following procedures will be performed for 
each potential subject prior to the first vaccination at Visit 1: 
• 
Obtaining informed consent from subject’s parent(s)/LAR(s).  
• 
Subject ID assignment 
• 
Screening the subject for eligibility based in the inclusion and exclusion criteria 
listed in Section 4. This includes all the following procedures: collecting 
demography and medical history, review of systems, collecting prior and 
concomitant medications (including vaccination history), and general physical 
examination by a qualified health care practitioner 
• 
Subject enrolment. 
• 
Subject randomization.  
If a pre-vaccination clinic visit was performed, the investigator will review and confirm 
subject eligibility on Day 1 (Visit 1) prior to first vaccination. Unless deemed necessary, 
procedures performed during pre-vaccination clinic visit should not be repeated on Day 1 
(Visit 1). If a pre-vaccination clinic visit did not occur, all procedures mentioned here 
will be performed at Visit 1 instead. 

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5.6.3. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. Refer to Section 5.1 for the requirements on 
how to obtain informed consent as appropriate. 
5.6.4. 
Check inclusion and exclusion criteria  
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 after 
obtaining informed consent and before randomization.  
5.6.5. 
Collect demographic data 
At Visit 1, record demographic data such as date of birth, gender, race and ethnic origin, 
weight and length in the subject’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the 
diversity of the trial participants, and to determine if the trial participants are truly 
representative of the impacted population. 
5.6.6. 
Medical history 
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. 
Medical history will be collected at Visit 1 (or pre-visit 1, if applicable), including but not 
limited to any medical history that may be relevant to subject eligibility for study 
participation such as prior vaccinations, concomitant medications (refer to Section 
5.6.13), and previous and ongoing illnesses or injuries. Relevant medical history can also 
include any medical history that contributes to the understanding of an AE that occurs 
during study participation, if it represents an exacerbation of an underlying disease/pre-
existing problem. 
Review of systems is a structured interview that queries the subjects’ parent(s)/legal 
guardian(s) as to any complaints the subject has experienced across each organ system. 
This will be performed before enrolment and used to guide physical examination. A 
general physical examination is to be performed by a qualified health care professional. 
“Qualified health care professional” refers to any licensed or certified health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. The physical examination 
will include a check of general appearance, the measurement of vital signs (rectal body 
temperature preferable [as subjects are <12 months of age], and heart rate), auscultation 
of heart and lungs, measurement of length and weight. The medical history-directed exam 
of other body parts and systems to assess eligibility will be performed during Visit 1. 

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5.6.7. 
Physical examination 
At Visits 2 through 7, a brief symptom-directed physical examination is to be performed 
if necessary according to symptoms the subject’s parent(s)/LAR(s) has reported. This is a 
physical examination that will include an examination of organ systems that are relevant 
to the investigator based only on review of the subject’s reported adverse events and 
concomitant medication use. This assessment may include measurement of heart rate and 
temperature.  
These data will be written in the source document. Should the physical assessment reveal 
any abnormal values or events, these must be documented in the eCRF Adverse Events 
Form. 
Treatment of any abnormality observed during this examination should be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
5.6.8. 
Check contraindications, warnings and precautions to 
vaccination  
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details.  
5.6.9. 
Assess pre-vaccination body temperature 
The body temperature of each subject needs to be measured prior to any study vaccines 
administration. If the subject has fever [fever is defined as a body temperature 
38.0°C/100.4°F regardless the location of measurement on the day of vaccination], the 
vaccination visit will be rescheduled within the allowed interval for this visit (see Table 6 
and Section 6.5). 
5.6.10. 
Study group and treatment number allocation 
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF. 
5.6.11. 
Sampling 
The following clinical specimen is required to be collected from each subject in this 
study: 
• 
Blood samples for serologic evaluation. 
Refer to the Module on Biospecimen Management in the SPM and the Central 
Laboratory Investigator Manual for detailed instructions for the collection, handling and 
processing of the samples. 

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5.6.11.1. 
Blood sampling for immune response assessments 
Blood samples will be obtained from each enrolled subject in both study groups at 3 
study visits as follows: 
• 
Visit 4 at Day 151, i.e., 30 (-9 to +30) days after the 3rd vaccination. 
• 
Visit 5 at Day 301, i.e., 180 (-7 to +91) days after the 3rd vaccination (pre-4th 
vaccination).  
• 
Visit 6 at Day 331 i.e., 30 (-9 to +30) days after the 4th vaccination. 
In order to support all serological assay testing, a volume of approximately 5 mL of 
whole blood (to provide approximately 2 mL of serum) should be drawn from each 
subject at each pre-defined timepoint mentioned above, resulting in a total of 
approximately 15 mL over the entire study period. After centrifugation, serum samples 
should be kept at –20°C/ –4°F or below until shipment. Refer to the SPM and Central 
Laboratory Investigator Manual for more details on sample storage conditions. 
A topical anesthetic (e.g. EMLA adhesives or cream) may be used at the site of blood 
sample draw, according to local practice, in order to minimize pain. 
The blood will be used for immunological assays, as described in Section 5.7.4. 
In clinic visits where a blood draw and a vaccination are planned, ensure all serology 
samples are taken prior to vaccination. The following are clinical circumstances that 
warrant delay of blood samples collection for immunogenicity assessments in this study:  
• 
Receipt of systemic antibiotics within the previous 3 days (72 hours) before blood 
sample collection 
In the event that a subject meets the criterion for delay of blood samples collection, blood 
samples collection may proceed once the appropriate window for delay has passed. 
5.6.12. 
Study vaccines administration 
• 
Study vaccination will be performed on Day 1 (Visit 1), Day 61 (Visit 2), Day 121 
(Visit 3), and Day 301 (Visit 5).  
• 
Prior to administration of each vaccination, confirm that the subject is eligible for 
additional study vaccinations and does not meet any criteria for delaying additional 
study vaccinations as described in Section 4 and Section 6.5. 
• 
Prior to the first vaccination (Visit 1) perform a general physical examination. Prior 
to the second, third and fourth vaccination (Visit 2, Visit 3 and Visit 5) perform a 
brief symptom-directed physical examination if necessary according to symptoms 
the subject’s parent(s)/LAR(s) has reported (see Section 5.6.5 and Section 5.6.7).  
• 
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccines will be administered intramuscularly (IM) or subcutaneously (SC) as 
described in Section 6.3. If the investigator or delegate determines that the subject’s 
health on the day of administration temporarily precludes vaccines administration, 

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the visit will be rescheduled within the allowed interval for this visit (refer to Table 
6). 
• 
Prophylactic administration of antipyretics at the time of and closely after 
vaccination is advised, as this can reduce post-vaccination febrile reactions. This 
may be initiated according to the investigator’s judgment. (See Section 6.5). 
• 
The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccines, with appropriate medical treatment readily available 
in case of anaphylaxis. 
For example, epinephrine 1:1000, diphenhydramine, and/or other medications for treating 
anaphylaxis should be available [CDC, 2015b]  
5.6.13. 
Post-vaccination procedures 
The following post-vaccination procedures for each subject will be performed on Day 1 
(Visit 1), Day 61 (Visit 2), Day 121 (Visit 3), and Day 301 (Visit 5). After vaccination, 
the subject will be observed for at least 30 minutes including observation for solicited and 
unsolicited AEs, including measurement of body temperature. Record all safety data 
collected during this time in the subject’s source document and eCRF. 
The site should schedule the next study activity clinic visit or safety follow-up call with 
the subject’s parent(s)/LAR (s). The subject’s parent(s)/LAR(s) should be reminded of 
the next planned study activity. Instruction regarding recording of safety data will be 
provided by the site based on the visit script  
In addition, the post-vaccination procedures related to the reporting of solicited AEs will 
be performed on Day 1 (Visit 1), Day 61 (Visit 2), Day 121 (Visit 3), and Day 301 (Visit 
5). The eDiary will be dispensed at Day 1 (Visit1) to subjects and the subject’s 
parent/LAR will bring the eDiary at each clinic visit. The eDiary will be collected by site 
staff at Day 151 (Visit 4). A new eDiary will be provided to the subjects again at Day 301 
(Visit 5) and collected by the site staff at Day 331(Visit 6). A script will be provided to 
site staff monitoring safety to advise the subjects parent(s)/LAR(s) on collecting and 
reporting of solicited safety data.  
At each vaccination visit, the vaccine injection sites(s) will be stored in the eDiary. 
The eDiary is the only source for collection of solicited local (administration site) and 
systemic AEs starting after the initial 30 minutes post-vaccination; therefore, it is critical 
that the subject’s parent(s)/LAR(s) complete the Subject Diary correctly. The 
subject’s parent(s)/LAR(s) will be instructed on how and when to complete each field of 
the Subject Diary (see Section 5.6.16.1).  
The subject’s parent(s)/LAR(s) should be instructed how to perform body temperature 
measurement (preferably rectal for subjects <12 months of age and the axilla for subjects 
≥12 months of age) using the thermometer provided by the site. If the subject is unusually 
hot or cold during the day, the subject’s parent(s)/LAR(s) should check body 
temperature. If the subject has fever, the highest body temperature observed that day 

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should be recorded in the eDiary. Temperature measurements should be taken prior to the 
administration of any antipyretic medication. 
The subject’s parent(s)/LAR(s) will be instructed to contact study personnel if a subject 
experiences temperature >39.5 °C (>103° F) during the 7-day post-vaccination period, in 
order to assess the extent of the event. 
Further details regarding the use of the eDiary are provided in Section 5.6.16.1. 
5.6.14. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions  
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7. 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8. 
5.6.14.1. 
Follow-up safety clinic visit 
Follow-up clinic visits will be performed in the clinic on Day 151 (Visit 4) and on Day 
331 (Visit 6).  
The subject’s parent(s)/legal guardian(s) will be interviewed to determine if any 
unsolicited AEs occurred and if any concomitant medications or vaccines were taken/ 
received in the time since the last clinic visit. The qualified healthcare professional 
reviewing these data will discuss the symptoms (if any) reported by the subject and will 
determine if any additional diagnoses and/or AEs are present. Adverse events reported by 
the subject’s parent(s)/LAR(s) at this follow-up clinic visit must be recorded in the 
subject’s source document and on an Adverse Events eCRF, as specified Section 7. 
A symptom-directed physical examination will be performed if necessary according to 
symptoms reported by the subject’s parent(s)/LAR(s). This is a physical examination that 
will include an examination of organ systems that are relevant to the investigator based 
on review of the subject’s reported AEs, concomitant medication use. This assessment 
may include: vital signs (at a minimum body temperature [rectal for subjects <12 months 
of age and axilla for subjects ≥12 months of age, preferably) and a check of general 
appearance. The physical assessment must be performed by the investigator or designee 
of the investigator, who is qualified to perform a physical assessment in accordance with 
their institutional policy (see glossary of terms for definition of a qualified healthcare 
provider). Any relevant clinical finding resulting from the symptom-directed physical 
examination should be documented in the subject’s source document and eCRF(s). 
At both visits on Day 151 (Visit 4) and Day 331 (Visit 6), the eDiary should be returned 
to the study site; the eDiary dispensed at Day 1 (Visit1) will be collected at Day 151 
(Visit 4) and the eDiary dispensed at Day 301 (Visit 5) will be collected at Day 331 
(Visit 6). For details on the eDiary see Section 5.6.16.1. A blood sample will also be 
collected for immunological evaluation at both visits. 

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The site should schedule the next study activity with the subject’s parent(s)/LAR(s). The 
subject’s parent(s)/LAR(s) will receive a written reminder of the next planned study 
activity. Instruction regarding recording of safety data will be provided by the site based 
on the visit script. 
5.6.15. 
Study procedures during special circumstances  
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, the 
following measures may be implemented for enrolled participants: 
• 
Visit 7 (Day 481 or Day 661): the study conclusion visit has been revised to allow 
for either a site visit or concluding telephone call. The telephone call is intended for 
safety data collection and will be considered equivalent to study conclusion visit. 
• 
The existing protocol-specified windows have been modified in keeping with ACIP 
guidelines to facilitate the safe scheduling of study visits (See allowed interval in 
Table 6).  
• 
If despite best efforts it is not possible to collect blood samples within the allowed 
interval between visits (see Table 6), then the interval may be extended as per the 
clinical judgement of the investigator.  
• 
If despite best efforts it is not possible to give the vaccine dose within the allowed 
interval between visits (see Table 6), then the interval may be extended as per the 
clinical judgement of the investigator and in keeping with ACIP guidelines. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
5.6.16. 
Recording of AEs, SAEs and AESIs 
• 
Refer to Section 7.2 for procedures for the investigator to record AEs, SAEs, and 
AESIs. Refer to Section 7.3 for guidelines and how to report SAE and AESI reports 
to GSK Biologicals. Refer to Section 7.2.4 for recording of COVID-19 infection 
related AEs. 
• 
The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious.  
5.6.16.1. 
Subject Diary 
A electronic Diary (eDiary) hereafter referred to as Subject Diary will be used in this 
study to capture solicited adverse events. The subject’s parent/LAR should be trained on 
how and when to complete each field of the Subject Diary. 

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Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject’s parent/LAR, but if a person other than the 
subject’s parent/LAR enters information into the Subject Diary, this person’s identity 
must be documented in the subject’s source record. Any individual that makes entries 
into the Subject Diary must receive training on completion of the Subject Diary at the 
time of the visit when Subject Diary is dispensed. This training must be documented in 
the subject’s source record. 
The same individual should preferably complete the Subject Diary throughout the course 
of the study. 
The subject’s parent(s)/LAR(s) should be trained on how to self-measure local solicited 
adverse events and body temperature.  
The measurement of solicited local AEs (administration site event) is to be performed 
using the ruler provided by the site. 
Subject’s parent(s)/LAR(s) will be instructed to measure and record the rectal (subjects 
<12 months of age) or axillary (subjects ≥12 months of age) body temperature in the 
evening. Should additional temperature measurements be performed at other times of 
day, subject’s parent(s)/LAR(s) will be instructed to record the highest temperature in the 
Subject Diary.” 
Subject Diary assignment and use (at Visit 1 and Visit 5): 
• 
Each subject’s parent/LAR will be assigned a Subject Diary and shown how to use 
the device – this will include how to access the diary, performing test data entry on 
sample questions, and how to charge and store the device. 
• 
The subject’s parent/LAR will self-select a numeric access code secret to 
themselves. The same individual should preferably make the assessments and 
complete the Subject Diary throughout the relevant reporting period.  
• 
The subject’s parent(s)/LAR(s) will select an alarm time that suits their daily 
routines whilst ensuring compliance with protocol requirements. 
Subject Diary instructions must ensure that the subject’s parent(s)/LAR(s) understands 
the following: 
• 
Timely completion of the Subject Diary on a daily basis is a critical component to 
study participation. 
• 
The Subject Diary will allow certain time windows for completion of each day’s 
observations. 
• 
The Subject Diary employs the use of audio-visual alarms to ensure timely 
completion of data entry. 
• 
The trained and assigned user of the Subject Diary must not share access codes with 
anyone. 

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• 
A helpdesk will be provisioned for users of subject diary in case of technical issues, 
though it must be stressed that the Helpdesk is not a replacement for normal medical 
care and no medical issues can be discussed with the agents. 
• 
The Subject Diary itself must never be considered a substitute for direct medical care 
and any concerns must be communicated to site staff as soon as possible. 
5.6.16.1.1. Subject diary alerts  
The subject’s parent(s)/LAR(s) will receive daily reminders via the Subject Diary 
device’s in-built audio-visual alarms to alert the user to complete the diary during the 
post vaccination period, which is from Day 1 to Day 7 after Visits 1, 2 and 3 (or until the 
solicited AE resolves) and from Day 1 to Day 30 after Visit 5.  
The Subject Diary system will also allow for regular alerts to be issued via email to site 
staff indicating where subjects may need to be contacted due to: 
• 
Non-compliance (i.e. failing to enter or transmit diary data), 
• 
Reporting of any severe solicited reactions, 
• 
Subject experienced any AE that required hospitalization or visit to the emergency 
room or medically attended events that were of concern to the parents/LAR(s). 
Sites must assess these alerts when received and contact subjects as necessary. Please 
refer to Section 8.2 on the premature withdrawals from the study and Section 7.2.3 on the 
evaluation of AEs for guidance on necessary action in the event of one of these alerts. 
5.6.16.2. 
Safety follow-up calls 
During the course of the trial, a total of 10 or 13 safety follow-up calls will be performed. 
Safety follow-up calls will be performed on the following time points: 
Treatment period: 
• 
Day 16 and Day 31 (15 and 30 days post 1st vaccination, respectively),  
• 
Day 76 and Day 91 (15 and 30 days post 2nd vaccination, respectively),  
• 
Day 136, Day 181 and Day 241 (15, 60 and 120 days post 3rd vaccination, 
respectively), 
• 
Day 316 (15 days post 4th vaccination). 
Follow-up period: 
• 
Day 361, Day 421, Day 481, Day 541 and Day 601 (60, 120, 180, 240, and 300 days 
post 4th vaccination, respectively). For subjects who have not yet reached the 6-
month safety follow-up after the last dose at the time protocol amendment 7 takes 
effect, Visit 7 will occur on Day 481 instead of the follow-up call, and follow-up 
calls at Day 541 and Day 601 will not be performed. 

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Safety follow-up calls are calls made to the subject’s parent(s)/LAR(s) by a qualified 
healthcare professional designated on the site log. These calls will follow a script which 
will facilitate the collection of relevant safety information. The subject’s 
parent(s)/LAR(s) will be interviewed according to the script, and information relating to 
unsolicited AEs [including serious adverse events (SAEs), AESIs, medically attended 
AEs, and AEs leading to vaccine/study withdrawal] and concomitant medications or 
vaccinations associated with those events. All safety information described by the 
subject’s parent(s)/LAR(s) must be written down in a designated location within the 
source document and not written on the script used for the telephone call.  
The site should schedule the next study activity (clinic visit or safety call) with the 
subject’s parent(s)/LAR(s). 
The subject’s parent(s)/LAR(s) will be reminded to contact the site if there are any 
questions and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.6.17. 
Study conclusion 
• 
The study termination visit will occur on Day 481 or Day 661 (Visit 7). The 
termination visit will be a clinic visit. 
• 
If Visit 7 is performed by telephone for subjects who are impacted by protocol 
amendment 7, reconsenting should be performed as per site and IRB guidelines. 
• 
The date of termination is the date of the last contact (clinic visit or telephone call) in 
which the subject’s health status was assessed or, in cases where the subject does not 
agree to any further safety follow-up, it is the date consent is withdrawn. This date 
should be recorded on the termination eCRF page. For visit procedures to be 
performed for a subject whose planned study participation ends prematurely, please 
see below. 
• 
At this clinic visit or telephone call, subject’s parent(s)/LAR(s) will be interviewed 
for any SAEs, medically attended AEs, AESIs (pIMDs, seizures, and/or arthritis) 
experienced by their child. Any concomitant medications associated with those 
events will also be collected and recorded in the subject’s records and on the eCRF. 
• 
The site will review with the subject’s parent(s)/legal guardian(s) the plan of when 
information relating to the subject’s participation in the study may be available (e.g., 
study results). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject’s parent(s)/LAR(s) choose to share this information or if it is required by 
local regulations. 
• 
At this visit or telephone call, subject’s parent(s)/LAR(s) will be asked if they can be 
contacted to participate in any future related study. If the subject’s parent(s)/LAR(s) 
are not interested in participating in future studies the reason for refusal will be 
documented in the subject’s eCRF. 

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• 
The site will complete the termination eCRF page and this will mark the completion 
of the subject’s participation in the study. 
Early termination:  
When a subject is withdrawn from treatment or withdraws from the study, the 
investigator will notify the Sponsor and, when possible, will perform the procedures 
listed below. The reason(s) for the early termination will be included in the subject’s 
source documentation and in the eCRF.  
If the Early Termination is at a clinic visit, the following procedures will be performed: 
review of Subject Diary (if applicable), review of systems, interview of subject’s 
parent(s)/LAR(s) to collect: unsolicited AEs, AESI, SAEs, medically attended AEs, AEs 
leading to vaccine/study withdrawal, interview of subject’s parent(s)/legal guardian(s) to 
collect concomitant medications/ vaccinations, symptom-directed physical assessment 
including vital signs (at a minimum rectal (subjects <12 months of age) or axillary (≥12 
months of age) body temperature preferably) and a check of general appearance, and 
blood sampling for immunogenicity (if applicable at the visit). 
If the Early Termination Visit is a telephone call, collect as much information as possible. 
Early Termination Visits also include subjects who were enrolled and or/randomized, but 
may or may not have been treated. 
The site will review with the subject’s parent(s)/LAR(s) the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results). It 
will also be discussed how information relating to the subject’s participation in the study 
will be shared with the subject’s healthcare provider, if the subject’s parent(s)/LAR(s) 
choose to share this information or if it is required by local regulations. 
The site will complete the termination eCRF page and this will mark the completion of 
the subject’s participation in the study. 
5.7. 
Biological sample handling and analysis 
Please refer to the SPM and Central Laboratory Investigator Manual for details on 
biospecimen management (handling, storage and shipment). Refer to Section 5.6.15 for 
changes in biological samples collection that may be implemented during special 
circumstances. 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 

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• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects parent(s)/LAR(s) will be asked to give a specific consent to allow GSK 
or a contracted partner to use the samples for future research. Future research will be 
subject to the laws and regulations in the US and will only be performed once an 
independent Ethics Committee or Review Board has approved this research. 
Although not planned, additional serologic testing may be performed in the future to 
further characterize the antibody response to the antigens included in the study vaccines 
or concomitantly administered vaccines (e.g. Rotavirus [HRV], hSBA against other 
meningococcal strains). 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.  
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).  
Refer also to Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).  
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed. 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
5.7.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the per-protocol analysis (See Section 9.2.5 for the 
definition of analysis sets to be analyzed). The investigator must ensure that his/her 
personnel and the laboratory(ies) under his/her supervision comply with this requirement. 
However, when GSK Biologicals does not provide material for collecting and storing 
clinical samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM. 
The above applies to any external partners designated by GSK Biologicals as well. 

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5.7.2. 
Biological samples 
The quantities of blood samples required and the corresponding timepoints are described 
in Table 8. Analysis of immune responses to the RIV antigens will be performed in 
immunogenicity subsets as described in Section 5.2.3 and Table 9.  
5.7.3. 
Laboratory assays 
The measures of immunogenicity used in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response). 
The immunogenicity of rMenB+OMV NZ is assessed in this study by measuring the 
serum bactericidal activity, which is a functional measure of the ability of antibodies, in 
conjunction with human complement, to kill meningococci, and is widely accepted and 
generally recognized as the serological surrogate of protection. 
Serological testing for immunogenicity to rMenB+OMV NZ, PCV13 (same 
pneumococcal serotypes panel (PCV13)will be used for subjects who received PCV20) 
and the other routine vaccines will be performed at a GSK Biologicals’ laboratory(ies) or 
in a laboratory(ies) designated by GSK Biologicals using standardized and validated 
procedures (refer to Table 7). 
Please refer to Appendix A for a detailed description of the assays performed in the 
study. Please refer to Appendix B for the address(es) of the clinical laboratories used for 
sample analysis. 
Table 7 
Humoral Immunity (Antibody determination)  
Syste
m 
Component 
Method 
Kit / 
Manufacture
r 
Unit* 
Cut-
off* 
Laboratory*
* 
Overall 
testing 
prioritizatio
n  
Serum 
N Men B M13520 (NHBA) 
Ab*,∞ 
hSBA 
In house 
1/dil 
4 
Laboratory 
designated 
by GSK 
Biologicals 
1 
N Men B NZ98/254 (PorA) 
Ab  
4 
N Men B M14459 (fHbp) 
Ab 
3 
N Men B 96217 (NadA) 
Ab  
6 
Serum 
Streptococcus 
pneumoniae.Polysacchari
de 01 Ab.IgG  
ECL  
In house 
µg/ 
mL 
0.08 
GSK 
Biologicals 
*** 
2 
Streptococcus 
pneumoniae.Polysacchari
de 03 Ab.IgG  
0.07
5  
Streptococcus 
pneumoniae.Polysacchari
de 04 Ab.IgG  
0.06
1  

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Syste
m 
Component 
Method 
Kit / 
Manufacture
r 
Unit* 
Cut-
off* 
Laboratory*
* 
Overall 
testing 
prioritizatio
n  
Streptococcus 
pneumoniae.Polysacchari
de 05 Ab.IgG  
0.19
8  
Streptococcus 
pneumoniae.Polysacchari
de 06A Ab.IgG  
0.11
1  
Streptococcus 
pneumoniae.Polysacchari
de 06B Ab.IgG  
0.10
2  
Streptococcus 
pneumoniae.Polysacchari
de 07F Ab.IgG  
0.06
3  
Streptococcus 
pneumoniae.Polysacchari
de 09V Ab.IgG  
0.06
6  
Streptococcus 
pneumoniae.Polysacchari
de 14 Ab.IgG  
0.16  
Streptococcus 
pneumoniae.Polysacchari
de 18C Ab.IgG  
0.11
1 
Streptococcus 
pneumoniae.Polysacchari
de 19A Ab.IgG  
0.19
9  
Streptococcus 
pneumoniae.Polysacchari
de 19F Ab.IgG  
0.16
3 
Streptococcus 
pneumoniae.Polysacchari
de 23F Ab.IgG  
0.07
3  
Serum 
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG  
ELI 
In-house 
IU/mL  
0.03
0  
GSK 
Biologicals 
*** 
10 
Clostridium tetani.Tetanus 
Toxoid Ab.IgG  
ELI 
In-house 
IU/mL  
0.03
7  
11 
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG  
ELI 
In-house 
IU/mL  
2.04
6  
4 
Bordetella 
pertussis.Pertussis Toxin 
Ab.IgG  
ELI 
In-house 
IU/mL  
2.69
3  
4 
Bordetella 
pertussis.Pertactin Ab.IgG  ELI 
In-house 
IU/mL  
2.18
7  
4 
Poliovirus Sabin Type 1 
Ab  
NEU 
In-house 
ED50  
8  
12 
Poliovirus Sabin Type 2 
Ab  
NEU 
In-house 
ED50  
8  
14 
Poliovirus Sabin Type 3 
Ab  
NEU 
In-house 
ED50  
8  
13 

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Syste
m 
Component 
Method 
Kit / 
Manufacture
r 
Unit* 
Cut-
off* 
Laboratory*
* 
Overall 
testing 
prioritizatio
n  
Hepatitis B Virus.Surface 
Ab  
CLIA 
mIU/m
L  
6.2  
5 
Serum 
Haemophilus influenzae 
type b.Polyribosyl Ribitol 
Phosphate Ab  
ELI* 
In-house 
µg/ 
mL  
0.06
6  
GSK 
Biologicals 
*** 
3 
Serum 
Measles Virus Ab.IgG  
Lumine
x 
In-house 
mIU/m
L 
TBD 
Laboratory 
designated 
by GSK 
Biologicals 
8 
Rubella Virus Ab.IgG  
Lumine
x 
In-house 
IU/mL 
TBD 
Laboratory 
designated 
by GSK 
Biologicals 
9 
Mumps Virus Ab IgG 
Lumine
x 
In-house 
AU/mL 
TBD 
Laboratory 
designated 
by GSK 
Biologicals 
6 
Serum 
Varicella Zoster Virus 
Ab.IgG  
ELI* 
In-house 
mIU/m
L 
97.0 
GSK 
Biologicals**
*  
7 
Ab: Antibody, CLIA: Chemiluminescence immunoassay, IgG: Immunoglobin G, µg: Microgram, mL: Milliliter, 1/dilution: 
reciprocal of the dilution; ECL: Electrochemiluminescent Assay, ELI: enzyme-linked immunosorbent assay (ELISA), 
MSBA: manual human serum bactericidal assay (hSBA), NEU: neutralization assay, TBD: to be determined.  
*Type of assays, the validated assay cut-offs and units might be subject to change during the course of the study (e.g. 
in case of requalification, revalidation or standardization, availability of assays). In case testing is done at another GSK 
designated laboratory, the validated assay cut-off may also need to be adapted accordingly. Any of these changes will 
be documented in a protocol amendment or clinical study report. The LLOQ for the meningococcal B strains are 
provided in Table 20. 
**Refer to Appendix B for the laboratory addresses. 
***GSK Biologicals laboratory refers to the Vaccines Clinical Laboratory and Assay Portfolio (Vx CL&AP) in 
Rixensart, Belgium; Wavre, Belgium. 
Additional exploratory testing on the vaccine and/or on the disease under study may be performed if deemed 
necessary for accurate interpretation of the data or should such assay(s) become available at GSK. These assays may 
not be represented in the objectives/endpoints of the study protocol.  
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
CCI

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5.7.4. 
Biological samples evaluation 
5.7.4.1. 
Immunological read-outs  
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided in Table 8. Testing 
against RIV antigens will be performed in immunogenicity subsets as defined in Section 
5.2.3 and in Table 9. 
Table 8 
Immunological Read-outs  
Blood sampling timepoint 
Group Name 
Max No. 
subjectsa 
Component 
Components 
priority rank 
Type of contact and 
timepoint 
Sampling 
timepoint 
Visit 4 (Day 151) 
Post-Vacc 3 
Group 
MenB+PCV, 
Placebo+PCVb 
1000 
hSBA-M13520 
hSBA-NZ98/254 
hSBA-M14459 
hSBA-96217 
1 
Groups 
MenB+PCV, 
Placebo+PCV 
800 
Anti-PCV13  
(1,3, 4, 5, 6°, 6B, 7F, 9V, 
14, 18C, 19°, 19F, 23F) 
2 
Groups 
MenB+PCV, 
Placebo+ PCV 
1200 
DT,TT, PT, FHA, PRN, 
HBs, Polio, Hiba 
See Table 9 a 
Visit 5 (Day 301) 
Pre-Vacc 4 
Groups 
MenB+PCV 
Placebo+PCVb 
1000 
hSBA-M13520 
hSBA-NZ98/254 
hSBA-96217 
hSBA-M14459 
1 
Groups 
MenB+PCV and 
Placebo+PCV 
1200 
M,M,R, V 
See Table 9 a 
Visit 6 (Day 331) 
Post-Vacc 4 
Groups 
MenB+PCV 
Placebo+PCVb 
1000 
hSBA-M13520 
hSBA-NZ98/254 
hSBA-96217 
hSBA-M14459 
1 
Groups 
MenB+PCV 
Placebo+PCV 
800 
Anti-PCV13 
(1,3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) 
2 
Groups 
MenB+PCV and 
Placebo+PCV 
1200 
M,M,R, V 
See Table 9 a 
DT: diphtheria toxoid, TT: tetanus toxoid, FHA: filamentous hemagglutinin, PT: pertussis toxin, PRN: pertactin, HBs: 
Hepatitis B surface antigen, Hib: Haemophilus influenzae type b antigen, MMR: measles, mumps, rubella virus 
antigens, PCV; pneumococcal serotype antigens; V: varicella virus antigens, NA, not applicable. 
* Laboratory assays 
Note: As testing against pneumococcal serotypes will be performed using a multiplex assay, no ranking is applicable.  
a Testing at Visit 4, Visit 5 and Visit 6 will be performed based on immunogenicity subsets, defined in Section 5.2.3 and 
in Table 9. 
b A subset (B1) of 200 subjects (120 evaluable) from Group Placebo+PCV will be tested against the 4 serogroup B 
strains in order to maintain the observer-blindness of the study during blood sample testing. 

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Table 9 
Immunogenicity Subsets  
Blood sampling timepoint 
Group Name 
Subset 
Max No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
 
 
 
 
 
Visit 4 (Day 151)  
Post-Vacc 3 
Group 
MenB+PCV 
A1 
400 
MenB 
PCV13 
Hib 
Pertussis 
Diphtheria 
Tetanus 
1 
2 
3 
4 
5 
5 
A2 
200 
MenB 
Hib 
Pertussis 
HepB 
1 
2 
3 
4 
A3 
200 
MenB 
Pertussis 
Polio 
1 
2 
3 
Group 
Placebo+PCV 
B1 
200 
MenB 
PCV13 
Hib 
Pertussis 
1 
2 
3 
4 
B2 
200 
PCV13 
Hib 
Pertussis 
HepB 
Diphtheria 
Tetanus 
Polio 
1 
2 
3 
4 
5 
5 
6 
Visit 5 (Day 301) 
Pre-Vacc 4 
Group 
MenB+PCV 
A1 
400 
MenB 
Measles 
Rubella 
Mumps 
Varicella 
1 
2 
2 
2 
3 
A2 
200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
A3 
200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
Group 
Placebo+PCV 
B1 
200 
MenB 
Measles 
Rubella 
Mumps 
Varicella 
1 
2 
2 
2 
3 
B2 
200 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
2 
2 

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Blood sampling timepoint 
Group Name 
Subset 
Max No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
 
 
 
 
 
Visit 6 (Day 331) 
Post-Vacc 4 
Group 
MenB+PCV 
A1 
400 
MenB 
PCV13 
Measles 
Rubella 
Mumps 
Varicella 
1 
2 
3 
3 
3 
4 
A2 
200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
A3 
200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
Group 
Placebo+PCV 
B1 
200 
MenB 
PCV13 
Measles 
Rubella 
Mumps 
Varicella 
1 
2 
3 
3 
3 
4 
B2 
200 
PCV13 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
Note: The individual components and the order of testing is given below: 
MenB: hSBA-M13520, hSBA-NZ98/254, hSBA-M14459, hSBA-96217. 
PCV13: 1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F – no ranking is applicable for pneumococcal serotypes as a 
multiplex assay will be used. 
Pertussis : Pertactin, Pertussis toxin, Filamentous Hemagglutinin. 
Polio: I, III, II. 
5.7.5. 
Immunological correlates of protection  
For pneumococcal conjugate vaccines for use in infants, pertussis, and rotavirus antigens 
no generally accepted immunological correlate of protection has been clearly identified 
yet.  
For the following antigens in the DTPa-HBV-IPV, Hib, MMR and VV vaccines, an 
immunological correlate of protection has been established: 
• 
Anti-D and anti-T concentrations 0.1 IU/mL (ELISA), 
• 
Anti-HBS concentration ≥10 mIU/mL (ELISA),  
• 
Polio ≥8 ED50 for types 1, 2 and 3 (neutralizing antibody assay), 
• 
Anti-PRP concentrations ≥0.15 µg/mL (ELISA), 
• 
Anti-measles ≥threshold to be defined 
• 
Anti-mumps ≥threshold to be defined 

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• 
Anti-rubella ≥threshold to be defined 
• 
The immunological assay results will be communicated to the investigator as soon as 
they become available. For antigens for which an immunological correlate of 
protection has been established, the following applies.  
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’ parent(s)/LAR(s). 
For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices. 
6. 
STUDY VACCINES AND ADMINISTRATION 
6.1. 
Description of study vaccines 
6.1.1. 
Study vaccines 
The study vaccines’ (see glossary of terms) will be provided by the Sponsor. All study 
participants are expected to receive these vaccines as specified by the study schedule. The 
study vaccines specific to this study are described below. In exceptional circumstances, 
in order to avoid any inconvenience for the participant, a commercially-acquired 
vaccine with identical formulation and brand of that reported in the study protocol can 
be administered to the participant. In this case this subject will still be eligible for the 
Per Protocol Set. 
• 
GSK Biologicals’ Meningococcal group-B vaccine, (rMenB+OMV NZ, Bexsero); 
• 
Pneumococcal polysaccharide conjugate vaccine, (13-valent Pneumococcal Vaccine) 
(PCV13, Prevnar13) (In order to comply with the change in the US NIP, 20-valent 
Pneumococcal Vaccine (PCV20, Prevnar20) will also be allowed as specified in 
the protocol);  
• 
Saline placebo vaccine. 
Standardized routine infant immunizations included in this study are described below. 
• 
GSK Biologicals’ Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, 
Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine (DTPa-HBV-IPV, 
Pediarix): a 3-dose vaccine given by IM injection at 2, 4, and 6 months of age. A 
single-dose prefilled syringes contains a 0.5-mL suspension for injection. 
• 
GSK Biologicals’ Rotavirus Vaccine, live, oral (HRV, Rotarix): a vaccine containing 
attenuated human strain P1AG1. HRV is a 2-dose vaccine typically given at 2 
months and 4 months of age; it is available in single-dose vials of lyophilized 
vaccine, accompanied by a prefilled oral applicator of liquid diluent.  
• 
GSK Biologicals’ Haemophilus influenzae type b vaccine (Hib, Hiberix): a vaccine 
indicated for active immunization for the prevention of invasive disease caused by 
Haemophilus influenzae type b. Hib is given as a 4-dose series by IM injection; the 
primary series consists of one dose each at 2, 4, and 6 months of age, followed by a 
booster dose at 12 through 15 months of age.  

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• 
Merck’s measles, mumps and rubella virus vaccine live (MMR, M-M-R II): a 
vaccine indicated for active immunization for simultaneous vaccination against 
measles, mumps, and rubella in individuals 12 months of age or older. Each 
lyophilized dose is approximately 0.5 mL after reconstitution and is administered by 
subcutaneous injection. 
• 
Merck’s varicella zoster virus vaccine live (VV, Varivax): a vaccine indicated for 
active immunization for the prevention of varicella in individuals 12 months of age 
or older. Each dose is approximately 0.5 mL after reconstitution and is administered 
by subcutaneous injection. 
The characteristics of the study vaccines are presented in Table 10.  
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained.  
The vaccines are labelled and packed according to applicable regulatory requirements. 
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics. 
Table 10 
Study Vaccines  
Treatment 
name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
Bexsero  
rMenB+OMV NZ 
rp936-741=50µg; rp287-
953=50µg; 
rp961c=50µg; OMV 
NZ98/254=25µg; 
Al(OH)3=1.5mg; 
Histidine=776µg; 
NaCl=3.125mg; 
Sucrose=10mg; 
water=0.5ml  
Prefilled syringe 
(liquid) 
0.5 mL  
4 
Prevnar13  
PCV13  
PS1=2.2µg CRM197; 
PS3=2.2µg CRM197; 
PS4=2.2µg CRM197; 
PS5=2.2µg CRM197; 
PS6A=2.2µg CRM197; 
PS6B=4.4µg CRM197; 
PS7F=2.2µg CRM197; 
PS9V=2.2µg CRM197; 
PS14=2.2µg CRM197; 
PS18C=2.2µg CRM197; 
PS19A=2.2µg CRM197; 
PS19F=2.2µg CRM197; 
PS23F=2.2µg CRM197; 
AlPO4=125µg Al3+  
Homogenous 
white 
suspension after 
shaking (in pre-
filled syringe) 
0.5 mL  
4** 

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Treatment 
name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
Prevnar20 
PCV20  
PS1(2.2 µg)¹,²;  
PS3(2.2 µg)¹,²;  
PS4(2.2 µg)¹,²;  
PS5(2.2 µg)¹,²; 
PS6A(2.2 µg)¹,²; 
PS6B(4.4 µg)¹,²; 
PS7F(2.2 µg)¹,²; 
PS8(2.2 µg)¹,²; 
PS9V(2.2 µg)¹,²; 
PS10A(2.2 µg)¹,²; 
PS11A(2.2 µg)¹,²; 
PS12F(2.2 µg)¹,²; 
PS14(2.2 µg)¹,²; 
PS15B(2.2 µg)¹,²; 
PS18C(2.2 µg)¹,²; 
PS19A(2.2 µg)¹,²; 
PS19F(2.2 µg)¹,²; 
PS22F(2.2 µg)¹,²; 
PS23F(2.2 µg)¹,²; 
PS33F(2.2 µg)¹,² 
Suspension for 
injection (in 
pre-filled-
syringe) 
0.5 mL 
1 
Placebo  
Placebo  
(NaCl)  
NaCl=150mM 
Prefilled syringe 
(liquid) 
0.65 mL* 
4 
Pediarix  
DTPa-HBV-IPV 
DT>=30IU; TT>=40IU; 
PT=25µg; FHA=25µg; 
PRN=8µg; 
HbsAg=10µg; 
Inactivated Poliovirus 
type 1 (Mahoney 
strain)=40DU; 
Inactivated Poliovirus 
type 2 (MEF-1 
strain)=8DU; Inactivated 
Poliovirus type 3 
(Saukett strain)=32DU; 
Aluminium=700µg Al3+  
Prefilled syringe 
(liquid) 
 
3 
Hiberix  
Hib 
PRP=10µg; TT~=25µg; 
Aluminium=120µg Al3+ 
Lyophilized cake 
to be 
reconstituted 
with saline 
diluent 
0.5 mL  
3 
Hib diluent (NaCl)  
NaCl=150mM  
Vial (liquid)  
Rotarix 
HRV Lyo  
HRV RIX4414 live 
attenuated 
>=106.0CCID50  
Lyophilized 
vaccine in a 
monodose glass 
vial.  
1 mL  
2 
HRV Diluent 
CaCO3=60mg 
Diluent for 
lyophilized 
vaccine (calcium 
carbonate liquid 
antacid) supplied 
separately in a 
prefilled oral 
applicator 

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Treatment 
name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
M-M-R II  
MMR-II 
Measles>=1.000TCID50; 
Mumps=12.500TCID50; 
Rubella=1.000TCID50 
Lyophilized 
pellet in a vial for 
reconstitution 
with water for 
injections 
0.5 mL  
1 
MMR-II diluent 
(Water for 
injection )  
Water=0.5ml  
vial  
Varivax  
Varivax  
Oka=1350pfu  
Monodose vial of 
lyophilized 
vaccine 
0.5 mL  
1 
Varivax Diluent 
(Water for 
injection) 
Water=0.5ml  
vial  
Note: Refer to the SPM for the volume after reconstitution. The fourth dose of Hib vaccine will be administered as an 
non-study vaccine at 13 months of age. 
CCID50:=median Cell Culture Infective Dose (quantity of virus causing infection in 50% of exposed cells) 
CaCO₃: Calcium carbonate, HRV: Human Rotavirus, Hib: Haemophilus influenzae type b vaccine, DT: diphtheria 
toxoid, TT: tetanus Toxoid, PT: pertactin, FHA: filamentous hemagglutinin, PRN: Pertactin, HbsAg: Hepatitis B surface 
antigen, PRP: Polyribosyl-ribitol phosphate, MMR: measles, mumps, rubella. 
* The volume of the saline syringe may be between 0.6mL and 0.8 mL. The full volume is to be injected. 
** For subjects who receive PCV20 at Visit 5, only 3 doses of PCV13 will be administered. 
¹conjugated to CRM₁₉₇ (51 µg);  
²adsorbed on AlPO₄ (0.125 mg Al³⁺); Water for injections 
6.1.2. 
Non-study vaccines 
The term ‘non-study vaccine’ refers to those vaccines which will be given to subjects 
during the study but do not have associated study objectives. Non-study vaccines are 
Non-Investigational Medicinal Products (NIMPs) and must be licensed in the country 
where they are administered. The Investigator is responsible for reporting AEs associated 
to the use of a non-study vaccine according to local laws and regulations in addition to 
the safety reporting procedures foreseen in this study. The Sponsor is responsible for the 
ongoing safety evaluation of the clinical trial subjects including events related to non-
study vaccines. 
The following non-study vaccine will be administered to all subjects in both groups at 13 
months of age, at Visit 6 (Day 331).  
• 
GSK Biologicals’ GSK Biologicals’ Diphtheria and Tetanus Toxoids and Acellular 
Pertussis Adsorbed Vaccine (DTPa, Infanrix): DTPa is a 5-dose vaccine given by IM 
injection at 2, 4, and 6 months of age, with a booster dose at 15 to 20 months of age 
and another booster dose at 4 to 6 years of age. A single-dose prefilled syringes 
contains a 0.5-mL suspension for injection. 
In order to complete the dosage scheme for DTPa, a single dose of DTPa (Infanrix) will 
be administered IM as a booster dose at Visit 6 (as subjects would have already received 
3 doses of Pediarix as an IMP study-vaccine).  
In addition, all subjects will receive the fourth dose of Hib (Hiberix) as a non-study 
vaccine during Visit 6. Details on the vaccine are provided in Section 6.1.1.  

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Non-study vaccines will be supplied by the Sponsor to ease the potential disruption to the 
standard vaccine schedule caused by participating to the study. They will be recorded in 
the subjects’ eCRF.  
Note: Other non-study vaccines whose use, depending on local requirements, may be 
foreseen in this trial includes, but are not limited to: monovalent Hepatitis B, Hepatitis A 
and influenza. If any of these vaccines are administered at Visit 4 or Visit 6, the 
administration should occur after the study blood draw at these visits. Any other vaccine 
not foreseen in the protocol should be administered outside a period of 14 days (or 28 
days for live vaccines and 7 days for influenza vaccines) pre- or post-administration of 
the study vaccines (forbidden window). For any vaccine administered outside the 
forbidden window, the Investigators will be allowed to choose the type, the timing and 
the number of doses of intercalated non-study vaccines to be administered, in accordance 
with local regulations and practices.  
6.2. 
Storage and handling of study and non-study vaccines 
Detailed vaccine supply, labeling, storage and tracking instructions will be provided to 
investigators in the Clinical Trial Supplies module in the SPM prior to study start. The 
below mentioned details on vaccine storage and handling are applicable to all vaccines 
used in the study, including NIMPs. 
All vaccines associated with this study must be checked for expiration date prior to use. 
Expired vaccines must not be administered to subjects. All vaccines associated with this 
study are to be stored separately from other vaccines and medications in a secure location 
under appropriate storage conditions with temperature monitoring. 
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines. 
For the Varivax vaccine, the antigen is to be stored between -25 C/-13 F to -15 C/5 F and 
the diluent at +4C/+39.2 F.  
Temperature excursions must be reported in degree Celsius. 
Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) or below -25 C/-13 or above -15.0°C/5 F (for -20°C/-4°F 
label storage condition) impacting investigational medicinal products (IMPs) must be 
reported in the appropriate (electronic) temperature excursion decision form (Advanced 
Temperature Excursion Analysis and Management [ATEAM]). The impacted IMPs must 
not be used and must be stored in quarantine at label temperature conditions until usage 
approval has been obtained from the sponsor. Refer to the Module on Clinical Trial 
Supplies in the SPM for details and instructions on the temperature excursion reporting 
and usage decision process, packaging and accountability of the study vaccines. 

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The Sponsor will ensure the following: 
• 
Supply the study vaccines and above mentioned non-study vaccines (single dose of 
DTPa and 4th dose of Hib). 
• 
Appropriate labelling of all study and non-study vaccines provided that complies 
with the legal requirements of each country where the study is to be performed. 
The investigator must ensure the following: 
• 
Acknowledge receipt of the supplied vaccines by a designated staff member at the 
site, including confirmation that the vaccines were received in good condition 
• 
SBIR system encoding in case of temperature excursion 
• 
Proper storage of the supplied vaccines, including: 
− 
Storage in a secure, locked, temperature-controlled location. 
− 
Proper storage according to the instructions specified on the labels. 
− 
Appropriate record keeping and inventory of the study vaccines, including 
regular documentation of adequate storage temperature. 
• 
Appropriate use of the supplied vaccines, including 
Use only in accordance with the approved protocol. 
Appropriate documentation of administration of vaccines to study subjects by 
unblinded study staff including: 
− 
Date, dosage, batch/lot numbers, expiration dates, unique identifying numbers 
assigned to subjects and study vaccines, and time of vaccine administration. 
This information will be maintained in an accountability log that will be 
reviewed by the site monitor. 
− 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were received, 
which vaccines were administered to subjects, which vaccines were destroyed at 
the site, and which vaccines were returned to the Sponsor, as applicable. 
• 
Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
• 
Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
− 
Copy of the site’s procedure for destruction of hazardous material. 
− 
Copy of Destruction Certificate 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides authorization for use. In the event that the use cannot 
be authorized, the Sponsor will make every effort to replace the vaccine supply. All 
vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 

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Monitoring of the supplied study and non-study vaccines’ accountability will be 
performed by the study monitor during site visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study and non-study vaccines, packaging and 
supplementary labels are destroyed locally (upon approval from Sponsor) or returned to 
the Sponsor. 
6.3. 
Dosage and administration of study vaccines  
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by personnel who are qualified to 
perform that function under applicable local laws and regulations for the specific study 
site. It is required that the vaccine administrator and the health care professional 
collecting safety information are different. The vaccine administrator for all the study 
vaccines would be an unblinded study staff (see glossary of terms).  
Refer to Section 5.6.15 in case of a change in the allowed interval to receive the vaccine 
dose between visits during special circumstances. 
Study vaccines should be administered using the preferred site locations shown in Table 
11 below. The rMenB+OMV NZ/Placebo vaccine should be administered at least 2.5 cm 
above the injection site of Hib, when concomitantly administered on the same thigh. 
Similarly, PCV13 (or PCV20) should be administered at least 2.5 cm above the injection 
site of DTPa-HBV-IPV, when concomitantly administered on the same thigh. The HRV 
vaccine will be administered orally. The MMR and VV vaccines should be given 
subcutaneously in the upper arm (deltoid region) by inserting the needle in a pinched-up 
fold of skin and subcutaneous tissue to prevent injection into muscle. 
Standard immunization practices are to be observed and care should be taken to 
administer the injection by the route described in Table 11 below. Before administering 
vaccine, the vaccination site is to be disinfected with a skin disinfectant as applicable 
(e.g., 70% alcohol). Allow the skin to dry. DO NOT inject intravascularly.  

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Table 11 
Dosage and Administration 
Study group 
Type of 
contact and 
timepoint 
Treatment 
name 
Vol. 
administered 
Route1 
Site3 
Location 
Directionality2 
Laterality 
MenB+PCV  
Visit 1 
(Day 1) 
 
Visit 2  
(Day 61) 
 
Visit 3 
Day 121) 
Bexsero  
0.5 mL 
IM 
Thigh 
Upper 
Right 
Prevnar13 
0.5 mL 
IM 
Thigh 
Upper 
Left 
Pediarix  
0.5 mL 
IM 
Thigh 
Lower 
Left 
Hiberix  
0.5 mL 
IM 
Thigh 
Lower 
Right 
Rotarix4 
1 mL 
O 
- 
- 
- 
Visit 5 
(Day 301) 
Bexsero 
0.5 mL 
IM 
Thigh 
- 
Right 
Prevnar135 
0.5 mL 
IM 
Thigh 
- 
Left 
M-M-R II  
0.5 mL 
SC 
Arm 
Upper 
Right 
Varivax  
0.5 mL 
SC 
Arm 
Upper 
Left 
Placebo+PCV  
Visit 1 
(Day 1) 
 
Visit 2 
(Day 61) 
 
Visit 3 
(Day 121) 
Placebo 
0.5 mL 
IM 
Thigh 
Upper 
Right 
Prevnar13  
0.5 mL 
IM 
Thigh 
Upper 
Left 
Pediarix  
0.5 mL 
IM 
Thigh 
Lower 
Left 
Hiberix  
0.5 mL 
IM 
Thigh 
Lower 
Right 
Rotarix4 
1 mL 
O 
- 
- 
- 
Visit 5 
(Day 301) 
Placebo 
0.5 mL 
IM 
Thigh 
- 
Right 
Prevnar135 
0.5 mL 
IM 
Thigh 
- 
Left 
M-M-R II 
0.5 mL 
SC 
Arm 
Upper 
Right 
Varivax 
0.5 mL 
SC 
Arm 
Upper 
Left 
1Oral (O)/ Intramuscular (IM)/Subcutaneous (SC). 
2Directionality is a qualifier for further detailing the location of the vaccine administration location (e.g. Upper, Lower).  
3 Site mentioned is the preferred location for injection. The site should be recorded in the eDiary. Please note however 
that the rMenB+OMV NZ vaccine and the PCV13 vaccine should not be administered in the same thigh.  
4 Only at Visit1 and Visit 2. 
5 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
The exact anatomic location of each injection must be carefully recorded in the Medical 
Chart and in the eCRF, as well as the Subject eDiary.  
The vaccines should be visually inspected for particulate matter and discoloration prior to 
administration. In the event of any foreign particulate matter and/or variation of physical 
aspect being observed, do not administer the vaccine. For all GSK vaccines, the issue 
should be reported to GSK as described in the SPM. The vaccine should not be discarded 
until authorized by GSK 
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the Clinical Trial Supplies module in the SPM prior to study start. 

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The other non-study vaccines (fourth dose of Hib and DTPa) are licensed pediatric 
vaccines and therefore must be prepared and administered according what is described in 
their approved product label/package insert. It is the responsibility of the investigator to 
maintain proper storage and use according to the instructions in the SMP. The 
investigator will also be responsible for documenting vaccine administration on the eCRF 
and keeping records of vaccines administered to subjects. 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of any of the study vaccines. Administration of a lower dosage should be recorded in the 
eCRF as well. 
An overdose would also occur if two doses of the study vaccine are administered within 
half the time of the recommended interval between doses, as defined in the protocol. 
Any unused medicinal product or waste material should be disposed of in accordance 
with local requirements. 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable.  
The investigator will use SBIR to obtain the replacement vaccine number. The 
replacement numbers will be allocated by dose for Bexsero and placebo vaccines. 
Replacement numbers will be allocated by components for all other products. The system 
will ensure, in a blinded manner, that the replacement treatment matches the formulation 
the subject was assigned to by randomization.  
6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
vaccines specified in the protocol. If any of these events occur during the study, the 
subject must not receive additional doses of vaccines but may continue other study 
procedures at the discretion of the investigator (see Section 7.4).  
• 
Anaphylaxis following the administration of vaccines. 
• 
Occurrence of a new pIMD or the exacerbation of an existing pIMD. Refer to 
Section 7.1.6.2 for the definition of pIMDs. 
• 
Any occurrence of an event listed in the exclusion criteria which must be always re- 
assessed by the investigator before administration of the next dose of study vaccine. 
Refer to Section 4.2.  
• 
Subjects who experience any SAE judged to be possibly or probably related to study 
vaccine, including hypersensitivity reactions. 

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• 
Subjects who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the subject if he/she continues to participate in the study. 
The following events constitute contraindications to administration of rMenB+OMV NZ 
at that point in time; if any of these events occur at the time scheduled for vaccination, 
the subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 5.5).  
• 
Body temperature elevation [≥ 100.4° F (≥38.0° C)] within the previous 3 days.  
• 
Significant acute illness within the previous 7 days. 
• 
Use of antipyretics and/or analgesic medications within the previous 6 hours. 
• 
Receipt of, or plan to receive, any other vaccine(s) than those listed as study or non-
study vaccines, within 14 days (or 28 days for live attenuated vaccines and 7 days for 
influenza vaccines) of study vaccination. 
For contraindications to administered other study vaccines, refer to their approved 
product label/package insert. 
6.6. 
Warnings and precautions 
Refer to the IB for rMenB+OMV NZ and to the approved product label/package insert 
for all vaccines administered during the study. 
6.7. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator or delegate should question the subject’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
subject. 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF. 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the 30 days post- vaccination period.  
• 
Any concomitant medications/products administered for treatment of an AE to be 
recorded as per the protocol-specified reporting period (see Table 13). 
• 
Any concomitant vaccination administered in the period starting from birth and 
ending at the last study visit (Day of birth to Day 481 or Day 661). 
• 
Any non-study concomitant vaccination (see Section 6.1.2). 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 

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E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 38.0°C/100.4°F regardless the location of measurement]. The preferred 
location for measuring temperature in this study will be the rectum for subjects < 12 
months of age and the axilla for subjects ≥1 year of age. 
• 
Any concomitant medications/products/vaccines listed in Section 6.7.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE/AESI to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE /AESI. In addition, concomitant medications relevant to SAEs 
and AESI need to be recorded on the expedited Adverse Event report. 
• 
The use of antipyretic and/or other medications to prevent (prophylactic use) and/or 
treat fever during the first 7 days after vaccination to be recorded in the eCRF as 
well. 
6.7.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 9.2 for analyses sets to be analyzed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period.  
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 15 days consecutive days in total) during the study period. Inhaled 
and topical steroids are allowed. 
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 
• 
Immunoglobulins and/or any blood products administered during the study period. 
• 
A vaccine not foreseen by the study protocol administered during the period of 14 
days (28 days for live vaccines, 7 days for influenza vaccines) pre- or post-
administration of the study vaccines (forbidden window) at Visit 1, Visit 2, Visit 3 
and Visit 5*. 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a 
pandemic) is organized by the public health authorities, outside the routine immunization 
program, the time period described above can be reduced if necessary for that vaccine 
provided it is licensed and used according to its Prescribing Information and according to 
the local governmental recommendations and provided a written approval of the Sponsor 
is obtained. 

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6.8. 
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses  
At each study visit subsequent to the first vaccination/the vaccination visit, it must be 
verified if the subject has experienced or is experiencing any intercurrent medical 
condition. If it is the case, the condition(s) must be recorded in the eCRF. 
7. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.  
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should they/the subject manifest any signs or symptoms they perceive as serious. 
7.1. 
Safety definitions 
7.1.1. 
Definition of an adverse event 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.  
Examples of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study vaccines administration even 
though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms temporally associated with study vaccines administration. 
• 
Significant failure of expected pharmacological or biological action.  
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 
Adverse Events to be recorded as solicited AEs are described in Section 7.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
Solicited AEs are derived from organized data collection systems, such as Subject 
Diaries.  

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Examples of an AE DO NOT include: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.  
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 
Since non-study vaccines described in this protocol will not be evaluated as part of the 
study objectives, no study specific safety assessment is foreseen for these vaccines.  
7.1.2. 
Definition of a serious adverse event  
A SAE is any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/incapacity,  
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 

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Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. 
All AEs which do not fall into these categories are defined as non-serious. It should be 
noted that a severe AE need not be serious in nature and that an SAE need not, by 
definition, be severe. All SAEs will be evaluated by the investigator for relationship of 
the event to study vaccine.  
7.1.3. 
Solicited adverse events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
parent(s)/LAR(s) for 7 consecutive days (with ongoing solicited AEs collected until 
resolution or day 30, whichever occurs first), using a pre-defined Subject Diary. 
Reactogenicity will be collected from all subjects after each vaccination visit (study Days 
1, 61, 121 and 301). In addition, specific solicited system AEs (parotid/salivary gland 
swelling, fever and rash) will be collected for 30 days following the MMR and VV 
vaccine administration at Visit 5. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported in the tables below.  
The collected data will be entered into the Subject Diary. Please see Section 5.6.16.1 for 
more detail.  
7.1.3.1. 
Solicited local adverse events (administration site event) 
Solicited local AEs (administration site event) will be collected following each study 
vaccine, by site of administration. 
• 
Hardness of skin at injection site (Induration at injection site), 
• 
Swelling of skin at injection site (Swelling at injection site),  
• 
Redness at injection site (Erythema at injection site), 
• 
Tenderness or discomfort to the touch at injection site (Tenderness at injection site). 
In the eCRF, solicited local AEs (administration site event) occurring within 30 minutes 
after vaccination are described as mentioned within brackets. 
7.1.3.2. 
Solicited systemic adverse events 
• 
Decreased eating (Change in eating habits),  

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• 
Increased sleepiness (Sleepiness),  
• 
Vomiting/throwing up (Vomiting), 
• 
Loose stools/diarrhea (Diarrhea), 
• 
Irritability (Irritability),  
• 
Persistent/continuous crying (Persistent crying), 
• 
Rash (only after MMR and VV administration at Visit 5), 
• 
Parotid/salivary gland swelling (only after MMR and VV administration at Visit 5), 
• 
Fever, defined as body temperature ≥38.0°C/100.4°F*. 
*Body temperature measurement; temperature should be taken preferably via the rectal 
route for subjects < 12 months of age and the axilla for subjects >1 year of age, ideally at 
the same time each day. Other routes of temperature measurement include axillary, oral 
and tympanic. Temperature measurements should be taken prior to administration of 
antipyretic medication. 
In the eCRF, solicited systemic AEs occurring within 30 minutes after vaccination are 
described as mentioned within brackets.  
The study staff must review the data entered into the Subject Diary as described in 
Section 10.2. 
7.1.3.3. 
Other solicited adverse events 
Solicited local (administration site) and systemic AEs that continued beyond day 7 after 
vaccination will not need to be entered as an AE in the AE eCRF or the subject’s source 
document. They will be collected via the eDiary. 
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 10.2) and also as an adverse event on the 
Adverse Event eCRF: 
• 
Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see Section 7.2.3.4). 
• 
Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse 
event leading to withdrawal). 
Solicited local or systemic adverse event that otherwise meets the definition of a serious 
adverse event (see Section 7.1.2). 
7.1.4. 
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a parent(s)/LAR(s) who has signed 
the informed consent. 

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Unsolicited AEs will be collected during interview with the parent(s)/LAR(s) and by 
review of available medical records at the next visit. Unsolicited AEs will be reviewed at 
the safety follow-up calls as well. 
Parent(s)/LAR(s) will be instructed to contact the site as soon as possible to report 
potential unsolicited AEs that required hospitalization, or emergency room visit, or visit 
to/by a health care provider that were of concern to the parent(s)/LAR(s). The detailed 
information about the reported unsolicited AEs will be collected by the qualified site 
personnel during the interview and will be documented in the subject’s records. 
All subjects’ parent(s)/ legal guardian(s) will be instructed to contact the site in case their 
child experiences unsolicited AEs which persist beyond 30 days after study vaccination.  
7.1.5. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events  
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments (e.g. x-ray imaging studies) that 
are judged by the investigator to be clinically significant will be recorded as AE or SAE 
if they meet the definition of an AE or SAE (refer to Sections 7.1.1 and 7.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. The investigator will exercise his or her medical and scientific judgement 
in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
7.1.6. 
Adverse events of special interest 
Adverse events of special interest (AESIs) are predefined (serious or non-serious) AEs of 
scientific and medical concern specific to the product or program, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be 
appropriate, because such an event might warrant further investigation in order to 
characterize and understand it.  
7.1.6.1. 
Febrile seizures 
Seizures are defined according to the Brighton Collaboration Working Group (BCWG) 
case definition of generalized convulsive seizure as an adverse event following 
immunization [Bonhoeffer, 2004]. 
The list of Preferred Terms (PTs) corresponding to the diagnosis of seizure, are those 
included in the Medical Dictionary for Regulatory Activities (MedDRA) Standard 
MedDRA Query (SMQ) Narrow “Generalized convulsive seizures following 
immunization”.  

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For any new diagnosis of generalized convulsive seizure (including febrile seizure), 
irrespective of seriousness, the investigator (or designate) must complete, an electronic 
Expedited Adverse Events Report and an ad-hoc eCRF page on seizures to further 
characterize this AESI. 
7.1.6.2. 
Arthritis 
Cases of arthritis are defined according to the following ad-hoc definition: 
• 
Presence of a physical exam findings of swelling, redness, heat, or limitation in 
range of motion and/or 
• 
Presence of a diagnostic imaging studies interpreted by a health care provider as 
demonstrating evidence of joint inflammation and/or arthrocentesis results 
evidencing inflammation. 
Due to the heterogeneity of the presentation of arthritis which can be either acute or 
chronic, the threshold of duration of symptoms of 6 weeks is to be considered. 
The list of PTs corresponding to the diagnosis of arthritis, are those included in the 
MedDRA SMQ Narrow “Arthritis”. For any new diagnosis of arthritis (serious or non-
serious) in a study subject, the investigator (or designate) must complete, an electronic 
Expedited Adverse Events Report and an ad-hoc eCRF page on arthritis to further 
characterize this AESI. 
7.1.6.3. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. The AEs that need to be recorded 
and reported as pIMDs include those listed in Table 12. 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD. 
Table 12 
List of Potential Immune-Mediated Diseases  
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and 
paresis (e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants. 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), 
including: 
- 
Diffuse Scleroderma 
- 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis  
- 
Polymyositis  
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 

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• 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants e.g.: non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic 
inflammatory 
demyelinating 
polyneuropathy,  
- 
Multifocal motor 
neuropathy  
- 
Polyneuropathies 
associated with 
monoclonal 
gammopathy. 
• 
Narcolepsy. 
• 
Anti-synthetase syndrome. 
• 
Rheumatoid Arthritis and 
associated conditions 
including:  
- 
Juvenile Idiopathic 
Arthritis 
- 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, 
including:  
- 
Ankylosing Spondylitis,  
- 
Reactive Arthritis 
(Reiter’s Syndrome), 
- 
Undifferentiated 
Spondyloarthritis, 
- 
Psoriatic Arthritis, 
- 
Enteropathic arthritis. 
• 
Relapsing Polychondritis. 
• 
Mixed Connective Tissue 
disorder. 
• 
Gout. 
• 
Localized Scleroderma 
(Morphoea). 
Vasculitis 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including:  
- 
Giant Cell Arteritis 
(Temporal Arteritis), 
- 
Takayasu’s Arteritis.  
• 
Medium sized and/or 
small vessels vasculitis 
including:  
- 
Polyarteritis nodosa, 
- 
Kawasaki’s disease,  
- 
Microscopic 
Polyangiitis,  
- 
Wegener’s 
Granulomatosis 
(granulomatosis 
with polyangiitis),  
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune 
glomerulonephritis 
including: 
- 
IgA nephropathy,  
- 
Glomerulonephritis 
rapidly progressive,  
- 
Membranous 
glomerulonephritis,  
- 
Membranoproliferative 
glomerulonephritis,  
- 
Mesangioproliferative 
glomerulonephritis.  
- 
Tubulointerstitial 
nephritis and uveitis 
syndrome. 
- 
Churg–Strauss 
syndrome (allergic 
granulomatous 
angiitis or 
eosinophilic 
granulomatosis with 
polyangiitis),  
- 
Buerger’s disease 
(thromboangiitis 
obliterans),  
- 
Necrotizing 
vasculitis 
 
• 
Ocular autoimmune 
diseases including: 
- 
Autoimmune uveitis  
- 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson 
syndrome. 
• 
Sjögren’s syndrome. 

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(cutaneous or 
systemic),  
- 
anti-neutrophil 
cytoplasmic 
antibody (ANCA) 
positive vasculitis 
(type unspecified), 
- 
Henoch-Schonlein 
purpura (IgA 
vasculitis),  
- 
Behcet’s syndrome, 
- 
Leukocytoclastic 
vasculitis. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary 
fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing 
cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel disease, 
including: 
- 
Crohn’s disease,  
- 
Ulcerative colitis,  
- 
Microscopic colitis,  
- 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave’s or Basedow’s 
disease. 
• 
Diabetes mellitus type I. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune 
syndrome. 
• 
Autoimmune hypophysitis. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of MedDRA preferred terms (PTs) and PT codes corresponding 
to the above diagnoses will be available to investigators at study start. 
7.2. 
Detecting and recording adverse events and serious 
adverse events 
7.2.1. 
Time period for detecting and recording adverse events and 
serious adverse events  
All AEs starting within 30 days following administration of each dose of study vaccines 
(Day 1 to Day 30 postvaccination) must be recorded onto/into the appropriate section of 
the eCRF, irrespective of intensity or whether or not they are considered vaccination-
related. 
The time period for collecting and recording SAEs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 6 months or 12 months following administration 
of the last dose of study vaccine for each subject (ie, study end). See Section 7.3 for 
instructions on reporting of SAEs. 

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All medically attended AEs will be collected and recorded from Day 1 (ie, the time of the 
first receipt of study vaccines) until 6 months or 12 months following administration of 
the last dose of study vaccine for each subject (ie, study end). 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
Day 1 (ie, the time of the first receipt of study vaccines) until 6 months or 12 months 
following administration of the last dose of study vaccine for each subject (ie, study end). 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
The time period for collecting and recording of AESIs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 6 months or 12 months following administration 
of the last dose of study vaccines (ie, study end). See section 7.3 for instructions on 
reporting of AESIs. Details regarding follow-up of AEs, SAEs and AESIs are given in 
Section 7.4. 
An overview of the protocol-required reporting periods for AEs, SAEs, medically 
attended AEs and AESIs is given in Table 13. 

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Table 13 
Reporting Periods for Collecting Safety Information 
Event 
Pre-V11 
V1 
D16 
D31  
 
V2 
D76 D91 
 
V3 
D136 
V4 
 D181D241 
V5 
D 316 
V6 
 D361, 
421, 
481, 
541, 
6012 
V7 
D1 
 
D61  
(2 M post-
vacc 1) 
 
D121 
(2 M post-
vacc 2) 
D151 
(1 M 
post-
vacc 
3) 
 
D301 
(6 M 
post-
vacc 3) 
D331 
(1 M 
post-
vacc 4) 
 
D481 or 
D661  
(6 M or 12 
M post-
vacc 4)3 
Solicited local and 
systemic AEs4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading 
to withdrawal from 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs (including 
SAEs related to 
study vaccine(s)) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 infection 
related AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M: month, V: Visit; D: Day, AE: adverse event, SAE: serious adverse event, AESI: adverse event of special interest, COVID-19: Coronavirus Disease 2019.  

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Note: All concomitant medications/products, except vitamins and dietary supplements, administered during the 30-days postvaccination period as well as those used to treat an AE or a 
SAE (throughout the study period), should be recorded in the eCRF and subject medical records. 
1 After informed consent is obtained. 
2For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol amendment 7 takes effect, follow-up calls on Day 481, Day 541 and Day 
601 will not be performed. 
3For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol amendment 7 takes effect, Visit 7 will occur on Day 481. 
4 Solicited AEs to be collected for 7 days following each vaccination, with ongoing solicited AEs collected until resolution or day 30, whichever occurs first. Specific solicited systemic 
AEs (parotid gland swelling, fever, rash) will be collected for 30 days following MMR/V vaccination a Visit 5 (Day 301). 
  

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7.2.2. 
Post-Study adverse events and serious adverse events 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 13. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study vaccines, the investigator will promptly notify the 
Study Contact for Reporting SAEs. 
For further details, please see Section 7.4.1.2. 
7.2.3. 
Evaluation of adverse events and serious adverse events 
7.2.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as: 
‘Has your child acted differently or felt different in any way since receiving the 
vaccine(s) or since the last visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
Pre-defined scripts will be used during the clinic visits and safety follow-up calls for 
instructing parents in recording safety data. 
7.2.3.2. 
Assessment of adverse events 
7.2.3.2.1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 

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Table 14 
Grading of Solicited Local Adverse Events (Administration Site 
Event) for All Subjects 
Adverse Events 
Grading of Severity 
Grade 0 
Mild 
Moderate 
Severe 
Tenderness or discomfort to touch at 
injection site 
None 
Minor reaction 
to touch 
Cried or 
protested to 
touch 
Cried when 
injected limb 
was moved 
Hardness of skin at the injection site 
0 mm 
1 – 25 mm 
26 - <50 mm 
>50 mm 
Swelling of skin at the injection site 
Redness at injection site 
Table 15 
Grading of Solicited Systemic Adverse Events for All Subjects 
Adverse Events 
Grading of Severity 
Grade 0 
Mild 
Moderate 
Severe 
Decreased 
eating 
None 
Eating less than 
normal for 1 – 2 
feeds/ meals 
Missed 1 or 2 feeds / 
meals 
Missed more than 2 
feeds/ meals 
Increased 
sleepiness 
None 
Shows an increased 
drowsiness 
Sleeps through feeds/ 
meals 
Sleeps most of the 
time and it is hard to 
arouse him/her 
Vomiting / 
throwing up 
None 
1-2 times in 24 hours 
3 – 5 times in 24 
hours 
6 or more times in 
24 hours or requires 
intravenous 
hydration 
Loose stools / 
Diarrhea 
Fewer than 2 loose 
stools in 24 hours 
2 – 3 loose stools in 
24 hours 
4 – 5 loose stools in 
24 hours 
6 or more loose 
stools in 24 hours or 
requires intravenous 
hydration 
Irritability 
None 
Requires more 
cuddling and is less 
playful than usual 
More difficult to settle 
Unable to console 
Persistent / 
continuous 
crying 
None 
Crying less than 1 
hour 
Crying for 1 up to 3 
hours 
Crying for 3 or more 
hours 
Rash1 
0 
1-50 lesions 
51-150 lesions 
>150 lesions 
Parotid/salivary 
gland swelling1 
None 
Swelling without 
difficulty moving the 
jaw 
Swelling with difficulty 
moving the jaw 
Swelling with 
accompanying 
general symptoms 
Fever2  
<38.0°C 
(<100.4°F) 
≥38.0 – 38.9°C  
(≥100.4 – 102.1°F) 
≥39.0 – 39.9°C 
(≥102.2 – 103.9°F) 
≥40.0°C  
(≥ 104.0°F) 
1.Rash and parotid/salivary gland swelling will be recorded only after receiving the MMR and VV vaccines at 12 months 
of age at Visit 5 (Day 301). These specific systemic AEs, along with fever, will be recorded for 30 days following the 
MMR and VV vaccine administration. 
2 Preferred location for measuring temperature is the rectum for subjects <12 months of age and the axilla for subjects 
≥12 months of age. Body temperature is to be recorded daily, ideally at the same time each day. 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
Every effort should be made by the investigator to evaluate safety information reported 
by a subject’s parent(s)/LAR(s) for an underlying diagnosis and to capture this diagnosis 
as the event in the AE page. In other words, the practice of reporting only symptoms 
(e.g., “cough” or “ear pain”) are better reported according to the underlying cause (e.g., 
“asthma exacerbation” or “otitis media”). 

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The severity of events reported on the Adverse Events eCRF will be determined by the 
investigator as: 
Mild: transient with no limitation in normal daily activity. 
Moderate: some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
7.2.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between study vaccine(s) and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined, the investigator should indicate the 
AE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine(s) will be considered and investigated. The investigator will also consult 
the IB and/or SmPC and/or Prescribing Information for marketed products to determine 
his/her assessment. 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
All solicited AEs will be considered causally related to vaccination. Causality of all other 
AEs should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES 
: 
There is a reasonable possibility that the study vaccine(s) contributed to 
the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine(s). There are other, more likely 
causes and administration of the study vaccine(s) is not suspected to 
have contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 7.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 

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Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine(s), if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
All AEs, regardless of severity, will be monitored by a qualified healthcare professional 
until resolution or until the investigator assesses them as chronic or stable, and recorded 
in the subject’s records. All subjects experiencing AEs – whether considered associated 
with the use of the study vaccine(s) or not – must be monitored until symptoms subside 
and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. The investigator’s assessment of 
ongoing AEs at the time of each subject’s last visit should be documented in the subject’s 
medical chart and eCRF. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is – for example – one that is not listed in the current Summary of 
Product Characteristics or the Investigator’s Brochure or an event that is by nature more 
specific or more severe than a listed event. 
7.2.3.3. 
Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
7.2.3.4. 
Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF 
and source documents.  

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7.2.4. 
Recording of AEs related to COVID-19 
For COVID-19 infection related AEs, sites should follow routing AE/SAE processes as 
outlined in the protocol using the following terms per WHO defined case definitions: 
• 
Suspected COVID-19 infection 
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection. 
7.2.4.1. 
WHO Case Definition 
• 
Suspected case 
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset; 
OR 
B. A patient with any acute respiratory illness AND having been in contact (see 
definition of “contact” below) with a confirmed or probable COVID-19 case (see 
definition of contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND requiring 
hospitalization) AND in the absence of an alternative diagnosis that fully explains 
the clinical presentation. 
• 
Probable case  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason.  
• 
Confirmed case  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms. 
• 
A contact is a person who experienced any one of the following exposures during the 
2 days before and the 14 days after the onset of symptoms of a probable or 
confirmed case: 
− 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes; 
− 
Direct physical contact with a probable or confirmed case; 

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− 
Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; 2OR 
− 
Other situations as indicated by local risk assessments. 
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 
days before through the 14 days after the date on which the sample was taken which 
led to confirmation. 
7.3. 
Reporting of serious adverse events and other events 
7.3.1. 
Prompt reporting of serious adverse events and other events to 
GSK Biologicals 
SAEs that occur in the time period defined in Section 7.2 will be reported promptly to 
GSK within the timeframes described in Table 16, once the investigator determines that 
the event meets the protocol definition of a SAE. 
AESIs that occur in the time period defined in Section 7.2 will be reported promptly to 
GSK within the timeframes described in Table 16, once the investigator determines that 
the event meets the protocol definition of an AESI. 
Table 16 
Timeframes for submitting serious adverse event and other events 
reports to GSK Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
Electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
AESIs 
24 hours** ‡ 
Electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
* Timeframe allowed after receipt or awareness of the information. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a AESI.  
‡ The investigator will be required to confirm review of the SAE/AESI causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/AESI. 
7.3.2. 
Contact information for reporting serious adverse events and 
AESIs 
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
Study Contact for Reporting SAEs and AESIs 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs and AESIs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
US sites only: 
Fax: 1-610-787-7053 
Email: RIX.CT-Safety-Vac@gsk.com 

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7.3.3. 
Completion and transmission of SAE reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
He investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
7.3.3.1. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the SPONSOR INFORMATION) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
7.3.4. 
Reporting of AESIs to GSK Biologicals 
Once an AESI is diagnosed (serious or non-serious) in a study subject, the investigator 
(or designate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis (Table 16). The 
report allows to specify that the event is an AESI and whether it is serious or non-serious. 
The report will always be completed as thoroughly as possible with all available details 
of the event. For pIMDs, the report will always be completed in accordance with the 
pIMD standard questionnaire provided. Even if the investigator does not have all 
information regarding an AESI, the report should still be completed within 24 hours. 
Once additional relevant information is received, the report should be updated WITHIN 
24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the AESI causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the AESI. 
Refer to Section 7.3.3.1 for back-up system in case the electronic reporting system does 
not work. 

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7.3.5. 
Updating of SAE and AESI information after removal of write 
access to the subject’s eCRF 
When additional SAE, or AESI information is received after removal of the write access 
to the subject’s eCRF, new or updated information should be recorded on the appropriate 
paper report, with all changes signed and dated by the investigator. The updated report 
should be faxed to the Study Contact for Reporting SAEs (refer to the SPONSOR 
INFORMATION) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 16. 
7.3.6. 
Regulatory reporting requirements for serious adverse events 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 7.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccine(s) and unexpected. The purpose of 
the report is to fulfil specific regulatory and GCP requirements, regarding the product 
under investigation. 
All SAEs must be reported by the investigator to his/her corresponding EC/IRB and/ or 
applicable regulatory authorities in accordance with institutional policy/regulatory 
requirements and adequate documentation of this notification must be provided to the 
Sponsor. 
7.4. 
Follow-up of adverse events and serious adverse events 
7.4.1. 
Follow-up of adverse events and serious adverse events  
7.4.1.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 16). 
All SAEs and AESIs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 

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7.4.1.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
• 
with SAEs, AESIs (serious or non-serious), or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilized, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up.  
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report as applicable. 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
7.5. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE / AESIs 
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 6.7). 
7.6. 
Unblinding 
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the study vaccines, prior to 
regulatory reporting. The GSK Biologicals’ Central Safety Physician is responsible for 
unblinding the treatment assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to Section 7.3.1). 
7.7. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator. 
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment. 

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The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system). 
GSK Biologicals’ Contact information for Emergency Unblinding 
24/24 hour and 7/7 day availability 
GSK Biologicals’ Central Safety Physician: 
For US only: 
+1 844 446 3133 (GSK Biologicals Central Safety Physician on-call) 
GSK Biologicals’ Central Safety Physician Back-up: 
For US only: 
GSK Helpdesk: 1-877-528-7677 or 1 877-221-2913 
Email: GSKClinicalSupportHD@gsk.com 
7.8. 
Subject card 
Study subjects / subjects’ parent(s)/LAR(s) must be provided with the address and 
telephone number of the main contact for information about the clinical study. 
The investigator (or designate) must therefore provide a “subject card” to each subject/ 
subject’s parent(s)/LAR(s). In an emergency situation this card serves to inform the 
responsible attending physician that the subject is in a clinical study and that relevant 
information may be obtained by contacting the investigator. 
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times during the study duration. 
7.9. 
Medical device deficiencies 
The study intervention is a combination product constituted of a device and biologic 
product (e.g. pre-filled syringes). Refer to the GLOSSARY OF TERMS for the definition 
of combination product and medical device deficiency.  
7.9.1. 
Detection, follow-up and prompt reporting of medical device 
deficiency 
The investigator is responsible for the detection, documentation and prompt reporting of 
any medical device deficiency occurring during the study to GSK. This applies to any 
medical device provided for the conduct of the study.  
Device deficiencies will be reported to GSK within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. Refer to 
Section 10.6 for definitions and details on recording and reporting of these events. 

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The investigator will ensure that follow-up includes any additional investigations to 
elucidate the nature and/or causality of the deficiency to the incident. Follow-up applies 
to all participants, including those who discontinue study intervention or the study. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
7.9.2. 
Regulatory reporting of medical device deficiency when used as 
combination product  
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study to GSK. GSK has a legal responsibility to notify 
appropriate regulatory authorities and other entities about safety information linked to 
medical devices being used in clinical studies. Refer to section 10.6.3 for details of 
reporting. 
The investigator, or responsible person according to local requirements (e.g. the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
8. 
SUBJECT COMPLETION AND WITHDRAWAL 
8.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
8.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
8.2.1. 
Subject withdrawal from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol.  
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 

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Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Unsolicited non-serious adverse event. 
• 
Solicited adverse event 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s) 
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject/subject’s parent(s)/LAR(s), in the eCRF. 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 7.4.1.2). 
Adverse Event: For any subject withdrawn from study participation prior to the planned 
Study Termination Visit, it is important to determine if an AE was associated with the 
reason for discontinuing the study. This AE must be identified on the AE eCRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until the event has resolved, subsided, stabilized, 
disappeared, or until the event is otherwise explained, or the subject is lost to follow-up. 
Subjects who develop an SAE judged to be possibly or probably related to the study 
vaccine, including hypersensitivity reactions, should not receive subsequent vaccination. 
Death: For any subject withdrawn from study participation due to death, this should be 
noted on the Study Termination eCRF page and the associated SAE that led to the death 
must be reported. 
Withdrawal of consent: The subject’s parent(s)/LAR(s) can withdraw consent for 
participation in the study at any time without penalty or loss of benefit to which the 
subject is otherwise entitled. Reason for early termination should be deemed as 
“withdrawal of consent” if the subject withdraws from participation due to a non-medical 
reason (i.e., reason other than AE).  
If the subject’s parent(s)/LAR(s) intend(s) to withdraw consent from the study, the 
investigator should clarify if the subject will withdraw completely from the study or if the 
subject will continue study participation for safety, or a subset of other study procedures. 

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If the subject’s parent(s)/LAR(s) requests complete withdrawal from the study, no further 
study interventions will be performed with the subject. 
Where applicable, if a subject’s parent(s)/LAR(s) withdraw(s) consent but does not 
revoke the HIPAA authorization, the Sponsor will have full access to the subject’s 
medical records, including termination visit information. If a subject’s parent(s)/LAR(s) 
revokes only the HIPAA authorization, the Sponsor will have full access to all of the 
subject’s medical records prior to the date and time of written revocation. 
Lost to follow-up: Investigators will make an attempt to contact those subjects who do 
not return for scheduled visits or follow-up. For subjects who fail to show up for final 
visits (clinic or telephone contacts), or for 3 consecutive visits, study staff are encouraged 
to make at least 3 documented attempts to contact the subject by telephone and at least 1 
documented written attempt to contact the subjects’ parent(s)/LAR(s) to encourage the 
completion of study termination procedures. These efforts to contact the subject should 
be recorded in the source document. The termination date for the subject to be captured 
on the Study Termination eCRF page is the date of the last successful contact (clinic visit 
or telephone) with the subject. 
Administrative Reason: Examples for subjects withdrawn from the study due to 
administrative reason can include: Sponsor decision to terminate the study, subject 
meeting a pre-specified withdrawal criterion, subject discontinuation for insurance issues, 
moving, no time, etc. This reason should be noted in the Study Termination eCRF page 
and any ongoing AEs at the time of study withdrawal must be followed as described 
above. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination eCRF page. 
Protocol violation (deviation): Investigators will apply due diligence to avoid protocol 
deviations. Under no circumstances should the investigator contact GSK or its agents, if 
any, monitoring the study to request approval of a protocol deviation, as no authorized 
deviations are permitted. If the investigator feels a change to the protocol would improve 
the conduct of the study this must be considered a protocol amendment, and unless such 
an amendment is agreed upon by GSK and approved by the IRB/EC and health 
authorities it cannot be implemented (see Section 5.1.1 and Investigator Agreement). 

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8.2.2. 
Subject withdrawal from study vaccine(s) 
A ‘withdrawal’ from the study vaccine(s) refers to any subject who does not receive the 
complete treatment, i.e. when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine(s) may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol.  
Information relative to premature discontinuation of the study vaccine(s) will be 
documented on the Vaccine Administration page/screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment was 
made by the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Unsolicited non-serious adverse event. 
• 
Solicited adverse event 
• 
Not willing to be vaccinated 
• 
Other (specify). 
8.3. 
Screen and baseline failures 
In the event that the individual is determined ineligible for study participation after 
signing the ICF, he/she is considered a screen failure. The reason for screen failure must 
be documented in the Screening and Enrolment log.  
9. 
STATISTICAL METHODS  
9.1. 
Determination of sample size  
The study sample size was determined by the revised study design while maintaining an 
adequate study power to achieve all co-primary objectives previously discussed with 
CBER. The multiplicity issue was dealt with by controlling the global α at the level of 
0.05 for all associated statistical hypotheses. This reduced number will also allow for 
enrolment of the minimum number of subjects exposed to rMenB+OMV NZ to fulfill 
initial Pediatric Study Plan (iPSP) commitment. The sample sizes were also calculated 
for the secondary objectives to evaluate the non-inferiority of RIV antigens. The 
evaluation will be performed by calculating the between-group differences/ratios and 
their 2-sided 95% CI. Therefore, no multiplicity was adjusted for the secondary 
objectives.  
Study Sample Size Determination by Co-Primary Objectives 
For the immune response to PCV13, sample size calculations were based on data from 
the PCV13 package insert and for the immune response to rMenB+OMV NZ sample size 
calculations were based on data from the previous GSK (legacy Novartis) V72P13 and 
V72P13E1, and from V72_56 study. 

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Using the procedure described in this section, the power for the study is presented in 
Table 17. In case of 40% drop-out rate and 1200 subjects to be enrolled in a 2:1 ratio, it’s 
assumed that 480 evaluable subjects from Group MenB+PCV and 240 evaluable subjects 
from Group Placebo+PCV could participate with data to the analyses. For PCV13 
antigens a sample size of 240 will have approximately 99% power to show non-
inferiority for all antigens. For MenB strains it’s assumed that 480 evaluable samples 
from Group MenB+PCV will be evaluated in the analyses. With 240 per group for 
PCV13 antigen tests and 480 evaluable subjects from Group MenB+PCV for 
rMenB+OMV NZ strain tests, there is approximately 99% probability to reject all 23 null 
hypotheses, and to claim that the primary objectives of the study will be met according to 
the predefined success criteria. 
Table 17 
Power to Show Non-Inferiority PCV13 Co-Primary Objective and 
Sufficiency rMenB+OMV NZ Co-Primary Objectives  
Co-Primary Objective 
Power 
Non-inferiority for GMCs for 13 antigens after the 3rd vaccination 
99.0% 
Sufficiency for % of subjects with titers ≥ LLOQ per each strain and all 4 strains combined (composite 
response) after the 3rd vaccination 
99.8% 
Sufficiency for % of subjects with hSBA titers≥ 8 (for strains M14459, NZ98/254, M13520) and ≥16 
(for strain 96217) individually and all 4 strains combined (composite response) after the 4th 
vaccination 
>99.999% 
Probability of rejection of all 23 null hypotheses. 
98.8% 
The power was estimated using simulations: 10.000 simulations per case. SAS 9.4 was 
used for the calculations. 
A short summary on the steps of simulation is presented below, in the example of 40% 
drop-out. The definition for families is given in Section 9.5.3.1. 
In total 10.000 simulations were performed, each simulation consisted of: 
a. 
For testing Family 1, 240 normal distributed data were drawn for two groups and 
hence two times thirteen antigens, according to the ratio of GMC and the SD, as 
described below Table 18. For PCV13, a GMC ratio of 0.8 was assumed. Correlation 
structure was made for between-antigen correlation of 0%. 
b. For testing Family 2 and 3, 480 normal distributed data were drawn for one single 
group and for the four strains, according to the GMTs (for post 3rd dose) and GMTs 
(for post 4th dose), as shown in Table 19, and the SDs as described below Table 18. 
Correlation structure was made for between-antigen correlation of 0%. 
c. 
Testing of Family 1: Shifted one-sided t-test was used to test the hypotheses and 
output the p-values (for the power calculation no center effect was assumed). 

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d. P-values were compared with the Family Wise Error Rate (FWER) to conclude on 
whether the null hypotheses were rejected or not. FWER for Family 1 is initially set 
to be 1/3 of the full alpha, which is rounded to 0.017. The FWER for Family 2 is 
0.033 and the initial FWER is 0 for Family 3. No multiplicity adjustment was 
performed within a family. Within family 1 all thirteen antigens were tested with the 
full FWER for family 1. If one or more test fail to reject the hypothesis for the 
antigen, family 1 fails. Consequently the alpha of family 1 will not be propagated 
(see bullet h. below). 
e. 
Preparing for testing Family 2 and 3, percentages were obtained by dichotomizing 
the normal random sets that were generated at step b, by applying the cut-off of 
LLOQ value for post 3rd or a cut-off of 8 (for strains M14459, NZ98/254, M13520) 
or 16 (for strain 96217) at post 4th. Per time point, composite endpoint was derived 
by looking into each subject if the titer is above the cut-off for all 4 individual strains 
and if it is then this subject is counted as “1”. Otherwise the subject is counted as 
“0”. 
f. 
For each of the ten percentages for rMenB+OMV NZ (4 individual strains and 1 
composite endpoint at post-3rd and post-4th) the lower confidence limit was generated 
by fitting the binomial distribution with the percentage obtained from the previous 
step and alpha that has been assigned or propagated to the family. If the lower 
confidence limit is greater or equal to the sufficiency margin, then the null 
hypothesis is rejected for the single test. For Family 2 and 3, it is required to reject 
the null hypothesis for each and all of strain M14459, 96217, NZ98/254, M13520, 
and the composite endpoint to be able to claim the success of the family.  
g.  Testing of Family 2: with the given FWER, if the LCL is greater or equal to 0.75 for 
each of strain M14459, 96217 and NZ98/254, M13520, and greater or equal to 0.65 
for the composite endpoint, then Family 2 is claimed for success. The FWER for 
Family 2 is set up as 2/3 of the full alpha, which is rounded to 0.033. 
h. Alpha propagation between Family 1, 2 and 3 was calculated for 4 scenarios:  
1) If Family 1 had succeeded and Family 2 not, then propagate ½ FWER from 
Family 1 to Family 3 and the other ½ FWER to Family 2, and re-test Family 2 
with the new FWER which is the sum of the original FWER from Family 2 plus 
the ½ of FWER from Family 1. If the null hypothesis were rejected during the 
2nd time test, then claim the success of Family 2 and propagate full FWER to 
Family 3; otherwise Family 2 fails and proceed with Family 3 testing with the ½ 
of FWER propagated from Family 1. 
2) If Family 2 had succeeded and Family 1 not, then propagate ½ FWER from 
Family 2 to Family 3 and the other ½ FWER to Family 1, and re-test Family 1 
with the new FWER which is the sum of the original FWER from Family 1 plus 
the ½ of FWER from Family 2. If the null hypothesis were rejected during the 
2nd time test, then claim the success of Family 1 and propagate full FWER to 
Family 3; otherwise Family 1 fails and proceed with Family 3 testing with the ½ 
of FWER propagated from Family 2. 
3) If both Family 1 and Family 2 had succeeded, then the FWER from both 
families were propagated to Family 3, and proceed to test Family 3; 

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4) If both Family 1 and Family 2 had failed, then no FWER will be propagated to 
Family 3, and we stop the testing globally.  
i. 
Testing of Family 3: with the given FWER, if the LCL is greater or equal to 0.6 for 
each of strain M14459, 96217 and NZ98/254, M13520, and greater or equal to 0.5 
for the composite endpoint, then Family 3 is claimed for success.  
j. 
Add a loop on top of the aforementioned steps for 10.000 times simulation, 
summarize the probability of have all hypotheses rejected for each and all families, 
and the probability to meet all the primary objectives. 
Based on the immune response observed in infant data from V72P13E1 and the PCV13 
package insert, the following assumptions were made for the calculations: 
1. As estimate for the SD of the different antigens and strains was taken the upper 80% 
CI limits of the common standard deviations for the log10 titers observed in GSK 
(legacy Novartis) study V72P13E1 and log10 ELISA concentrations observed from 
PCV13 studies. SDs that were used in the sample size calculations are presented in 
the table below. 
Table 18 
Two-sided 80% Upper Confidence Limit of Standard Deviations  
 
80% UCL of SDs 
rMenB+OMV NZ strains 
Post 4th vaccination (SDs of GMT) 
Post 3rd vaccination (SDs of 
GMT) 
M14459 
0.45097 
0.32193 
96217 
0.63454 
0.36900 
NZ98/254 
0.53796 
0.51670 
M135202 
0.36477 
0.45023 
PCV13 antigen1 
Post 3rd vaccination (SDs of GMC) 
1 
0.36629 
3 
0.41572 
4 
0.34261 
5 
0.43567 
6A 
0.39552 
6B 
0.44974 
7F 
0.34352 
9V 
0.32548 
14 
0.32445 
18C 
0.33550 
19A 
0.24439 
19F 
0.45638 
23F 
0.37567 
1.Estimated SDs for PCV13 antigens are the upper confidence limit of 2-sided 80% CI of back-calculated SDs, based 
on information (degree of freedom, 95% CI) provided on table 17 of Prevnar13 Package Insert (dated on July 2016) 
and assuming the underlying SDs fulfill a t-distribution. 
2 The assumptions for M13520 are cited from study V72_56 (205240) ad-hoc analysis on additional NHBA strains. 
2. Underlying GMC ratios for each PCV13 antigens is assumed as 0.8. 
3. For the sufficiency objectives, the following mean (log10(GMT)) were used in 
simulation based on observed data from previous studies (studies V72P13 and 
V72P13E1 and V72_56): 

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Table 19 
GMTs at One Month Post 3rd Dose and GMRs at One Month Post 4th 
rMenB+OMV NZ Vaccination  
rMenB+OMV NZ strains 
GMTs* Post 4th vaccination  
GMTs* Post 3rd vaccination  
M13520 
1.41225 
1.10501 
NZ98/254 
1.57978 
1.15836 
M14459 
1.53148 
1.26400  
96217 
3.06183 
2.66753 
*log-scale 
4. The LODs and LLOQs associated with the 4-fold definition are assumed to be: 
Table 20 
Limits of Detection and Lower Limits of Quantitation for 
rMenB+OMV NZ strains  
rMenB+OMV NZ strains 
LOD  
LLOQ  
M13520 
4 
4 
NZ98/254 
4 
6 
M14459 
3 
5 
96217 
6 
15 
LOD: lower limit of detection, LLOQ: lower limit of quantitation. 
Note: Other than for strain M13520, these LODs and LLOQs were cited from the latest lab assay validation report 
released in 2018. For strain M13520, the LOD and LLOQ are validated and cited from the latest laboratory assay 
validation report released in 2020.  
5. That each comparison is statistically independent. 
In conclusion, assuming a 40% drop-out rate in this age group, a total of 1200 subjects to 
be enrolled in a 2:1 ratio, which will lead to 480 subjects evaluable in Group MenB+PCV 
and 240 subjects evaluable in Group Placebo+PCV, there will be 99% power to conclude 
that: 
a. 
13 PCV13 antigens will be shown non-inferiority of PCV13 vaccine when co-
administrated with rMenB+OMV NZ vaccine, compared to PCV13 vaccine that is 
administered alone, at one month post 3rd vaccination 
b. The percentage of subjects with titers ≥ LLOQ is more than or equal to 60% for 
strain M14459, 96217, NZ98/254 and M13520, and more than or equal to 50% for 
all 4 rMenB+OMV NZ strains at one month post 3rd vaccination. 
c. 
Percentage of subjects with 4-fold increase is more than or equal to 75% for strain 
M14459, 96217, NZ98/254 and M13520, and more than or equal to 65% for all four 
rMenB+OMV NZ strains, at one month post 4th vaccination. 
Determination of the Immunogenicity Subsets Sizes for the Secondary Objectives: 
As described in detail in Table 9, due to limited serum volume available subjects will be 
randomly assigned to test different sets of RIV antigens. Subjects will either be assigned 
to subset A1, A2, A3 in Group MenB+PCV or assigned to subset B1 and B2 in Group 
Placebo+PCV (see Section 5.2.3). The below tables (Table 21 and Table 22) show the 
likelihood to achieve non-inferiority for each of the RIV antigens (excluding polio) with 
the proposed sample sizes for immunogenicity subsets. 

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Table 21 
Non-inferiority to Each Individual Antigen (excluding polio antigens) 
in Pediarix and Hiberix, at One Month After 3rd Dose 
of rMenB+OMV NZ 
Component 
Endpoint 
Non-
inferiority 
Margin 
Reference 
# Evaluable 
Subjects per 
Immunogenicity 
Subset (MenB 
group/Placebo 
group)* 
Power 
Difference 
in %/ratio (Co-
ad vs routine) 
% in 
Routine group 
or SD 
Diphtheria 
%≥0.1IU/mL 
10% 
Diff=0% 
99.4% 
240/120 
>99.9% 
Tetanus 
%≥0.1IU/mL 
5% 
Diff=0% 
100% 
240/120 
>99.9% 
PT 
GMC 
1.5 
Ratio=0.8 
SD: 0.31535 
480/240 
88.7% 
FHA 
GMC 
1.5 
Ratio=0.84 
SD: 0.3111 
480/240 
98.3% 
PRN 
GMC 
1.5 
Ratio=0.83 b 
SD: 0.43427 
480/240 
79.1% 
HepB 
%≥10.0mIU/mL 
10% 
diff=-2% 
97.7% 
120/120 
93.5% 
Hib 
%≥0.15µg/mL 
5% 
diff=0%a 
96.6% 
360/240 
91.2% 
%≥1µg/mL 
10% 
diff=0% 
81.2% 
360/240 
86.7% 
Abbreviations: SD, standard deviation; GMC, geometric mean concentrations; PT, pertussis toxin; FHA, Filamentous 
hemagglutinin; PRN, pertactin; HepB, Hepatitis B; Hib, Haemophilus influenzae type B; diff, difference 
Note: The sources are V72P13 clinical study report and the package insert of vaccines, unless otherwise indicated. 
SDs for Pertussis were taken from GSK study Hib-97. 
aSource: V72P12 CSR. 
b Source: V72P16 Table 14.2.1.14 Group B+OMV versus MenC. 
* Considering an estimated drop-out rate of 40%. 
Table 22 
Non-inferiority to Each Individual Antigen in MMR II and Varivax, at 
One Month After 4th Dose of rMenB+OMV NZ  
Component 
Endpoint 
Non-
inferiority 
Margin 
Reference 
# Evaluable 
Subjects per 
Immunogenicity 
Subset (MenB 
group/Placebo 
group)* 
Power 
Ratio (co-
ad vs routine) 
SD 
Measles 
GMC 
1.5 
ratio=0.9 
SD: 0.45a 
480/240 
95.5% 
Mumps 
GMC 
1.5 
ratio=0.9 
SD: 0.38 a 
480/240 
99.1% 
Rubella 
GMC 
1.5 
ratio=0.9 
SD: 0.34 a 
480/240 
99.8% 
Varicella 
GMC 
1.5 
ratio=0.9 
SD: 0.45 b 
480/240 
95.5% 
a Reference for sample size calculation: GSK Study MMR-161. 
b Reference for sample size calculation: GSK Study MMR-160. 
* Considering an estimated drop-out rate of 40%. 
9.2. 
Analysis Sets 
9.2.1. 
Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments and are randomized and have received a Subject ID, 
regardless of the subject’s treatment status in the study. 

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9.2.2. 
Exposed Set 
All subjects in the Enrolled Set who receive a study vaccination. 
9.2.3. 
Safety Sets 
9.2.3.1. 
Solicited Safety Set (solicited local and systemic adverse events and 
other solicited adverse events) 
All subjects in the Exposed Set with any solicited adverse event data. 
9.2.3.2. 
Unsolicited Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set with unsolicited adverse event data. 
9.2.4. 
Full Analysis Set (FAS) for Immunogenicity  
All subjects in the Exposed Set and provide immunogenicity data at either one month 
after their 4th vaccination or one month after their 3rd vaccination for at least 1 
antigen/strain. 
In case of vaccination error, subjects in the FAS sets will be analyzed “as randomized” 
(i.e., according to the vaccine a subject was designated to receive, which may be different 
from the vaccine the subject actually received). 
9.2.5. 
Per Protocol (PP) Set for Immunogenicity  
All subjects in the FAS Immunogenicity who: 
• 
Correctly receive the vaccine (i.e., receive the vaccine to which the subjects is 
randomized and at the scheduled time points). 
• 
Have no protocol deviations leading to exclusion as defined prior to unblinding / 
analysis. 
• 
Are not excluded due to other reasons defined prior to unblinding or analysis 
Examples for subjects excluded due to other reasons than protocol deviations are: 
• 
Subjects who withdrew informed consent. 
• 
Subjects who did not receive all the study vaccines up to Dose 3 for primary 3 doses 
analyses or up to Dose 4 for the 4th dose analyses; 
• 
who received a vaccine not specified or forbidden in the protocol up to Visit 4 for 
primary 3 doses or up to Visit 6 for the 4th dose; 
• 
who received a medication/product leading to exclusion from a per-protocol analysis 
as listed in Section 6.7.2 up to Visit 4 for primary 3 doses or up to Visit 6 for the 4th 
dose. 

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• 
who presented a medical condition leading to exclusion from a per-protocol analysis 
as listed in Section 6.8 up to Visit 4 for primary 3 doses or up to Visit 6 for the 4th 
dose. 
• 
who did not comply with the post Dose 3 (for primary 3 doses) or post Dose 4 (for 
the 4th dose) blood sample schedule (Table 6). 
• 
who had no immunogenicity results post Dose 3 (for primary 3 doses) or post Dose 4 
(for the 4th dose). 
The allowed intervals between each study visit are given in Table 6. Subjects will not be 
eligible for inclusion in the per-protocol cohort for analysis of primary 3 doses if the 
study visit is performed outside this interval up to visit 4, and they will not be eligible for 
analysis of the 4th dose if the study visit is performed outside this interval up to Visit 6. 
9.2.6. 
Other Analysis Sets 
Not applicable. 
9.2.7. 
Subgroups  
The following descriptive analyses will be performed by gender, race, ethnic origin and 
age group (6-8 weeks or ≥8 weeks) for the following parameters: 
• 
GMCs and ratios of GMCs for PVC (Group MenB+PCV vs Group Placebo+PCV) at 
one month after the 3rd and 4th vaccination. 
• 
Percentages of subjects with hSBA titers ≥LLOQ; for each of the 4 rMenB+OMV 
NZ strains and for the combined strains at one month after the 4th vaccination in 
Group MenB+PCV and Group Placebo+PCV. 
• 
Percentages of subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217); for each of the 4 rMenB+OMV NZ strains and 
for the combined strains at one month after the 4th vaccination in Group MenB+PCV 
and Group Placebo+PCV. 
Analyses will be performed on the FAS.  
Additional subgroup analyses may be performed to assess the impact of COVID-19. 
More details will be provided in the Statistical Analysis Plan.  
9.3. 
Derived and transformed data 
Immunogenicity: 
• 
The GMTs/GMCs calculations are performed by taking the anti-log of the mean of 
the log titer transformations. Values to be used for the antibody concentrations/titres 
below the assay cut-off will be described in the Statistical Analysis Plan (SAP). 
• 
Handling of missing data: Missing immunogenicity values are assumed to be missing 
completely at random (MCAR) and therefore may not contain information that 
impact the results of the analysis (i.e. not informative). Imputation methods will not 
be used. 

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Reactogenicity and Safety: 
• 
First-line analyses will be performed without missing values. To minimize the effect 
of dropouts and missing safety data the study period will be divided into time 
intervals for statistical analysis of safety data. 
• 
Unsolicited AEs: Unsolicited AEs are collected for 30 days post vaccination, and are 
analyzed as such without division of the time interval. 
• 
AEs/SAEs leading to withdrawal from the study, SAEs (including SAEs related to 
study vaccine(s)), SAEs related to study participation or concurrent GSK 
medication/vaccine, AESIs, and Medically attended AEs: The entire study period 
will be divided into the following disjoint intervals: Day 1 through Day 30 post 
vaccination, Day 31 post vaccination until either the next vaccination or study 
termination. 
• 
Solicited adverse events: For solicited AEs the solicited study period (30 minutes 
through Day 7) will be divided into the following intervals: 30 minutes and 6 hours 
through Day 7. Analyses may be performed on 6 hours through Day 3 and Day 4 
through Day 7, if needed. For MMR and VV-specific solicited systemic AEs 
(parotid/salivary gland swelling, rash) collected after Visit 5 (30 minutes through 
Day 30 post-vaccination), the study period will be divided into the following 
intervals: 6 hours through day 7, day 8 though day 30. 
For each of the intervals the following algorithm will be applied: 
− 
If less than 20% of subjects are without any solicited AE data (i.e., none of the 
solicited adverse events have been captured) for the respective time interval, 
then only the solicited safety sets pertaining to the interval will be analyzed. If 
20% or more of subjects are without any solicited AE data, the missing 
mechanism will be analyzed by vaccine group using a newly created variable 
indicating whether a subject is missing the respective AE-value or not (1=AE 
record present; 0=AE record not present). 
9.4. 
Analysis of demographics 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight at enrolment will be calculated overall and by vaccine group. 
Distributions of subjects by sex, race, ethnic origin, geographic region and age group (6-
8 weeks or ≥8 weeks) will be summarized overall and by vaccine group. 
9.5. 
Analysis of immunogenicity  
The primary population for the primary immunogenicity analyses will be the PPS. All 
primary and selected secondary immunogenicity analyses (NI assessments to other RIVs) 
will be repeated on the FAS. 

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9.5.1. 
Within groups assessment  
For each study group, at each timepoint that a blood sample result is available, the 
following endpoints will be assessed related to MenB strains and PCV13 strains: 
• 
the percentages of subjects with hSBA titers ≥ LLOQ for each of the M14459, 
96217, NZ98/254 and M13520 test strains  
• 
the percentages of subjects with hSBA titers ≥ LLOQ for all strains combined 
(composite endpoint) at one month after the 3rd vaccination  
• 
the percentages of subjects with hSBA titers ≥5, ≥8 and ≥16 for each of the M14459, 
96217, NZ98/254 and M13520 test strains 
• 
the percentages of subjects with hSBA titers ≥8 for each of the test strains (M14459, 
NZ98/254 and M13520), ≥16 for test strain 96217, and for all strains combined 
(composite endpoint) at one month after the 4th vaccination 
• 
the percentages of subjects with 4-fold increase at post-4th (from pre-4th) for each of 
the M14459, 96217, NZ98/254 and M13520 test strains  
• 
GMCs/GMTs and within group GMRs (for post-4th versus pre-4th titers) will be 
tabulated for antibodies for each antigen 
• 
Percentage of subjects with serum pneumococcal anti-capsular polysaccharide IgG 
≥0.35 μg/mL at one month after the 3rd and 4th vaccination in Group MenB+PCV and 
Group Placebo+PCV. 
The CIs will be calculated as 2-sided 95%, and will be calculated at given alpha at the 
testing step for the primary objectives that are associated with statistical hypothesis 
testing.  
Endpoints associated with the other RIV will be assessed within-group as specified in 
Section 2. The 2-sided 95% CIs will be calculated.  
9.5.2. 
Between groups assessment  
For PCV antigens, at each blood sampling timepoint and for each antibody for which 
results are available, for Diphtheria, Tetanus, Pertussis and Hepatitis B antigens, at blood 
sampling timepoint one month after the 3rd vaccination, for VV and MMR, at blood 
sampling timepoint one month after the 4th vaccination and for each antibody for which 
results are available: 
• 
The CIs of the between-group GMC ratios (i.e. study group minus control group) 
will be computed using an analysis of variance (ANOVA) model on the logarithm10 
transformation of the concentrations.  
For Diphtheria, Tetanus, Hib, Polio and Hepatitis B antigens, at blood sampling timepoint 
one month after the 3rd vaccination, for VV and MMR, at blood sampling timepoint one 
month after the 4th vaccination and for each antibody for which results are available: 
• 
The CIs of the between-group percentage differences (i.e. study group minus control 
group) will be computed. 

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9.5.3. 
Analysis of Primary Immunogenicity Objectives  
9.5.3.1. 
Statistical Hypotheses  
In total 23 hypotheses will be tested for the primary objectives. A step-wise statistical 
approach will be used for the 23 statistical tests. The hypotheses will be grouped into 
three families, based on the different immunogenicity objectives: 
Family 1:13 statistical hypotheses related to non-inferiority of PCV13 with 
rMenB+OMV NZ as measured by the GMCs of the 13 PCV13 antigens, after 
the 3rd vaccination. 
Family 2: 5 statistical hypotheses related to sufficiency objective on percentages of 
subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) and 
≥16 (for strain 96217) at one month post 4th dose, and the composite endpoint 
Family 3: 5 statistical hypotheses related to sufficiency objective on percentages of 
subjects with hSBA titers ≥ LLOQ at one month post 3rd dose for each of the 
four strains M14459, 96217, NZ98/254, and M13520, and the composite 
endpoint. 
Each family of hypotheses is linked to an objective, as follows: 
• 
Family 1 is related to the “immunological non-inferiority of rMenB+OMV NZ + 
PCV 13 compared to PCV13 after the 3rd vaccination” objective.  
• 
Families 2 and 3 are related to the “sufficiency of the immune response to 
rMenB+OMV NZ” objective at one month post 4th dose and one month post 3rd dose, 
respectively. 
The statistical hypotheses for each and all families are formulated as below: 
Family1: Non-inferiority of rMenB+OMV NZ + PCV13 to PCV13 with respect to GMCs 
at one month post 3rd vaccination 
Non-inferiority will be claimed if the following null hypothesis will be rejected for 13 
PCV13 antigens: 
H01j: μAj – μBj ≤ δ vs. H11j : μAj – μBj > δ, j=1,..13, 
 
where δ denotes the non-inferiority margin (log10(0.5)), μA, and μB denote the means of 
log 10-transformed concentrations at one month after the 3rd vaccination from Group 
MenB+PCV and Group Placebo+PCV, respectively, and j refers to the 13 antigens. 

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Family 2: Percentage of subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) and the composite endpoint, at one month post-4th 
vaccination 
Sufficiency will be claimed for each of the 4 strains and the composite endpoint, 
separately, if the following null hypothesis will be rejected: 
H02j: PAj < Aj vs. H12j : PAj ≥ Aj, 
 
where PAj denotes the percentage of subjects with hSBA titers ≥ 8 (for strains M14459, 
NZ98/254, M13520) and ≥16 (for strain 96217) at one month after the 4th vaccination for 
strain j, (j=1, 2, 3, 4, and composite). Aj represents the level of sufficient immune 
response for each of the four strains and composite endpoint. The immune response at 
one month following the 4th vaccination, will be sufficient for rMenB+OMV against 
each individual strain if the lower limit of the adjusted CI for the percentage of subjects 
with hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) and ≥16 (for strain 
96217) is ≥75% for the individual N. meningitidis serogroup B test strains, and is ≥65% 
for the composite endpoint. 
Family 3: Percentage of subjects with hSBA≥LLOQ for each of the four strains (M14459, 
96217, NZ98/254, M13520) and the composite endpoint, one month post post-3rd. 
vaccination 
Sufficiency will be claimed for each of the 4 strains, separately, if the following null 
hypothesis will be rejected: 
H03j : PAj < Aj vs. H13j : PAj ≥ Aj, 
 
where PAj denotes the percentage of subjects hSBA≥LLOQ at one month after the 3rd 
vaccination for strain j, j=1, 2, 3,4, and composite. Aj represents the level of sufficient 
immune response for each of the four strains and composite endpoint. The immune 
response at one month following the 3rd vaccination, will be sufficient for rMenB+OMV 
NZ against each individual strain if the lower limit of the adjusted CI for the percentage 
of subjects with hSBA titer ≥LLOQ is ≥60% for the N. meningitidis serogroup B test 
strains, and ≥50% for the composite endpoint. 
9.5.3.2. 
Statistical Methods  
For statistical analyses of the concentration/titer data, the concentrations/titers will be 
logarithmically transformed (base10), to fulfill Gaussian distribution assumption. 
The Global Type I error rate will be controlled globally at a 5%/2.5% level (2-/1-sided, 
respectively). If applicable, the α-level will be propagated as described below [Hommel, 
2007]. The sequence of testing the different families is presented in Figure 2 and 
described in more detail thereafter. 

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Figure 2 
Testing Strategy for Three Families with Corresponding α 
Propagation  
 
The initial α is 0.0167 (2-sided) for Family 1 and 0.033 (2-sided) for Family 2, while it is 
zero for Family 3.  
Step 1: Family 1 and Family 2 
i. 
Start test Family 1 and Family 2 as the first step.  
− 
For testing Family 1 the hypotheses per antigen the p-values will be obtained 
from an ANOVA model, with vaccination group and center as independent 
variables and log transformed titers/concentrations as response variable. The 
null hypotheses will be rejected if the p-values < FWER for all thirteen antigens. 
− 
For testing Family 2, if the lower limits of the 2-sided 96.67% CIs are greater or 
equal to the sufficiency margins for each of the four strains and composite 
endpoint, then Family 2 is successful. Otherwise, Family 2 fails. 
ii. If Family 1 had succeeded and Family 2 not, then propagate ½ FWER from Family 1 
to Family 3 and the other ½ FWER to Family 2, and re-test Family 2 with the new 
FWER which is the sum of the original FWER from Family 2 plus the ½ of FWER 
from Family 1. If the null hypothesis were rejected during the 2nd time test, then 
claim the success of Family 2 and propagate full FWER to Family 3; otherwise 
Family 2 fails and proceed with Family 3 testing with the ½ of FWER propagated 
from Family 1. 
iii. If Family 2 had succeeded and Family 1 not, then propagate ½ FWER from Family 2 
to Family 3 and the other ½ FWER to Family 1, and re-test Family 1 with the new 
FWER which is the sum of the original FWER from Family 1 plus the ½ of FWER 
from Family 2. If the null hypothesis were rejected during the 2nd time test, then 
claim the success of Family 1 and propagate full FWER to Family 3; otherwise 
Family 1 fails and proceed with Family 3 testing with the ½ of FWER propagated 
from Family 2. 

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iv. If both Family 1 and Family 2 had succeeded, then the FWER from both families 
were propagated to Family 3, and proceed to test Family 3; 
v. If both Family 1 and Family 2 had failed, then no FWER will be propagated to 
Family 3, and we stop the testing globally and success can be claimed on none of the 
three families.  
Step 2: Family 3:  
If all null hypotheses are rejected, then propagate 1/2 FWER to Family 1 and Family 2 
respectively, and success can be claimed for Family 3, as well as for Family 1 and/or 
Family 2 whichever was successful in Step 1; otherwise stop testing globally, and success 
can be claimed for Family 1 and/or Family 2 whichever was successful in Step 1. 
Step 3: Family 1 or Family 2 
In case one of Family 1 and Family 2 failed in step 1, with the alpha passed down by 
Family 3, it is possible to re-test the family that failed once and again test it with ½ 
FWER from Family 3. If all null hypotheses are rejected, then success can be claimed for 
this family as well. 
9.5.4. 
Analysis of Secondary Immunogenicity Objectives  
The statistical hypotheses associated with the non-inferiority tests in the secondary 
immunogenicity objectives are described as below: 
H0 : μA – μB ≤ δ vs. H1j : μA – μB > δ  
Where δ denotes the non-inferiority margin, and μA, and μB denote either the means of 
log 10-transformed concentrations/titers or the percentage of subjects achieving the 
threshold response for binary variables. 
Note that statistical hypotheses testing is not applicable for the seroresponse rates of 
antigens tested for Polio, MMR and VV vaccines. Instead, descriptive analysis will be 
performed. For each antigen tested, the percentage of subjects with anti-polio type 1, 2 
and 3 neutralization antibody titers ≥8, or the percentage of subjects with post-
vaccination anti-measles, anti-rubella, anti-mumps and anti-VZV virus antibody 
concentration ≥ a protective threshold will be presented as point estimates along with the 
associated 2-sided 95% Clopper-Pearson CIs. 
9.5.4.1. 
Statistical Methods 
Concentration and titer data will be summarized by vaccine group, strain and time point. 
Additionally, within-subject GMRs will be computed for GMTs at one month after 4th 
vaccination versus pre-4th vaccination. As for GMTs, the GMRs and 95% CIs will be 
computed by exponentiating (base 10) the corresponding means and 95% CIs from an 
ANOVA model. 

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For the binary variables, for example, percentage of subjects with hSBA titer ≥ LLOQ, 
percentage of subjects with serum pneumococcal anti-capsular polysaccharide IgG ≥0.35 
μg/mL, the number and percentage of subjects and associated 2-sided 95% Clopper-
Pearson CIs will be computed for each antigen/strain by vaccine group and by time-point. 
Between group-differences with 95% CIs will be derived using the Miettinen and 
Nurminen method [Miettinen, 1985]. 
9.6. 
Analysis of safety  
Distribution of subjects by vaccinations will be summarized by vaccine group for the 
Exposed Set. The primary analysis will be performed on the Solicited/Unsolicited Safety 
Set. 
9.6.1. 
Within groups assessment 
9.6.1.1. 
Analysis of Solicited Adverse events  
All solicited AEs will be summarized according to defined severity grading scales, see 
Section 7.2.3.2.1.  
Frequencies and percentages of subjects (with 95% CI) experiencing each AE will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic AE overall and at each time point will also be presented. 
Post-vaccination solicited AE reported from Day 1 to Day 7 will be summarized for the 
interval Day 1-7 (and Day 1-3, Day 4-7 if needed) by maximal severity and by vaccine 
group, excluding the 30-minute measurement, which will be summarized separately. For 
MMR and VV-specific solicited systemic AEs (parotid/salivary gland swelling, fever, 
rash) collected after Visit 5 (30 minutes through Day 30 post-vaccination), the study 
period will be divided into the following intervals: 6 hours through Day 7, Day 8 though 
Day 30. 
The severity of solicited local AEs (administration site event), including redness at 
injection site, swelling of skin at injection site, and hardness of skin at injection site will 
be summarized according to categories based on linear measurement: None (0mm); Mild 
(1mm to 25mm); Moderate (26mm to 50mm); Severe (>50mm).  
Injection site tenderness and systemic reactions (except fever) occurring up to 7 days 
after each vaccination will be summarized according to “mild”, “moderate” or “severe”. 
Fever, derived from measured body temperature (≥38.0°C/100.4°F), will be summarized 
according to “Grade 0 (none)” (< 38.0°C), “mild “(≥ 38.0 - 38.9°C), “moderate” (≥ 39.0 - 
39.9°C) and “severe” (≥ 40.0°C). 
Each solicited local (administration site) and systemic AE will also be further 
summarized as “none” versus “any” (for fever the latter will be ≥38.0°C/100.4°F). 

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Use of antipyretics and analgesics will be summarized by type of use (prophylactic 
versus treatment) and percentage of subjects (with 95% CI) reporting use. 
Body temperature will be summarized by 0.5°C increments from 36.0°C up to ≥40°C and 
will be broken down according by route of measurement, if applicable. Frequencies and 
percentages of subjects (with 95% CI) with temperatures ≥38.0°C and temperatures 
≥40.0°C will also be presented. 
9.6.1.2. 
Analysis of Unsolicited Adverse Events 
This analysis applies to all AEs occurring during the study, judged either as probably 
related, possibly related, or not related to vaccination by the investigator, recorded in AE 
eCRF, with a start date on or after the date of first vaccination. All AE starting prior to 
the first vaccination will only be listed. The original verbatim terms used by investigators 
to identify AEs in the eCRFs will be mapped to preferred terms using the MedDRA 
dictionary. The AEs will then be grouped by MedDRA preferred terms into frequency 
tables (with 95% CI) according to system organ class. 
All reported AEs, as well as AEs judged by the investigator as related to study vaccine, 
will be summarized according to system organ class and preferred term within system 
organ class. These summaries will be presented by vaccine group and by interval of study 
observation. When an AE occurs more than once for a subject, the maximal severity and 
strongest relationship to the vaccine group will be counted. 
Serious adverse events, withdrawal due to AEs and AESIs will be described in detail. 
Separate summaries will be produced for the following categories:  
• 
Serious adverse events (SAE) 
• 
Adverse events related to vaccine 
• 
Adverse events of special interest 
• 
Adverse event leading to withdrawal 
• 
Adverse events leading to a medically attended visit 
These summaries will also be presented by the 0-6/6-12 months safety follow-up periods 
after the last study vaccination. 
Data listings of all AEs will be provided by subject. In addition, AEs in the categories 
above will be provided as listed data. 
Local and systemic AEs will be analyzed by point estimates with associated 95% CIs 
[Clopper, 1934]. 
9.6.2. 
Between groups assessment 
Not applicable. 

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9.7. 
Interpretation of analyses 
Except for analyses on objectives with a pre-defined success criterion and an appropriate 
Type I error control (see Section 2), analyses will be descriptive with the aim to 
characterize the reactogenicity and immunogenicity within each group.  
9.8. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
9.8.1. 
Sequence of analyses  
Any analyses (including a possible interim analysis) will be conducted on data as clean as 
possible. All data will be analyzed at the end of the study, after availability of all 
immunogenicity and safety data, and presented in a final clinical study report.  
If needed, an interim analysis including data up to visit 6 may be performed. Selected 
immunogenicity objectives and solicited safety data from all timepoints up to Visit 6 will 
be analyzed. The interim analysis will be performed by an independent statistician, in 
order to maintain the observer-blindness of the study. Study unblinding will be performed 
only after the final database lock. The data or the results from this interim analysis will 
not be used to make any decision on the continuation of this trial. Therefore no impact on 
the conduct or subsequent full data analysis of the trial is expected. All remaining 
objectives and remaining safety data will be analyzed at the end of the study and an 
integrated clinical report will be generated, which contains all data from the trial. 
9.8.2. 
Statistical considerations for interim analyses  
If performed, interim analysis will be conducted on final immunogenicity data and the 
safety analyses will be descriptive. Therefore no statistical adjustment for the interim 
analysis is required. 
10. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.  
10.1. 
Electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.  
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 

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While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data.  
The investigator will be provided with an electronic format in read only mode of the final 
version of the data generated at the investigational site once the database is archived and 
the study report is complete and approved by all parties. 
10.2. 
Subject Diary 
Electronic Diaries (eDiaries), hereafter referred to as Subject Diaries will be the only 
source document allowed for solicited local (administration site) and systemic adverse 
events (including body temperature measurements), starting after the initial 30 minute 
post-vaccination period at the clinic. The following additional rules apply to 
documentation of safety information collected in the Subject Diary. 
The Investigator or delegated staff should monitor the Subject’s Diary status throughout 
the study for compliance and any solicited local (administration site) and systemic 
adverse events that were of concern to the subject’s parent(s)/LAR(s). 
• 
No corrections or additions of data recorded by the parent(s)/LAR(s) will be allowed 
once diary completion for that day has been performed. 
• 
The Subject Diary will be designed in such a way as to prevent any blank, 
incomplete or biologically implausible entries. Parent(s)/LAR(s) will be instructed to 
fully complete the Subject Diary each day, as per the instructions provided. 
• 
At or just in advance of each subject visit, site staff must review the Subject Diary 
data via the provider’s web portal. It is necessary for site staff to acknowledge in the 
source documents that review of Subject Diary data for the preceding post-
vaccination period has been performed. It is necessary for the investigator to 
acknowledge in the eCRF that the review of Subject Diary data has been performed 
for each subject. This is to be performed at Visit 6 (Day 331), when the subjects’ 
parent/LAR returns the Subject Diary to the clinic.. 
• 
For vaccination visits, site staff must ensure that each subject’s Diary is prepared for 
data capture in the ensuing post-vaccination period by confirming the visit within the 
eDiary/eDiary system. 
• 
Any new safety information reported during the site visit (including a solicited 
reaction) cannot be entered into the Subject Diary. Such information must be 
described in the source notes as a verbally-reported event. Any adverse reaction 
reported in this fashion must be described as an unsolicited reaction and therefore 
entered on the adverse event page of the eCRF. 

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10.3. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst other items, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.  
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.  
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.  
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
10.4. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 

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GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.  
10.5. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
10.6. 
Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and 
unanticipated SADE (USADE) 
10.6.1. 
Definition of medical device AE and adverse device effect (ADE) 
• 
Medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether considered related to a medical device or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medical device. This definition includes events related to the medical device 
or comparator and events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of a medical device. This 
definition includes any AE resulting from: 
− 
insufficient or inadequate instructions for use (i.e. user error), or 
− 
any malfunction of a medical device, or 
− 
intentional misuse of the medical device. 

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10.6.2. 
Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
− 
A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
− 
A permanent impairment of a body structure or a body function. 
− 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
− 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product 
Serious Adverse Device Effect (SADE) definition 
• 
A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the IB. 
10.6.3. 
Recording and reporting of medical device AE, ADEs, SADEs and 
USADE 
• 
Any device deficiency must be reported to GSK within 24 hours after the 
investigator determines that the event meets the definition of a device deficiency. 
• 
E-mail/Facsimile transmission of the paper ‘Medical device or combination product 
with device deficiency/incident report form’ is the preferred method to transmit this 
information to the sponsor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of ‘Medical device or combination product with 
device deficiency/incident report form’ sent by overnight mail or courier service. 

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• 
Contacts for reporting can be found in the Investigator’s instruction within the 
‘Medical device or combination product with device deficiency/incident report form’ 
and for guidance on reporting also refer to Section 7.9. 
• 
GSK will review all device deficiencies, determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs/IECs as required by national regulations. 
10.7. 
Posting of information on publicly available clinical trial 
registers and publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol. 
As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in paediatric conducted in at least one EU member state will be posted on publicly 
available EMA registers within 6 months of EoS (as defined in the protocol) in the 
concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within 6 months in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification.  
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors. 
10.8. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 

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10.9. 
Data Sharing 
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions. 
11. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable.  

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12. 
REFERENCES 
Adams DA, Thomas KR, Jajosky R, Foster L, Sharp P, Onweh DH, Schley AW, 
Anderson WJ. Summary of Notifiable Infectious Diseases and Conditions — United 
States, 2014. Morb Mortal Wkly Rep (MMWR) 2016; 63:1-152 
BEXSERO (Meningococcal Group B Vaccine) Prescribing Information, April 2023 
Bonhoeffer J, Menkes J, Gold MS, de Souza Brito G, Fisher MC, Halsey N, Vermeer P, 
The Brighton Collaboration Working Group. Generalized convulsive seizure as an 
adverse event following immunization: case definition and guidelines for data collection 
analysis, and presentation. Vaccine, 2004 22: 557-562. 
Camargo ME, Silveira L, Furuta JA, Oliveira EPT, Germek OA. Immunoenzymatic assay 
44.of anti-diphtheria toxin antibodies in human serum. 1984. J Clin Microbiol 20(4):772–
774. 
Centers for Disease Control and Prevention (CDC). Hepatitis B virus: a comprehensive 
strategy for eliminating transmission in the United States through universal childhood 
vaccination: recommendations of the Immunization Practices Advisory Committee 
(ACIP).1991. Morb Mortal Wkly Rep (MMWR) 40, (No. RR-13). 
Centers for Disease Control and Prevention (CDC). Active Bacterial Core Surveillance 
Report, Emerging Infections Program Network, Neisseria meningitidis, 2015a. 
Centers for Disease Control and Prevention (CDC). Epidemiology and Prevention of 
Vaccine-Preventable Diseases. Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. 
Washington D.C. Public Health Foundation, 2015b. 
Clopper C J, Pearson ES. The use of confidential or fiducial limits illustrated in the case 
of the binomial. Biometrika. 1934; 26: 401-403. 
Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez, IR, Briere EZ, Meissner, HC, Baker, 
CJ, Messonnier, NE. Prevention and Control of Meningococcal Disease: 
Recommendations of the Advisory Committee on Immunization Practices (ACIP). 
MMWR Recomm Rep. 2013; 62(RR-2):1–22. 
European Centre for Disease Prevention and Control (ECDC); Annual Epidemiological 
Report 2016 [2014 data]– Invasive meningococcal disease. 
http://ecdc.europa.eu/en/publications-data/invasive-meningococcal-disease-annual-
epidemiological-report-2016-2014-data  
Goldblatt D, Plikaytis BD, Akkoyunlu M, et al. Establishment of a new pneumococcal 
standard reference serum, 007sp. Clin. Vaccine. Immunol. 2011; 18(10): 1728-36. 
Harrison OB, Claus H, Jiang Y, et al. Description and nomenclature of N. meningitidis 
capsule locus. Emerging Infectious Diseases. 2013; 19 (4):566-573. 

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Hommel G, Bretz F, Maurer W. Powerful Short-Cuts for Multiple Testing Procedures 
with Special Reference to Gatekeeping Strategies. Statistics in Medicine. 2007; 26, 4063–
4073. 
ICH (2018) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices 
E6(R2): Integrated Addendum to E6(R1);. Federal Register, 83 (41): 8882-8883. 
IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. 2011. 
Washington, DC: The National Academies Press. 
Khatami A, Pollard AJ. The epidemiology of meningococcal disease and the impact of 
vaccines. Expert Rev. Vaccines., 2010; 9(3); 285–298.  
Melville-Smith ME, Seagroatt VA & Watkins JT. A comparison of enzyme-linked 
immunosorbent assay (ELISA) with the toxin neutralization test in mice as a method for 
the estimation of tetanus antitoxin in human sera. 1983. J Biol Stand 11: 137–144.  
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med, 1985; 4: 213-26. 
Pizza M, Scarlato V, Masignani V, Giuliani MM, et al. Identification of vaccine 
candidates against serogroup B meningococcus by whole-genome sequencing. Science 
2000; 287:1816–1820 
Prymula R, Esposito S, Zuccotti GV, Xie F, Toneatto D, Kohl I, Dull P. A phase 2 
randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I). 
Effects of prophylactic paracetamol on immunogenicity and reactogenicity of routine 
infant vaccines and 4CMenB. Human Vaccines & Immunotherapeutics. 2014; 10:7, 
2003–2014. 
Tingle AJ, Allen M, Petty RE Rubella-associated arthritis. I. Comparative study of joint 
manifestations associated with natural rubella infection and RA 27/3 rubella 
immunisation. Ann Rheum Dis. 1986 Feb;45(2):110-4. 
World Health Organization (WHO). Guidelines for WHO/EPI Collaborative Studies on 
poliomyelitis: standard procedure for determining immunity to poliovirus using the 
microneutralization test. 1993. WHO/EPI/GEN/93.9. WHO, Geneva, Switzerland. 
World Health Organization (WHO). Meningococcal vaccines: WHO position paper, 
Weekly epidemiological record. No. 47, 2011, 86, 521–540. 

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APPENDIX A 
LABORATORY ASSAYS  
MenB serum bactericidal assays using human complement (hSBA): 
Serum bactericidal activity against rMenB+OMV NZ will be determined by performing 
hSBA against a standard panel consisting of 4 meningococcal B test strains M14459, 
96217, NZ98/254 and M13520. Each of these strains measures bactericidal activity 
primarily directed against one of the major bactericidal antigens included in the vaccine: 
strain M14459 measures hSBA against the 741 part of the 936-741 antigen, also known 
as fHbp variant 1.1; strain 96217 measures hSBA against antigen 961c, also known as 
NadA; and strain NZ98/254 measures hSBA against PorA P1.4, the immunodominant 
antigen in the OMV NZ vaccine component; strain M13520 measures hSBA against the 
287 part of the 287-953 antigen, also known as NHBA. 
PCV13 Electrochemiluminescence (ECL) assay: 
Pneumococcal serotype-specific immunoglobin G (IgG) antibodies (antibodies to against 
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) will each be measured 
by validated multiplex assays (ECL1 and ECL2 assays). The antibody concentration will 
be determined by logistic log comparison of the assay curves with a standard reference 
serum sp007 available from the US FDA for which concentration of IgG to each of the 13 
serotypes is known in µg/mL [Goldblatt, 2011]. The cut-off of the ECL assay for each of 
the anti-pneumococcal serotype serologies is set at the serotype-specific LLOQ. The ECL 
threshold for non-inferiority assessment has been defined to be of 0.35µg/mL and is 
under assessment by FDA. 
Diphtheria toxoid (anti-diphtheria) and tetanus toxoid (anti-tetanus) ELISAs, and 
pertussis component ELISAs: 
Specific antibodies against diphtheria toxoid (anti-diphtheria IgG’s) and tetanus toxoid 
(anti-tetanus IgG’s) will be measured by ELISA. The clinical acceptable cut-off of 
ELISA was set at 0.1 International Units per mL (IU/mL), which provided a conservative 
estimate of the percentage of subjects deemed to be protected [Melville-Smith, 1983; 
Camargo, 1984]. 
Antibodies (IgG’s) against the pertussis components PT, FHA and PRN will be measured 
by ELISA to evaluate the immunogenicity of acellular B. pertussis containing vaccines. 
The seropositivity for all three pertussis antibodies will be based on new respective 
ELISA cut-offs,, where subjects with antibody concentration below the cut-off being 
considered seronegative. 
In 2014, GSK decided to redevelop and re-validate ELISA’s used for quantitative 
determination of anti-DI, -TE, -PT, -FHA and -PRN IgG in human serum in accordance 
with most recent CBER guidelines and accepted practices (guidance for Industry 
“Bioanalytical Method Validation” from September 2013). Set-up, qualification and 
validation of the new assays was performed from 2014 till 2016, and both assay units and 
assay cut-offs were adapted. 

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As per CBER’s recommendation, all values within the analytical range of the new 
ELISA’s (i.e. within [Lower Limit of Quantification (LLOQ)-Upper Limit of 
Quantification (ULOQ)]) will be used in estimating GMCs. The new ELISA’s cut-off 
will be the LLOQ. 
The newly validated DTPa ELISA’s have a lower assay cut-off as compared to the initial 
ones. Prior to their qualification, the new ELISA’s for PT, FHA and PRN were calibrated 
against the WHO International Standard (NIBSC 06/140). This allowed the expression of 
concentrations measured with the new ELISA’s in IU/mL instead of the formerly used 
ELISA units per milliliter (ELU/mL). 
Hepatitis B Virus surface Ab CLIA:  
Antibodies against the hepatitis B surface antigen (anti-HBs) will be measured using a 
ChemiLuminescence ImmunoAssay (CLIA). The cut-off of the test has been set at 
6.2 mIU/mL. An antibody concentration 10 mIU/mL defines seroprotection [CDC, 
1991]. 
Poliovirus Sabin Type 1, Type 2 & Type 3 Ab neutralization tests:  
Antibodies against poliovirus types 1, 2 and 3 will be determined by a virus 
micro-neutralization test adapted from the WHO Guidelines for WHO/EPI Collaborative 
Studies on Poliomyelitis [WHO, 1993]. Titres will be expressed in terms of the reciprocal 
of the dilution resulting in 50% inhibition. 
Hib capsular polysaccharide polyribosyl-ribitol phosphate (PRP) ELISA: 
Concentrations of IgG antibodies against the Hib polysaccharide PRP will be measured 
by an ELISA. 
MMRV Luminex based immuno assay 
Antibodies against measles, mumps and rubella viruses will be determined by a 
quantitative Luminex assay. Inactivated native viruses from measles, mumps, rubella 
and varicella are coupled to their assigned Luminex MicroPlex microsphere type. 
Each microsphere type has its own distinct fluorescent dye that can be recognized by 
excitation with a red laser. The red laser classifies the microsphere type and 
determines the corresponding assigned virus that is being detected. The microsphere 
are incubated with human serum. Following this, the microspheres are washed to 
remove excess sera and incubated with R-Phycoerythrin (PE) conjugated goat anti-
human IgG antibody. The fluorescent signal from the PE-labeled conjugate, 
recognized by excitation with a green laser, is proportional to the anti-virus IgG 
concentration in the serum sample tested.  

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IgG concentrations are derived from the MMRV Secondary Standard curve, which is 
made of pooled sera with positive reactivity to all 4 viruses and is aligned to the WHO 
International reference standards for measles (NIBSC reference# 97/648), rubella 
(NIBSC reference# RUBI-1-94) and VZV (NIBSC reference# W1044) and to NIBSC 
QC Reagent for mumps (NIBSC reference# 15/B664). The MMRV Secondary 
Standard is 2-fold serially diluted in duplicate to create a 10-point (STD1 to STD10) 
standard curve for each virus. Standard curve for each virus is calculated using a 3 
Parameter Logistic (3PL) curve fit. Results are expressed in milli International 
Unit/mL (mIU/mL) for measles and varicella, Arbitrary Unit/mL (AU/mL) for 
mumps, and International Unit/mL (IU/mL) for rubella.  
This 4-plex (MMRV) immunoassay will only be used to quantify the IgG antibodies 
specific to measles, mumps, and rubella, while antibodies specific to varicella will be 
quantified with the anti-gE ELISA. 
Varicella anti-gE ELISA 
Anti-gE ELISA is a two-step ELISA based on the antibody and antigen interaction, 
which allows the detection and the quantification of specific IgG antibodies directed 
against gE in tested serum samples. Briefly, diluted serum samples are added onto a 
96  polystyrene-well microplate pre-coated with gE. After a washing step, goat 
antibodies directed against human IgG antibodies and conjugated to HRP (a-IgG-
HRP) are added and will bind to anti-gE IgG if present. After a washing step, the 
addition of a chromogen-substrate solution specific for HRP will provide means of 
detecting the anti- gE specific for the pre-coated antigen. The HRP catalyzes an 
enzymatic reaction which is stopped by the addition of sulfuric acid, resulting in a 
color change from blue to yellow. The optical density recorded is proportional to the 
concentration of the anti-gE antibodies present in the serum sample. Antibody titer is 
expressed in mIU/mL. 

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APPENDIX B 
CLINICAL LABORATORIES 
Table 23 
GSK Biologicals’ Laboratories  
Laboratory 
Address 
GSK Biological’s Vaccines Clinical 
Laboratory and Assay Portfolio (Vx CL&AP), 
Rixensart  
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium  
GSK Biological’s Vaccines Clinical 
Laboratory and Assay Portfolio (Vx CL&AP), 
Wavre-Nord Noire Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
Nexelis Marburg a Q2 Solutions Company 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 

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APPENDIX C 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 2 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 2 
Amendment date: 
11-Dec-2017 
Co-ordinating author: 
 
Rationale/background for changes:  
• 
As the sponsorship of the study has changed from Novartis Vaccines to GSK 
Biologicals, the protocol has been transcribed to the GSK protocol template (DS-
BIO-CLIN-1006 v1) and all applicable mandatory sections have been included.  
• 
Based on feedback received from the Center for Biologics Evaluation and 
Research (CBER), the following changes in study design were implemented: 
− 
Only two study groups (Group A: rMenB+OMV NZ+PCV13 and Group B: 
Placebo+PCV13) are to be assessed, with both receiving certain ACIP 
recommended infant vaccinations. Study Group C has been removed. The 
study is to enrol 2700 subjects, in a 2:1 ratio. 
− 
Additional ACIP recommended routine infant vaccinations will be included in 
the assessment of immunogenicity, safety and tolerability as part of the 
secondary objectives. 
− 
The study will be observer-blind.  
− 
All subjects in both groups will have 3 blood draws at the same timepoints, ie, 
at 1 month post-third, pre- and post-fourth vaccinations. Group A will not 
comprise of sub-cohorts A1 and A2, and there will be no baseline blood draw. 
− 
The concomitant vaccines have been modified from the DTaP5/IPV/Hib 
(diphtheria, tetanus toxoids, five component acellular pertussis adsorbed, 
inactivated poliovirus and Haemophilus influenzae type b conjugate (Hib)) 
and human rotavirus (HRV) vaccines to DTPa-HBV-IPV (diphtheria, tetanus 
toxoids and acellular pertussis adsorbed, hepatitis B and inactivated 
poliovirus, Pediarix), HRV (Rotarix) and Hib (Hiberix) vaccines. In addition, 
measles, mumps and rubella vaccine (MMR, MMR II) and varicella (VV, 
PPD

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Varivax) vaccine have been included. All concomitant vaccines are now 
considered as investigational medicinal products (IMPs), ie study vaccines. 
− 
Additionally, a single dose of Diphtheria and Tetanus Toxoids and Acellular 
Pertussis Vaccine (DTPa, Infanrix) and the fourth dose of Hib vaccine will be 
administered at 13 months but not considered as IMPs (ie, not included in the 
safety & immunogenicity assessments). 
− 
The success criteria for the primary and key secondary objectives have been 
updated. 
− 
The immunogenicity responses for all concomitant IMP study vaccines 
(DTPa-HBV-IPV, Hib, HRV, MMR and V) will now be analyzed as 
secondary objectives. Corresponding endpoints have been included. 
− 
An interim analysis may be performed at 1 month post-4th vaccination (ie, up 
to Visit 6). This analysis will evaluate all primary and secondary 
immunogenicity objectives and solicited safety data in all subjects, rather than 
only safety data from first 2000 enrolled subjects up to Visit 2 (1 month post-
first vaccination). If this analysis was to be performed, the final analysis will 
then include all safety data up to Visit 7 (12 months after the 4th vaccination). 
− 
Solicited local and systemic adverse events (AEs) will be collected for all 
subjects and not in only 50% of subjects. 
− 
Three additional safety follow-up calls will be conducted. Safety follow-up 
calls will now take place every two months instead of every three months, 
starting at 1 month post-last blood draw at Visit 6 (ie, at Day 361, Day 421, 
Day 481, Day 541 and Day 601). The safety call between Visit 4 and Visit 5 
at Day 211 has now been replaced by safety calls at Day 181 and Day 241. 
• 
Details regarding the collection of a recruitment/randomization agreement have 
been removed as this process is not applicable in the country(ies) selected for the 
study. The first study visit will be performed at the clinic/study site. 
• 
For testing of the 13 valent pneumococcal conjugate vaccine (PCV13) antigens, 
the enzyme linked immunosorbant assay (ELISA) has been replaced by GSK 
Biologicals’multiplex, immunochemistry assay based on mesoscale discovery 
technology (electro-chemiluminescence assay, ECL). The assay cut-offs are 
specific for each of the 13 serotypes. 
• 
A pre-defined script to be used during clinic visits for providing instructions for 
safety monitoring to parent is now included. 
• 
Arthritis has been included as an adverse event of special interest (AESI). 

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The major changes made to this amendment were with regard to transferring the protocol 
to the hybrid GSK protocol template (DS-BIO-CLIN-1006 v1) and the incorporation of 
protocol template-specified mandatory text. These changes have not been listed here. The 
changes with regard to CBER feedback in the main sections of the protocol are described 
here.  
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Objectives:  
The study objectives (synopsis and Section 2.1) have been updated based on the feedback 
from CBER. 
Primary safety objectives: 
• 
To assess the safety and tolerability of and rMenB+OMV NZ ,and PCV13 and other 
RIV when administered concomitantly/non-concomitantly to healthy infants at 2, 4, 
6 and 12 months of age, throughout the study duration. 
Co-Primary immunogenicity objectives: 
• 
To demonstrate the sufficiency of the immune response to rMenB+OMV NZ when 
administered concomitantly with PCV13 and other RIV to healthy infants at 2, 4 
and 6 months of age, at one month after the 3rd vaccination. 
Criteria: The sufficiency of the immune response to rMenB+OMV NZ after the 3rd 
vaccination will be demonstrated if the adjusted lower confidence limit for the 
percentage of subjects achieving serum bactericidal assay using human 
complement (hSBA) titers ≥ Lower Limit of Quantitation (LLOQ) is ≥ 60% for the 
N. meningitidis serogroup B test strains M14459, 96217, NZ98/254 and ≥12% for 
strain M07-0241084 (individually); and is ≥10% for all strains combined 
(composite endpoint). 
• 
To demonstrate the sufficiency of the immune response to rMenB+OMV NZ when 
administered non-concomitantly with PCV13 and other RIV to healthy infants at 2, 
4, 6 and 12 months of age, at one month after the 4th vaccination 
− 
Demonstration of the sufficiency of the immune response to rMenB+OMV 
NZ at one month after the 4th vaccination will be measured by the 
percentage of subjects with serum bactericidal assay using human 
complement (hSBA) titers ≥ Lower Limit of Quantitation (LLOQ) for each 
and for all the N. meningitidis serogroup B test strains M14459 (fHbp), 
96217 (NadA), NZ98/254 (PorA) and M07-0241084 (NHBA) 
Criteria: The sufficiency of the immune response to rMenB+OMV NZ will be 
demonstrated if the adjusted lower confidence limit for the percentage of 
subjects achieving a 4-fold rise in hSBA titers (from pre-4th) is ≥70% for N. 
meningitidis serogroup B test strains M14459, 96217, NZ98/254 and ≥50% for 
strain M07-0241084 (individually); and is ≥40% for all strains combined 
(composite endpoint).  

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• 
To demonstrate the immunological non-inferiority of rMenB+OMV NZ when 
administered concomitantly with PCV13 to healthy infants 2, 4, 6 and 12 months of 
age, compared to rMenB+OMV NZ without PCV13, at one month after the 4th 
vaccination. 
Demonstration of the immunological non-inferiority of rMenB+OMV NZ after the 
3rd and the 4th vaccination will be measured by 
− 
the hSBA geometric mean titers (GMTs) against the M14459, 96217, 
NZ98/254 and M07-0241084 test strains 
− 
the percentage of subjects with hSBA titers ≥ LLOQ for each and for all the 
M14459, 96217, NZ98/254 and M07-0241084 test strains 
• 
To demonstrate the immunological non-inferiority of PCV13 when administered 
concomitantly with rMenB+OMV NZ and other RIV to healthy infants 2, 4, 6 and 
12 months of age, compared to PCV13 without rMenB+OMV NZ, at one month 
after the 3rd vaccination 
• 
To demonstrate the immunological non-inferiority of PCV13 when administered 
concomitantly with rMenB+OMV NZ to healthy infants 2, 4, 6 and 12 months of 
age, compared to PCV13 without rMenB+OMV NZ, at one month after the 4th 
vaccination 
Demonstration of the immunological non-inferiority of PCV13 after the 3rd and the 
4th vaccination will be measured by the enzyme linked immunosorbent assay 
(ELISA) geometric mean concentrations (GMCs) for each of the thirteen (4, 9V, 14, 
18C, 19F, 23F, 6B, 1, 3, 5, 6A, 7F, 19A) PCV13 antigens. 
Criterion: The immunological non-inferiority of PCV13 will be demonstrated if 
the adjusted lower confidence limit for the between-group ratio of 
electrochemiluminescence (ECL) assay Geometric Mean Concentrations (GMCs) 
is >0.5 for each of the 13 PCV13 antigens. 
Secondary objectives 
• 
To demonstrate the immunological non-inferiority of PCV13 when administered 
concomitantly with rMenB+OMV NZ and other RIV to healthy infants 2, 4, 6 and 
12 months of age, compared to PCV13 alone, at one month after the 4th 
vaccination. 
Criteria: The immunological non-inferiority of PCV13 will be demonstrated if the 
lower limit of 2-sided 95% CI for the between-group-ratio of ECL assay GMCs is 
>0.5 for each of the 13 PCV13 antigens. 
• 
To demonstrate the immunological non-inferiority of PCV13 when administered 
concomitantly with rMenB+OMV NZ and other RIV to healthy infants at 2, 4, 6 
and 12 months of age compared to PCV13 alone, at both one month after the 3rd 
and the 4th vaccinations. 

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Criteria: The immunological non-inferiority of PCV13 will be demonstrated if the 
lower limit of the 2-sided 95% CI for the group differences in percentage of 
subjects with IgG ≥ 0.35 µg/mL is > -10% for each of the 13 PCV13 antigens at 
one month after both 3rd and 4th vaccination. 
• 
To demonstrate the immunological non-inferiority 2of DTaP-HBV-IPV and Hib 
vaccines when administered concomitantly with rMenB+OMV NZ and PCV13 to 
healthy infants at 2, 4, and 6 months compared to DTaP-HBV-IPV and Hib 
vaccines concomitantly administered with PCV13 without rMenB+OMV NZ, at 
one month after the 3rd vaccination.  
Criteria: The immunological non-inferiority will be demonstrated if the lower limit 
of the 2-sided 95% CI for the between-group differences is greater than the margin 
for each antigen at one month after 3rd vaccination.  
• 
To demonstrate the immunological non-inferiority of MMR and VV vaccines when 
administered concomitantly with rMenB+OMV NZ and PCV13 to healthy subjects 
at 12 months compared to MMR and VV vaccines concomitantly administered with 
PCV13, without rMenB+OMV NZ, at one month after vaccination.  
Criteria: The immunological non-inferiority will be demonstrated if the lower limit 
of the 2-sided 95% CI for the between-group differences is greater than the margin 
for each antigen at one month after the MMR and VV vaccinations. 
• 
To evaluate the immune response to rMenB+OMV NZ when administered 
concomitantly/non-concomitantly with PCV13 and other RIV to healthy infants at 2, 
4, 6 and 12 months of age, at one month after the 3rd vaccination, at 6 months after 
the 3rd vaccination (immediately before the 4th vaccination), and at one month after 
the 4th vaccination against the M14459, 96217, NZ98/254 and M07-0241084 test 
strains. 
− 
at pre-vaccination (baseline) and six months after the 3rd vaccination 
(immediately before the 4th vaccination), as measured by the GMTs and the 
percentage of subjects with hSBA titers ≥ LLOQ against the M14459, 
96217, NZ98/254 and M07-0241084 test strains 
• 
To evaluate immune responses to routine infant vaccines DTaP-HBV-IPV, Hib, 
MMR and VV vaccines when administered concomitantly with rMenB+OMV NZ 
and PCV13. 
• 
To evaluate the immune response to PCV13 when administered concomitantly/non-
concomitantly with rMenB+OMV NZ to healthy infants at 2, 4, 6 and 12 months of 
age 
− 
at one month after the 3rd and the 4th vaccination, as measured by the 
percentage of subjects with serum pneumococcal anticapsular 
polysaccharide IgG ≥ 0.35 µg/mL for each of the thirteen PCV13 antigens 

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Concomitant vaccines: 
The concomitant non-study vaccines have been modified from the DTaP5/IPV/Hib 
(diphtheria, tetanus toxoids, five component acellular pertussis adsorbed, inactivated 
poliovirus and Haemophilus influenzae type b conjugate (Hib)) and rotavirus (HRV) 
vaccines to concomitant study vaccines DTPa-HBV-IPV (diphtheria, tetanus toxoids and 
acellular pertussis adsorbed, hepatitis B and inactivated poliovirus), HRV, Hib, MMR 
and VV vaccines. A fourth dose or Hib and a single dose of DTPa are now added as non-
study vaccines. 
Section 6.1.1: 
The term ‘study vaccine’ refers to those vaccines The study vaccines’ (see glossary of 
terms) will be provided by the Sponsor., which will be evaluated as part of the study 
objectives. All study participants are expected to receive these vaccines as specified by 
the study schedule. The study vaccines specific to this study are described below. 
• 
Vaccine A: GSK Meningococcal group-B Vaccine, (rMenB+OMV NZ) (Bexsero®); 
• 
Vaccine B: Pneumococcal polysaccharide conjugate vaccine, (13-valent 
Pneumococcal Vaccine) (PCV13) (Prevnar13®); 
• 
GSK Biologicals’ Meningococcal group-B vaccine, (rMenB+OMV NZ, Bexsero); 
• 
Pneumococcal polysaccharide conjugate vaccine, (13-valent Pneumococcal 
Vaccine) (PCV13, Prevnar13); 
• 
Saline placebo vaccine. 
Standardized routine infant immunizations included in this study are described below. 
• 
GSK Biologicals’ Diphtheria and Tetanus Toxoids and Acellular Pertussis 
Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine (DTPa-
HBV-IPV, Pediarix): a 3 dose vaccine given by IM injection at 2, 4, and 6 months 
of age. A single-dose prefilled syringes contains a 0.5-mL suspension for injection. 
• 
GSK Biologicals’ Rotavirus Vaccine, live, oral (HRV, Rotarix): a vaccine 
containing attenuated human strain P1AG1. HRV is a 2-dose vaccine typically 
given at 2 months and 4 months of age; it is available in single-dose vials of 
lyophilized vaccine, accompanied by a prefilled oral applicator of liquid diluent.  
• 
GSK Biologicals’ Haemophilus influenzae type b vaccine (Hib, Hiberix): a vaccine 
indicated for active immunization for the prevention of invasive disease caused by 
Haemophilus influenzae type b. Hib is given as a 4 dose series by IM injection; the 
primary series consists of one dose each at 2, 4, and 6 months of age, followed by a 
booster dose at 12 through 15 months of age.  
• 
Merck’s measles, mumps and rubella virus vaccine live (MMR, M-M-R II): a 
vaccine indicated for active immunization for simultaneous vaccination against 
measles, mumps, and rubella in individuals 12 months of age or older. Each 
lyophilized dose is approximately 0.5 mL after reconstitution and is administered 
by subcutaneous injection. 

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• 
Merck’s varicella zoster virus vaccine live (VV, Varivax): a vaccine indicated for 
active immunization for the prevention of varicella in individuals 12 months of age 
or older. Each dose is approximately 0.5 mL after reconstitution and is 
administered by subcutaneous injection. 
Section 6.1.2:. 
• 
Diphtheria and Tetanus Toxoids and [five component] acellular Pertussis Adsorbed, 
Inactivated Poliovirus and Haemophilus influenzae type b (Tetanus Toxoid 
Conjugate) Vaccine (DTaP5/IPV/Hib). Two types of DTaP5/IPV/Hib containing the 
same antigen components will be used in this study. In one, available in the United 
States, the Hib component is lyophilized and the vaccine needs reconstitution; the 
other, not available in the United States but available in several European countries 
and elsewhere, is fully liquid and does not need reconstitution. The non-antigenic 
ingredients of the two formulations (e.g. the excipients) are not identical. It is 
possible that the immune response to the two vaccines may not be identical; the 
potential clinical significance of this difference is not well understood. Where 
available the US licensed product will be used preferentially, but the antigenically 
identical alternative will be used where the US licensed product is not available.  
• 
Rotavirus Vaccine, Live, Oral (RV): a vaccine containing attenuated human strain 
P1AG1 (RV1). RV1 is a two dose vaccine typically given at 2 months and 4 months 
of age; it is available in single-dose vials of lyophilized vaccine, accompanied by a 
prefilled oral applicator of liquid diluent.  
The following non-study vaccine will be administered to all subjects in both groups at 
13 months of age, at Visit 6 (Day 331).  
• 
GSK Biologicals’ GSK Biologicals’ Diphtheria and Tetanus Toxoids and Acellular 
Pertussis Adsorbed Vaccine (DTPa, Infanrix): DTPa is a 5 dose vaccine given by 
IM injection at 2, 4, and 6 months of age, with a booster dose at 15 to 20 months of 
age and another booster dose at 4 to 6 years of age. A single-dose prefilled syringes 
contains a 0.5-mL suspension for injection. 
In order to complete the dosage scheme for DTPa, a single dose of DTPa (Infanrix) 
will be administered IM as a booster dose at Visit 6 (as subjects would have already 
received 3 doses of Pediarix as an IMP study-vaccine).  
In addition, all subjects will receive the fourth dose of Hib (Hiberix) as a non-study 
vaccine during Visit 6. Details on the vaccine are provided in Section 6.1.1.  
Endpoints (Synopsis and section 9.1 and 9.2) 
Safety endpoints: 
Only AESIs predefined as serious will be recorded as SAEs in the eCRF, and not all 
AESIs. Arthritis has been included as an AESI. The safety endpoint of summarizing the 
percentage of subjects with AESIs has been modified.  
• 
The percentage of subjects with solicited local AEs and systemic AEs during the 7 
days (including the day of vaccination) after the 1st, the 2nd, the 3rd and the 4th 
vaccination (Visits 1, 4, 7 and 112, 3 and 5). 

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• 
The percentage of subjects with solicited systemic AEs of parotid/salivary gland 
swelling, fever and rash during the 30 days (including the day of vaccination) after 
the 4th vaccination (Visit 5). 
• 
The percentage of subjects with all any other (unsolicited) AEs (including SAEs, 
AEs leading to withdrawal, AESIs and medically attended AEs) during 30 days 
(including the day of vaccination) after the 1st, the 2nd, the 3rd and the 4th vaccination 
(Visits 1, 2,3,and 5 4, 7 and 11). 
• 
The percentage of subjects with SAEs, AEs leading to withdrawal, AESIs and 
medically attended AEs from study Day 1 (Visit 1) until study end (12 months after 
last study vaccination, Visit 177). 
• 
The percentage of subjects with AESI and seizures from study Day 1 (Visit 1) until 
study end (12 months after last study vaccination, Visit 17). 
Primary immunogenicity endpoints: 
Primary immunogenicity endpoints have been updated based on changes made to the 
study objectives. Endpoints for the different routine infant vaccines (now considered 
study vaccines) have been included. 
• 
For rMenB+OMV NZ, the following endpoints will be calculated:  
• 
at one month after the 3rd and the 4th vaccinations. 
− 
the percentage of subjects with hSBA titers ≥ LLOQ for each of the M14459, 
96217, NZ98/254 and M07-0241084 test strains 
− 
the percentage of subjects with hSBA titers ≥ LLOQ for all strains combined 
(composite endpoint) 
− 
the hSBA GMTs  
• 
At one month after the 4th vaccination:  
− 
the percentage of subjects with 4-fold rise (from pre-4th vaccination) in hSBA 
titers for each of the M14459, 96217, NZ98/254 and M07-0241084 test strains. 
− 
the percentage of subjects with 4-fold rise (from pre-4th vaccination) in hSBA 
titers for all strains combined (composite endpoint). 
A 4-fold rise in hSBA titers is defined as: 
− 
if pre-vaccination titer <Limit of Detection (LOD), then a post-vaccination 
titer ≥LLOQ; 
− 
if pre-vaccination titer is ≥LOD but ≤LLOQ, then a post-vaccination titer 
≥4 times the LLOQ; 
if pre-vaccination titer is ≥ LLOQ, then a post-vaccination titer ≥4 times the pre-
vaccination titer. 
• 
For PCV13 the following endpoint will be calculated at one month after the 3rd and 
the 4th vaccination: 
− 
the ELISA GMCs for each of the 13 PCV13 antigens. 

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Secondary immunogenicity endpoints: 
For rMenB+OMV NZ, the following secondary endpoints will be calculated: 
• 
at pre-vaccination (baseline) and At 1 six months after the 3rd vaccination 
(immediately before the 4th vaccination): 
− 
the percentage of subjects with hSBA titers ≥5 and ≥8 LLOQ for each of the 
M14459, 96217, NZ98/254 and M07-0241084 test strains 
− 
the hSBA GMTs  
• 
At 6 months after the 3rd vaccination (immediately before the 4th vaccination): 
− 
the percentage of subjects with hSBA titers ≥ LLOQ for each of the M14459, 
96217, NZ98/254 and M07-0241084 test strains. 
− 
the percentage of subjects with hSBA titers ≥ 5 and ≥8 for each of the 
M14459, 96217, NZ98/254 and M07-0241084 test strains. 
− 
the hSBA GMTs against each strain. 
• 
At 1 month after the 4th vaccination:  
− 
the percentage of subjects with hSBA titers ≥LLOQ; for each of the M14459, 
96217, NZ98/254 and M07-0241084 test strains. 
− 
the percentage of subjects with hSBA titers ≥5 and ≥8 for each of the M14459, 
96217, NZ98/254 and M07-0241084 test strains. 
− 
hSBA GMTs and geometric mean ratios (GMRs) over pre-4th vaccination. 
− 
Additionally, the GMR will be calculated at one month after the 4th vaccination 
to pre-fourth vaccination. 
For PCV13 the following endpoint will be calculated: 
• 
At one month after the 4th vaccination the ECL GMCs for each of the 13 PCV13 
antigens. 
• 
At one month after the 3rd and the 4th vaccination, the percentage of subjects with 
serum pneumococcal anti-capsular polysaccharide IgG ≥0.35 μg/mL 
For DTPa-HBV-IPV, the following endpoints will be calculated at one month after the 
3rd vaccination 
• 
Pertussis: 
− 
GMCs against the 4 pertussis antigens (pertussis toxin [PT], pertactin [PRN], 
filamentous hemagglutinin [FHA]). 
• 
Hepatitis B:  
− 
Percentage of subjects with concentrations ≥10 mIU/mL and ≥100 mIU/mL. 
− 
Anti-HBsAg GMTs. 

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• 
Polio:  
− 
Percentage of subjects with anti-polio type 1, 2 and 3 neutralization antibody 
titers ≥ 8. 
• 
Diphtheria and Tetanus: 
− 
Percentage of subjects with anti-diphtheria and anti-tetanus concentrations ≥ 
0.1 IU/mL and ≥ 1 IU/mL. 
− 
Anti-diphtheria and anti-tetanus antibody GMTs. 
• 
Hib: 
− 
The percentage of subjects with anti-PRP concentration ≥0.15 µg/mL and 
≥1 µg/mL. 
For VV, the following endpoint will be calculated at 1 month after the 4th vaccination: 
• 
Seroresponse, defined as post-vaccination anti-VZV antibody concentration ≥75 
mIU/mL among children who were seronegative (antibody concentration <25 
mIU/mL) before vaccination. 
For MMR, the following endpoints will be calculated at 1 month after the 4th 
vaccination:  
• 
Seroresponse as defined by the post-vaccination anti-measles virus antibody 
concentration ≥ 200 mIU/mL (ELISA, Enzygnost) in subjects seronegative 
(antibody concentration <150 mIU/mL) before vaccination. 
• 
Seroresponse as defined as post-vaccination anti-mumps virus antibody 
concentration ≥ a threshold in subjects seronegative (antibody concentration < 
assay cut-off) before vaccination.  
Note: A suitable ELISA assay for analysis of anti-mumps virus antibody 
concentrations is yet to be selected and/or developed. 
• 
Seroresponse, defined as post-vaccination anti-rubella virus antibody 
concentration ≥10 IU/mL (ELISA, Enzygnost) in subjects seronegative (antibody 
concentration <4 IU/mL) before vaccination. 
Interim analysis: 
Details regarding the interim analysis have been modified to include immunogenicity 
analysis and to change the time point of the analysis. 
Section 9.10: 
An interim analysis may be performed to provide Health Authorities with preliminary 
information on the primary and secondary objectives and solicited safety data. The 
analyses if performed will occur at 1 month post-4th vaccination (ie, up to Visit 6 at 
Day 331). and tolerability of rMenB+OMV NZ and PCV13 administered either 
concomitantly or alone, one month after the third dose. The interim analysis will include 
approximately the first 2000 all enrolled subjects., and the analyses will be performed on 
safety data from Visit 1 to Visit 4 (i.e. two months post first vaccination).This analysis 

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will be descriptive. For 2nd and 3rd vaccination the data will be provided as available at 
that point in time for these subjects. The interim analysis will include all enrolled 
subjects. All immunogenicity objectives will be analyzed. The safety analysis will be 
performed on solicited safety data from all timepoints up to Visit 6. The interim 
analysis will be performed by independent statistician, in order to maintain the 
observer-blindness of the study. Study unblinding will be performed only after database 
lock. The data or the results from this interim analysis will not be used to make any 
decision on the continuation of this open label trial. Therefore no impact on the conduct 
or subsequent full data analysis of the trial is expected.  
A final analysis related to the tolerability, safety and immunogenicity may be also 
performed after all subjects complete Visit 13 (i.e. one month post 4th vaccination).The 
locked data or the results from this final analysis will include the relevant endpoints, 
analysis sets and methods aligning with the primary and secondary immunogenicity 
objectives of this study and with the safety objectives of this study up to the above 
mentioned timepoint. If this final analysis is performed, the The remaining safety 
analyses up to study termination at Visit 7 will be provided in an addendum to the 
Clinical Study Report additional study report 
Change in assay for PCV13:  
ELISA has been replaced by the ECL assay for testing the PCV13 antigens, and the assay 
cut-off has been updated.  
Criterion for objectives: 
Demonstration of the immunological non-inferiority of PCV13 after the 3rd and the 4th 
vaccination will be measured by the enzyme linked immunosorbent pneumococcal 
polysaccharide (PnPs) multiplex electrochemiluminescence (ECL) assay (ELISA) 
geometric mean concentrations (GMCs) for each of the thirteen (4, 9V, 14, 18C, 19F, 
23F, 6B, 1, 3, 5, 6A, 7F, 19A) PCV13 antigens 
Laboratory assays (Section 5.7.3 and Appendix 1):  
The antibody responses to PCV13 will be determined by ELISA. The ELISA measures 
13 serotype specific anti S. pneumoniae IgG capsular polysaccharide antibodies present 
in human sera. The respective antibody concentration is measured in µg/mL. 
Beside the classical Sandwich ELISA there are alternative anti-S. pneumoniae IgG 
detection methods developed (e.g. Multiplex fluorescent bead assay).  
Pneumococcal serotype specific total IgG antibodies (antibodies to 1, 3, 4, 5, 6A, 6B, 
7F, 9V, 14, 18C, 19A, 19F and 23F) will each be measured by a multiplex 
immunochemistry assay based on mesoscale discovery technology (electro-
chemiluminescence assay, ECL) 

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The antibody concentration will be determined by logistic log comparison of the ECL 
curves with a standard reference serum SP007 available from the US Food and Drug 
Administration (FDA). The cut-off of the assay was defined at serotype-specific LLOQ 
for each serology (see ). The ECL assay has been bridged to the WHO reference 22F-
ELISA and the derived threshold for IPD licensure for the ECL assay, corresponding 
to the 0.35µg/mL, was found to be 0.32µg/mL. 
Other indicators of reactogenicity 
Solicited indicators of reactogenicity updated to include medically attended fever and use 
of analgesics/antipyretics. Fever is now categorized as a solicited systemic AE. 
Other solicited adverse events (Section 7.1.3.3): 
Fever, defined as body temperature ≥38°C; temperature should be taken preferably via 
the rectal route, ideally at same time each day. Other routes of temperature measurement 
include axillary, oral and tympanic. 
The following will also be measured and recorded as other solicited events in the 
Subject Diary (eDiary). 
• 
Body temperature *, 
• 
Medically-attended fever, and  
• 
Use of analgesics/antipyretics for either prophylactic or treatment purposes. 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 3 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 3 
Amendment date: 
25 APR 2018 
Co-ordinating author: 
 
Rationale/background for changes:  
• 
The definition of a qualified healthcare professional has been clarified to include 
any licensed or certified health care professional, rather than only state-licensed 
health care professionals. 
• 
The text regarding allocation of treatment numbers to subjects has been corrected. 
Individual treatment numbers will now be allocated to subjects for each vaccine, 
instead of a single treatment number throughout the study. 
• 
The definition of 4-fold rise in hSBA titers has been corrected. 
• 
The storage temperature for the Varivax vaccine is updated to range from -15°C to 
-25°C. The range for acceptable temperature excursions is changed accordingly. 
• 
The formulation for the HRV vaccine (Rotarix) in Table 10 is updated to describe 
details related to the lyophilized formulation (‘HRV lyo’). 
• 
Minor changes to text on location of administration of the placebo vaccine, route 
of administration for all vaccines and recording of injection site in the eDiary, to 
align with the dosage and administration table (Table 11). 
• 
The time period for recording of concomitant vaccinations modified to begin from 
birth, rather than 14 days (28 for live attenuated vaccines) before the first study 
vaccine dose. 
• 
Text in various sections updated to clarify that solicited AEs ongoing after the 7-
day reporting period will continue to be collected in the eDiaries, until resolution. 
• 
Time intervals for analyses of unsolicited AEs clarified to specify that only certain 
AEs (SAEs, AEs leading to withdrawal, medically attended AEs etc.) will be 
analyzed after 30 days post-vaccination. 
• 
Other minor changes to correct typos, and improve clarity and alignment within 
the document. 
PPD

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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Definition of Qualified Healthcare Provider (Glossary and Section 5.6.6) 
A state licensed Any licensed or certified healthcare professional who is permitted by 
institutional policy to perform protocol required procedures, and who is identified within 
the Study Staff Signature Log. 
Allocation of treatment numbers  
Section 5.2.2.2 Treatment allocation to the subject: 
The treatment numbers will be allocated by dose for Bexsero and placebo vaccines. 
Treatment allocation will be by components for all other products. Throughout the 
study, a single treatment number will identify the vaccine doses to be administered to the 
same subject. 
Section 6.4 Replacement of unusable vaccine doses: 
The investigator will use SBIR to obtain the replacement vaccine number. The 
replacement numbers will be allocated by dose for Bexsero and placebo vaccines. 
Replacement numbers will be allocated by components for all other products. The 
system will ensure, in a blinded manner, that the replacement treatment vial matches the 
formulation the subject was assigned to by randomization. 
Clarification of definition of 4-fold rise (Synopsis and Section 9.1.2 Primary 
immunogenicity endpoints) 
The second criterion of the definition has been updated as below: 
A 4-fold rise in hSBA titers is defined as 
− 
if pre-vaccination titer <Limit of Detection (LOD), then a post-vaccination titer 
≥LLOQ; 
− 
if pre-vaccination titer is ≥LOD but <LLOQ, then a post-vaccination titer 
≥4 times the LLOQ;  
− 
if pre-vaccination titer is ≥LLOQ, then a post-vaccination titer ≥4 times the pre-
vaccination titer. 
Section 6.2 Storage and handling of study and non-study vaccines 
Varivax storage temperature updated as follows:  
For the Varivax vaccine, the antigen is to be stored at - 20C/-4 F between - 25C/-13 F to 
- 15C/5 F and the diluent at +4C/+39.2 F. 
Range for temperature excursions updated accordingly and clarification that the process 
for reporting of temperature exclusions applies to NIMPs as well: 

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Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) or below - 25C/-13 or above -15.0°C/5 F (for -20°C/-4°F 
label storage condition) impacting investigational medicinal products (IMPs) must be 
reported in the appropriate (electronic) temperature excursion decision form (Advanced 
Temperature Excursion Analysis and Management [ATEAM]). The impacted IMPs must 
not be used and must be stored in quarantine at label temperature conditions until usage 
approval has been obtained from the sponsor. This applies for the NIMPs as well. 
Formulation of Rotarix vaccine (Table 10 Study Vaccines) 
The vaccine name and formulation was updated to the HRV lyophilized version.  
Rotarix  
HRV HRV lyo 
HRV RIX4144=106.5 CCID50 HRV 
RIX4144 live attenuated 
>=106.0CCID50 
Lyophilized vaccine 
in a monodose glass 
vial. 
HRV Diluent 
CaCO3=60mg 
Diluent for 
lyophilized vaccine 
(calcium carbonate 
liquid antacid) 
supplied separately 
in a prefilled oral 
applicator 
Overview of Study Design (Figure 1) 
The first safety follow-up visit was corrected to ‘D16’, as it previously read ‘D15’. 
Update of ICH version (Section 5.1 Regulatory and ethical considerations, including 
the informed consent process and Section 12 References) 
The ICH GCP version was updated to reflect the most recent version. 
Properly constituted IRB/EC is defined in ICH Guideline for GCP E6 (R1 R2), Section 3 
[ICH, 1997 2018]. 
The corresponding reference was updated as follows: 
ICH (2018 1997) ICH Harmonized Tripartite ICH Guideline for Good Clinical Practices 
E6(R1 R2): Integrated Addendum to E6(R1);. Federal Register, 62 (90): 25691-25709 
83 (41): 8882-8883. 
List of Study Procedures (Table 5) 
The row for inclusion/exclusion criteria check was updated to remove the check at Visit 4 
(Day 151). The row for training of eDiary was changed at Visit 5 (Day 301) from an 
open bullet indicating it is not required to be documented in the eCRF to a closed bullet 
(ie, required to be documented in the eCRF). 
Location of administration of placebo, update of route of vaccine administration 
and recording of injection site (Section 6.3 Dosage and administration of study 
vaccines) 
The location for administration of the placebo vaccines was included in the text. 

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The rMenB+OMV NZ/Placebo vaccine should be administered at least 2.5 cm above the 
injection site of Hib, when concomitantly administered on the same thigh.  
The route of administration was updated to refer to the Dosage and Administration table 
instead: 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly by the route described in Table 11 below.  
Text added to clarify that site of injection should be recorded in the eDiary as well: 
The exact anatomic location of each injection must be carefully recorded in the Medical 
Chart and in the eCRF, as well as the Subject eDiary.  
Clarification of timepoint of assessment of exclusion criteria (Section 6.5 
Contraindications to subsequent vaccination) 
The text on assessment of exclusion criteria was clarified to describe that it should be 
performed before each dose. 
• 
Any occurrence of an event listed in the exclusion criteria which must be always re- 
assessed by the investigator before administration of the second next dose of study 
vaccine. Refer to Section 4.2.  
Time period of recording of concomitant vaccinations (Section 6.7.1 Recording of 
concomitant medications/products and concomitant vaccinations) 
Criteria updated to record concomitant vaccinations from birth, rather than 14/28 days 
prior to first study vaccine dose.  
• 
Any concomitant vaccination administered in the period starting from birth 14 days 
(or 28 days for live attenuated vaccines) before the first dose of study vaccine(s) and 
ending at the last study visit (Day -14 to Day 661).  
Recording of solicited AEs only via eDiary (Section 7.1.1 Definition of an adverse 
event) 
Solicited AEs are derived from organized data collection systems, such as Subject 
Diaries, or interview.  
Recording of solicited AEs in the eCRF (Section 7.1.3.3 Other solicited adverse 
events) 
Solicited local and systemic AEs that continued beyond day 7 after vaccination will not 
need to be entered as an AE in the AE eCRF or the subject’s source document. They will 
be collected via the eDiary. 
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 10.2) and also as an adverse event on the 
Adverse Event eCRF: 
• 
Solicited local or systemic adverse event that continues beyond day 7 after 
vaccination.  

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• 
Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see Section 7.2.3.4). 
• 
Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse 
event leading to withdrawal). 
Solicited AEs ongoing after 7 days post-vaccination 
Solicited AEs that are ongoing after the 7-day reporting period will continue to be 
recorded in the eDiary until resolution or up to 30 days post-vaccination (ie, recording 
period for unsolicited AEs). 
Table 5 List of Study Procedures: Footnote added as 11 Solicited AEs that are ongoing 
after the 7-day reporting period will continue to be recorded in the eDiary until 
resolution. 
Section 5.6.15.1.1: The subject’s parent(s)/LAR(s) will receive daily reminders via the 
Subject Diary device’s in-built audio-visual alarms to alert the user to complete the diary 
during the post vaccination period, which is from Day 1 to Day 7 after Visits 1, 2 and 3 
(or until the solicited AE resolves) and from Day 1 to Day 30 after Visit 5. 
Section 7.1.3: The term “reactogenicity” refers to solicited signs and symptoms 
(“solicited adverse events”) occurring in the hours and days following a vaccination, to 
be collected by the parent(s)/LAR(s) for 7 consecutive days (with ongoing solicited AEs 
collected until resolution or day 30, whichever occurs first), using a pre-defined Subject 
Diary. 
Table 13 Footnote 2: Solicited AEs to be collected for 7 days following each vaccination, 
with ongoing solicited AEs collected until resolution or day 30, whichever occurs first. 
Specific solicited systemic AEs (parotid gland swelling, fever, rash) will be collected for 
30 days following MMR/V vaccination a Visit 5 (Day 301). 
Pre-vaccination temperature recording (Section 5.6.9 Assess pre-vaccination body 
temperature) 
Included a cross-reference to section on contraindications to subsequent vaccinations: 
If the subject has fever [fever is defined as a body temperature 38.0°C/100.4°F 
regardless the location of measurement on the day of vaccination], the vaccination visit 
will be rescheduled within the allowed interval for this visit (see Table 6 and Section 
6.5). 
Alignment of post-vaccination procedures with Table 5 (Section 5.6.13 Post-
vaccination procedures) 
The following post-vaccination procedures for each subject will be performed on Day 1 
(Visit 1), Day 61 (Visit 2), Day 121 (Visit 3), and Day 301 (Visit 5). After vaccination, 
the subject will be observed for at least 30 minutes including observation for solicited 
and unsolicited AEs. Record all safety data collected during this time in the subject’s 
source document and eCRF.  

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Safety information to be reported by parent(s)/LAR(s) (Section 7.2.3.2.1 Assessment 
of intensity and Section 10.2 Subject Diary) 
Text updated in various sections to make clear that it is the parent/LAR who will be 
providing the safety information, and not the subject. 
Section 5.6.15: The subjects/subjects’ parent(s)/LAR(s) will be instructed to contact the 
investigator immediately should the subjects manifest any signs or symptoms they 
perceive as serious.  
Section 5.6.15.1: Subject Diary assignment and use (at Visit 1 and Visit 5): 
• 
Each subject’s parent(s)/LAR(s) will be assigned a Subject Diary and shown how to 
use the device – this will include how to access the diary, performing test data entry 
on sample questions, and how to charge and store the device. 
• 
The subject’s parent(s)/LAR(s) will self-select a numeric access code secret to 
themselves. The same individual should preferably make the assessments and 
complete the Subject Diary throughout the relevant reporting period.  
Section 5.6.15.2: Safety follow-up calls are calls made to the subject’s parent(s)/LAR(s) 
by a qualified healthcare professional designated on the site log. 
Section 5.7: Any sample testing will be done in line with the consent of the individual 
subject/subject’s parent(s)/LAR(s).  
Section 7.2.3.2.1: Every effort should be made by the investigator to evaluate safety 
information reported by a subject’s parent(s)/LAR(s) for an underlying diagnosis and to 
capture this diagnosis as the event in the AE page. 
Section 10.2: The Investigator or delegated staff should monitor the Subject’s Diary 
status throughout the study for compliance and any solicited local and systemic adverse 
events that were of concern to the subject’s parent(s)/LAR(s). 
Time period for collecting SAEs, medically attended AEs, AEs leading to 
withdrawal (Section 7.2.1 Time period for detecting and recording adverse events 
and serious adverse events) 
Text updated to clarify that recording of these AEs will start from Day 1, which would 
also be at the first receipt of study vaccines. 
The time period for collecting and recording SAEs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 12 months following administration of the last 
dose of study vaccine for each subject (ie, study end). See Section 7.3 for instructions on 
reporting of SAEs. 
All medically attended AEs will be collected and recorded from Day 1 (ie, the time of the 
first receipt of study vaccines) until 12 months following administration of the last dose 
of study vaccine for each subject (ie, study end). 

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All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
Day 1 (ie, the time of the first receipt of study vaccines) until 12 months following 
administration of the last dose of study vaccine for each subject (ie, study end). 
The time period for collecting and recording of AESIs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 12 months following administration of the last 
dose of study vaccines (ie, study end).  
Alignment of terminology for visits and follow-up calls (Section 7.2.3.1 Active 
questioning to detect adverse events and serious adverse events) 
Pre-defined scripts will be used during the clinic safety visits and safety follow-up calls 
for instructing parents in recording safety data. 
Analyses of unsolicited AEs clarified (Section 9.5 Derived and Transformed data) 
The time intervals for the analysis of unsolicited AEs have been updated to clarify that 
only certain AEs will be analyzed post-30 days after vaccination. 
• 
Unsolicited AEs: For unsolicited AEs, the entire study period will be divided into the 
following disjoint intervals: Day 1 through Day 30, Day 31 until next vaccination or 
study termination. Unsolicited AEs are collected for 30 days post vaccination, and 
are analyzed as such without division of the time interval 
• 
AEs/SAEs leading to withdrawal from the study, SAEs (including SAEs related to 
study vaccine(s)), SAEs related to study participation or concurrent GSK 
medication/vaccine, AESIs, and Medically attended AEs: The entire study period 
will be divided into the following disjoint intervals: Day 1 through Day 30 post 
vaccination, Day 31 post vaccination until either the next vaccination or study 
termination. 
Footnote for Table 19 (GMTs at One Month Post 3rd Dose and GMRs at One Month 
Post 4th rMenB+OMV NZ Vaccination) 
The footnote for Table 19 has been removed as it is no longer applicable. 
Post 3rd vaccination results not available for M07-0241084. It is calculated assuming that 
post-3rd vaccination GMT is -0.3 to the post-4th vaccination GMT, because a difference 
of -0.2 to -0.4 were observed from the data of the other three strains. 
Time period for investigator acknowledgment (Section 10.2 Subject Diary) 
Added time period to specify when investigator needs to provide acknowledgment of 
subject diary review. 
 It is necessary for the investigator to acknowledge in the eCRF that the review of Subject 
Diary data has been performed for each subject. This is to be performed at Visit 6 (Day 
331), when the subjects’ parent/LAR returns the Subject Diary to the clinic. 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 4 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 4 
Amendment date: 
02 NOV 2018 
Co-ordinating author: 
 
Rationale/background for changes:  
• 
Request received from the Center for Biologics Evaluation and Research (CBER) 
on 10 JUL 2018 to amend the study protocol to revise the endpoints and success 
criteria based on using the strain M10713, for evaluating immune responses to the 
NHBA antigen. Sections describing endpoints, success criteria for sufficiency of 
immune response and all corresponding statistical methods have been updated 
accordingly. The testing strategy for the primary objective has been reduced from 
5 hypotheses families to 3. 
• 
CBER asked to maintain a sample size of 2700 and hence the power has been 
recalculated, based on certain assumptions and sufficiency criteria for the M10713 
strain and composite endpoint. 
• 
Exclusion criteria modified to allow administration of one dose of Hepatitis B 
vaccine (HBV) up to 4 weeks prior to informed consent, in line with local practice. 
• 
Confirmation of hSBA cut-off values following completion of the assay 
validation, including both lower limits of detection (LODs) and lower limits of 
quantitation (LLOQs) for the 3 MenB indicator strains M14459 (fHbp), 
96217(NadA) and NZ98/254 (PorA). 
• 
In alignment with eDiaries, clarified that site staff to contact the subjects 
parents/LAR(s) when subjects experienced either solicited or unsolicited AE(s) 
that required hospitalization or visit to the emergency room or medically attended 
events that were of concern to the parents/LAR(s). 
• 
Temperature categories for grading of fever in Fahrenheit updated. 
• 
Other minor changes to correct typos, and improve clarity and alignment within 
the document. 
PPD

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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Objectives:  
The study objectives (synopsis and Section 2.1) and endpoints (synopsis and Sections 9.1 
and 9.2 ) have been updated based on the feedback from CBER to change the NHBA 
strain. 
Co-Primary immunogenicity objectives: 
• 
To demonstrate the sufficiency of the immune response to rMenB+OMV NZ when 
administered concomitantly with PCV13 and other RIV to healthy infants at 2, 4 and 
6 months of age, at one month after the 3rd vaccination. 
Criteria: The sufficiency of the immune response to rMenB+OMV NZ after the 3rd 
vaccination will be demonstrated if the adjusted lower confidence limit for the 
percentage of subjects achieving serum bactericidal assay using human complement 
(hSBA) titers ≥ Lower Limit of Quantitation (LLOQ) is ≥ 60% for the N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254 and ≥12 55% for strain M07-
0241084 M10713 (individually); and is ≥10 43% for all strains combined (composite 
endpoint). 
• 
To demonstrate the sufficiency of the immune response to rMenB+OMV NZ when 
administered non-concomitantly with PCV13 and other RIV to healthy infants at 2, 
4, 6 and 12 months of age, at one month after the 4th vaccination 
Criteria: The sufficiency of the immune response to rMenB+OMV NZ will be 
demonstrated if the adjusted lower confidence limit for the percentage of subjects 
achieving a 4-fold rise in hSBA titers (from pre-4th) is ≥70% for N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254 and ≥50 66% for strain M07-
0241084M10713 M10713 (individually); and is ≥4048% for all strains combined 
(composite endpoint).  
Secondary objective: 
• 
To evaluate the immune response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to healthy infants at 2, 4, 6 and 12 months 
of age, at one month after the 3rd vaccination, at 6 months after the 3rd vaccination 
(immediately before the 4th vaccination), and at one month after the 4th vaccination 
against the M14459, 96217, NZ98/254 and M07-0241084 M10713 test strains. 
Immunogenicity endpoints: 
Primary: 
For rMenB+OMV NZ, the following endpoints will be calculated:  
• 
At one month after the 3rd vaccination  
− 
the percentage of subjects with hSBA titers ≥LLOQ; for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
− 
the percentage of subjects with hSBA titers ≥LLOQ for all strains combined 
(composite endpoint). 

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• 
At one month after the 4th vaccination  
− 
the percentage of subjects with 4-fold rise (from pre-4th vaccination) in hSBA 
titers for each of the M14459, 96217, NZ98/254 and M07-0241084M10713 test 
strains. 
Secondary: 
For rMenB+OMV NZ, the following secondary endpoints will be calculated: 
• 
At 1 month after the 3rd vaccination 
− 
the percentage of subjects with hSBA titers ≥5 and ≥8 for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
• 
At 6 months after the 3rd vaccination (immediately before the 4th vaccination) 
− 
the percentage of subjects with hSBA titers ≥LLOQ for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
− 
the percentage of subjects with hSBA titers ≥5 and ≥8 for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
• 
At 1 month after the 4th vaccination  
− 
the percentage of subjects with hSBA titers ≥LLOQ; for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
− 
the percentage of subjects with hSBA titers ≥5 and ≥8for each of the M14459, 
96217, NZ98/254 and M07-0241084 M10713 test strains. 
Strain name and cut-off in Table 7: 
Table 7 
Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritization  
Serum 
N Men B M10713 M07-
0231084 (NHBA) Ab  
MSBA  
In house 
1/DIL 
16 4  
GSK 
Biologicals 
*** or 
laboratory 
designated 
by GSK 
Biologicals 
1.1 
N Men B NZ98/254 (PorA) 
Ab  
6  
1.2 
N Men B M14459 (fHbp) 
Ab 
5  
1.3 
N Men B 96217 (NadA) Ab  
15 
1.4 
Rationale for the study and study design (Synopsis and Section 1.2.1) 
Furthermore, the immune response of the rMenB+OMV NZ vaccine against test strains 
M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4) and M07_024108 M10713 
(NHBA) has not been evaluated yet in a US pediatric population. These strains are 
considered by the Center for Biologics Evaluation and Research (CBER) to better 
evaluate the protective response of the vaccine in the US population.  

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Statistical methods 
Statistical methods in Section 9 were updated to reflect the change in strain and reduction 
in number of hypotheses families. 
Section 9.3 Determination of sample size: 
With 250 per group for PCV13 antigen tests and 1170 evaluable subjects from Group 
MenB+PCV for rMenB+OMV NZ strain tests, there is approximately 90% 94% 
probability to reject all 23 null hypotheses, and to claim that the primary objectives of the 
study will be met according to the predefined success criteria, assuming that the 
correlation between the rMenB+OMV NZ strains is 25%. 
Table 17 
Power to Show Non-Inferiority PCV13 Co-Primary Objective and 
Sufficiency rMenB+OMV NZ Co-Primary Objectives  
 
With 20% 
Correlation1 
With 25% 
Correlation1 
With 50% 
Correlation1 
 
N=1170 
(N=250 for 
PCV13) 
N=1170 
(N=250 for 
PCV13) 
N=1170  
(N=250 for PCV13) 
Success:  
- Non-inferiority for GMCs for 13 antigens after the 3rd 
vaccination 
Sufficiency for % of subjects with titers ≥ LLOQ  
 per each strain and all 4 strains combined (composite 
response) after the 3rd vaccination 
Sufficiency for % of subjects with 4-fold increase (from pre-
4th to post-4th) per each strain and all 4 strains combined 
(composite response) after the 4th vaccination 
 
 
 
Probability of rejection of all 23 null hypotheses  
75 80% 
90 94% 
99 98% 
1 With correlation assumption, it is assuming that there is a certain level of dependence between the results among the 
strains/antigens. The correlation value can range from 0 to 1. The higher the value is, the more dependent the results 
are among the strains. From V72P13 and V72P13E1 T10 strains results it showed that the between-strain correlation 
is are mostly within the range of 0.25 0.17 and 0.457. For robustness of results power calculations were repeated 
using correlation matrices between strains with pairwise correlations taken from V72P13 and V72P13E1 where 
needed imputed 0.25. The resulting power is 95% for individual pairwise correlations, which is consistent with 
the result 94% when all pairwise correlations are chosen constant equal to 0.25. 
The power was estimated using simulations: 10.000 simulations per case. SAS 9.2 9.4 
was used for the calculations. 
e. 
For testing Family 2 and 3 to 5, 1170 normal distributed data were drawn for one 
single group and for the four strains, according to the GMTs (for post 3rd dose) and 
GMRs (for post 4th dose), as shown in Table 19, and the SDs as described below in 
Table 18. Correlation structure was made for between-antigen correlation of 20%, 
25% or 50%, respectively. 
f. 
Testing of Family 1: Shifted one-sided t-test was used to test the hypotheses and 
output the p-values (for the power calculation no center effect was assumed). 
g. P-values were adjusted for multiplicity using the “Bonferroni-Holm” method (SAS 
procedure PROC MULTTEST, option “holm”). 

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h. P-values Adjusted p-values were compared with the Family Wise Error Rate 
(FWER) to conclude on whether the null hypotheses were rejected or not. FWER for 
Family 1 is initially set to be 1/3 of the full alpha, which is rounded to 0.017. The 
FWER for Family 2 is 0.033 and the initial FWER is 0 for Family 3, 4 and 5. No 
multiplicity adjustment was performed within a family. Within family 1 all thirteen 
antigens were tested with the full FWER for family 1. If one or more test fail to 
reject the hypothesis for the antigen, family 1 fails. Consequently the alpha of family 
1 will not be propagated (see bullet h. below). 
i. 
Preparing for testing Family 2 and 3 to 5, percentages were obtained by 
dichotomizing the normal random sets that were generated at step b, by applying the 
cut-off of LLOQ value for post 3rd or a cut-off of 4 at post 4th. By applying a cut-off 
of 4 to the GMRs at post-4th this will generate a percentage of subjects who had a 4-
fold increase for their GMT value at post-4th compared to pre-4th, which is an 
approximation of the percentage of 4-fold increase using LOD and LLOQ values. A 
check step has been performed by comparing the percentages generated from this 
step with the true percentages observed from clinical trials. The results were 
comparable. Per time point, composite endpoint was derived by looking into each 
subject if the titer is above the cut-off for all 4 individual strains and if it is then this 
subject is counted as “1”. Otherwise the subject is counted as “0”. 
j. 
For each of the ten percentages for rMenB+OMV NZ (4 individual strains and 1 
composite endpoint at post-3rd and post-4th) the lower confidence limit was generated 
by fitting the binomial distribution with the percentage obtained from the previous 
step and alpha that has been assigned or propagated to the family. If the lower 
confidence limit is greater or equal to the sufficiency margin, then the null 
hypothesis is rejected for the single test. For Family 2 and 3, it is required to reject 
the null hypothesis for each and all of strain M14459, 96217, and NZ98/254, 
M10713, and the composite endpoint to be able to claim the success of the family. 
For family 4 and 5, it is required to reject the null hypothesis for both M07-0241084 
and the composite endpoint to be able to claim the family success. 
k.  Testing of Family 2: with the given FWER, if the LCL is greater or equal to 0.7 for 
each of strain M14459, 96217 and NZ98/254, greater or equal to 0.66 for strain 
M10713, and greater or equal to 0.48 for the composite endpoint, then Family 2 is 
claimed for success. The FWER for Family 2 is set up as 2/3 of the full alpha, which 
is rounded to 0.33 0.033. 
l. 
Testing of Family 3: with the given FWER, if the LCL is greater or equal to 0.6 for 
each of strain M14459, 96217 and NZ98/254, greater or equal to 0.55 for strain 
M10713, and greater or equal to 0.43 for the composite endpoint, then Family 3 is 
claimed for success. Propagate the FWER from Family 3 to Family 4 and continue to 
test Family 4. Otherwise, if Family 3 fails, then stop testing globally. 
m. Testing of Family 4: with the given FWER, if the LCL is greater or equal to 0.5 for 
strain M07-0241084 and the LCL is greater or equal to 0.4 for the composite 
endpoint, then Family 4 is claimed for success. Propagate FWER from Family 4 to 
Family 5 and continue to test Family 5. Otherwise, if Family 4 fails, then stop testing 
globally.  

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n. Testing of Family 5: with the given FWER, if the LCL is greater or equal to 0.12 for 
strain M07-0241084 and the LCL is greater or equal to 0.1 for the composite 
endpoint, then Family 5 is claimed for success. Otherwise, Family 5 fails. 
Table 18 
Two-sided 80% Upper Confidence Limit of Standard Deviations  
 
80% UCL of SDs 
rMenB+OMV NZ strains 
Post 4th vaccination (SDs of GMR) 
Post 3rd vaccination (SDs of 
GMT) 
M14459 
0.54372 
0.32221 
962172 
0.77760 
0.36900 
NZ98/254 
0.51794 
0.51967 
M07-0241084M10713 
0.66918 
0.39959 0.522 
PCV13 antigen1 
Post 3rd vaccination (SDs of GMC) 
1 
0.36629 
3 
0.41572 
4 
0.34261 
5 
0.43567 
6A 
0.39552 
6B 
0.44974 
7F 
0.34352 
9V 
0.32548 
14 
0.32445 
18C 
0.33550 
19A 
0.24439 
19F 
0.45638 
23F 
0.37567 
1. Estimated SDs for PCV13 antigens are the upper confidence limit of 2-sided 80% CI of back-calculated SDs, based 
on information (degree of freedom, 95% CI) provided on table 17 of Prevnar13 Package Insert (dated on July 2016) 
and assuming the underlying SDs fulfill a t-distribution. 
2 The SD for 96217 at post-4th vaccination GMR is not available and hence assumed the SD of GMR from Strain 
GB394. 
3 For strain M07-0241084 as no pre-4th vaccination data available, GMR was calculated by post-4th/post-3rd 
vaccination. 
Table 20 
Limit of Detection and Lower Limit of Quantitation for rMenB+OMV 
NZ strains 
rMenB+OMV NZ strains 
LOD  
LLOQ  
M07-024180 M10713 
43  
4 16 
NZ98/254 
4 
6 
M14459 
3 
5 
96217 
6 
15 
LOD: lower limit of detection, LLOQ: lower limit of quantitation. 
Note: Other than for strain M10713, tThese LODs and LLOQs were cited from the latest lab assay pre-validation 
report released in 2018Q2 2017. For strain M10713, the LOD and LLOQ are to be determined. They are subject to 
change upon CBER’s potential comments on the validation plan. 
b. The percentage of subjects with titers ≥ LLOQ is more than or equal to 60% for 
strain M14459, 96217 and NZ98/254, and more than or equal to 12 % 55% for strain 
M07-0241084 M10713, and more than or equal to 10% 43% for all 4 rMenB+OMV 
NZ strains at one month post 3rd vaccination. 

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c. 
Percentage of subjects with 4-fold increase is more than or equal to 70% for strain 
M14459, 96217 and NZ98/254, and more than or equal to 50%66% for strain M07-
0241084 M10713, and more than or equal to 40%48% for all four rMenB+OMV NZ 
strains , at one month post 4th vaccination.  
Section 9.7.1 Within groups assessment: 
For each study group, at each timepoint that a blood sample result is available, the 
following endpoints will be assessed related to MenB strains and PCV13 strains: 
• 
the percentage of subjects with hSBA titers ≥ LLOQ for each of the M14459, 96217, 
NZ98/254 and M07-0241084M10713 test strains  
• 
the percentage of subjects with hSBA titers ≥ LLOQ for all strains combined 
(composite endpoint)  
• 
the percentage of subjects with hSBA titers ≥5 and ≥8 for each of the M14459, 
96217, NZ98/254 and M07-0241084M10713 test strains 
• 
the percentage of subjects with 4-fold increase at post-4th (from post-3rd pre-4th) for 
each of the M14459, 96217, NZ98/254 and M07-0241084M10713 test strains. 
9.7.3.1 Statistical Hypotheses: 
In total 23 hypotheses will be tested for the primary objectives. A step-wise statistical 
approach will be used for the 23 statistical tests. The hypotheses will be grouped into five 
three families, based on the different immunogenicity objectives: 
Family 1:13 statistical hypotheses related to non-inferiority of PCV13 with 
rMenB+OMV NZ as measured by the GMCs of the 13 PCV13 antigens, after 
the 3rd vaccination. 
Family 2: 3 5 statistical hypotheses related to sufficiency objective on percentage of 
subjects with 4-fold increase at post 4th dose (from pre-4th dose) for each of 
the three four strains M14459, 96217, NZ98/254, and M10713, and the 
composite endpoint 
Family 3: 3 5 statistical hypotheses related to sufficiency objective on percentage of 
subjects with hSBA titers ≥ LLOQ at post 3rd dose for each of the three four 
strains M14459, 96217, NZ98/254, and M10713, and the composite 
endpoint. 
Family 4: 2 statistical hypotheses related to sufficiency objective on percentage of 
subjects with 4-fold increase at post 4th dose (from pre-4th dose) for strain 
M07-021084 and for all strains combined 
Family 5: 2 statistical hypotheses related to sufficiency objective on percentage of 
subjects with hSBA titers ≥ LLOQ at post 3rd dose for strain M07-021084 and 
for all strains combined 
Families 2 and 53 are related to the “sufficiency of the immune response to rMenB+OMV 
NZ” objective at one month post3rd 4th dose and one month post-3rd 4th dose, respectively.  

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Family 2: Percentage of subjects with 4-fold increase for each of the three four strains 
(M14459, 96217, NZ98/254, M10713) and the composite endpoint, post-4th  
Sufficiency will be claimed for each of the 4 strains and the composite endpoint, 
separately, if the following null hypothesis will be rejected: 
H02j: PAj < Aj vs. H12j : PAj ≥ Aj, 
 
where PAj denotes the percentage of subjects with 4-fold increase at one month after the 
4th vaccination (from pre-4th dose) for strain j, (j=1, 2, 3, 4, and composite), which is 
assumed to be at least 90% for each of the three strains M14459, 96217, and NZ98/254, 
72% for strain M10713, and 54% for the composite endpoint (estimate based on 
assumption of 25% correlation). Aj represents the level of sufficient immune response 
for each of the three four strains and composite endpoint. The immune response at one 
month following the 4th vaccination, will be sufficient for rMenB+OMV against each 
individual strain if the lower limit of the adjusted CI for the percentage of subjects with 
4-fold increase is ≥70% for strains M14459, 96217, NZ98/254, ≥66% for strain M10713, 
and ≥48% for the composite endpoint. 
Family 3: Percentage of subjects with hSBA≥LLOQ for each of the four strains 
(M14459, 96217, NZ98/254, M10713) and the composite endpoint, post-3rd  
Sufficiency will be claimed for each of the 4 strains, separately, if the following null 
hypothesis will be rejected: 
H03j : PAj < Aj vs. H13j : PAj ≥ Aj, 
 
where PAj denotes the percentage of subjects hSBA≥LLOQ at one month after the 3rd 
vaccination for strain j, j=1, 2, 3,4, and composite)), which is assumed to be at least 90% 
for strains M14459 and 96217, 80% for NZ98/254, 61% for strain M10713, and 49% for 
the composite endpoint. Aj represents the level of sufficient immune response for each of 
the four strains and composite endpoint (estimate based on assumption of 25% 
correlation). The immune response at one month following the 3rd vaccination, will be 
sufficient for rMenB+OMV NZ against each individual strain if the lower limit of the 
adjusted CI for the percentage of subjects with hSBA titer ≥LLOQ is ≥60% for strains 
M14459, 96217, NZ98/254, ≥55% for strain M10713, and ≥43% for the composite 
endpoint. 
Family 3: Percentage of subjects with hSBA≥LLOQ for each of the three four strains 
(M14459, 96217, NZ98/254, M10713) and the composite endpoint, post-3rd  
Sufficiency will be claimed for each of the 3 4 strains, separately, if the following null 
hypothesis will be rejected: 
H03j : PAj < Aj vs. H13j : PAj ≥ Aj, 
 
where PAj denotes the percentage of subjects hSBA≥LLOQ at one month after the 3rd 
vaccination for strain j, j=1, 2, 3,4, and composite)), which is assumed to be at least 90% 
for strains M14459 and 96217, and 80% for NZ98/254, 61% for strain M10713, and 
49% for the composite endpoint. Aj represents the level of sufficient immune response 
for each of the three four strains and composite endpoint. The immune response at one 

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month following the 3rd vaccination, will be sufficient for rMenB+OMV NZ against each 
individual strain if the lower limit of the adjusted CI for the percentage of subjects with 
hSBA titer ≥LLOQ is ≥60% for strains M14459, 96217, NZ98/254, ≥55% for strain 
M10713, and ≥43% for the composite endpoint. 
Family 4: Percentage of subjects with 4-fold increase for strain M07-0241084 and for 
the four strains combined, post-4th  
Sufficiency will be claimed, if the following null hypothesis will be rejected: 
H04j : PAj < Aj vs. H14j : PAj ≥ Aj, 
where PAj denotes the percentage of subjects with 4-fold increase at one month after the 
4th vaccination for strain M07-0241084 (j=1) and for the composite endpoint with all 4 
strains combined (j=2), which are assumed to be 60% and 45% respectively. Aj 
represents the sufficient level for this composite endpoint, and is set to 50% for A1 and 
40% for A2. The immune response at one month following the 4th vaccination, will be 
sufficient for M07-0241084, if the lower limit of the adjusted CI for the percentage of 
subjects with 4-fold increase for M07-0241084 is ≥50%.The immune response at one 
month following the 4th vaccination, will be sufficient for rMenB+OMV NZ for all 
strains combined, if the lower limit of the adjusted CI for the percentage of subjects with 
4-fold increase for all strains combined is ≥40%. 
Family 5: Percentage of subjects with hSBA≥LLOQ for strain M07-0241084 and for the 
four strains combined, post-3rd  
Sufficiency will be claimed, if the following null hypothesis will be rejected: 
H05j : PAj < Aj vs. H12j : PAj ≥ Aj, 
where PAj denotes the percentage of subjects with hSBA≥LLOQ at one month after the 
3rd vaccination for strain M07-0241084 (j=1) and for the composite endpoint with all 4 
strains combined (j=2), which are assumed to be 18% and 15% respectively. Aj 
represents the sufficient level for this composite endpoint, and is set to 12% for A1 and 
10% for A2 The immune response at one month following the 3rd vaccination, will be 
sufficient for M07-0241084, if the lower limit of the adjusted CI for the percentage of 
subjects with hSBA titer ≥LLOQ for M07-0241084 is ≥12%.The immune response at one 
month following the 3rd vaccination, will be sufficient for rMenB+OMV NZ for all strain 
combined, if the lower limit of the adjusted CI for the percentage of subjects with hSBA 
titer ≥ LLOQ for all strains combined is ≥10%. 
The initial α is 0.0167 (2-sided) for Family 1 and 0.033 (2-sided) for Family 2, while it is 
zero for all the other families family 3.  
Step 1: Family 1 and Family 2 
i. 
Start test Family 1 and Family 2 as the first step. Within Family 1, the Bonferroni-
Holm method will be applied to correct for multiplicity. 

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− 
For testing Family 1 the hypotheses per antigen the p-values will be obtained 
from an ANOVA model, with vaccination group and center as independent 
variables and log transformed titers/concentrations as response variable. P-
values will be adjusted by the Bonferroni-Holm method, new (Bonferroni 
stepdown) p-values will be generated and outputted. 
− 
 The null hypotheses will be rejected if the new, for multiplicity adjusted p-
values < FWER for all thirteen antigens. 
− 
For testing Family 2, if the lower limits of the 2-sided 96.9698.33% CIs are 
greater or equal to the sufficiency margins for each of the three four strains and 
composite endpoint, then Family 2 is successful. Otherwise, Family 2 fails. 
ii. If Family 1 had succeeded and Family 2 not, then propagate ½ FWER from Family 1 
to Family 3 and the other ½ FWER to Family 2, and re-test Family 2 with the new 
FWER which is the sum of the original FWER from Family 2 plus the ½ of FWER 
from Family 1. If the null hypothesis were rejected during the 2nd time test, then 
claim the success of Family 2 and propagate full FWER to Family 3; otherwise 
Family 2 fails and proceed with Family 3 testing with the ½ of FWER propagated 
from Family 1. 
iii. If Family 2 had succeeded and Family 1 not, then propagate ½ FWER from Family 2 
to Family 3 and the other ½ FWER to Family 1, and re-test Family 1 with the new 
FWER which is the sum of the original FWER from Family 1 plus the ½ of FWER 
from Family 2. If the null hypothesis were rejected during the 2nd time test, then 
claim the success of Family 1 and propagate full FWER to Family 3; otherwise 
Family 1 fails and proceed with Family 3 testing with the ½ of FWER propagated 
from Family 2. 
iv. If both Family 1 and Family 2 had succeeded, then the FWER from both families 
were propagated to Family 3, and proceed to test Family 3; 
v. If both Family 1 and Family 2 had failed, then no FWER will be propagated to 
Family 3, and we stop the testing globally and success can be claimed on none of the 
five three families.  
Step 2: Family 3: 
If all null hypotheses are rejected, the propagate full FWER to Family 4; otherwise stop 
testing globally, and success can be claimed for Family 1 and/or Family 2 whichever was 
successful in Step 1.  
Step 3: Family 4:  
If all null hypotheses are rejected, the propagate full FWER to Family 5; otherwise stop 
testing globally, and success can be claimed for Family 3, as well as for Family 1 and/or 
Family 2 whichever was successful in Step 1.  

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Step 4 2: Family 5 3:  
If all null hypotheses are rejected, then propagate 1/2 FWER to Family 1 and Family 2 
respectively, and success can be claimed for Family 3, Family 4 and Family 5 as well as 
for Family 1 and/or Family 2 whichever was successful in Step 1; otherwise stop testing 
globally, and success can be claimed for Family 3 and Family 4, as well as for Family 1 
and/or Family 2 whichever was successful in Step 1. 
Step 53: Family 1 or Family 2: 
In case one of Family 1 and Family 2 failed in step 1, with the alpha passed down by 
Family 53, it is possible to re-test the family that failed once and again test it with ½ 
FWER from Family 53. If all null hypotheses are rejected, then success can be claimed 
for this family as well. 
Appendix A Laboratory Assays  
MenB serum bactericidal assays using human complement (hSBA): 
Serum bactericidal activity against rMenB+OMV NZ will be determined by performing 
hSBA against a standard panel consisting of 4 meningococcal B test strains M14459, 
96217, NZ98/254 and M07-0241084M10713. Each of these strains measures bactericidal 
activity primarily directed against one of the major bactericidal antigens included in the 
vaccine: strain M14459 measures hSBA against the 741 part of the 936-741 antigen, also 
known as fHbp variant 1.1; strain 96217 measures hSBA against antigen 961c, also 
known as NadA; and strain NZ98/254 measures hSBA against PorA P1.4, the 
immunodominant antigen in the OMV NZ vaccine component; strain M10713 measures 
hSBA against the 287 part of the 287-953 antigen 287-953, also known as NHBA.  
Exclusion criteria for enrolment 
Exclusion criteria in Section 4.3 modified to allow for administration of one dose of HBV 
up to 4 weeks prior to study enrollment. 
• 
Received a dose of DTPa-HBV-IPV (receipt of one dose of HBV at birth is allowed), 
HRV, MMR, VV and/or Hib at any time prior to informed consent. Receipt of one 
dose of HBV up to 4 weeks prior to informed consent is allowed. 
Collection of body temperature measurements post-vaccination 
Clarified that collection of 30-minutes post-vaccination solicited data includes body 
temperature measurement. 
Section 5.6.1 Data collected from subject: 
• 
30 minutes post-vaccination immediate reactions: signs or symptoms of anaphylaxis, 
allergic phenomena (such as rashes, itching, or other allergic manifestations). 
Solicited local and systemic data (including e.g., use of medication to treat or prevent 
fever and/or pain, body temperature measurement). 

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Section 5.6.13 Post-vaccination procedures 
After vaccination, the subject will be observed for at least 30 minutes including 
observation for solicited and unsolicited AEs, including measurement of body 
temperature.  
Table 5 List of study procedures: 
30 Minutes post-injection assessment (including body temperature measurement). 
Typo in Section 7.1.1 (missing text)  
All other AEs will be recorded as UNSOLICITED AEs. 
Typo in strain number of Rotarix vaccine (Table 10 Study Vaccines) 
The strain number in Table 10 the for the Rotarix vaccine was corrected.  
Rotarix  
HRV lyo 
HRV RIX41444414 live attenuated 
>=106.0CCID50 
Lyophilized vaccine 
in a monodose glass 
vial. 
Section 5.4 Method of blinding – alignment within section: 
To work in an observer-blind manner, vaccine preparation and administration will be 
done by authorized medical personnel who will not participate in any of the study clinical 
evaluation assays or procedures. 
See the glossary of terms for definition of unblinded study staff. Two teams of study 
personnel will hence be set up: 
• 
A team of unblinded personnel (responsible for the preparation and the 
administration of the vaccines).  
• 
A team of blinded personnel (responsible for the clinical evaluation of the subjects 
including blood sampling).  
Access to SBIR: 
Both blinded and unblinded study staff will have access to the SBIR system, in alignment 
with blinding strategy for the study. 
Section 5.2.2.2.1 Study group and treatment number allocation:  
After obtaining the signed and dated ICF from the subject’s parent/ LAR and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. 
Section 5.2.2.2.2 Treatment number allocation for subsequent doses:  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 

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Treatment allocation to the subject (correction from amendment 3): 
Text in section 5.2.2.2 updated based on change made in amendment 3. 
The treatment numbers will be allocated by dose for Bexsero and placebo vaccines. 
Treatment allocation will be by components for all other products. Throughout the study, 
a single treatment number will identify the vaccine doses to be administered to the same 
subject. 
Definition of unsolicited AEs: 
Text in section 7.1.4 Unsolicited Adverse Events updated to clarify that solicited AEs 
ongoing after the reporting period will be recorded in the eDiary, and not considered as 
unsolicited AEs 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a parent(s)/LAR(s) who has signed 
the informed consent or a solicited local or systemic AE that continues beyond the 
solicited period after vaccination. 
Subject Diary Alerts: 
Text in section 5.6.15.1.1 updated to clarify that site staff to contact subjects 
parents/LAR(s) when subjects experienced both solicited or unsolicited AE(s) that 
required hospitalization or visit to the emergency room or medically attended events that 
were of concern to the parents/LAR(s).  
• 
Subject experienced an unsolicited any AE that required hospitalization or visit to 
the emergency room or medically attended events that were of concern to the 
parents/LAR(s). 
Temperature grading for fever 
The temperature grading in Table 15 for fever was updated to avoid measurements up to 
2 decimal places. 
Table 15 
 Grading of Solicited Systemic Adverse Events for All Subjects 
Adverse Events 
Grading of Severity 
Grade 0 
Mild 
Moderate 
Severe 
Fever2  
<38.0°C 
(<100.4°F) 
≥38.0 - 38.9°C  
(≥100.4 – 102.02 102.1°F) 
≥39.0 - 39.9°C 
(≥102.2 – 103.82 
103.9°F) 
≥40.0°C  
(≥ 104.0°F) 
Correction on correlate of protection: 
Text in section 5.7.3 Laboratory assays was corrected to clarify that serum bactericidal 
activity is a surrogate of protection. Text on lab blinding was removed as already stated 
previously. 

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The immunogenicity of rMenB+OMV NZ is assessed in this study by measuring the 
serum bactericidal activity, which is a functional measure of the ability of antibodies, in 
conjunction with human complement, to kill meningococci, and is widely accepted and 
generally recognized as the serological correlate surrogate of protection. Testing will be 
conducted in a blinded manner towards the study group and the visit.  
Addition of text on possible testing of other meningococcal strains: 
Text in section 5.7 Biological sample handling and analysis updated to include possible 
testing of additional meningococcal strains if needed.  
Although not planned, additional serologic testing may be performed in the future to 
further characterize the antibody response to the antigens included in the study vaccines 
or concomitantly administered vaccines (e.g. Rotavirus [HRV], hSBA against other 
meningococcal strains). 
Correction on typos in storage temperatures:  
The typos in representing the temperature in section 6.2 Storage and handling of study 
and non-study vaccines is corrected. 
For the Varivax vaccine, the antigen is to be stored between -25 C/-13 F to -15 C/5 F and 
the diluent at +4C/+39.2 F.  
Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) or below -25 C/-13 or above -15.0°C/5 F (for -20°C/-4°F 
label storage condition) impacting investigational medicinal products (IMPs) must be 
reported in the appropriate (electronic) temperature excursion decision form (Advanced 
Temperature Excursion Analysis and Management [ATEAM]). 
Correction in cut-off for pneumococcal anti-capsular polysaccharide IgG in Section 
9.7.4.1: 
For the binary variables, percentage of subjects with hSBA titer ≥ LLOQ, percentage of 
subjects with serum pneumococcal anti-capsular polysaccharide IgG ≥0.350.32 μg/mL, 
the number and percentage of subjects and associated 2-sided 95% Clopper-Pearson CIs 
will be computed for each antigen/strain by vaccine group and by time-point. 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 5 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 5 
Amendment date: 
10 April 2020 
Co-ordinating author: 
 
Rationale/background for changes:  
This protocol amendment 5 outlines measures that may be applicable during 
special circumstances (e.g., COVID-19 pandemic). The purpose of the 
amendment is to protect subject’s welfare, and as far as possible ensure the 
potential benefit to the subject and promote data integrity. 
The measures include the following, 
• 
Allow increased flexibility in schedule and procedures to optimize site staff and 
patient safety. 
• 
Assist the ability to complete study specific visits and procedure in order to 
preserve study integrity. 
• 
Allow specific reporting of COVID-19 events for surveillance and increased 
specificity for safety data analysis at study conclusion. 
• 
The definition of ‘medically attended AEs’ has been revised to include tele visit. 
If possible all study specified visits and procedures should be completed according to 
the protocol, taking into account clinical judgment and local public health guidance to 
protect the safety of staff and subjects. 
Additional revisions: 
• 
A minor typographical error in grading of severity solicited local adverse events 
for all subjects in Table 14 has been corrected. 
• 
The range for temperature excursions for non-investigational medicinal products 
(NIMPs) has been corrected in Section 6.2. 
• 
Risk assessment of Bexsero has been aligned as per the EU-RMP. 
• 
A minor typographical error in the footnote of Table 3 has been corrected. 
• 
The definition of ‘enrolled set’ (Section 9.4.1) has been revised to align with the 
study. 
PPD

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− 
Minor revisions have been made in the sections 5.2.2.2.1, 5.6.4 and 9.4.4.1 to 
align with the revised definition of ‘enrolled set’. 
• 
Footnotes 1 and 2 from Table 5 (List of study procedures) have been converted 
into notes to address the minor finding from the site audit conducted in 2019. 
• 
Addition of the ‘Subject ID assignment’ to pre-vaccination procedures (Section 
5.6.2). 
• 
The location for the administration of MMR and VV vaccines has been corrected 
to deltoid region. 
• 
A minor typographical error in recording of concomitant vaccination has been 
corrected. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
List of Abbreviations 
COVID-19 
Coronavirus Disease 2019 
Glossary of Terms 
Enrolled 
All screened subjects who provide informed consent 
and provide demographic and/or baseline screening 
assessments and are randomized and have received a 
Subject ID, regardless of the subject’s treatment status 
in the study. 
Medically attended 
adverse events: 
Symptoms or illnesses requiring hospitalization, or 
emergency room visit, or tele visit or visit to/by a health 
care provider.  
Section 1.3.1. Risk Assessment 
Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
IMP: Bexsero 
Important potential risk: 
Decrease of 
immunogenicity secondary 
to prophylactic use of 
acetaminophen 
(paracetamol) 
Prophylactic use of acetaminophen 
(paracetamol) reduces the incidence and 
severity of fever without affecting the 
immunogenicity of either Bexsero or 
routine vaccines [Prymula, 2014]. The 
effect of antipyretics other than 
acetaminophen (paracetamol) on the 
immune response has not been studied. 
Prophylactic use of 
analgesic/antipyretic medications to 
reduce febrile reactions during the 
first 7 days after vaccination is 
allowed on a voluntary basis, but 
must be recorded in the source 
document and the eCRF (see Section 
6.7.1). 

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Section 3. Study design overview 
Addition of the following footnote to Figure 1 (Overview of study design) 
Refer to Section 7.2.4 for study procedures to be considered during special 
circumstances 
Addition of the following statement to the section, 
Refer to Section 7.2.4 for study procedures to be considered during special 
circumstances. 
Table 3 
Overview of the Study Design: Blood Draws and Study vaccines 
Clinic Visits 
(Study Day) 
Visit 1 
(Day 1) 
Visit 2 
(Day 61) 
Visit 3 
(Day 
121) 
Visit 4 
(Day 
151) 
Visit 5 
(Day 301) 
Visit 6 
(Day 
331) 
Months of Age (MoA) 
~2 MoA1 
4 MoA 
6 MoA 
7 MoA 
12 MoA 
13 MoA3 
Study Vaccines 
Group MenB+PCV 
N=1800 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
Blood 
Draw23 
Blood 
Draw23 
rMenB+ 
OMV NZ 
PCV13 
Blood 
Draw23, 34 
Group 
Placebo+PCV 
N=900 
Placebo 
PCV13 
Placebo 
PCV13 
Placebo 
PCV13  
Blood 
Draw23 
Placebo 
PCV13 
Routine Study 
Vaccines 
Both groups 
N=2700 
DTPa-
HBV-IPV 
HRV 
Hib 
DTPa-HBV-IPV 
HRV 
Hib 
DTPa-
HBV-
IPV 
Hib 
 
MMR 
VV 
 
MOA, months of age. 
.1. Age at enrollment can be between 6 weeks to 12 weeks of age.  
2. Study visits do not include safety follow-up calls. Although not conducted face-to-face, safety calls are intended for 
safety data collection. For details, refer to Table 5. 
23 Blood draw to be performed prior to any vaccination (study or non-study). 
43. Subjects in both groups will receive a fourth dose of Hib vaccine (Hiberix) and a single dose of DTPa vaccine 
(Infanrix) at 13 months of age, i.e. Visit 6 at Day 331. No immunogenicity or safety assessments will be performed 
following these Visit 6 vaccinations. 
Note: Study visits do not include safety follow-up calls. Although not conducted face-to-face, safety calls are 
intended for safety data collection. For details, refer to Table 5. 
• 
Sampling schedule: The sampling schedule for both study groups is the same. Three 
blood samples of approximately 5 mL each are to be taken at: 
− 
Visit 4 (Day 151), i.e., 30 (-9 -7 to +3014) days after the 3rd vaccination. 
− 
Visit 5 (Day 301), i.e., 180 (-7 to 91+21) days after the 3rd vaccination (pre-4th 
vaccination). 
− 
Visit 6 (Day 331), i.e., 30 (-7 -9 to +1430) days after the 4th vaccination. 
The same above changes in sampling schedule are applicable for Section 5.6.11.1 (Blood 
sampling for immune response assessments) 

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Section 5.2.2.2.1. Study group and treatment number allocation 
Enrolled subjects Subjects will be randomized in the SBIR system to one of the two 
groups in a 2:1 ratio to receive: 
Section 5.5. Outline of study procedures 
Table 5 
List of Study Procedures  
Age 
(approxim
ate) 
~2 
mo
a 
 
 4 moa  
 6 moa  
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
mo
a 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of 
contact 1, 2  Vis
it 1 
SF
C 1 
SF
C 2 
Visit 
2 
SF
C 3 
SF
C 4 
Visit 
3 
SF
C 5 Visit 4 SF
C 6 
SF
C 7 
Visit 
5 
SF
C 8 Visit 6 SFC 
9 
SFC 
10 
SF
C 
11 
SF
C 
12 
SF
C 
13 
Vis
it 
710 
Visit 
window 
(days) 2 4 
-5 
-
3/+
3 
3/+
3 
-
317/+
21 
-
3/+
3 
-
3/+
3 
-
317/+
21 
-
3/+
3 
-
97/+30
14 
-
3/+
3 
-
3/+
3 
-
7/+91
21 
-
3/+
3 
-
97/+30
14 
-
7/+2
1 
7/+2
1 
-7/ 
+2
1 
-7/ 
+2
1 
-7/ 
+2
1 
--7/ 
+2
1 
Recording 
of all 
unsolicite
d AEs 
within 30 
days post-
vaccinatio
n11  
● 
● ● 
● 
●  ●  
● 
● 
● 
 
 
● 
● 
● 
 
 
 
 
 
 
Recording 
of SAEs, 
medically 
attended 
AEs, AEs 
leading to 
withdrawal 
and AESIs 
7, 11  
● 
● ● 
● 
● ● 
● 
● 
● 
● ● 
● 
● 
● 
● 
● 
● ● ● ● 
Note: Procedures to be performed prior to any vaccination.  
Although not conducted face-to-face, safety follow-up calls are intended for safety data collection and considered 
equivalent to clinic study visits.  
The double line after Visit 6 at Day 331 indicates the potential interim analysis time period. 
1. Although not conducted face-to-face, safety follow-up calls are intended for safety data collection and considered 
equivalent to clinic study visits.  
2. Procedure to be performed prior to any vaccination.  
10. Visit 7 may be a telephone contact during special circumstances. Refer to Section 5.6.15 for study 
procedures to be considered during special circumstances. 
11. COVID-19 infection related AEs and SAEs should be recorded in a separate eCRF. 

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Table 6 
Intervals Between Study Visits 
Interval 
Optimal length of interval 
Allowed interval1, 2 
Visit 1 → Visit 2  
60 days 
53 29 days - 81 days  
Visit 2 → Visit 3  
60 days  
53 29 days - 81 days 
Visit 3 → Visit 4 
30 days  
2321 days - 44 60 days 
Visit 3 → Visit 5  
180 days  
173 days - 201 271 days  
Visit 5 → Visit 6  
30 days  
23 21 days - 44 60 days  
Visit 5 → Visit 7 (Study termination 
360 days  
353 days - 381 days  
1The investigator should arrange study visits within this interval as subjects may not be eligible for inclusion in the PPS 
cohorts if they make the study visit outside this interval. All visits and windows should be planned using the day of last 
vaccination as the reference point 
2The allowed interval have been modified in keeping with ACIP guidelines to facilitate the safe scheduling of 
study visits during the COVID-19 pandemic situation. 
Section 5.6. Detailed description of study procedures. 
During special circumstances, exemplified by the COVID-19 pandemic, certain study 
procedures may be adapted to protect the subject and promote data integrity. Refer to 
Section 5.6.15 for further details. 
Section 5.6.2. Pre-vaccination procedures (Visit 1)  
A pre-vaccination clinic visit may occur within 5 days prior and up to the time of the 
vaccination Visit 1 on Day 1 (inclusive). The following procedures will be performed for 
each potential subject prior to the first vaccination at Visit 1: 
• 
Obtaining informed consent from subject’s parent(s)/LAR(s).  
• 
Subject ID assignment 
Section 5.6.4 Check inclusion and exclusion criteria 
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
after obtaining informed consent and before randomization enrolment.  
Section 5.6.15. Study procedures during special circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled participants: 
• 
Visit 7 (Day 661): the study conclusion visit has been revised to allow for either a 
site visit or concluding telephone call. The telephone call is intended for safety 
data collection and will be considered equivalent to study conclusion visit.  
• 
The existing protocol-specified windows have been modified in keeping with ACIP 
guidelines to facilitate the safe scheduling of study visits (See allowed interval in 
Table 6).  

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• 
If despite best efforts it is not possible to collect blood samples within the allowed 
interval between visits (see Table 6), then the interval may be extended as per the 
clinical judgement of the investigator.  
• 
If despite best efforts it is not possible to give the vaccine dose within the allowed 
interval between visits (see Table 6), then the interval may be extended as per the 
clinical judgement of the investigator and in keeping with ACIP guidelines. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
Section 5.6.16. Recording of AEs, SAEs and AESIs 
• 
Refer to Section 7.2 for procedures for the investigator to record AEs, SAEs, and 
AESIs. Refer to Section 7.3 for guidelines and how to report SAE and AESI reports 
to GSK Biologicals. Refer to Section 7.2.4 for recording of COVID-19 infection 
related AEs. 
Section 5.6.17. Study conclusion 
• 
The study termination visit will occur on Day 661 (Visit 7). The termination visit 
will be a clinic visit or a telephone call. 
• 
At this clinic visit or telephone call, subject’s parent(s)/LAR(s) will be interviewed 
for any SAEs, medically attended AEs, AESIs (pIMDs, seizures, and/or arthritis) 
experienced by their child. Any concomitant medications associated with those 
events will also be collected and recorded in the subject's records and on the eCRF. 
• 
At this visit or telephone call, subject’s parent(s)/LAR(s) will be asked if they can be 
contacted to participate in any future related study. If the subject’s parent(s)/LAR(s) 
are not interested in participating in future studies the reason for refusal will be 
documented in the subject’s eCRF. 
Early termination: 
If the Early Termination is at a clinic visit, the following procedures will be performed: 
review of Subject Diary (if applicable), review of systems, interview of subject’s 
parent(s)/LAR(s) to collect: unsolicited AEs, AESI, SAEs, medically attended AEs, AEs 
leading to vaccine/study withdrawal, interview of subject’s parent(s)/legal guardian(s) to 
collect concomitant medications/ vaccinations, symptom-directed physical assessment 
including vital signs (at a minimum rectal (subjects <12 months of age) or axillary (≥12 
months of age) body temperature preferably) and a check of general appearance, and 
blood sampling for immunogenicity (if applicable at the visit). 
Section 5.7. Biological sample handling and analysis 
Refer to Section 5.6.15 for changes in biological samples collection that may be 
implemented during special circumstances. 

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Section 6.2. Storage and handling of study and non-study vaccines 
Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) or below -25 C/-13 or above -15.0°C/5 F (for -20°C/-4°F 
label storage condition) impacting investigational medicinal products (IMPs) must be 
reported in the appropriate (electronic) temperature excursion decision form (Advanced 
Temperature Excursion Analysis and Management [ATEAM]). The impacted IMPs must 
not be used and must be stored in quarantine at label temperature conditions until usage 
approval has been obtained from the sponsor. This applies for the NIMPs as well. Refer 
to the Module on Clinical Trial Supplies in the SPM for details and instructions on the 
temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
Section 6.3. Dosage and administration of study vaccines 
Refer to Section 5.6.15 in case of a change in the allowed interval to receive the 
vaccine dose between visits during special circumstances. 
The MMR and VV vaccines should be given subcutaneously in the upper arm (deltoid 
triceps region) by inserting the needle in a pinched-up fold of skin and subcutaneous 
tissue to prevent injection into muscle. 
Section 6.7.1. Recording of concomitant medications/products and concomitant 
vaccinations 
• 
Any concomitant vaccination administered in the period starting from birth and 
ending at the last study visit (Day -14 of birth to Day 661). 
Section 7.2.1. Time period for detecting and recording adverse events and serious 
adverse events 
Table 13 
Reporting Periods for Collecting Safety Information 
Event Pre-
V11 
V1 D1
6 
D31  
V2 D76 D91  
V3 D136 V4 
 D181D24
1 
V5 
D 
316 
 
V6 
 D361, 
421, 
481, 
541, 
601 
V7 
D
1 
 D61  
(2 M 
post-
vacc 
1) 
 D121 
(2 M 
post-
vacc 
1) 
D151 
(1 M 
post-
vacc 
3) 
 
D301 
(6 M 
post-
vacc 
3) 
 D331 
(1 M 
post-
vacc 
4) 
 
D6
61  
(12 
M 
po
st-
vac
c 4) 
COVI
D-19 
infecti
on 
relate
d AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M: month, V: Visit; D: Day, AE: adverse event, SAE: serious adverse event, AESI: adverse event of special interest, 
COVID-19: Coronavirus Disease 2019. 

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Section 7.2.3.2.1. Assessment of intensity 
Table 14 
Grading of Solicited Local Adverse Events for All Subjects 
Adverse Events 
Grading of Severity 
Grade 0 
Mild 
Moderate 
Severe 
Tenderness or discomfort to touch at 
injection site 
None 
Minor light 
reaction to 
touch 
Cried or 
protested to 
touch 
Cried when 
injected limb 
was moved 
Hardness of skin at the injection site 
0 mm 
1 - 24 25 mm 
25 26 - <50 mm 
≥>50 mm 
Swelling of skin at the injection site 
Redness at injection site 
Section 7.2.4. Recording of AEs related to COVID-19 
For COVID-19 infection related AEs, sites should follow routing AE/SAE processes as 
outlined in the protocol using the following terms per WHO defined case definitions: 
• 
Suspected COVID-19 infection 
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection. 
Section 7.2.4.1. WHO Case Definition 
• 
Suspected case 
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset; 
OR 
B. A patient with any acute respiratory illness AND having been in contact (see 
definition of “contact” below) with a confirmed or probable COVID-19 case (see 
definition of contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that fully 
explains the clinical presentation. 
• 
Probable case  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason.  
Confirmed case  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms. 

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• 
A contact is a person who experienced any one of the following exposures during 
the 2 days before and the 14 days after the onset of symptoms of a probable or 
confirmed case: 
− 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes; 
− 
Direct physical contact with a probable or confirmed case; 
− 
Direct care for a patient with probable or confirmed COVID-19 disease 
without using proper personal protective equipment; 2OR 
− 
Other situations as indicated by local risk assessments. 
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 
days before through the 14 days after the date on which the sample was taken 
which led to confirmation. 
Section 9.4.1. All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments and are randomized and have received a Subject ID, 
regardless of the subject’s randomization and treatment status in the study and received a 
Subject ID. 
Section 9.4.4.1. Full Analysis Set Immunogenicity 
All subjects in the All Enrolled Set who are randomized, receive at least one study 
vaccination and provide immunogenicity data at either one month after their 4th 
vaccination or/ one month after their 3rd vaccination for at least 1 antigen/strain. 
Section 9.4.5. Per Protocol (PP) Set for Immunogenicity Set 
Examples for subjects excluded due to other reasons than protocol deviations are: 
• 
who did not comply with the post Dose 3 (for primary 3 doses) or post Dose 4 (for 
the 4th dose) blood sample schedule (Table 6), i.e. 23 to 44 days post the vaccination. 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 6 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 6 
Amendment date: 
9 December 2021 
Co-ordinating author: 
 (post-CBER feedback) 
Rationale/background for changes:  
• 
This study was initiated in July 2018 but faced difficulties in meeting the expected 
recruitment levels in spite of various efforts put in place i.e. protocol changes, 
recruitment material developed with a third party and additional investigators 
meetings. Despite all actions taken, the recruitment rate remained well below 
expectations. In addition, the COVID-19 (Coronavirus Disease 2019) pandemic 
has impacted enrolment as well as the timely completion of the scheduled 
vaccinations as well as collection of blood samples for already enrolled subjects. 
• 
As a result of both the continual slow enrolment and the impact of COVID-19 
pandemic, it was estimated by the study team that reaching the target of 2700 
subjects would only be possible with a significant extension of study timelines that 
would negatively impact the study feasibility. 
• 
The study team investigated alternative study endpoints in order to deliver a 
meaningful analysis with adequate power in a reasonable time. The change of the 
endpoints for assessment of rMenB+OMV NZ sufficiency after the 4th dose 
allowed to decrease the number of enrolled subjects to about 1200, permitting to 
end the study in a reasonable time and also fulfill the commitment in the initial 
Pediatric Study Plan (iPSP). 
• 
The revised study design will still allow a powered primary assessment of the 
sufficiency of rMenB+OMV NZ response after 3rd dose and 4th dose. The study 
will also assess as a powered primary objective, the non-inferiority of the immune 
response to PCV-13 after the 3rd dose, when co-administered with rMenB+OMV 
NZ and other routine vaccines compared with routine vaccines alone. 
Overall, the following changes are being implemented in the study: 
• 
The criteria for the primary and key secondary objectives have been updated, 
PPD

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− 
The sufficiency of the immune response to rMenB+OMV NZ when 
administered concomitantly with PCV13 and other RIV to healthy infants 
after the 3rd vaccination has been revised. 
− 
The sufficiency of the immune response to rMenB+OMV NZ when 
administered concomitantly with PCV13 and other RIV after the 4th 
vaccination has been revised. 
• 
The total number of enrolled subjects was revised (N)=1200,  
− 
Group MenB+PCV: N=800 
− 
Group Placebo+PCV: N=400 
• 
Assuming a 40% drop-out rate and with 1200 subjects to be enrolled in a 2:1 ratio, 
480 evaluable subjects from Group MenB+PCV and 240 evaluable subjects from 
Group Placebo+PCV would be evaluable for the primary analyses. 
Additional revisions: 
• 
NHBA strain was revised based on Center for Biologics Evaluation and Research 
(CBER) recommendation to use the strain M13520, for evaluating immune 
responses to the NHBA antigen. 
• 
Based on CBER recommendation, geometric mean concentrations (GMCs) will be 
included as an endpoint for evaluating NI for each of the individual antigens in the 
MMR and VV vaccines. GMCs, being a continuous variable and more sensitive to 
detect small differences between groups, is considered more appropriate for this 
assessment. The seroresponse rates of antigens tested for polio, MMR and VV 
vaccines will be assessed in a descriptive manner. 
• 
The end of Study (EoS) has been changed from Last Subject Last Visit (LSLV) to 
the date of the last testing/reading released of the Human Biological Samples 
(HBS), related to primary and secondary endpoints. EoS must be achieved no later 
than 8 months after LSLV. 
• 
The revision in the number of subjects assigned to different immunogenicity 
subsets belonging to either Group MenB+PCV (800 subjects will be randomly 
assigned into 3 subsets) or Group Placebo+PCV (400 subjects will be randomly 
assigned into 2 subsets). 
• 
In method of blinding, the laboratory in charge of the testing will be blinded to the 
treatment as well as to the subject number. In addition, a different subject code 
will be used for each timepoint tested. 
• 
Change in placebo volume from 0.5 mL to 0.65 mL, also adding a footnote – 
between 0.6 mL and 0.8 mL, full volume to be administered; to be aligned with 
the Certificate of Analysis and product lifecycle management (PLM) dictionary. 
• 
Emergency unblinding contact information has been revised. 
• 
The serological assays for the determination of antibodies against measles, 
mumps, rubella and varicella viruses are yet to be selected and/or developed and 
therefore the endpoints have been revised to reflect this change. 

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• 
For sequence of analyses, if needed, an interim analysis including data up to Visit 
6 may be performed on final immunogenicity data. Selected immunogenicity 
objectives and solicited safety data from all timepoints up to Visit 6 will be 
analyzed. 
• 
Additional information on medical device deficiencies and medical device AE 
have been provided in Section 7.9 and Section 10.6, respectively. 
• 
The objectives and endpoints have been presented in a tabular format under 
Section 2 and the endpoints description have been removed from Section 9. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Co-ordinating authors: 
 Scientific Writing. 
Contributing authors: 
(Amendment 6 onward) Clinical Research and 
Development Lead; 
 Amendment 6 onward) Study Delivery Lead; 
(Amendment 6 onward) Global Regulatory Affairs; 
 
(Amendment 6 onward) Clinical Laboratory Sciences Read-Out Team Lead; 
 
 (Amendment 6 onward) ,Clinical and Epidemiology Project Leader (CEPL), 
Siena RDC 
Sponsor signatory: Pavitra Keshavan Daniela Toneatto,  
Clinical and Epidemiology Research & Development Project Lead 
List of abbreviations 
HBS 
Human Biological Samples  
iPSP 
initial Pediatric Study Plan  
NadA: 
Neisserial adhesin A 
NHBA: 
Neisserial Heparin Binding Antigen 
Section 1.1: Background 
GSK recombinant Meningococcal B vaccine with the OMV derived from New Zealand 
strain) is based on three proteins: i) factor H binding protein (fHbp), ii) Neisserial adhesin 
A (NadA) and iii) Neisserial Heparin Binding Antigen (NHBA) or 287 
Synopsis and Section 1.2.1: Rationale for the study 
Previous clinical studies conducted in European and other countries worldwide have 
shown that rMenB+OMV NZ demonstrated a robust immune response in all age groups 
against indicator test strains, H44/76 (fHbp), 5/99 (NadA), NZ98/254 (PorA P1.4) and 
M10713 (NHBA) and that the concomitant administration of rMenB+OMV NZ does not 
clinically interfere with response to the vaccine antigens present in routinely administered 
infant vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, 
inactivated poliomyelitis, hepatitis B, measles, mumps, rubella, varicella and 7-valent 
pneumococcal conjugate vaccine. However, no data on the concomitant use of 
rMenB+OMV NZ with PCV13 and routine infant vaccines in North American infants is 
currently available. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Furthermore, the immune response of the rMenB+OMV NZ vaccine against additional 
test strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4) and M10713 (NHBA) 
has not been evaluated yet in a US pediatric population. These 3 strains M14459 (fHbp), 
96217 (NadA), NZ98/254 (PorA P1.4) in addition to M13520 strain are considered by 
the Center for Biologics Evaluation and Research (CBER) to better evaluate the 
protective response of the vaccine in the US population. 
Synopsis and Section 2: Objectives and endpoints 
Objectives 
Endpoints 
Primary Safety 
• 
To assess the safety and tolerability of 
rMenB+OMV NZ, PCV13 and other RIV when 
administered concomitantly to healthy infants at 2, 
4, 6 and 12 months of age, throughout the study 
duration. 
• 
The percentages of subjects with solicited local 
Adverse events (AEs) and systemic AEs during 
the 7 days (including the day of vaccination) after 
the 1st, the 2nd, the 3rd and the 4th vaccination 
(Visits 1, 2, 3 and 5). 
• 
The percentages of subjects with solicited 
systemic AEs of parotid/salivary gland swelling, 
fever and rash during the 30 days (including the 
day of vaccination) after the 4th vaccination (Visit 
5). 
• 
The percentages of subjects with all unsolicited 
AEs (including SAEs, AEs leading to withdrawal, 
AESIs, and medically attended AEs) during 30 
days (including the day of vaccination) after the 
1st, the 2nd, the 3rd and the 4th vaccination (Visits 1, 
2, 3 and 5). 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs from study Day 1 (Visit 1) until study 
end (12 months after last study vaccination, 
Visit 7). 
Co-Primary Immunogenicity 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4 and 6 months of age, at one 
month after the 3rd vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ at one month after the 3rd vaccination 
will be demonstrated if the adjusted lower confidence 
limit for the percentage of subjects achieving serum 
bactericidal assay using human complement (hSBA) 
titers ≥ Lower Limit of Quantitation (LLOQ) is ≥ 60% for 
the N. meningitidis serogroup B test strains M14459, 
96217, NZ98/254, M13520 (individually); and is ≥ 
50% for all strains combined (composite endpoint). 
M14459, 96217, NZ98/254 and ≥55% for strain M10713 
(individually); and is ≥43% for all strains combined 
(composite endpoint). 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ; for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for all strains combined (composite 
endpoint). 

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Objectives 
Endpoints 
• 
To demonstrate the sufficiency of the immune 
response to rMenB+OMV NZ when administered 
concomitantly with PCV13 and other RIV to 
healthy infants at 2, 4, 6 and 12 months of age, at 
one month after the 4th vaccination. 
Criteria: The sufficiency of the immune response to 
rMenB+OMV NZ will be demonstrated if the adjusted 
lower confidence limit for the percentage of subjects 
with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217) is ≥75% for the 
individual N. meningitidis serogroup B test strains 
and is ≥65% for all strains combined (composite 
endpoint) achieving a 4-fold rise in hSBA titers (from 
pre-4th vaccination) is ≥70% for N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254 and 
≥66% for strain M10713 (individually); and is ≥48% for 
all strains combined (composite endpoint). 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
the percentages of subjects with 4-fold rise 
(from pre-4th vaccination) in hSBA titers ≥ 8 
(for strains M14459, NZ98/254, M13520) 
and ≥16 (for strain 96217) for each of the 
test strains for each of the M14459, 96217, 
NZ98/254 and M10713 test strains. 
− 
the percentages of subjects with 4-fold rise 
(from pre-4th vaccination) in hSBA titers ≥ 8 
(for strains M14459, NZ98/254, M13520) 
and ≥16 (for strain 96217) for all strains 
combined (composite endpoint). 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4 and 6 months of age, compared to PCV13 
without rMenB+OMV NZ, at one month after the 
3rd vaccination. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the adjusted lower confidence 
limit for the between-group ratio of 
electrochemiluminescence (ECL) assay GMCs is >0.5 
for each of the 13 PCV13 antigens. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
the ECL GMCs for each of the 13 PCV13 
antigens. 
Secondary Immunogenicity 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
2, 4, 6 and 12 months of age, compared to PCV13 
and other RIV alone, at one month after the 4th 
vaccination. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of 2-sided 95% CI 
for the between-group-ratio of ECL assay GMCs is >0.5 
for each of the 13 PCV13 antigens. 
• 
At one month after the 4th vaccination (Day 331): 
− 
The ECL GMCs for each of the 13 PCV13 
antigens. 
• 
To demonstrate the immunological non-inferiority 
of PCV13 when administered concomitantly with 
rMenB+OMV NZ and other RIV to healthy infants 
at 2, 4, 6 and 12 months of age compared to 
PCV13 and other RIV alone, at both one month 
after the 3rd and the 4th vaccinations. 
Criterion: The immunological non-inferiority of PCV13 
will be demonstrated if the lower limit of the 2-sided 95% 
CI for the group differences in percentage of subjects 
with IgG ≥ 0.35 µg/mL is >-10% for each of the 13 
PCV13 antigens at one month after both 3rd and 4th 
vaccination. 
• 
At 1 month after the 3rd (Day 151) and the 4th 
vaccination (Day 331): 
− 
Percentages of subjects with serum 
pneumococcal anti-capsular polysaccharide 
IgG ≥0.35 μg/mL for each of the 13 PCV13 
antigens. 

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Objectives 
Endpoints 
• 
To demonstrate the immunological non-inferiority 
of DTaP-HBV-IPV and Hib vaccines when 
administered concomitantly with rMenB+OMV NZ 
and PCV13 to healthy infants at 2, 4, and 6 
months compared to DTaP-HBV-IPV and Hib 
vaccines concomitantly administered with PCV13 
without rMenB+OMV NZ, in terms of D, T, PT, 
FHA, PRN, Hep B and Hib, at one month after 
the 3rd vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI for 
the between-group differences is greater than the pre-
specified margin† for each antigen at one month after 
3rd vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
GMCs against the 3 pertussis antigens 
(Pertussis toxin [PT], pertactin [PRN], 
filamentous hemagglutinin [FHA]). 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥10 mIU/mL. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations ≥0.1 IU/mL. 
− 
Percentages of subjects with anti-PRP 
concentration ≥0.15 µg/mL and ≥1 µg/mL. 
• 
To demonstrate the immunological non-inferiority 
of MMR and VV vaccines when administered 
concomitantly with rMenB+OMV NZ and PCV13 to 
healthy subjects at 12 months compared to MMR 
and VV vaccines concomitantly administered with 
PCV13, without rMenB+OMV NZ, at one month 
after vaccination. 
Criterion: The immunological non-inferiority will be 
demonstrated if the lower limit of the 2-sided 95% CI for 
the between-group ratio of GMCs is >0.67 at one month 
after the MMR and VV vaccinations. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
GMCs against measles, mumps, rubella 
and VZV antigens. 
• 
To evaluate the immune response to rMenB+OMV 
NZ when administered concomitantly with PCV13 
and other RIV to healthy infants at 2, 4, 6 and 12 
months of age, at one month after the 3rd 
vaccination, at 6 months after the 3rd vaccination 
(immediately before the 4th vaccination), and at 
one month after the 4th vaccination against the 
M14459, 96217, NZ98/254 and M10713 M13520 
test strains. 
• 
At 1 month after the 3rd vaccination (Day 151) 
− 
the percentages of subjects with hSBA titers 
≥5, ≥8 and ≥16 for each of the M14459, 
96217, NZ98/254 and M10713M13520 test 
strains. 
− 
the hSBA geometric mean titers (GMTs) 
against each strain. 
• 
At 6 months after the 3rd vaccination (Day 301, 
immediately before the 4th vaccination): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥5 and ≥8 for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains. 
− 
the hSBA GMTs against each strain. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
the percentages of subjects with hSBA titers 
≥LLOQ for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains. 
− 
the percentages of subjects with hSBA titers 
≥5 for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains. 
− 
the hSBA GMTs and geometric mean ratios 
(GMRs) over pre-4th vaccination against 
each strain. 

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Objectives 
Endpoints 
− 
the percentages of subjects with 4-fold 
rise* in hSBA titers (from pre-4th 
vaccination) for each of the M14459, 
96217, NZ98/254 and M13520 test strains. 
• 
To evaluate immune responses to routine infant 
vaccines DTaP-HBV-IPV, Hib, MMR and VV 
vaccines when administered concomitantly with 
rMenB+OMV NZ and PCV13 to healthy infants 
at 2, 4, 6 and 12 months of age, at one month 
after the 3rd vaccination, at 1 month after the 
4th vaccination. 
• 
At 1 month after the 3rd vaccination (Day 151): 
− 
Percentages of subjects with anti-HBs 
antibody concentrations ≥100 mIU/mL. 
− 
Anti-HBsAg GMCs. 
− 
Percentages of subjects with anti-diphtheria 
and anti-tetanus concentrations ≥1 IU/mL. 
− 
Anti-diphtheria and anti-tetanus antibody 
GMCs. 
− 
Percentage of subjects with anti-polio 
type 1, 2 and 3 neutralization antibody 
titers ≥8. 
• 
At 1 month after the 4th vaccination (Day 331): 
− 
Seroresponse, defined as post-vaccination 
anti-VZV virus, anti-measles virus, anti-
mumps virus and anti-rubella virus antibody 
concentration^ ≥ a protective threshold 
among subjects who were seronegative 
(antibody concentration <assay cut-off) 
before vaccination. 
^ A suitable ELISA assay for analysis of anti-VZV, anti-
measles virus, anti-mumps virus and anti-rubella 
virus antibody concentrations is yet to be selected 
and/or developed. 
Seroresponse, defined as post-vaccination anti-VZV 
antibody concentration ≥75 mIU/mL (ELISA, Enzygnost) 
among children who were seronegative (antibody 
concentration <25 mIU/mL) before vaccination. 
Seroresponse as defined by the post-vaccination anti-
measles virus antibody concentration ≥ 200 mIU/mL 
(ELISA, Enzygnost) in subjects seronegative (antibody 
concentration <150 mIU/mL) before vaccination 
Seroresponse, defined as post-vaccination anti-rubella 
virus antibody concentration ≥10 IU/mL (ELISA, 
Enzygnost) in subjects seronegative (antibody 
concentration <4 IU/mL) before vaccination 
* A 4-fold rise in hSBA titers is defined as 
- if pre-vaccination titer <Limit of Detection (LOD), then a post-vaccination titer ≥ 4 times the LOD or ≥ LLOQ, 
whichever is greater; 
- if pre-vaccination titer is ≥LOD but <LLOQ, then a post-vaccination titer ≥4 times the LLOQ;  
- if pre-vaccination titer is ≥LLOQ, then a post-vaccination titer ≥4 times the pre-vaccination titer, 
where pre-vaccination titer=pre-4th dose titers (Day 301) 
† The endpoints and thresholds used for evaluation of the non-inferiority criteria for DTaP-HBV-IPV and Hib 
vaccines can be found in Table 21 and the thresholds and endpoint for evaluating the non-inferiority criteria 
for MMR and VV vaccines can be found in Table 22. 
Note 1: In the context of this study, the following are considered as RIVs at different visits: 
Visit 1 and Visit 2: DTPa-HBV-IPV, HRV, Hib; 
Visit 3: DTPa-HBV-IPV, Hib; 
Visit 5: MMR and VV. 

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Synopsis and Section 3: Study design 
 
 

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• 
End of Study (EoS): Date of the last testing/reading released of the Human 
Biological Samples (HBS) related to primary and secondary endpoints. Study 
completion must be achieved no later than 8 months after LSLV.Last subject last 
visit (Visit 7).  
Synopsis Table 1 and Section 3 Table 1 
Study groups and epochs foreseen in the 
study 
Study Groups 
Number of 
subjects 
Age (Min – Max) 
Epochs 
Epoch 001  
Epoch 002 
Epoch 003 
MenB+PCV 
1800800 
6 weeks – 12 weeks 
x  
x  
x  
Placebo+PCV 
900400 
6 weeks – 12 weeks 
x  
x 
x  
Number of subjects: Target enrolment is approximately 27001200 subjects who will be 
randomly assigned to the 2 study groups in a 2:1 ratio. 
 
Randomization (2:1) 
N=1200 
Group MenB+PCV (N=800) 
Group Placebo+PCV (N=400) 
Visit 1 
D 1 
Visit 2  
D 61 
Visit 3  
D 121 
Visit 4 
D 151 
Visit 5  
D 301 
Visit 6 D 
331 
Visit 7  
D 661 
Vacc. 
Group 
MenB+PCV 
rMenB+ 
OMV NZ  
PCV13  
RIV  
Group 
Placebo+PCV 
PCV13  
Placebo  
RIV 
Safety FU  
D 16, 31 
Safety FU  
D 76,91 
Safety FU  
D 136 
Safety FU  
D 181, 241 
Safety FU  
D 316 
Safety FU  
D: 361,421, 481, 541, 601 
Vacc: 
Group 
MenB+PCV 
rMenB+ 
OMV NZ 
PCV13 
RIV 
Group 
Placebo+PCV 
PCV13 
Placebo 
RIV 
Vacc:  
Group 
MenB+PCV 
rMenB+ 
OMV NZ 
PCV13 
RIV 
Group 
Placebo+PCV
PCV13 
Placebo 
RIV 
Blood 
draw 
Blood draw 
Vacc: 
Group 
MenB+PCV 
rMenB+ 
OMV NZ 
PCV13 
RIV 
Group 
Placebo+PCV
PCV13 
Placebo 
RIV
Blood draw 
Vacc: 
Group 
MenB+PCV 
RIV 
Group 
Placebo+PCV 
RIV
Study 
end 

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Table 3 
Overview of the Study Design: Blood Draws and Study vaccines 
Clinic Visits 
(Study Day) 
Visit 1 
(Day 1) 
Visit 2 
(Day 61) 
Visit 3 
(Day 
121) 
Visit 4 
(Day 
151) 
Visit 5 
(Day 301) 
Visit 6 
(Day 
331) 
Months of Age (MoA) 
~2 MoA1 
4 MoA 
6 MoA 
7 MoA 
12 MoA 
13 MoA3 
Study Vaccines 
Group MenB+PCV 
N=1800 800 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
Blood 
Draw2 
Blood Draw2 
rMenB+ 
OMV NZ 
PCV13 
Blood 
Draw2, 3 
Group 
Placebo+PCV 
N=900 400 
Placebo 
PCV13 
Placebo 
PCV13 
Placebo 
PCV13  
Blood Draw2 
Placebo 
PCV13 
Routine Study 
Vaccines 
Both groups 
N=2700 1200 
DTPa-
HBV-IPV 
HRV 
Hib 
DTPa-HBV-IPV 
HRV 
Hib 
DTPa-
HBV-
IPV 
Hib 
 
MMR 
VV 
 
Section 4.1: Number of subjects/centers 
Approximately 2700 1200 healthy subjects, 42 through 84 days of age (i.e. 6 through 12 
weeks) will be enrolled in a 2:1 ratio. 
Section 5.2.2.2.1: Study group and treatment number allocation 
The target will be to enroll approximately 2700 1200 eligible subjects who will be 
randomly assigned to 2 study groups in a 2:1 ratio. 
Section 5.2.3: Allocation of subjects to assay subsets 
Group MenB+PCV: All 1800 800 subjects will be randomly assigned into one of the 4 3 
immunogenicity subsets: 
• 
Subset A1: 385 400 subjects  
• 
Subset A2: 515 200 subjects  
• 
Subset A3: 385 200 subjects 
• 
Subset A4: 515 subjects 
Group Placebo+PCV: A total of 900 400 subjects will be randomly assigned into 2 
immunogenicity subsets: 
• 
Subset B1: 100 200 subjects 
• 
Subset B2: 385 200 subjects 
In addition, subjects from subset B1 (100200 subjects) will also be tested against the 4 
serogroup B strains at all 3 timepoints in order to maintain the observer-blindness of the 
study during the blood sample testing. 

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Section 5.3: Method of blinding 
The laboratory in charge of the laboratory testing will be blinded to the treatment, subject 
and visit number, and codes will be used to link the subject, visit and study (without any 
link to the treatment attributed to the subject) to each sample.  
The laboratory in charge of the laboratory testing will be blinded to the treatment as 
well as to the subject number. In addition, a different subject code will be used for each 
timepoint tested. This subject coding will prevent the laboratory from linking the 
consecutive visits to a specific subject. 
The serological data, which would lead to the unblinding of the study groups, will not 
be available during the course of the study to any investigator or any person involved 
in the clinical conduct of the study (including data cleaning). 
Section 5.7.3: Laboratory assays 
Table 7 
Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritization  
Serum 
N Men B 
M10713M13520 (NHBA) 
Ab*,∞ 
hSBA 
In house 
1/dil 
4TBD 
GSK 
Biologicals 
*** or 
laboratory 
designated 
by GSK 
Biologicals 
1 
1.1 
 
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG  
ELI 
In-house 
IU/mL  0.057 
0.030 
GSK 
Biologicals 
*** or 
laboratory 
designated 
by GSK 
Biologicals 
10 
 
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG  
ELI 
In-house 
IU/mL  
0.043 
0.037 
11 
Serum 
Measles Virus Ab.IgG  
ELI* 
Siemens 
Enzygnost 
Anti-measles 
virus IgG TBD 
TBD 
TBD 
GSK 
Biologicals*** 
or laboratory 
designated 
by GSK 
Biologicals 
8 
Rubella Virus Ab.IgG  
ELI* 
Siemens 
Enzygnost 
Anti-rubella 
virus IgG TBD 
TBD 
TBD 
GSK 
Biologicals*** 
or laboratory 
designated 
by GSK 
Biologicals 
9 
Mumps Virus Ab IgG 
ELI* 
TBD 
TBD 
TBD 
GSK 
Biologicals*** 
or laboratory 
designated 
by GSK 
Biologicals 
6 

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System 
Component 
Method 
Kit / 
Manufacturer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritization  
Varicella Zoster Virus 
Ab.IgG  
ELI* 
TBD 
TBD 
TBD 
GSK 
Biologicals*** 
or laboratory 
designated 
by GSK 
Biologicals  
7 
∞ The NHBA indicator strain is provisional and assay cut-offs may be adjusted during further characterization of the 
assay, should another indicator strain be used to characterize NHBA bactericidal responses.  
Section 5.7.4: Immunological read-outs 
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided in Table 8. Testing 
against RIV antigens will be performed in immunogenicity subsets as defined in Section 
5.2.3 and in Table 9. 
Table 8 
Immunological Read-outs 
Blood sampling timepoint 
Group Name 
Max No. 
subjectsa 
Component 
Components 
priority rank 
Type of contact and 
timepoint 
Sampling 
timepoint 
Visit 4 (Day 151) 
Post-Vacc 3 
Group 
MenB+PCV, 
Placebo+PCVb 
19001000 
hSBA-M10713M13520 
hSBA-NZ98/254 
hSBA-M14459 
hSBA-96217 
1 
1.1 
1.2 
1.3 
1.4 
Groups 
MenB+PCV, 
Placebo+PCV 
770800 
Anti-PCV13  
(1,3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) 
2 
Groups 
MenB+PCV, 
Placebo+ PCV 
27001200 
DT,TT, PT, FHA, PRN, 
HBs, Polio, Hiba 
See Table 9 a 
Visit 5 (Day 301) 
Pre-Vacc 4 
Groups 
MenB+PCV 
Placebo+PCVb 
19001000 
hSBA-M10713M13520 
hSBA-NZ98/254 
hSBA-96217 
hSBA-M14459 
1 
1.1 
1.2 
1.3 
1.4 
Groups 
MenB+PCV and 
Placebo+PCV 
21851200 
MMR, V 
See Table 9a 
Visit 6 (Day 331) 
Post-Vacc 4 
Groups 
MenB+PCV 
Placebo+PCVb 
19001000 
hSBA-M10713M13520 
hSBA-NZ98/254 
hSBA-96217 
hSBA-M14459 
1 
1.1 
1.2 
1.3 
1.4 
Groups 
MenB+PCV 
Placebo+PCV 
770800 
Anti-PCV13 
(1,3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) 
2 
Groups 
MenB+PCV and 
Placebo+PCV 
21851200 
M,M,R, Va 
See Table 9 a 
b A subset (B1) of 100 200 subjects (65 120 evaluable) from Group Placebo+PCV will be tested against the 4 
serogroup B strains in order to maintain the observer-blindness of the study during blood sample testing. 

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Table 9 
Immunogenicity Subsets 
Blood sampling timepoint 
Group Name 
Subset 
Max No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 4 (Day 151)  
Post-Vacc 
3 
Group 
MenB+PCV 
A1 
385400 
MenB 
PCV13 
Hib 
Pertussis 
1 
2 
3 
4 
A2 
515200 
MenB 
Hib 
Pertussis 
HepB 
1 
2 
3 
4 
A3 
385200 
MenB 
Pertussis 
Polio 
HepB 
Diphtheria 
Tetanus 
1 
2 
3 
4 
A4 
515 
MenB 
Polio 
1 
2 
 
 
Group 
Placebo+PCV 
B1 
100 200 
MenB 
PCV13 
Hib 
Pertussis 
Polio 
1 
2 
3 
4 
 
 
B2 
385200 
PCV13 
Hib 
Pertussis 
HepB 
Diphtheria 
Tetanus 
Polio 
1 
2 
3 
4 
5 
6 
7 
 
 
B3 
41550 
PCV13 
Hib 
Pertussis 
Polio 
1 
2 
3 
4 
Visit 5 (Day 301) 
Pre-Vacc 4 
Group 
MenB+PCV 
A1 
385 400 
MenB 
Measles 
Rubella 
Mumps 
Varicella 
1 
2 
2 
2 
3 
A2 
515 200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
A3 
385 200 
MenB 
Varicella 
Measles 
Mumps 
Rubella 
1 
2 
3 
3 
3 

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Blood sampling timepoint 
Group Name 
Subset 
Max No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
 
 
Group 
Placebo+PCV 
B1 
100 200 
MenB 
Measles 
Rubella 
Mumps 
Varicella 
Varicella 
Measles 
1 
2 
2 
2 
3 
2 
3 
 
 
B2 
385 200 
Mumps 
Varicella 
Measles 
Rubella 
Mumps 
1 
1 
2 
3 
4 
 
 
B3 
415 50 
Measles 
Mumps 
Rubella 
Varicella 
Varicella 
Measles 
1 
1 
1 
2 
1 
2 
Visit 6 (Day 331) 
Post-Vacc 
4 
Group 
MenB+PCV 
A1 
385400 
MenB 
PCV13 
Measles 
Rubella 
Mumps 
Varicella 
Varicella 
Measles 
1 
2 
3 
3 
3 
4 
3 
A2 
515200 
MenB 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 
A3 
385 200 
MenB 
Varicella 
Measles 
Mumps 
Rubella 
1 
2 
3 
3 
3 
 
 
Group 
Placebo+PCV 
B1 
100 200 
MenB 
PCV13 
Measles 
Rubella 
Mumps 
Varicella 
Varicella 
Measles 
1 
2 
3 
3 
3 
4 
 
 
B2 
385200 
PCV13 
Mumps 
Varicella 
Measles 
Rubella 
Mumps 
1 
2 
3 
3 
3 

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Blood sampling timepoint 
Group Name 
Subset 
Max No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
 
 
B3 
41550 
Varicella 
Measles 
PCV13 
Measles 
Mumps 
Rubella 
Varicella 
1 
2 
2 
2 
3 
Note: The individual components and the order of testing is given below: 
MenB: hSBA-M10713M13520, hSBA-NZ98/254, hSBA-M14459, hSBA-96217. 
Section 5.7.5: Immunological correlates of protection 
• 
Anti-varicella concentrations ≥75 U/mL (ELISA), ≥threshold to be defined based on 
the ELISA assay to be selected (ELISA), 
• 
Anti-measles ≥200 mIU/mL (ELISA), ≥threshold to be defined based on the ELISA 
assay to be selected (ELISA), 
• 
Anti-rubella ≥10 IU/mL (ELISA) ≥threshold to be defined based on the ELISA 
assay to be selected (ELISA) 
Section 6.1.1: Study vaccines 
Table 10 
Study Vaccines 
Treatment name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
Placebo  
Placebo  
(NaCl)  
NaCl=150mM 
Prefilled 
syringe (liquid) 
0.65 mL*0.5 
mL  
4 
Note: Refer to the SPM for the volume after reconstitution. The fourth dose of Hib vaccine will be administered as an 
non-study vaccine at 13 months of age. 
CCID50:=median Cell Culture Infective Dose (quantity of virus causing infection in 50% of exposed cells) 
CaCO₃: Calcium carbonate, HRV: Human Rotavirus, Hib: Haemophilus influenzae type b vaccine, DT: diphtheria 
toxoid, TT: tetanus Toxoid, PT: pertactin, FHA: filamentous hemagglutinin, PRN: Pertactin, HbsAg: Hepatitis B surface 
antigen, PRP: Polyribosyl-ribitol phosphate, MMR: measles, mumps, rubella. 
* * The volume of the saline syringe may be between 0.6mL and 0.8 mL. The full volume is to be injected. 
Section 7.7: Emergency unblinding 
GSK Biologicals’ Contact information for Emergency Unblinding 
24/24 hour and 7/7 day availability 
GSK Biologicals’ Central Safety Physician: 
For US only: 
+ 1 844 344 4389 1 844 446 3133 (GSK Biologicals Central Safety Physician on-call) 
GSK Biologicals’ Central Safety Physician Back-up: 
For US only: 
+ 1 844 344 4390 877.870.0019 

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Section 7.9: Medical device deficiencies 
The study intervention is a combination product constituted of a device and biologic 
product (e.g. pre-filled syringes). Refer to the Glossary of Terms for the definition of 
combination product and medical device deficiency.  
Section 7.9.1: Detection, follow-up and prompt reporting of medical device deficiency 
The investigator is responsible for the detection, documentation and prompt reporting 
of any medical device deficiency occurring during the study to GSK. This applies to 
any medical device provided for the conduct of the study.  
Device deficiencies will be reported to GSK within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. Refer to 
Section 10.6 for definitions and details on recording and reporting of these events.  
The sponsor will be the contact for the receipt of device deficiency reports. 
The investigator will ensure that follow-up includes any additional investigations to 
elucidate the nature and/or causality of the deficiency. Follow-up applies to all 
participants, including those who discontinue study intervention or the study. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
Section 7.9.2: Regulatory reporting of medical device deficiency when used as 
combination product 
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical studies. 
Refer to section 10.6.3. for details of reporting. 
The investigator, or responsible person according to local requirements (e.g. the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
Section 9.1: Determination of sample size 
The study sample size was determined by the revised study design while maintaining an 
adequate study power to achieve all co-primary objectives previously discussed with 
CBER. The multiplicity issue was dealt with by controlling the global α at the level of 
0.05 for all associated statistical hypotheses. This reduced number will also allow for 
enrolment of the minimum number of subjects exposed to rMenB+OMV NZ to fulfill 
initial Pediatric Study Plan (iPSP) commitment. The sample sizes were also calculated 
for the secondary objectives to evaluate the non-inferiority of RIV antigens. The 
evaluation will be performed by calculating the between-group differences and their 2-
sided 95% CI. Therefore, no multiplicity was adjusted for the secondary objectives. 

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This reduced number will also allow for enrolment of the minimum number of subjects 
exposed to rMenB+OMV NZ to fulfill initial Pediatric Study Plan (iPSP) 
commitment.For the co-primary objectives, multiplicity issue was dealt with by 
controlling the global α at the level of 0.05 for all associated statistical hypotheses.  
Study Sample Size Determination by Co-Primary Objectives 
For the immune response to PCV13, sample size calculations were based on data from 
the PCV13 package insert and for the immune response to rMenB+OMV NZ sample size 
calculations were based on data from the previous GSK (legacy Novartis) V72P13 and 
V72P13E1, and from V72_56 study. 
Using the procedure described in this section, the power for the study is presented in 
Table 17. In case of 3540% drop-out rate and 27001200 subjects to be enrolled in a 2:1 
ratio, 1170it’s assumed that 480 evaluable subjects from Group MenB+PCV and 585240 
evaluable subjects from Group Placebo+PCV could participate with data to the analyses. 
For PCV13 antigens a sample size of 250 there240 will behave approximately 99% 
power to show non-inferiority for all antigens. For MenB strains 1170it’s assumed that 
480 evaluable samples from Group MenB+PCV will be evaluated in the analyses. With 
250 240 per group for PCV13 antigen tests and 1170480 evaluable subjects from Group 
MenB+PCV for rMenB+OMV NZ strain tests, there is approximately 9499% probability 
to reject all 23 null hypotheses, and to claim that the primary objectives of the study will 
be met according to the predefined success criteria. assuming that the correlation between 
the rMenB+OMV NZ strains is 25%. 
Table 17 
Power to Show Non-Inferiority PCV13 Co-Primary Objective and 
Sufficiency rMenB+OMV NZ Co-Primary Objectives 
Co-Primary Objective 
Power 
Non-inferiority for GMCs for 13 antigens after the 3rd vaccination 
99.0% 
Sufficiency for % of subjects with titers ≥ LLOQ per each strain and all 4 strains combined (composite 
response) after the 3rd vaccination 
99.8% 
Sufficiency for % of subjects with with 4-fold increase (from pre-4th to post-4th) per each strain hSBA 
titers≥ 8 (for strains M14459, NZ98/254, M13520) and ≥16 (for strain 96217) individually and all 4 
strains combined (composite response) after the 4th vaccination 
>99.999% 
Probability of rejection of all 23 null hypotheses. 
9898.8% 
The power was estimated using simulations: 10.000 simulations per case. SAS 9.4 was 
used for the calculations. 
A short summary on the steps of simulation is presented below, in the example of 40% 
drop-out. The definition for families is given in Section 9.5.3.1. 

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In total 10.000 simulations were performed, each simulation consisted of: 
a. 
For testing Family 1, 250 240 normal distributed data were drawn for two groups and 
hence two times thirteen antigens, according to the ratio of GMC and the SD, as 
described below Table 18. For PCV13, a GMC ratio of 0.8 was assumed. Correlation 
structure was made for between-antigen correlation of 20%, 25% or 50%, 
respectively.0%. 
b. For testing Family 2 and 3, 1170 480 normal distributed data were drawn for one 
single group and for the four strains, according to the GMTs (for post 3rd dose) and 
GMRsGMTs (for post 4th dose), as shown in Table 19, and the SDs as described 
below Table 18. Correlation structure was made for between-antigen correlation of 
20%, 25% or 50%, respectively 0%. 
c. 
Testing of Family 1: Shifted one-sided t-test was used to test the hypotheses and 
output the p-values (for the power calculation no center effect was assumed). 
d. P-values were compared with the Family Wise Error Rate (FWER) to conclude on 
whether the null hypotheses were rejected or not. FWER for Family 1 is initially set 
to be 1/3 of the full alpha, which is rounded to 0.017. The FWER for Family 2 is 
0.033 and the initial FWER is 0 for Family 3. No multiplicity adjustment was 
performed within a family. Within family 1 all thirteen antigens were tested with the 
full FWER for family 1. If one or more test fail to reject the hypothesis for the 
antigen, family 1 fails. Consequently the alpha of family 1 will not be propagated 
(see bullet h. below). 
e. 
Preparing for testing Family 2 and 3, percentages were obtained by dichotomizing 
the normal random sets that were generated at step b, by applying the cut-off of 
LLOQ value for post 3rd or a cut-off of 4 at post 4th. By applying a cut-off of 4 to the 
GMRs at post-4th this will generate a percentage of subjects who had a 4-fold 
increase for their GMT value at post-4th compared to pre-4th, which is an 
approximation of the percentage of 4-fold increase using LOD and LLOQ values 8 
(for strains M14459, NZ98/254, M13520) or 16 (for strain 96217) at post 4th. Per 
time point, composite endpoint was derived by looking into each subject if the titer is 
above the cut-off for all 4 individual strains and if it is then this subject is counted as 
“1”. Otherwise the subject is counted as “0”. 
f. 
For each of the ten percentages for rMenB+OMV NZ (4 individual strains and 1 
composite endpoint at post-3rd and post-4th) the lower confidence limit was generated 
by fitting the binomial distribution with the percentage obtained from the previous 
step and alpha that has been assigned or propagated to the family. If the lower 
confidence limit is greater or equal to the sufficiency margin, then the null 
hypothesis is rejected for the single test. For Family 2 and 3, it is required to reject 
the null hypothesis for each and all of strain M14459, 96217, NZ98/254, M10713 
M13520, and the composite endpoint to be able to claim the success of the family.  
g.  Testing of Family 2: with the given FWER, if the LCL is greater or equal to 0.775 
for each of strain M14459, 96217 and NZ98/254, M10713 M13520, and greater or 
equal to 0.65 for the composite endpoint, then Family 2 is claimed for success. The 
FWER for Family 2 is set up as 2/3 of the full alpha, which is rounded to 0.033. 

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h. Alpha propagation between Family 1, 2 and 3 was calculated for 4 scenarios:  
5) If Family 1 had succeeded and Family 2 not, then propagate ½ FWER from 
Family 1 to Family 3 and the other ½ FWER to Family 2, and re-test Family 2 
with the new FWER which is the sum of the original FWER from Family 2 plus 
the ½ of FWER from Family 1. If the null hypothesis were rejected during the 
2nd time test, then claim the success of Family 2 and propagate full FWER to 
Family 3; otherwise Family 2 fails and proceed with Family 3 testing with the ½ 
of FWER propagated from Family 1. 
6) If Family 2 had succeeded and Family 1 not, then propagate ½ FWER from 
Family 2 to Family 3 and the other ½ FWER to Family 1, and re-test Family 1 
with the new FWER which is the sum of the original FWER from Family 1 plus 
the ½ of FWER from Family 2. If the null hypothesis were rejected during the 
2nd time test, then claim the success of Family 1 and propagate full FWER to 
Family 3; otherwise Family 1 fails and proceed with Family 3 testing with the ½ 
of FWER propagated from Family 2. 
7) If both Family 1 and Family 2 had succeeded, then the FWER from both 
families were propagated to Family 3, and proceed to test Family 3; 
8) If both Family 1 and Family 2 had failed, then no FWER will be propagated to 
Family 3, and we stop the testing globally.  
i. 
Testing of Family 3: with the given FWER, if the LCL is greater or equal to 0.6 for 
each of strain M14459, 96217 and NZ98/254, M10713 M13520, and greater or equal 
to 0.5 for the composite endpoint, then Family 3 is claimed for success.  
j. 
Add a loop on top of the aforementioned steps for 10.000 times simulation, 
summarize the probability of have all hypotheses rejected for each and all families, 
and the probability to meet all the primary objectives. 
k. For each of the scenarios (correlation=0.2, 0.25 or 0.5), 10,000 times simulation was 
performed. 
Based on the immune response observed in infant data from V72P13E1 and the PCV13 
package insert, the following assumptions were made for the calculations: 
1. As estimate for the SD of the different antigens and strains was taken the upper 80% 
CI limits of the common standard deviations for the log10 titers observed in GSK 
(legacy Novartis) study V72P13E1 and log10 ELISA concentrations observed from 
PCV13 studies. SDs that were used in the sample size calculations are presented in 
the table below. 

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Table 18 
Two-sided 80% Upper Confidence Limit of Standard Deviations 
 
80% UCL of SDs 
rMenB+OMV NZ strains 
Post 4th vaccination (SDs of 
GMRGMT) 
Post 3rd vaccination (SDs of 
GMT) 
M14459 
0.5437245097 
0.3222132193 
96217296217 
0.7776063454 
0.36900 
NZ98/254 
0.5179453796 
0.5196751670 
M10713M135202 
0.6691836477 
0.52245023 
PCV13 antigen1 
Post 3rd vaccination (SDs of GMC) 
1 
0.36629 
3 
0.41572 
4 
0.34261 
5 
0.43567 
6A 
0.39552 
6B 
0.44974 
7F 
0.34352 
9V 
0.32548 
14 
0.32445 
18C 
0.33550 
19A 
0.24439 
19F 
0.45638 
23F 
0.37567 
1.Estimated SDs for PCV13 antigens are the upper confidence limit of 2-sided 80% CI of back-calculated SDs, based 
on information (degree of freedom, 95% CI) provided on table 17 of Prevnar13 Package Insert (dated on July 2016) 
and assuming the underlying SDs fulfill a t-distribution. 
2 The assumptions for M13520 are cited from study V72_56 (205240) ad-hoc analysis on additional NHBA 
strains. 
2. Underlying GMC ratios for each PCV13 antigens is assumed as 0.8. 
3. For the sufficiency objectives, the following mean (log10(GMT)) were used in 
simulation based on observed data from previous studies (studies V72P13 and 
V72P13E1 and V72_56): 
Table 19 
GMTs at One Month Post 3rd Dose and GMRs at One Month Post 4th 
rMenB+OMV NZ Vaccination 
rMenB+OMV NZ 
strains 
GMRs* Post 4th 
vaccination  
GMTs* Post 3rd 
vaccination  
GMTs* Post 4th 
vaccination  
GMTs* Post 3rd 
vaccination  
M10713 M13520 
0.99 
1.35362 
1.41225 
1.10501 
NZ98/254 
1.27 
1.15836 
1.57978 
1.15836 
M14459 
1.25 
1.26400  
1.53148 
1.26400  
96217 
~1.36 
2.66753 
3.06183 
2.66753 
*log-scale 
4. The LODs and LLOQs associated with the 4-fold definition are assumed to be: 

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Table 20 
Limits of Detection and Lower Limits of Quantitation for rMenB+OMV 
NZ strains 
rMenB+OMV NZ strains 
LOD  
LLOQ  
M13520 M10713 
34 
164 
NZ98/254 
4 
6 
M14459 
3 
5 
96217 
6 
15 
LOD: lower limit of detection, LLOQ: lower limit of quantitation. 
Note: Other than for strain M13520, these LODs and LLOQs were cited from the latest lab assay validation report 
released in 2018. For strain M13520, the LOD and LLOQ are validated and cited from the latest laboratory assay 
validation report released in 2020.  
5. That each comparison is statistically independent. 
In conclusion, assuming a 35 40% drop-out rate in this age group, a total of 2700 1200 
subjects to be enrolled in a 2:1 ratio, which will lead to 1170 480 subjects evaluable in 
Group MenB+PCV and 250 240 subjects evaluable in Group Placebo+PCV, there will be 
99% power to conclude that: 
a. 
13 PCV13 antigens will be shown non-inferiority of PCV13 vaccine when co-
administrated with rMenB+OMV NZ vaccine, compared to PCV13 vaccine that is 
administered alone, at one month post 3rd vaccination 
b. The percentage of subjects with titers ≥ LLOQ is more than or equal to 60% for 
strain M14459, 96217, NZ98/254 and M13520, and more than or equal to 55% for 
strain M10713, and more than or equal to 43 50% for all 4 rMenB+OMV NZ strains 
at one month post 3rd vaccination. 
c. 
Percentage of subjects with 4-fold increase is more than or equal to 70 75% for strain 
M14459, 96217, NZ98/254 and M13520, and more than or equal to 66% for strain 
M10713, and more than or equal to 48 65% for all four rMenB+OMV NZ strains, at 
one month post 4th vaccination. 
Determination of the Immunogenicity Subsets Sizes for the Secondary Objectives: 
As described in detail in Table 9, due to limited serum volume available subjects will be 
randomly assigned to test different sets of RIV antigens. Subjects will either be 
assigned to subset A1, A2, A3 in Group MenB+PCV or assigned to subset B1, B2 and 
B3 in Group Placebo+PCV (see Section 5.2.3). The below tables (Table 21 and 
Table 22) show the likelihood to achieve non-inferiority for each of the RIV antigens 
(excluding polio) with the proposed sample sizes for immunogenicity subsets. 

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Table 21 
Non-inferiority to Each Individual Antigen (excluding polio antigens) 
in Pediarix and Hiberix, at One Month After 3rd Dose of rMenB+OMV NZ - 
Preliminary Results^ 
Component 
Endpoint 
Non-
inferiority 
Margin 
Reference 
# Evaluable 
Subjects per 
Immunogenicity 
Subset (MenB 
group/Placebo 
group)* 
Power 
Difference 
in %/ratio (Co-
ad vs routine) 
% in 
Routine group 
or SD 
Diphtheria 
%≥0.1IU/mL 
10% 
Diff=0% 
99.4% 
120/120 
>99.9% 
Tetanus 
%≥0.1IU/mL 
5% 
Diff=0% 
100% 
120/120 
>99.9% 
PT 
GMC 
1.5 
Ratio=0.8 
SD: 0.31535 
480/240 
88.7% 
FHA 
GMC 
1.5 
Ratio=0.84 
SD: 0.3111 
480/240 
98.3% 
PRN 
GMC 
1.5 
Ratio=0.83 b 
SD: 0.43427 
480/240 
79.1% 
HepB 
%≥10.0mIU/mL 
10% 
diff=-2% 
97.7% 
120/120 
93.5% 
Hib 
%≥0.15µg/mL 
5% 
diff=0%a 
96.6% 
360/240 
91.2% 
%≥1µg/mL 
10% 
diff=0% 
81.2% 
360/240 
86.7% 
^ Data Not Quality-Assured 
Abbreviations: SD, standard deviation; GMC, geometric mean concentrations; PT, pertussis toxin; FHA, 
Filamentous hemagglutinin; PRN, pertactin; HepB, Hepatitis B; Hib, Haemophilus influenzae type B; diff, 
difference 
Note: The sources are V72P13 clinical study report and the package insert of vaccines, unless otherwise 
indicated. SDs for Pertussis were taken from GSK study Hib-97. 
aSource: V72P12 CSR. 
b Source: V72P16 Table 14.2.1.14 Group B+OMV versus MenC. 
* Considering an estimated drop-out rate of 40%. 
Table 22 
Non-inferiority to Each Individual Antigen in MMR II and Varivax, at 
One Month After 4th Dose of rMenB+OMV NZ - Preliminary Results^ 
Component 
Endpoint 
Non-
inferiority 
Margin 
Reference 
# Evaluable 
Subjects per 
Immunogenicity 
Subset (MenB 
group/Placebo 
group)* 
Power 
Ratio (co-
ad vs routine) 
SD 
Measles 
GMC 
1.5 
ratio=0.9 
SD: 0.451 
480/240 
95.5% 
Mumps 
GMC 
1.5 
ratio=0.9 
SD: 0.381 
480/240 
99.1% 
Rubella 
GMC 
1.5 
ratio=0.9 
SD: 0.341 
480/240 
99.8% 
Varicella 
GMC 
1.5 
ratio=0.9 
SD: 0.452 
480/240 
95.5% 
^ Data Not Quality-Assured 
1 Reference for sample size calculation: GSK Study MMR-161. 
2 Reference for sample size calculation: GSK Study MMR-160. 
* Considering an estimated drop-out rate of 40%. 
Section 9.4.7: Subgroups 
• 
GMTs, GMCs and ratios of GMCs for PVC (Group MenB+PCV vs Group 
Placebo+PCV) at one month after the 3rd and 4th vaccination. 
• 
Percentages of subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217); for each of the 4 rMenB+OMV NZ strains 
and for the combined strains at one month after the 4th vaccination in Group 
MenB+PCV and Group Placebo+PCV. 

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Analyses will be performed on the PPSFAS.  
Safety endpoints may also be analyzed for each category of the subgroup factors gender, 
race and ethnic origin. The subgroup analyses will include summaries by vaccination of i) 
subjects with solicited AE (per solicited AE), ii) subjects with any unsolicited AE, iii) 
subjects with any possibly or probably related unsolicited AE and iv) subjects with 
serious unsolicited AEs. 
Additional subgroup analyses may be performed to assess the impact of COVID-19. 
More details will be provided in the Statistical Analysis Plan.  
Section 9.7: Analysis of immunogenicity 
The primary population for the primary immunogenicity analyses will be the PPS. All 
primary and selected secondary immunogenicity analyses (NI assessments to other 
RIVs) will be repeated on the FAS.; however, selected analyses will be repeated on the 
FAS.  
Section 9.7.1: Within groups assessment 
For each study group, at each timepoint that a blood sample result is available, the 
following endpoints will be assessed related to MenB strains and PCV13 strains: 
• 
the percentages of subjects with hSBA titers ≥ LLOQ for each of the M14459, 
96217, NZ98/254 and M10713M13520 test strains  
• 
the percentages of subjects with hSBA titers ≥ LLOQ for all strains combined 
(composite endpoint) at one month after the 3rd vaccination  
• 
the percentages of subjects with hSBA titers ≥5 for each of the M14459, 96217, 
NZ98/254 and M10713M13520 test strains 
• 
the percentages of subjects with hSBA titers ≥8 for each of the test strains 
(M14459, NZ98/254 and M13520), ≥16 for test strain 96217, and for all strains 
combined (composite endpoint) at one month after the 4th vaccination 
• 
the percentages of subjects with 4-fold increase at post-4th (from pre-4th) for each of 
the M14459, 96217, NZ98/254 and M10713M13520 test strains  
• 
the percentages of subjects with 4-fold increase at post-4th vaccination (from pre-4th 
vaccination) for all strains combined (composite endpoint) 
• 
GMCs/GMTs and within group GMRs (for post-4th versus pre-4th titers) will be 
tabulated for antibodies for each antigen 
• 
the ECL GMCs and within group GMRs for each of the 13 PCV13 antigens at one 
month post 4th vaccination 
• 
Percentage of subjects with serum pneumococcal anti-capsular polysaccharide IgG 
≥0.35 μg/mL at one month after the 3rd and 4th vaccination in Group MenB+PCV and 
Group Placebo+PCV. 
The CIs will be calculated for 2-sided 95% for exploratory objectives, and CIs will be 
calculated for given alpha at the testing step for the primary objectives that are associated 
with statistical hypothesis testing.  

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Endpoints associated with the other RIV will be assessed within-group for their endpoints 
mentioned in the endpoints section as specified in Section 9.2. The 2-sided 95% CI will 
be calculated.  
Section 9.7.2: Between groups assessment 
For PCV antigens, at each blood sampling timepoint and for each antibody for which 
results are available, for Diphtheria, Tetanus, Pertussis and Hepatitis B antigens, at 
blood sampling timepoint one month after the 3rd vaccination and for each antibody for 
which results are available: 
• 
The CI of the between-group GMC ratios (i.e. study group minus control group) will 
be computed using an analysis of variance (ANOVA) model on the logarithm10 
transformation of the concentrations.  
For Diphtheria, Tetanus, Hib and Hepatitis B antigens, at blood sampling timepoint 
one month after the 3rd vaccination, for VV and MMR, at blood sampling timepoint 
one month after the 4th vaccination and for each antibody for which results are 
available: 
• 
The CI of the between-group percentage differences (i.e. study group minus 
control group) will be computed. 
Section 9.7.3: Analysis of Primary Immunogenicity 
Section 9.7.3.1: Statistical Hypotheses 
In total 23 hypotheses will be tested for the primary objectives. A step-wise statistical 
approach will be used for the 23 statistical tests. The hypotheses will be grouped into 
three families, based on the different immunogenicity objectives: 
Family 2: 5 statistical hypotheses related to sufficiency objective on percentages of 
subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) and 
≥16 (for strain 96217) 4-fold increase at one month post 4th dose (from pre-4th 
dose) for each of the four strains M14459, 96217, NZ98/254, and M10713, and 
the composite endpoint 
Family 3: 5 statistical hypotheses related to sufficiency objective on percentages of 
subjects with hSBA titers ≥ LLOQ at one month post 3rd dose for each of the 
four strains M14459, 96217, NZ98/254, and M10713M13520, and the 
composite endpoint. 
The statistical hypotheses for each and all families are formulated as below: 
Family1: Non-inferiority of rMenB+OMV NZ + PCV13 to PCV13 with respect to GMCs 
at one month post 3rd vaccination 
Family 2: Percentage of subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, 
M13520) and ≥16 (for strain 96217)4-fold increase for each of the four strains (M14459, 
96217, NZ98/254, M10713) and the composite endpoint, at one month post-4th 
vaccination 

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Sufficiency will be claimed for each of the 4 strains and the composite endpoint, 
separately, if the following null hypothesis will be rejected: 
H02j: PAj < Aj vs. H12j : PAj ≥ Aj, 
where PAj denotes the percentage of subjects with hSBA titers ≥ 8 (for strains M14459, 
NZ98/254, M13520) and ≥16 (for strain 96217) 4-fold increase at one month after the 4th 
vaccination (from pre-4th dose) for strain j, (j=1, 2, 3, 4, and composite), which is 
assumed to be at least 90% for each of the three individual strains M14459, 96217, and 
NZ98/254, and M13520 72% for strain M10713, and 54at least 70% for the composite 
endpoint (estimate based on assumption of 250% correlation). Aj represents the level of 
sufficient immune response for each of the four strains and composite endpoint. The 
immune response at one month following the 4th vaccination, will be sufficient for 
rMenB+OMV against each individual strain if the lower limit of the adjusted CI for the 
percentage of subjects with hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) 
and ≥16 (for strain 96217)4-fold increase is ≥7075% for the individual N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254, ≥66% for strain M10713, and is 
≥4865% for the composite endpoint. 
Family 3: Percentage of subjects with hSBA≥LLOQ for each of the four strains (M14459, 
96217, NZ98/254, M10713M13520) and the composite endpoint, one month post post-
3rd. vaccination 
Sufficiency will be claimed for each of the 4 strains, separately, if the following null 
hypothesis will be rejected: 
H03j : PAj < Aj vs. H13j : PAj ≥ Aj, 
where PAj denotes the percentage of subjects hSBA≥LLOQ at one month after the 3rd 
vaccination for strain j, j=1, 2, 3,4, and composite)), which is assumed to be at least 90% 
for strains M14459, and 96217, 80% for M13520, and 70% for NZ98/254, 61% for strain 
M10713M13520, and 49at least 60% for the composite endpoint (estimate based on 
assumption of 250% correlation). Aj represents the level of sufficient immune response 
for each of the four strains and composite endpoint. The immune response at one month 
following the 3rd vaccination, will be sufficient for rMenB+OMV NZ against each 
individual strain if the lower limit of the adjusted CI for the percentage of subjects with 
hSBA titer ≥LLOQ is ≥60% for the N. meningitidis serogroup B test strains M14459, 
96217, NZ98/254, ≥55% for strain M10713, and ≥4350% for the composite endpoint. 

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Section 9.7.3.2: Statistical Methods 
Figure 2 
Testing Strategy for Three Families with Corresponding α Propagation 
 
 
The initial α is 0.0167 (2-sided) for Family 1 and 0.033 (2-sided) for Family 2, while it is 
zero for family 3.  
Section 9.8.1.1: Analysis of Solicited Adverse events 
Due to ediary software issue, a subject may be able to enter solicited adverse events in 
the ediary more than once per day, giving rise to duplicated records in the database. 
Discrepant records will not be included in the solicited safety analysis, but will be 
reported in the listing. 

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Section 9.8.1.2: Analysis of Unsolicited Adverse Events 
Local and systemic AEs will be analyzed by point estimates with associated 95% CIs 
[Clopper, 1934]. 
Section 9.8.1.2: Between groups assessment 
Not applicable. 
Section 9.10.1: Sequence of analyses 
Any analyses (including a possible interim analysis) will be conducted on data as clean 
as possible. All data will be analyzed at the end of the study, after availability of all 
immunogenicity and safety data, and presented in a final clinical study report.  
If needed, an interim analysis including data up to visit 6 may be performed. Selected 
immunogenicity objectives and solicited safety data from all timepoints up to Visit 6 
will be analyzed. The interim analysis will be performed by an independent statistician, 
in order to maintain the observer-blindness of the study. Study unblinding will be 
performed only after the final database lock. The data or the results from this interim 
analysis will not be used to make any decision on the continuation of this trial. 
Therefore no impact on the conduct or subsequent full data analysis of the trial is 
expected. All remaining objectives and remaining safety data will be analyzed at the 
end of the study and an integrated clinical report will be generated, which contains all 
data from the trial. 
Any analyses (including a possible interim analysis) will be conducted on data as clean as 
possible. If performed, the analyses will be done stepwise:  
• 
An interim analysis may be performed to provide Health Authorities with 
information on the primary and secondary objectives and safety data. The analyses if 
performed will occur at 1 month post-4th vaccination (ie, up to Visit 6). 
The interim analysis will include all enrolled subjects.  
All immunogenicity objectives will be analyzed. The safety analysis will be 
performed on solicited safety data from all timepoints up to Visit 6. 
The interim analysis will be performed by independent statistician, in order to 
maintain the observer-blindness of the study. Study unblinding will be performed 
only after the final database lock. The data or the results from this interim analysis 
will not be used to make any decision on the continuation of this trial. Therefore no 
impact on the conduct or subsequent full data analysis of the trial is expected. 
• 
The remaining safety analyses up to study termination at Visit 7 will be provided in 
an additional study report.  
An integrated clinical study report containing all data will be written and made available 
to the investigators. 

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Section 9.10.2: Statistical considerations for interim analyses 
Interim analysis will be conducted on final immunogenicity data and the safety analyses 
will be descriptive. Therefore no statistical adjustment for the interim analysis is required.  
If performed, interim analysis will be conducted on final immunogenicity data and the 
safety analyses will be descriptive. Therefore no statistical adjustment for the interim 
analysis is required. 
Section 10.6: Definition of medical device AE, adverse device effect (ADE), serious 
adverse device effect (SADE) and unanticipated SADE (USADE) 
Section 10.6.1: Definition of medical device AE and adverse device effect (ADE) 
• 
Medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether considered related to a medical device or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medical device. This definition includes events related 
to the medical device or comparator and events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of a medical device. 
This definition includes any AE resulting from: 
− 
insufficient or inadequate instructions for use (i.e. user error), or 
− 
any malfunction of a medical device, or 
− 
intentional misuse of the medical device. 
Section 10.6.2: Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted 
in: 
− 
A life-threatening illness or injury. The term ‘life-threatening' in the 
definition of ‘serious' refers to an event in which the participant was at risk 
of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
− 
A permanent impairment of a body structure or a body function. 
− 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
− 
Medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function 

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c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. [Is a suspected transmission of any infectious agent via a medicinal product] 
(include after consultation with study safety physician) 
Serious Adverse Device Effect (SADE) definition 
• 
A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• 
Any device deficiency that might have led to an SAE if appropriate action had 
not been taken or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome 
has not been identified in the current version of the IB. 
Section 10.6.3: Recording and reporting of medical device AE, ADEs, SADEs and 
USADE 
• 
Any device deficiency must be reported to GSK within 24 hours after the 
investigator determines that the event meets the definition of a device deficiency. 
• 
E-mail/Facsimile transmission of the paper ‘Medical device or combination 
product with device deficiency/incident report form’ is the preferred method to 
transmit this information to the sponsor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of ‘Medical device or combination product 
with device deficiency/incident report form’ sent by overnight mail or courier 
service. 
• 
Contacts for reporting can be found in Section 7.9. 
• 
GSK will review all device deficiencies, determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
APPENDIX A: LABORATORY ASSAYS 
MenB serum bactericidal assays using human complement (hSBA): 
Serum bactericidal activity against rMenB+OMV NZ will be determined by performing 
hSBA against a standard panel consisting of 4 meningococcal B test strains M14459, 
96217, NZ98/254 and M10713M13520. Each of these strains measures bactericidal 
activity primarily directed against one of the major bactericidal antigens included in the 
vaccine: strain M14459 measures hSBA against the 741 part of the 936-741 antigen, also 
known as fHbp variant 1.1; strain 96217 measures hSBA against antigen 961c, also 
known as NadA; and strain NZ98/254 measures hSBA against PorA P1.4, the 
immunodominant antigen in the OMV NZ vaccine component; strain M10713M13520 
measures hSBA against the 287 part of the 287-953 antigen, also known as NHBA. 

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Mumps, measles, rubella and varicella tests: 
Serological assays for the determination of antibodies against measles, mumps, rubella 
and varicella viruses are yet to be developed and/or selected. They will be performed on 
human serum by ELISA GSK Biologicals, or in another validated laboratory designated 
by GSK Biologicals using standardized and validated procedures. 
Anti-measles antibody concentrations will be measured using a commercial ELISA kit 
(Enzygnost/Dade Behring), which is based on a single point quantification antibody 
method (sera tested at a 1:231 dilution). This corresponds to a measles antibody 
concentration of 150 mIU/mL (as determined by the manufacturer using a standard 
serum); all sera which have titres equal to or above this value (i.e. are positive at this 
dilution) are considered as positive. 
Anti-rubella antibody concentrations will be measured using also commercial ELISA kits 
(Enzygnost/Dade Behring), which are also based on a single point quantification Ab 
method. 
Anti-VZV IgG Ab concentrations will be measured by using the commercial CE labeled 
ELISA kit Enzygnost from Siemens (former Dade Behring). Solid phase of the assay (96 
wells microplate) consist of wells coated with native VZV antigens derived from cells 
infected with VZV Virus (Ellen strain, ATCC VR-586). 
The anti-mumps IgG antibody (Ab) concentrations will be measured by using an ELISA 
assay. Because of the unavailability of the ELISA assay that was used by GSK in other 
clinical development programs (MMR-161 GSK study), a new ELISA has either to be 
developed and validated by GSK or selected from commercially available sources of 
validated ELISA against anti-mumps IgG antibodies. This selection is not yet made.  
Therefore the type of ELISA, the assay characteristics (e.g. validated assay cut-offs and 
units) will be determined during the course of the study. Any of these changes will be 
documented in a protocol amendment or in the clinical study report. 
APPENDIX B CLINICAL LABORATORIES 
GSK Vaccines GmbH 
Clinical Laboratory Sciences,Nexelis 
Marburg GmbH 
Marburg, Germany 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 
 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 7 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 7 
Amendment date: 
24 October 2022 
Co-ordinating author: 
 
Rationale/background for changes:  
The purpose of the amendment 7 is to shorten the safety follow-up period to 6 
months in subjects who have not reached the 6-month safety follow-up after the 
last dose, at the time this amendment takes effect. Shortening the safety follow-
up period is not expected to jeopardize the safety of subjects, as rMenB+OMV 
NZ has been extensively studied in long term clinical studies in infants, and has 
showed a favorable benefit-risk profile. In addition, more than 700 out of 1200 
subjects enrolled in the study will be followed up for 12 months after the last 
vaccination. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Synopsis and Section 2: Objectives and endpoints 
Objectives 
Endpoints 
Primary Safety 
• 
To assess the safety and tolerability of 
rMenB+OMV NZ, PCV13 and other RIV when 
administered concomitantly to healthy infants at 2, 
4, 6 and 12 months of age, throughout the study 
duration. 
• 
The percentages of subjects with solicited local 
Adverse events (AEs) and systemic AEs during 
the 7 days (including the day of vaccination) after 
the 1st, the 2nd, the 3rd and the 4th vaccination 
(Visits 1, 2, 3 and 5). 
• 
The percentages of subjects with solicited 
systemic AEs of parotid/salivary gland swelling, 
fever and rash during the 30 days (including the 
day of vaccination) after the 4th vaccination (Visit 
5). 
• 
The percentages of subjects with all unsolicited 
AEs (including SAEs, AEs leading to withdrawal, 
AESIs, and medically attended AEs) during 30 
days (including the day of vaccination) after the 
1st, the 2nd, the 3rd and the 4th vaccination (Visits 1, 
2, 3 and 5). 
PPD

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Objectives 
Endpoints 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs from study Day 1 (Visit 1) until study 
end (6 months or 12 months after last study 
vaccination, Visit 7¥). 
¥ Visit 7 will occur either on Day 481 (for subjects who have not yet reached the 6-month follow-up after the 
last dose at the time protocol amendment 7 takes effect) or on Day 661 (for all other subjects). 
Figure 1: Overview of Study Design - V71_57 
 
Synopsis and Section 3: Study design 
• 
Duration of the study: 
− 
Epoch 001 Primary starting at Visit 1 (Day 1) and ending at Visit 5 (Day 301). 
− 
Epoch 002: Secondary starting at Visit 5 (Day 301) and ending at Visit 6 (Day 
331). 
− 
Epoch 003: Safety follow-up period starting at Visit 6 (Day 331) and ending at 
Visit 7 (Day 481 or Day 661). For subjects who have not yet reached the 6-
month safety follow-up after the last dose at the time protocol amendment 7 
takes effect, Visit 7 will take place on Day 481. 
• 
Primary completion date (PCD): Visit 7 (Day 481 or Day 661). 

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Table 5: List of Study Procedures 
Age (approximate) ~2 moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 1 SFC 1 
SFC 2 
Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 1 Day 16 Day 31 Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-
vaccination 1  
0 
15 days 
post-
vacc 1 
30 days 
post-
vacc 1 
60 days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 
-3/+3 
-31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
10 For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol amendment 7 takes effect, Visit 7 will occur on Day 481. 

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Table 6: Intervals Between Study Visits 
Interval 
Optimal length of interval 
Allowed interval1, 2 
Visit 1 →Visit 2 
60 days 
29 days – 81 days  
Visit 2 → Visit 3  
60 days  
29 days – 81 days 
Visit 3 → Visit 4 
30 days  
21 days – 60 days 
Visit 3 → Visit 5  
180 days  
173 days – 271 days  
Visit 5 → Visit 6  
30 days  
21 days – 60 days  
Visit 5 → Visit 7 (Study termination)3 
180 days 
173 days – 271 days 
Visit 5 → Visit 7 (Study termination) 
360 days 
353 days – 381 days 
1The investigator should arrange study visits within this interval as subjects may not be eligible for inclusion in the PPS 
cohorts if they make the study visit outside this interval. All visits and windows should be planned using the day of last 
vaccination as the reference point 
2The allowed interval have been modified in keeping with ACIP guidelines to facilitate the safe scheduling of study 
visits during the COVID-19 pandemic situation. 
3 For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol 
amendment 7 takes effect, Visit 7 will occur on Day 481. 
Section 5.6.15: Study procedures during special circumstances 
• 
Visit 7 (Day 481 or Day 661): the study conclusion visit has been revised to allow 
for either a site visit or concluding telephone call. The telephone call is intended for 
safety data collection and will be considered equivalent to study conclusion visit.  
Section 5.6.16.2: Safety follow-up calls 
During the course of the trial, a total of 10 or 13 safety follow-up calls will be performed. 
Safety follow-up calls will be performed on the following time points: 
Treatment period: 
• 
Day 16 and Day 31 (15 and 30 days post 1st vaccination, respectively),  
• 
Day 76 and Day 91 (15 and 30 days post 2nd vaccination, respectively),  
• 
Day 136, Day 181 and Day 241 (15, 60 and 120 days post 3rd vaccination, 
respectively), 
• 
Day 316 (15 days post 4th vaccination). 
Follow-up period: 
• 
Day 361, Day 421, Day 481, Day 541 and Day 601 (60, 120, 180, 240, and 300 days 
post 4th vaccination, respectively). For subjects who have not yet reached the 6-
month safety follow-up after the last dose at the time protocol amendment 7 takes 
effect, Visit 7 will occur on Day 481 instead of the follow-up call, and follow-up 
calls at Day 541 and Day 601 will not be performed. 
Section 5.6.17: Study conclusion 
• 
The study termination visit will occur on Day 481 or Day 661 (Visit 7). The 
termination visit will be a clinic visit. 
• 
If Visit 7 is performed by telephone for subjects who are impacted by protocol 
amendment 7, reconsenting should be performed as per site and IRB guidelines. 

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Section 6.7.1: Recording of concomitant medications/products and concomitant 
vaccinations 
• 
Any concomitant vaccination administered in the period starting from birth and 
ending at the last study visit (Day of birth to Day 481 or Day 661). 
Section 7.2.1 Time period for detecting and recording adverse events and serious 
adverse events 
The time period for collecting and recording SAEs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 6 months or 12 months following administration 
of the last dose of study vaccine for each subject (ie, study end). See Section 7.3 for 
instructions on reporting of SAEs. 
All medically attended AEs will be collected and recorded from Day 1 (ie, the time of the 
first receipt of study vaccines) until 6 months or 12 months following administration of 
the last dose of study vaccine for each subject (ie, study end). 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
Day 1 (ie, the time of the first receipt of study vaccines) until 6 months or 12 months 
following administration of the last dose of study vaccine for each subject (ie, study end). 
The time period for collecting and recording of AESIs will begin at Day 1 (ie, the first 
receipt of study vaccines) and will end 6 months or 12 months following administration 
of the last dose of study vaccines (ie, study end). See section 7.3 for instructions on 
reporting of AESIs. Details regarding follow-up of AEs, SAEs and AESIs are given in 
Section 7.4  
Table 13: Reporting Periods for Collecting Safety Information 
Eve
nt 
Pre-
V11 
V1 
D1
6 
D31  
V2 D76 D91  
V3 D136 V4 
 D181D24
1 
V5 
D 
316 
V6 
 D361, 
421, 
481, 
541, 
6012 
V7 
D
1 
 D61  
(2 M 
post-
vacc 
1) 
 D121 
(2 M 
post-
vacc 
2) 
D151 
(1 M 
post-
vacc 
3) 
 
D301 
(6 M 
post-
vacc 
3) 
D331 
(1 M 
post-
vacc 
4) 
 
D48
1 or 
D66
1  
(6 
M 
or 
12 
M 
pos
t-
vac
c 
4)3 
2For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol 
amendment 7 takes effect, follow-up calls on Day 481, Day 541 and Day 601 will not be performed. 
3For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol 
amendment 7 takes effect, Visit 7 will occur on Day 481. 

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Section 7.7 Emergency unblinding 
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals. 
Section 9.2.1 All Enrolled Set 
Section 9.2.2 All Exposed Set  
All subjects in the Enrolled Set who receive a study vaccination. 
Section 9.6 Analysis of Safety 
Distribution of subjects by vaccinations will be summarized by vaccine group for the 
Enrolled Set. The primary analysis will be performed on the all Exposed Set 
Section 9.3 Derived and transformed data 
Immunogenicity: 
• 
The GMTs/GMCs calculations are performed by taking the anti-log of the mean of 
the log titer transformations. Values to be used for the antibody concentrations/titres 
below the assay cut-off will be described in the Statistical Analysis Plan (SAP). 
Section 9.5.1 Between group assessments 
• 
the ECL GMCs and within group GMRs for each of the 13 PCV13 antigens at one 
month post 4th vaccination 
The CIs will be calculated for as 2-sided 95% for exploratory objectives, and CIs will be 
calculated for at given alpha at the testing step for the primary objectives that are 
associated with statistical hypothesis testing. 
Section 9.6.1.2 Analysis of Unsolicited Adverse Events 
Separate summaries will be produced for the following categories:  
• 
Serious adverse events (SAE) 
• 
Adverse events related to vaccine 
• 
Adverse events of special interest 
• 
Adverse event leading to withdrawal 
• 
Adverse events leading to a medically attended visit 
These summaries will also be presented by the 0-6/6-12 months safety follow-up 
periods after the last study vaccination. 

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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 8 
eTrack study number 
and Abbreviated Title 
205239 (MENB REC 2ND GEN [V72_57]) 
IND number 
IND-011561 
EudraCT number 
2016-003268-37 
Amendment number: 
Amendment 8 
Amendment date: 
19 Dec 2023 
Co-ordinating author: 
 
Rationale/background for changes:  
The purpose of the amendment 8 is to align the protocol with the recent update of 
CDC’s ACIP for the US NIP (National Immunization Program). According to 
this ACIP update, the 20-valent pneumococcal conjugate vaccine (PCV20) is 
listed as one of the recommended vaccines for the immunization of 
pneumococcal disease in children in U.S while PCV13 is no longer 
recommended for full series of pneumococcal vaccination. Children who 
received 3 PCV13 doses before 12 months but have not received their fourth 
booster dose, have now the option to receive PCV20 or PCV13. Therefore, to 
incorporate the current ACIP recommendations, subjects who have not reached 
their visit 5 at the time when this protocol amendment becomes effective have the 
option to receive either PCV13 or PCV20 based on the investigator judgment 
and/or parent’s preference. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Synopsis, Section 3: STUDY DESIGN OVERVIEW, Section 5.2.2.2.1. Study group 
and treatment number allocation 
• 
Study groups: 
− 
Group MenB+PCV: rMenB+OMV NZ given concomitantly with PCV13 at 2, 4, 
6, and 12 months of age. Either PCV13 or PCV20 is allowed to be given at 12 
months of age (Visit 5) for subjects who have not reached Visit 5 at the time 
this protocol amendment 8 becomes effective. Subjects will also 
receivedreceive routine infant vaccines (DTPa-HBV-IPV, HRV, Hib, MMR, 
VV) at applicable timepoints. 
PPD

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− 
Group Placebo+PCV: Placebo and PCV13 at 2, 4, 6, and 12 months of age. 
Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) 
for subjects who have not reached Visit 5 at the time this protocol amendment 
8 becomes effective. Subjects will also receivedreceive routine infant vaccines 
(DTPa-HBV-IPV, HRV, Hib, MMR, VV) at applicable timepoints. 
Table 2: Study Groups and Treatment Foreseen in the Study 
Treatment name 
Vaccine name 
Study Groups 
MenB+PCV  
Placebo+PCV  
Bexsero  
rMenB+OMV NZ 
X 
- 
Prevnar13 
PCV13* 
X 
X 
Prevnar 20 
PCV20* 
X 
X 
Placebo 
NaCl 
- 
X 
Pediarix  
DTPa-HBV-IPV  
X 
X 
Rotarix 
HRV 
X 
X 
Hiberix  
Hib 
X 
X 
M-M-R II 
MMR  
X 
X 
Varivax  
VV 
X 
X 
Note: Subjects in both groups will receive a fourth dose of Hib vaccine (Hiberix) and a single dose of DTPa vaccine 
(Infanrix) as non-study vaccines at Visit 6. 
* Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
Synopsis and Section 2: OBJECTIVES AND ENDPOINTS: 
Objectives 
Endpoints 
Primary Safety 
• 
To assess the safety and tolerability of 
rMenB+OMV NZ, PCV13 and other RIV when 
administered concomitantly to healthy infants at 2, 
4, 6 and 12 months of age, throughout the study 
duration. 
• 
The percentages of subjects with solicited local 
Adverse events (AEs) (administration site 
event) and systemic AEs during the 7 days 
(including the day of vaccination) after the 1st, the 
2nd, the 3rd and the 4th vaccination (Visits 1, 2, 3 
and 5). 
• 
The percentages of subjects with solicited 
systemic AEs of parotid/salivary gland swelling, 
fever and rash during the 30 days (including the 
day of vaccination) after the 4th vaccination (Visit 
5). 
• 
The percentages of subjects with all unsolicited 
AEs (including serious adverse events [SAEs], 
AEs leading to withdrawal, adverse event of 
special interest [AESIs], and medically attended 
AEs) during 30 days (including the day of 
vaccination) after the 1st, the 2nd, the 3rd and the 
4th vaccination (Visits 1, 2, 3 and 5). 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs from study Day 1 (Visit 1) until study 
end (6 months or 12 months after last study 
vaccination, Visit 7¥). 

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Note 1: To control the risk of erroneously concluding, a hierarchical procedure will be used for the multiple 
confirmatory study objectives, with the possibility to conclude on the study success based on the results of 
the co-primary objectives alone (refer to Section 9.5.3 for details). 
Section: GLOSSARY OF TERMS 
Co-administered 
(concomitant) products 
A product given to clinical trial participants as 
required in the protocol as part of their standard care 
for a condition which is not the indication for which 
the IMP is being tested and is therefore not part of the 
objective of the study. 
Comparator 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorised form, 
or when used for an unauthorised indication, or when 
used to gain further information about the authorised 
form.A pharmaceutical form of an active ingredient 
being tested in a clinical trial, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use.  
Placebo 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Section: TRADEMARKS 
Trademarks not owned by the GSK group of 
companies 
 
Generic description 
M-M-R II (Merck & Co., Inc.) 
 
Measles, Mumps and Rubella Virus Vaccine Live 
Prevnar 13 (Wyeth Pharmaceuticals Inc./Pfizer 
Inc.) 
 
Pneumococcal polysaccharide conjugate vaccine (13-
valent, adsorbed) 
Prevnar 20 (Wyeth Pharmaceuticals Inc./Pfizer 
Inc.) 
 
Pneumococcal polysaccharide conjugate vaccine 
(20-valent, adsorbed) 
Varivax (Merck & Co., Inc.) 
 
Varicella Virus Vaccine Live 

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Section 1.3.1: Risk Assessmentz 
Important Potential/ 
Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
IMP: Prevnar13* and Prevnar20* 
Hypersensitivity and 
anaphylaxis 
Hypersensitivity including anaphylaxis to 
one or several components of the vaccine 
can rarely occur. 
Hypersensitivity reaction including face 
oedema, dyspnea, bronchospasm is listed 
in the clinical trial section of Prevnar13 US 
PI as well as anaphylactic /anaphylactoid 
reaction including shock is a listed adverse 
reaction from the post-marketing 
experience. 
Anaphylaxis following vaccine 
administration constitutes an absolute 
contraindication to subsequent 
vaccination (see Section 6.5). The 
subjects will be observed closely for at 
least 30 minutes following the 
administration of the vaccines, with 
appropriate medical treatment readily 
available in case of anaphylaxis (see 
Section 5.6.12).  
Seizures (including 
febrile seizures) 
The febrile convulsion is a risk for the infant 
and toddler groups. Seizures (including 
febrile seizures) are listed adverse 
reactions in the clinical trial section of 
Prevnar13 US PI. 
Close monitoring of all seizures, as 
reported in Section 7.1.6.1. Seizure will 
be monitored through the AESI 
collection.  
Fever 
Fever may occur following vaccination. 
Fever is listed in the Prevnar13 and 
Prevnar20 US PI. 
Any febrile illness constitutes a 
contraindication to administration of the 
vaccine at the time scheduled for 
vaccination e study (see Section 6.5). 
Prophylactic use of analgesic/antipyretic 
medications during the first 7 days after 
vaccination is allowed on a voluntary 
basis, but must be recorded in the 
source document and in the eCRF (see 
Section 6.7.1). 
Erythema multiforme 
Erythema multiforme is listed in the post-
marketing section of the Prevnar13 US PI. 
No specific mitigation in this study: SAE 
collection is part of the study protocol. 
* information derived from the publicly available data. 
Note 1: According to the label, events from clinical trials and post marketing experience of Prevnar and 
Prevnar 13 are applicable also to Prevnar 20 
Section 1.3.2: Benefit Assessment 
• 
Receiving Prevnar 13 during the study may prevent occurrence of pneumococcal 
pneumonia and invasive disease caused by 13 Streptococcus pneumoniae strains (1, 
3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). For subjects who received 
PCV20 at visit 5, PCV20 may prevent occurrence of pneumococcal pneumonia 
and invasive disease caused by 20 Streptococcus pneumoniae strains (1, 3, 4, 5, 
6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F). 

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Figure 1 
Overview of Study Design – V72_57 
 
Section 1.3.3: Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks in association with the rMenB+OMV NZ, PCV13 
(or PCV20 ), DTPa-HBV-IPV, HRV, Hib, MMR and VV vaccines are justified by the 
potential benefits (prevention) that may be afforded to subject(s) receiving these 
vaccines. 

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Table 24 
Overview of the Study Design: Blood Draws and Study vaccines  
Clinic Visits 
(Study Day) 
Visit 1 
(Day 1) 
Visit 2 
(Day 61) 
Visit 3 
(Day 
121) 
Visit 4 
(Day 
151) 
Visit 5 
(Day 301) 
Visit 6 
(Day 
331) 
Months of Age (MoA) 
~2 MoA1 
4 MoA 
6 MoA 
7 MoA 
12 MoA 
13 MoA3 
Study Vaccines 
Group MenB+PCV 
N=800 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV NZ 
PCV13 
rMenB+ 
OMV 
NZ 
PCV13 
Blood 
Draw2 
Blood Draw2 
rMenB+ 
OMV NZ 
PCV13PCV134 
Blood 
Draw2, 3 
Group 
Placebo+PCV 
N=400 
Placebo 
PCV13 
Placebo 
PCV13 
Placebo 
PCV13  
Blood Draw2 
Placebo 
PCV13PCV134 
Routine Study 
Vaccines 
Both groups 
N=1200 
DTPa-
HBV-IPV 
HRV 
Hib 
DTPa-HBV-IPV 
HRV 
Hib 
DTPa-
HBV-
IPV 
Hib 
 
MMR 
VV 
 
4 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
Section 5.1. 
Regulatory and ethical considerations, including the informed consent 
process 
Potential subjects’ parent(s)/LAR(s) or the designee must be informed that their 
participation is voluntary. They will be required to physically or digitally sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, HIPAA requirements, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
 

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Table 5: List of Study Procedures 
Age (approximate) 
~2 
moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 
1 SFC 1 SFC 2 Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 
1 
Day 
16 
Day 
31 
Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-vaccination 1  
0 
15 
days 
post-
vacc 
1 
30 
days 
post-
vacc 
1 
60 
days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 -3/+3 
-
31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
Sampling timepoints 
 
 
 
 
 
 
 
 
Post-
vacc 
3 
 
 
Pre-
vacc 
4 
 
Post-
vacc 
4 
 
 
 
- 
 
 
- 
Informed consent 3  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion 
criteria  
● 
 
 
O  
 
 
O  
 
 
 
 
 O  
 
 
 
 
 
 
 
 
 
Medical history  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History directed physical 
examination  
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom directed physical 
examination  
 
 
 
O 
 
 
O 
 
O 
 
 
O 
 
O 
 
 
 
O 
 
 
O 
Check contraindications and 
warnings and precautions to 
vaccination  
O 
 
 
O 
 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
 
 
Pre-vaccination body 
temperature  
● 
 
 
● 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Study group and/or treatment 
number allocation  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Age (approximate) 
~2 
moa 
 
 
4 moa 
 
 
6 moa 
 
7 moa 
 
 
12 
moa 
 
13 
moa 
 
24 
moa 
Epoch 
Epoch 001 
Epoch 002 
Epoch 003 
Type of contact  
Visit 
1 SFC 1 SFC 2 Visit 2 SFC 
3 
SFC 4 Visit 3 SFC 
5 
Visit 
4 
SFC 
6 
SFC 7 Visit 5 SFC 8 Visit 6 SFC 9 SFC 
10 
SFC 
11  
Visit 
710 
SFC 
12 
SFC 
13 
Visit 
711 
Timepoints 
Day 
1 
Day 
16 
Day 
31 
Day 61 Day 
76 
Day 
91 
Day 121 Day 
136 
Day 
151 
Day 
181 
Day 
241 
Day 
301 
Day 
316 
Day 
331 
Day 
361 
Day 
421 
Day 481 
Day 
541 
Day 
601 
Day 
661 
Days post-vaccination 1  
0 
15 
days 
post-
vacc 
1 
30 
days 
post-
vacc 
1 
60 
days 
post-
vac 1 
15 
days 
post 
vacc 
2 
30 
days 
post 
vacc 
2 
60 days 
post-
vacc 2 
15 
days 
post-
vacc 
3 
30 
days 
post-
vacc 
3 
60 
days 
post-
vacc 
3 
120 
days 
post-
vacc 
3 
180 
days 
post-
vacc 
3 
15 
days 
post-
vacc 
4 
30 
days 
post-
vacc 
4 
60 
days 
post-
vacc 4 
 
120 
days 
post-
vacc 4 
180 days 
post-vacc 
4 
240 
days 
post-
vacc 
4 
300 
days 
post-
vacc 
4 
360 
days 
post-
vacc 
4 
Visit window (days) 2  
-5 
-3/+3 -3/+3 
-
31/+21 -3/+3 -3/+3 -31/+21 -3/+3 -9/+30 -3/+3 -3/+3 -7/+91 -3/+3 -9/+30 -7/+21 -7/+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
-7/ 
+21 
Sampling timepoints 
 
 
 
 
 
 
 
 
Post-
vacc 
3 
 
 
Pre-
vacc 
4 
 
Post-
vacc 
4 
 
 
 
- 
 
 
- 
Treatment number allocation for 
subsequent doses  
 
 
 
● 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Vaccines administration 4  
● 
 
 
● 
 
 
● 
 
 
 
 
●13 
 
● 5  
 
 
 
 
 
 
 
Recording of solicited local 
(administration site) and 
systemic AEs (Days 1–7 post 
vaccination) in eDiary 9  
O 
 
 
O 
 
 
O 
 
 
 
 
O 
 
 
 
 
 
 
 
 
 
13 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached Visit 5 at the time the protocol amendment 8 becomes 
effective. 
 

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Intervals Between Study Visits 
Interval 
Optimal length of interval 
Allowed interval1, 2 
Visit 1 →Visit 2 
60 days 
29 days – 81 days  
Visit 2 → Visit 3  
60 days  
29 days – 81 days 
Visit 3 → Visit 4 
30 days  
21 days – 60 days 
Visit 3 → Visit 5  
180 days  
173 days – 271 days  
Visit 5 → Visit 6  
30 days  
21 days – 60 days  
Visit 5→ Visit 7 (Study termination)3 
180 days 
173 days – 271201 days 
Visit 5→ Visit 7 (Study termination) 
360 days 
353 days – 381 days 
Section 5.6.5. Collect demographic data 
At Visit 1, record demographic data such as date of birth, gender, race and ethnic origin, 
weight and length in the subject’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the 
diversity of the trial participants, and to determine if the trial participants are truly 
representative of the impacted population. 
Section 5.6.14.1. 
Follow-up safety clinic visit 
A blood sample will also be collected for immunological evaluation at both visits.  
At both visits on Day 151 (Visit 4) and Day 331 (Visit 6), the eDiary should be returned 
to the study site and ; the eDiary dispensed at Day 1 (Visit1) will be collected at Day 151 
(Visit 4) and the eDiary dispensed at Day 301 (Visit 5) will be collected at Day 331 
(Visit 6). For details on the eDiary see Section 5.6.16.1. A blood sample will also be 
collected for immunological evaluation at both visits.  
Section 5.7.3. Laboratory assays 
Serological testing for immunogenicity to rMenB+OMV NZ, PCV13 (same 
pneumococcal serotypes panel (PCV13)will be used for subjects who received PCV20) 
and the other routine vaccines will be performed at a GSK Biologicals’ laboratory(ies) or 
in a laboratory(ies) designated by GSK Biologicals using standardized and validated 
procedures (refer to Table 7). 
Table7: Humoral Immunity (Antibody determination)  
Syste
m 
Component 
Method 
Kit / 
Manufact
urer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritizat
ion  
Serum 
N Men B M13520 
(NHBA) Ab*,∞ 
hSBA 
In house 
1/dil 
4 
GSK Biologicals 
*** or 
laboratoryLabor
atory 
designated by 
GSK Biologicals 
1 
N Men B NZ98/254 
(PorA) Ab  
4 
N Men B M14459 
(fHbp) Ab 
3 

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Syste
m 
Component 
Method 
Kit / 
Manufact
urer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritizat
ion  
N Men B 96217 
(NadA) Ab  
6 
Serum 
Streptococcus 
pneumoniae.Polysacc
haride 01 Ab.IgG  
ECL  
In house 
µg/ 
mL 
0.08 
GSK Biologicals 
*** 
2 
Streptococcus 
pneumoniae.Polysacc
haride 03 Ab.IgG  
0.075  
Streptococcus 
pneumoniae.Polysacc
haride 04 Ab.IgG  
0.061  
Streptococcus 
pneumoniae.Polysacc
haride 05 Ab.IgG  
0.198  
Streptococcus 
pneumoniae.Polysacc
haride 06A Ab.IgG  
0.111  
Streptococcus 
pneumoniae.Polysacc
haride 06B Ab.IgG  
0.102  
Streptococcus 
pneumoniae.Polysacc
haride 07F Ab.IgG  
0.063  
Streptococcus 
pneumoniae.Polysacc
haride 09V Ab.IgG  
0.066  
Streptococcus 
pneumoniae.Polysacc
haride 14 Ab.IgG  
0.16  
Streptococcus 
pneumoniae.Polysacc
haride 18C Ab.IgG  
0.111 
Streptococcus 
pneumoniae.Polysacc
haride 19A Ab.IgG  
0.199  
Streptococcus 
pneumoniae.Polysacc
haride 19F Ab.IgG  
0.163 
Streptococcus 
pneumoniae.Polysacc
haride 23F Ab.IgG 0 
0.073  
Serum 
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG  
ELI 
In-house 
IU/mL  
0.030  
GSK Biologicals 
*** or laboratory 
designated by 
GSK 
Biologicals*** 
10 
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG  
ELI 
In-house 
IU/mL  
0.037  
11 
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG  
ELI 
In-house 
IU/mL  
2.046  
4 
Bordetella 
pertussis.Pertussis 
Toxin Ab.IgG  
ELI 
In-house 
IU/mL  
2.693  
4 

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Syste
m 
Component 
Method 
Kit / 
Manufact
urer 
Unit* 
Cut-
off* 
Laboratory** 
Overall 
testing 
prioritizat
ion  
Bordetella 
pertussis.Pertactin 
Ab.IgG  
ELI 
In-house 
IU/mL  
2.187  
4 
Poliovirus Sabin Type 
1 Ab  
NEU 
In-house 
ED50  
8  
12 
Poliovirus Sabin Type 
2 Ab  
NEU 
In-house 
ED50  
8  
14 
Poliovirus Sabin Type 
3 Ab  
NEU 
In-house 
ED50  
8  
13 
Hepatitis B 
Virus.Surface Ab  
CLIA 
mIU/mL  
6.2  
5 
Serum 
Haemophilus 
influenzae type 
b.Polyribosyl Ribitol 
Phosphate Ab  
ELI* 
In-house 
µg/ 
mL  
0.066  
GSK Biologicals 
*** or laboratory 
designated by 
GSK 
Biologicals*** 
3 
Serum 
Measles Virus Ab.IgG  ELI*Lumi
nex 
TBDIn-
house 
TBDmIU/
mL 
TBD 
GSK 
Biologicals*** or 
laboratoryLabor
atory 
designated by 
GSK Biologicals 
8 
Rubella Virus Ab.IgG  
ELI*Lumi
nex 
TBDIn-
house 
TBDIU/m
L 
TBD 
GSK 
Biologicals*** or 
laboratoryLabor
atory 
designated by 
GSK Biologicals 
9 
Mumps Virus Ab IgG 
ELI*Lumi
nex 
TBDIn-
house 
TBDAU/
mL 
TBD 
GSK 
Biologicals*** or 
laboratoryLabor
atory 
designated by 
GSK Biologicals 
6 
Serum 
Varicella Zoster Virus 
Ab.IgG  
ELI* 
TBDIn-
house 
TBDmIU/
mL 
TBD9
7.0 
GSK 
Biologicals*** or 
laboratory 
designated by 
GSK Biologicals  
7 
Ab: Antibody, CLIA: Chemiluminescence immunoassay, IgG: Immunoglobin G, µg: Microgram, mL: Milliliter, 1/dilution: 
reciprocal of the dilution; ECL: Electrochemiluminescent Assay, ELI: enzyme-linked immunosorbent assay (ELISA), 
MSBA: manual human serum bactericidal assay (hSBA), NEU: neutralization assay, TBD: to be determined.  
*Type of assays, the validated assay cut-offs and units might be subject to change during the course of the study (e.g. 
in case of requalification, revalidation or standardization, availability of assays). In case testing is done at another GSK 
designated laboratory, the validated assay cut-off may also need to be adapted accordingly. Any of these changes will 
be documented in a protocol amendment or clinical study report. The LLOQ for the meningococcal B strains are 
provided in Table 20 (to be determined for the NHBA strain).. 
**Refer to Appendix B for the laboratory addresses. 
CCI

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***GSK Biologicals laboratory refers to the Vaccines Clinical Laboratory Sciences (CLSand Assay Portfolio (Vx 
CL&AP) in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany. 
Additional exploratory testing on the vaccine and/or on the disease under study may be performed if deemed 
necessary for accurate interpretation of the data or should such assay(s) become available at GSK. These assays may 
not be represented in the objectives/endpoints of the study protocol.  
Section 5.7.5: Immunological correlates of protection 
For the following antigens in the DTPa-HBV-IPV, Hib, MMR and VV vaccines, an 
immunological correlate of protection has been established: 
• 
Anti-D and anti-T concentrations 0.1 IU/mL (ELISA), 
• 
Anti-HBS concentration ≥10 mIU/mL (ELISA),  
• 
Polio ≥8 ED50 for types 1, 2 and 3 (neutralizing antibody assay), 
• 
Anti-PRP concentrations ≥0.15 µg/mL (ELISA), 
• 
Anti-varicella concentrations ≥threshold to be defined based on the ELISA assay to 
be selected (ELISA), 
• 
Anti-measles ≥threshold to be defined based on the ELISA assay to be selected 
(ELISA), 
• 
Anti-mumps ≥threshold to be defined based on the ELISA assay to be selected 
(ELISA), 
• 
Anti-rubella ≥threshold to be defined based on the ELISA assay to be selected 
(ELISA) 
• 
The immunological assay results will be communicated to the investigator as soon as 
they become available. For antigens for which an immunological correlate of 
protection has been established, the following applies.  
Section 6.1.1. Study vaccines 
The study vaccines’ (see glossary of terms) will be provided by the Sponsor. All study 
participants are expected to receive these vaccines as specified by the study schedule. The 
study vaccines specific to this study are described below. In exceptional circumstances, 
in order to avoid any inconvenience for the participant, a commercially-acquired 
vaccine with identical formulation and brand of that reported in the study protocol can 
be administered to the participant. In this case this subject will still be eligible for the 
Per Protocol Set. 
• 
GSK Biologicals’ Meningococcal group-B vaccine, (rMenB+OMV NZ, Bexsero); 
• 
Pneumococcal polysaccharide conjugate vaccine, (13-valent Pneumococcal Vaccine) 
(PCV13, Prevnar13) (In order to comply with the change in the US NIP, 20-valent 
Pneumococcal Vaccine (PCV20, Prevnar20) will also be allowed as specified in 
the protocol);  
• 
Saline placebo vaccine. 

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Table 10 
Study Vaccines 
Treatment 
name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
Bexsero  
rMenB+OMV NZ 
rp936-741=50µg; rp287-
953=50µg; 
rp961c=50µg; OMV 
NZ98/254=25µg; 
Al(OH)3=1.5mg; 
Histidine=776µg; 
NaCl=3.125mg; 
Sucrose=10mg; 
water=0.5ml  
Prefilled syringe 
(liquid) 
0.5 mL  
4 
Prevnar13  
PCV13  
PS1=2.2µg CRM197; 
PS3=2.2µg CRM197; 
PS4=2.2µg CRM197; 
PS5=2.2µg CRM197; 
PS6A=2.2µg CRM197; 
PS6B=4.4µg CRM197; 
PS7F=2.2µg CRM197; 
PS9V=2.2µg CRM197; 
PS14=2.2µg CRM197; 
PS18C=2.2µg CRM197; 
PS19A=2.2µg CRM197; 
PS19F=2.2µg CRM197; 
PS23F=2.2µg CRM197; 
AlPO4=125µg Al3+  
Homogenous 
white 
suspension after 
shaking (in pre-
filled syringe) 
0.5 mL  
4** 
Prevnar20 
PCV20  
PS1(2.2 µg)¹,²; PS3(2.2 
µg)¹,²; PS4(2.2 µg)¹,²; 
PS5(2.2 µg)¹,²; 
PS6A(2.2 µg)¹,²; 
PS6B(4.4 µg)¹,²; 
PS7F(2.2 µg)¹,²; 
PS8(2.2 µg)¹,²; 
PS9V(2.2 µg)¹,²; 
PS10A(2.2 µg)¹,²; 
PS11A(2.2 µg)¹,²; 
PS12F(2.2 µg)¹,²; 
PS14(2.2 µg)¹,²; 
PS15B(2.2 µg)¹,²; 
PS18C(2.2 µg)¹,²; 
PS19A(2.2 µg)¹,²; 
PS19F(2.2 µg)¹,²; 
PS22F(2.2 µg)¹,²; 
PS23F(2.2 µg)¹,²; 
PS33F(2.2 µg)¹,² 
Suspension for 
injection (in 
pre-filled-
syringe) 
0.5 mL 
1 
Placebo  
Placebo  
(NaCl)  
NaCl=150mM 
Prefilled syringe 
(liquid) 
0.65 mL* 
4 
Pediarix  
DTPa-HBV-IPV 
DT>=30IU; TT>=40IU; 
PT=25µg; FHA=25µg; 
PRN=8µg; 
HbsAg=10µg; 
Inactivated Poliovirus 
type 1 (Mahoney 
strain)=40DU; 
Inactivated Poliovirus 
type 2 (MEF-1 
Prefilled syringe 
(liquid) 
 
3 

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Treatment 
name 
Vaccine 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of 
doses 
strain)=8DU; Inactivated 
Poliovirus type 3 
(Saukett strain)=32DU; 
Aluminium=700µg Al3+  
Hiberix  
Hib 
PRP=10µg; TT~=25µg; 
Aluminium=120µg Al3+ 
Lyophilized cake 
to be 
reconstituted 
with saline 
diluent 
0.5 mL  
3 
Hib diluent (NaCl)  
NaCl=150mM  
Vial (liquid)  
Rotarix 
HRV Lyo  
HRV RIX4414 live 
attenuated 
>=106.0CCID50  
Lyophilized 
vaccine in a 
monodose glass 
vial.  
1 mL  
2 
HRV Diluent 
CaCO3=60mg 
Diluent for 
lyophilized 
vaccine (calcium 
carbonate liquid 
antacid) supplied 
separately in a 
prefilled oral 
applicator 
M-M-R II  
MMR-II 
Measles>=1.000TCID50; 
Mumps=12.500TCID50; 
Rubella=1.000TCID50 
Lyophilized 
pellet in a vial for 
reconstitution 
with water for 
injections 
0.5 mL  
1 
MMR-II diluent 
(Water for 
injection )  
Water=0.5ml  
vial  
Varivax  
Varivax  
Oka=1350pfu  
Monodose vial of 
lyophilized 
vaccine 
0.5 mL  
1 
Varivax Diluent 
(Water for 
injection) 
Water=0.5ml  
vial  
** For subjects who receive PCV20 at Visit 5, only 3 doses of PCV13 will be administered. 
¹conjugated to CRM₁₉₇ (51 µg);  
²adsorbed on AlPO₄ (0.125 mg Al³⁺); Water for injections 
Section 6.3. 
Dosage and administration of study vaccines 
Study vaccines should be administered using the preferred site locations shown in Table 
11 below. The rMenB+OMV NZ/Placebo vaccine should be administered at least 2.5 cm 
above the injection site of Hib, when concomitantly administered on the same thigh. 
Similarly, PCV13 (or PCV20) should be administered at least 2.5 cm above the injection 
site of DTPa-HBV-IPV, when concomitantly administered on the same thigh. The HRV 
vaccine will be administered orally. The MMR and VV vaccines should be given 
subcutaneously in the upper arm (deltoid region) by inserting the needle in a pinched-up 
fold of skin and subcutaneous tissue to prevent injection into muscle. 

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Table 11 
Dosage and Administration 
Study group 
Type of 
contact 
and 
timepoint 
Treatment name 
Vol. 
administered 
Route1 
Site3 
Location 
Directionality2 
Laterality 
MenB+PCV  
Visit 1 
(Day 1) 
 
Visit 2  
(Day 61) 
 
Visit 3 
Day 121) 
Bexsero  
0.5 mL 
IM 
Thigh 
Upper 
Right 
Prevnar13 
0.5 mL 
IM 
Thigh 
Upper 
Left 
Pediarix  
0.5 mL 
IM 
Thigh 
Lower 
Left 
Hiberix  
0.5 mL 
IM 
Thigh 
Lower 
Right 
Rotarix4 
1 mL 
O 
- 
- 
- 
Visit 5 
(Day 301) 
Bexsero 
0.5 mL 
IM 
Thigh 
- 
Right 
Prevnar135 
0.5 mL 
IM 
Thigh 
- 
Left 
M-M-R II  
0.5 mL 
SC 
Arm 
Upper 
Right 
Varivax  
0.5 mL 
SC 
Arm 
Upper 
Left 
Placebo+PCV  
Visit 1 
(Day 1) 
 
Visit 2 
(Day 61) 
 
Visit 3 
(Day 121) 
Placebo 
0.5 mL 
IM 
Thigh 
Upper 
Right 
Prevnar13  
0.5 mL 
IM 
Thigh 
Upper 
Left 
Pediarix  
0.5 mL 
IM 
Thigh 
Lower 
Left 
Hiberix  
0.5 mL 
IM 
Thigh 
Lower 
Right 
Rotarix4 
1 mL 
O 
- 
- 
- 
Visit 5 
(Day 301) 
Placebo 
0.5 mL 
IM 
Thigh 
- 
Right 
Prevnar135 
0.5 mL 
IM 
Thigh 
- 
Left 
M-M-R II 
0.5 mL 
SC 
Arm 
Upper 
Right 
Varivax 
0.5 mL 
SC 
Arm 
Upper 
Left 
5 Either PCV13 or PCV20 is allowed to be given at 12 months of age (Visit 5) for subjects who have not reached 
Visit 5 at the time this protocol amendment becomes effective. 
Section 6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
rMenB+OMV NZ, PCV 13 and other RIVs.vaccines specified in the protocol. If any of 
these events occur during the study, the subject must not receive additional doses of 
vaccines but may continue other study procedures at the discretion of the investigator 
(see Section 7.4).  
Section 7.3.2. Contact information for reporting serious adverse events and AESIs 
Study Contact for Reporting SAEs and AESIs 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs and AESIs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 

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US sites only: 
Fax: 1-610-787-7053 
Email: RIX.CT-Safety-Vac@gsk.com 
Section 7.7: Emergency unblinding 
GSK Biologicals’ Contact information for Emergency Unblinding 
24/24 hour and 7/7 day availability 
GSK Biologicals’ Central Safety Physician: 
For US only: 
+1 844 446 3133 (GSK Biologicals Central Safety Physician on-call) 
GSK Biologicals’ Central Safety Physician Back-up: 
For US only: 
877.870.0019GSK Helpdesk: 1-877-528-7677 or 1 877-221-2913 
Email: GSKClinicalSupportHD@gsk.com 
Section 9.2.3.3: Overall Safety Set 
All subjects who are in the Solicited Safety Set and/or Unsolicited Safety Set. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
Section 9.2.4. Full Analysis Set (FAS) for Immunogenicity Set 
Section 9.2.4.1. 
Full Analysis Set Immunogenicity 
All subjects in the Enrolled Set, who receive at least one study vaccinationExposed Set 
and provide immunogenicity data at either one month after their 4th vaccination or one 
month after their 3rd vaccination for at least 1 antigen/strain. 
Section 9.2.7. Subgroups 
The following descriptive analyses will be performed by gender, race, and ethnic origin 
and age group (6-8 weeks or ≥8 weeks) for the following parameters: 
Section 9.4. 
Analysis of demographics 
Distributions of subjects by sex, race, ethnic origin and, geographic region and age group 
(6-8 weeks or ≥8 weeks) will be summarized overall and by vaccine group. 
Section 9.5.1. Within groups assessment 
For each study group, at each timepoint that a blood sample result is available, the 
following endpoints will be assessed related to MenB strains and PCV13 strains: 
• 
GMCs/GMTs and within group GMRs (for post-4th versus pre-4th titers) will be 
tabulated for antibodies for each antigen 
• 
the ECL GMCs for each of the 13 PCV13 antigens at one month post 4th vaccination 

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• 
Percentage of subjects with serum pneumococcal anti-capsular polysaccharide IgG 
≥0.35 μg/mL at one month after the 3rd and 4th vaccination in Group MenB+PCV and 
Group Placebo+PCV. 
Section 9.5.4.1. 
Statistical Methods 
Concentration and titer data will be summarized by vaccine group, meningococcal B 
strain and time point. Additionally, within-subject GMRs will be computed for GMTs at 
one month after 4th vaccination versus pre-4th vaccination. As for GMTs, the GMRs and 
95% CIs will be computed by exponentiating (base 10) the corresponding means and 
95% CIs from an ANOVA model. 
9.6. 
Analysis of safety 
Distribution of subjects by vaccinations will be summarized by vaccine group for the 
EnrolledExposed Set. The primary analysis will be performed on the Exposed Set. 
Solicited/Unsolicited Safety Set. 
Section 9.6.1.1: Analysis of Solicited Adverse events 
Post-vaccination solicited AE reported from Day 1 to Day 7 will be summarized for the 
interval Day 1-7 (and Day 1-3, Day 4-7 if needed) by maximal severity and by vaccine 
group, excluding the 30-minute measurement, which will be summarized separately. For 
MMR and VV-specific solicited systemic AEs (parotid/salivary gland swelling, fever, 
rash) collected after Visit 5 (30 minutes through Day 30 post-vaccination), the study 
period will be divided into the following intervals: 6 hours through Day 7, Day 8 though 
Day 30. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects (with 95% CI) reporting use. 
Section 12: REFERENCES 
Adams DA, Thomas KR, Jajosky R, Foster L, Sharp P, Onweh DH, Schley AW, 
Anderson WJ. Summary of Notifiable Infectious Diseases and Conditions — United 
States, 2014. Morb Mortal Wkly Rep (MMWR) 2016; 63:1-152 
BEXSERO (Meningococcal Group B Vaccine) Prescribing Information, April 2023 
Section 5.6.1: Data collected from subjects, Section 5.6.13: Post-vaccination 
procedures, Section 7.1.3.3: Other solicited adverse events, Section 9.6.1.1: Analysis 
of Solicited Adverse events, and Section 10.2: Subject Diary 
Solicited Local (administration site) 
5.6.16.1. 
Subject Diary, 7.1.3.1. 
Solicited local adverse events 
(administration site event), Grading of Solicited Local Adverse Events 
(Administration Site Event) for All Subjects, 9.6.1.1. 
Analysis of Solicited 
Adverse events 
solicited local AEs (administration site event), 

Signature Page for  205239 TMF-17734745 v1.0
Signature Page for TMF-17734745 v1.0
Reason for signing: Approved
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Role: Approver
Date of signature: 19-Dec-2023 11:03:13 GMT+0000
PPD