A Phase IIIB, Randomized, Observer-blind, Multicenter Study to Assess the Safety and Immunogenicity of GSK's Meningococcal Group B Vaccine When Administered Concomitantly With GSK's Meningococcal MenACWY Conjugate Vaccine to Healthy Subjects of 16-18 Years of Age
Phase: PHASE3
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

Protocol Amendment 7
Study ID:  205419
Official Title of Study: Safety and Immunogenicity Study of GSK Meningococcal 
Group B Vaccine Bexsero (GSK3536829A) when Administered Concomitantly 
with GSK Meningococcal MenACWY Conjugate Vaccine Menveo 
(GSK3536820A) to Healthy Subjects 16-18 Years of Age
NCT number: NCT04318548
Date of Document: 14-Oct-2022

CONFIDENTIAL 
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Protocol Amendment 7 Final 
11 October 2022 
1 
 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89,  
1330 Rixensart, Belgium 
Primary Study 
vaccine(s)/product(s) 
and number(s) 
• 
GlaxoSmithKline (GSK) Biologicals’ meningococcal 
group-B vaccine Bexsero (GSK3536829A) 
• 
GSK Biologicals’ Meningococcal MenACWY 
Conjugate Vaccine Menveo (GSK3536820A) 
eTrack study number 
and abbreviated title 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
Investigational New 
Drug (IND) number 
IND-011561 
EudraCT number 
2016-003722-16 
Date of protocol 
Final Version 1: 28 June 2016 
Date of protocol 
amendment 
Amendment 1 Final: 14 August 2019 
Amendment 2 Final: 23 January 2020 
Amendment 3 Final: 29 September 2020 
Amendment 4 Final: 26 November 2020 
Amendment 5 Final: 13 April 2021 
Amendment 6 Final: 21 June 2022 
Amendment 7 Final: 11 October 2022 
Title 
Safety and Immunogenicity Study of GSK Meningococcal 
Group B Vaccine Bexsero (GSK3536829A) when 
Administered Concomitantly with GSK Meningococcal 
MenACWY Conjugate Vaccine Menveo (GSK3536820A) 
to Healthy Subjects 16-18 Years of Age. 
Short title 
A Phase IIIB, Randomized, Observer-blind, Multicenter 
Study to Assess the Safety and Immunogenicity of GSK 
Meningococcal Group B Vaccine when Administered 
Concomitantly with GSK Meningococcal MenACWY 
Conjugate Vaccine to Healthy Subjects 16-18 Years of Age. 
Co-ordinating author 
 
Scientific Writing 
Contributing authors 
(Amended 11 October 
2022) 
• 
, 
Clinical Sciences Lead 
• 
 Study 
Delivery Lead 
• 
 
, Local Delivery Lead 
PPD
PPD
PPD
PPD

CONFIDENTIAL 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
Protocol Amendment 7 Final 
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2 
eTrack study number 
and abbreviated title 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
Investigational New 
Drug (IND) number 
IND-011561 
EudraCT number 
2016-003722-16 
Short title 
A Phase IIIB, Randomized, Observer-blind, Multicenter 
Study to Assess the Safety and Immunogenicity of GSK 
Meningococcal Group B Vaccine when Administered 
Concomitantly with GSK Meningococcal MenACWY 
Conjugate Vaccine to Healthy Subjects 16-18 Years of Age.  
Contributing authors 
(continued) 
(Amended 11 October 
2022) 
• 
, 
Oversight Data Manager 
• 
 
, Clinical Trials Supply Manager  
• 
 Clinical Laboratory 
Sciences Study Manager 
• 
, Clinical 
Read-out Team Leader 
• 
 
 
• 
, SERM Principal 
Scientist 
• 
 
Global Regulatory Affairs 
• 
, Study Data Manager 
• 
, Global 
Patent 
• 
, Study Statistician 
• 
, Lead Statistician 
• 
, 
, Clinical Project 
Lead from Protocol Amendment 3 onwards and 
, Associate Clinical Project 
Lead from Protocol Amendment 6 onwards. 
GSK Biologicals’ Protocol DS v 16.0 
©2016 GSK group of companies or its licensor. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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205419 (MENB REC 2ND GEN-045 (V72_79)) 
Protocol Amendment 7 Final 
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Protocol Amendment 7 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
IND number 
IND-011561 
EudraCT number 
2016-003722-16 
Date of protocol amendment 
Amendment 7 Final: 11 October 2022 
Title 
Safety and Immunogenicity Study of GSK 
Meningococcal Group B Vaccine Bexsero 
(GSK3536829A) when Administered Concomitantly 
with GSK Meningococcal MenACWY Conjugate 
Vaccine Menveo (GSK3536820A) to Healthy 
Subjects 16-18 Years of Age. 
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 7 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. 
• 
That I will comply with the terms of the site agreement. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ s study vaccine and other study-related duties and functions as 
described in the protocol. 
• 
To supervise any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site. 
• 
To ensure that any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site are qualified to perform those trial-related 
duties and functions. 
• 
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. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the trial. 
• 
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 vaccine, 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. 

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205419 (MENB REC 2ND GEN-045 (V72_79)) 
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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 1 year following completion of the study.  
• 
Agree that GSK Biologicals may disclose any information 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 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
IND number  
IND-011561 
EudraCT number 
2016-003722-16 
Date of protocol amendment 
Amendment 7 Final: 11 October 2022 
Title 
Safety and Immunogenicity Study of GSK 
Meningococcal Group B Vaccine Bexsero 
(GSK3536829A) when Administered Concomitantly 
with GSK Meningococcal MenACWY Conjugate 
Vaccine Menveo (GSK3536820A) to Healthy 
Subjects 16-18 Years of Age. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 

CONFIDENTIAL 
205419 (MENB REC 2ND GEN-045 (V72_79)) 
Protocol Amendment 7 Final 
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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals SA 
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 12.5.9.3. 
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.4.6.1. 

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PROTOCOL AMENDMENT 7 SUMMARY OF CHANGES TABLE 
Table 1 
Document history 
Document 
Date 
Protocol Amendment 7 
11 October 2022 
Protocol Amendment 6 
21 June 2022 
Protocol Amendment 5 
13 April 2021 
Protocol Amendment 4 
26 November 2020 
Protocol Amendment 3 
29 September 2020 
Protocol Amendment 2 
23 January 2020 
Protocol Amendment 1 
14 August 2019 
Original Protocol 
28 June 2016 
Amendment 7: 11 October 2022 
Overall Rationale for the Amendment change 
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, as the comprehensive safety data in this population 
indicates that the safety of the trial participants is not jeopardized and does not pose any 
meaningful threat. These data include all previous pivotal clinical studies, the recently 
completed V72_72 study in the same population and post-marketing experience in 
countries where Menveo and Bexsero are marketed, and in majority of cases are given 
concomitantly.  
The purpose of this amendment is also to extend the visit window to 28 days post 
reference day to mitigate the impact of COVID pandemic, including quarantine, 
mandatory vaccination, or other disturbances in the study procedures. 
Table 2 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Contributing authors 
Updated job titles 
Internal update in name of job titles 
Sponsor signatory page  
Updated job title 
Internal update in name of job title 
Section 1 
Updated objectives and endpoints table 
Updated overall design figure 
Updated text 
To incorporate 2 additional primary 
endpoints 
To incorporate a shortened safety follow-
up into the overall design figure 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
safety follow-up (SFU) 5 (Day 271) at the 
time this amendment takes effect  
Table 3 
Added a bullet mark for study 
conclusion also under SFU 5 and added 
a footnote with details 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 4 
Updated 
To extend the visit window to 28 days 
post reference day 
Table 5 
Addition of footnote 
To introduce a shortened safety follow-up 
period in subjects who have not reached 

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Section # and Name 
Description of Change 
Brief Rationale 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 6 
Updated 
To incorporate 2 additional primary 
endpoints 
Figure 1 
Updated 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Section 5.2 
Section 5.4 
Section 7.5.1 
Section 8.4.3 
Section 8.6 
Section 12.5.8 
 
Addition of text 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 14 
Table revised 
To provide clarity on what assay to be 
performed at which visit. 
Table 15 
Table title edited 
To clarify that study conclusion at Day 
451 is applicable in subjects who have 
crossed Day 271 
Table 16 
New table created 
 
To clarify that study conclusion at Day 
271 is applicable in subjects who have 
not reached Day 271 
 

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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 7 
1. 
SYNOPSIS ............................................................................................................. 18 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 24 
3. 
INTRODUCTION .................................................................................................... 27 
3.1. 
Study rationale ............................................................................................ 27 
3.2. 
Background ................................................................................................ 27 
3.3. 
Benefit/Risk assessment ............................................................................. 29 
3.3.1. 
Risk assessment .......................................................................... 30 
3.3.2. 
Benefit assessment ..................................................................... 32 
3.3.3. 
Overall Benefit: Risk conclusion ................................................... 32 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 32 
5. 
STUDY DESIGN .................................................................................................... 35 
5.1. 
Scientific rationale for study design ............................................................. 35 
5.1.1. 
Rationale for the use of placebo .................................................. 36 
5.2. 
Overall design (Amended 11 October 2022) ............................................... 36 
5.3. 
Number of subjects ..................................................................................... 39 
5.4. 
Subject and study completion ..................................................................... 39 
6. 
STUDY POPULATION ........................................................................................... 40 
6.1. 
Inclusion criteria for enrolment .................................................................... 40 
6.2. 
Exclusion criteria for enrolment ................................................................... 41 
6.2.1. 
Medical conditions ....................................................................... 41 
6.2.2. 
Prior/Concomitant therapy ........................................................... 41 
6.2.3. 
Prior/Concurrent clinical study experience ................................... 42 
6.2.4. 
Other exclusions .......................................................................... 42 
6.3. 
Criteria for temporary delay for vaccination ................................................. 42 
6.4. 
Screen and baseline failures ....................................................................... 43 
7. 
TREATMENTS ....................................................................................................... 43 
7.1. 
Treatments administered ............................................................................ 43 
7.2. 
Method of treatment assignment ................................................................. 47 
7.2.1. 
Subject identification .................................................................... 47 
7.2.2. 
Randomization of treatment ......................................................... 47 
7.2.2.1. 
Randomization of supplies .......................................... 47 
7.2.2.2. 
Treatment allocation to the subject ............................. 47 
7.2.2.2.1. 
Study group and treatment 
number allocation ................................... 47 
7.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 48 
7.3. 
Blinding and unblinding ............................................................................... 48 
7.3.1. 
Emergency unblinding ................................................................. 49 
7.4. 
Handling, storage and replacement of study vaccine(s)/product(s) ............. 50 
7.4.1. 
Storage and handling of study vaccines ....................................... 50 
7.4.2. 
Replacement of unusable vaccine doses ..................................... 51 

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7.5. 
Concomitant medication(s)/product(s) and concomitant vaccinations ......... 52 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations (Amended 11 October 2022) ............... 52 
7.5.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 53 
7.6. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 53 
7.7. 
Contraindications to subsequent vaccine(s) administration ......................... 53 
7.8. 
Warnings and precautions .......................................................................... 54 
7.9. 
Treatment after completion of the study ...................................................... 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 54 
8.1. 
General study aspects ................................................................................ 55 
8.2. 
Pre-vaccination procedures ........................................................................ 55 
8.2.1. 
Data Collected from Subjects ....................................................... 55 
8.2.2. 
Collection of demographic data .................................................... 56 
8.2.3. 
Medical history ............................................................................. 56 
8.2.4. 
Physical examination ................................................................... 56 
8.2.5. 
Pregnancy test ............................................................................. 57 
8.2.6. 
Pre-vaccination body temperature ............................................... 57 
8.3. 
Efficacy assessments ................................................................................. 58 
8.3.1. 
Use of specified study materials .................................................. 58 
8.3.2. 
Biological samples ....................................................................... 59 
8.3.2.1. 
Blood sampling for immunogenicity response 
assessments .............................................................. 59 
8.3.2.2. 
Other biological samples ............................................ 60 
8.3.3. 
Laboratory assays ....................................................................... 60 
8.3.4. 
Biological samples evaluation ...................................................... 62 
8.3.4.1. 
Immunological read-outs ............................................ 62 
8.3.5. 
Immunological correlates of protection ......................................... 63 
8.4. 
Safety Assessments ................................................................................... 63 
8.4.1. 
Safety definitions ......................................................................... 63 
8.4.2. 
Follow-up Clinic Visit .................................................................... 63 
8.4.3. 
Safety Follow-up calls (Amended 11 October 2022) .................... 64 
8.4.4. 
Time period and frequency for collecting AE and serious 
adverse event (SAE) information ................................................. 65 
8.4.5. 
Method of detecting AEs and SAEs ............................................. 68 
8.4.6. 
Reporting of serious adverse events, pregnancies, and 
other events ................................................................................. 68 
8.4.6.1. 
Contact information for reporting of serious 
adverse events (SAEs), AESIs, pregnancies 
and study holding rules ............................................... 69 
8.4.6.2. 
Regulatory reporting requirements for SAEs .............. 69 
8.4.7. 
Medical device deficiencies ......................................................... 69 
8.4.7.1. 
Detection, follow-up and prompt reporting of 
medical device deficiency ........................................... 70 
8.4.8. 
Follow-up of AEs and SAEs ......................................................... 71 
8.4.9. 
Treatment of adverse events ....................................................... 71 
8.4.10. 
Subject card ................................................................................. 71 
8.5. 
Genetic Research (Pharmacogenetics) ...................................................... 71 
8.6. 
Study conclusion ......................................................................................... 71 
8.6.1. 
Early Termination ......................................................................... 72 

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8.7. 
Study procedures during special circumstances ......................................... 73 
9. 
DISCONTINUATION CRITERIA ............................................................................. 73 
9.1. 
Discontinuation from the study .................................................................... 73 
9.2. 
Discontinuation of study vaccine(s) ............................................................. 76 
9.3. 
Lost to follow-up.......................................................................................... 77 
10. STATISTICAL CONSIDERATIONS ........................................................................ 77 
10.1. 
Sample size determination .......................................................................... 77 
10.1.1. 
Hypotheses related to primary and secondary objectives ............ 77 
10.1.1.1. Primary Immunogenicity Objectives ............................ 77 
10.1.1.2. Secondary Immunogenicity Objectives ....................... 78 
10.1.2. 
Sample size calculation ............................................................... 80 
10.2. 
Populations for analyses ............................................................................. 83 
10.3. 
Statistical analyses ..................................................................................... 83 
10.3.1. 
Subjects disposition ..................................................................... 83 
10.3.2. 
Demography and baseline characteristics analyses ..................... 83 
10.3.3. 
Immunogenicity analyses ............................................................. 84 
10.3.4. 
Safety analyses ........................................................................... 85 
10.3.5. 
Other analyses ............................................................................ 86 
10.3.6. 
Interim analyses ........................................................................... 86 
10.4. 
Sequence of analyses................................................................................. 86 
11. REFERENCES ....................................................................................................... 87 
12. APPENDICES ........................................................................................................ 89 
12.1. 
Appendix 1: Abbreviations, glossary of terms and trademarks .................... 89 
12.1.1. 
List of abbreviations (Amended 11 October 2022) ....................... 89 
12.1.2. 
Glossary of terms ......................................................................... 91 
12.1.3. 
Trademarks ................................................................................. 96 
12.2. 
Appendix 2: Clinical laboratory assays ........................................................ 96 
12.3. 
Appendix 3: Clinical laboratories ................................................................. 98 
12.4. 
Appendix 4: Study governance considerations ........................................... 98 
12.4.1. 
Regulatory and ethical considerations ......................................... 98 
12.4.1.1. Responsibilities of the Investigator ............................. 99 
12.4.1.2. Protocol Amendments .............................................. 100 
12.4.2. 
Financial disclosure ................................................................... 100 
12.4.3. 
Informed consent process .......................................................... 100 
12.4.4. 
Data protection .......................................................................... 102 
12.4.5. 
Publication policy ....................................................................... 102 
12.4.6. 
Dissemination of clinical study data ........................................... 102 
12.4.7. 
Data quality assurance .............................................................. 103 
12.4.8. 
Source documents ..................................................................... 104 
12.4.9. 
Study and site closure................................................................ 104 
12.5. 
Appendix 5: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting .......................................... 105 
12.5.1. 
Definition of AE .......................................................................... 105 
12.5.1.1. AE Definition............................................................. 105 
12.5.1.2. Events Meeting the AE Definition ............................. 105 
12.5.1.3. Events NOT Meeting the AE Definition ..................... 106 
12.5.2. 
Definition of SAE ........................................................................ 106 
12.5.3. 
Solicited adverse events ............................................................ 107 

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12.5.3.1. Other Solicited Adverse Events ................................ 108 
12.5.4. 
Unsolicited adverse events ........................................................ 108 
12.5.5. 
Adverse events of special interest (AESIs) ................................ 109 
12.5.5.1. Arthritis ..................................................................... 109 
12.5.5.2. Potential immune-mediated diseases ....................... 109 
12.5.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events .......................................................................... 112 
12.5.7. 
Events or outcomes not qualifying as adverse events or 
serious adverse events .............................................................. 112 
12.5.7.1. Pregnancy ................................................................ 112 
12.5.8. 
Detecting and recording adverse events, serious adverse 
events and pregnancies ............................................................. 113 
12.5.8.1. Post-vaccination reminders ...................................... 115 
12.5.8.1.1. Subject Diary Alerts .............................. 115 
12.5.8.2. Time period for detecting and recording 
adverse events, serious adverse events and 
pregnancies .............................................................. 116 
12.5.8.3. Evaluation of adverse events and serious 
adverse events ......................................................... 117 
12.5.8.3.1. Active questioning to detect 
adverse events and serious 
adverse events ..................................... 117 
12.5.8.3.2. Assessment of adverse events ............. 117 
12.5.8.3.3. Medically attended visits ....................... 121 
12.5.8.4. Recording of AEs related to COVID-19 ..................... 121 
12.5.9. 
Reporting of serious adverse events, pregnancies, and 
other events ............................................................................... 121 
12.5.9.1. Prompt reporting of serious adverse events, 
pregnancies, and other events to GSK 
Biologicals ................................................................ 121 
12.5.9.2. SAEs requiring expedited reporting to GSK 
Biologicals ................................................................ 122 
12.5.9.3. Back-up system in case the electronic 
reporting system does not work ................................ 122 
12.5.9.4. Completion and transmission of pregnancy 
reports to GSK Biologicals ........................................ 122 
12.5.9.5. Reporting of AESI’s to GSK Biologicals .................... 122 
12.5.10. Updating of SAE, pregnancy, and AESI information after 
removal of write access to the subject’s eCRF ........................... 123 
12.5.11. Follow-up of adverse events, serious adverse events, and 
pregnancies ............................................................................... 123 
12.5.11.1. Follow-up of adverse events and serious 
adverse events ......................................................... 123 
12.5.11.1.1. Follow-up during the study .................... 123 
12.5.11.1.2. Follow-up after the subject is 
discharged from the study .................... 123 
12.5.11.2. Follow-up of pregnancies.......................................... 124 
12.6. 
Appendix 6: Contraceptive guidance and collection of pregnancy 
information ................................................................................................ 125 
12.6.1. 
Definitions .................................................................................. 125 
12.6.1.1. Woman of Childbearing Potential (WOCBP) ............. 125 

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12.6.1.1.1. Women in the following categories 
are not considered WOCBP .................. 125 
12.6.2. 
Contraception guidance ............................................................. 126 
12.6.3. 
Collection of pregnancy information ........................................... 127 
12.6.3.1. Female Subjects who become pregnant ................... 127 
12.7. 
Appendix 7: Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and unanticipated 
SADE (USADE) ........................................................................................ 127 
12.7.1. 
Definition of medical device AE and adverse device effect 
(ADE) ......................................................................................... 127 
12.7.2. 
Definition of medical device SAE, SADE and USADE ................ 128 
12.7.3. 
Recording and reporting of medical device AE, ADEs, 
SADEs and USADE ................................................................... 128 
12.8. 
Appendix 8: Protocol Amendment History ................................................. 129 
 

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LIST OF TABLES 
PAGE 
Table 1 
Document history ..................................................................................... 8 
Table 2 
List of main changes in the protocol and their rationale ............................ 8 
Table 3 
Schedule of Activities (Amended 11 October 2022) ............................... 24 
Table 4 
Intervals between study visits (Amended 11 October 2022) ................... 27 
Table 5 
Intervals between study visits and safety follow-up calls 
(Amended 11 October 2022) .................................................................. 27 
Table 6 
Study objectives and endpoints (Amended 11 October 2022) ................ 32 
Table 7 
Study groups, treatment and epochs foreseen in the study .................... 38 
Table 8 
Overview of study design: Vaccination and Blood Draw Schedule ......... 38 
Table 9 
Treatments administered ........................................................................ 44 
Table 10 
Administration and Laterality .................................................................. 45 
Table 11 
Contact information for emergency unblinding ....................................... 49 
Table 12 
Biological samples ................................................................................. 60 
Table 13 
Humoral Immunity (Antibody determination) ........................................... 61 
Table 14 
Immunological read-outs (Amended 11 October 2022) .......................... 62 
Table 15 
Reporting periods for collecting safety information in subjects 
who have crossed D271 (Amended 11 October 2022) ........................... 66 
Table 16 
Reporting periods for collecting safety information in subjects 
who have not reached D271 (Amended 11 October 2022) ..................... 67 
Table 17 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ................................................. 68 
Table 18 
Contact information for reporting of serious adverse events 
(SAEs), AESIs, and pregnancies ............................................................ 69 
Table 19 
Observed SDs with the Upper Limits of the Two-Sided 80% CI 
for the Logarithmically (base of 10) Transformed hSBA Titers ................ 81 
Table 20 
Power (in %) for the Individual and for the Overall MenB Strains ........... 81 
Table 21 
Power (in %) for the Individual Serogroups and for the Overall 
MenACWY Serogroups .......................................................................... 82 

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Table 22 
Power (in %) for the Individual and for the Overall MenACWY 
Serogroups Using ELISA GMCs ............................................................ 82 
Table 23 
Overall Power (in %) for the 3 Hypothesis Combined ............................. 83 
Table 24 
GSK Biologicals laboratories .................................................................. 98 
Table 25 
Outsourced laboratories (potential) ........................................................ 98 
Table 26 
Solicited local adverse events* ............................................................. 107 
Table 27 
Solicited systemic adverse events ........................................................ 108 
Table 28 
List of potential immune-mediated diseases (pIMDs) ........................... 110 
Table 29 
Intensity scales for solicited symptoms in adults and children of 6 
years of age or more ............................................................................ 118 
Table 30 
Highly Effective Contraceptive Methods ............................................... 126 
 

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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview (Amended 11 October 2022) .............................. 36 
 

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1. 
SYNOPSIS 
Indication: 
Active immunization against invasive disease caused by N. 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: 
• 
Rationale for the study 
Data from clinical studies conducted in several age groups show that rMenB+OMV NZ 
and MenACWY are well tolerated and immunogenic when administered with a number 
of other vaccine antigens, including Diphtheria, Tetanus and acellular Pertussis (DTPa). 
Data from an infant study showed that both rMenB+OMV NZ and MenACWY were well 
tolerated and immunogenic when administered concomitantly in healthy infants. No data 
is currently available on the concomitant use of rMenB+OMV NZ and MenACWY in 
adolescents. 
The purpose of this clinical study is to evaluate the immunogenicity, the safety, and the 
tolerability of rMenB+OMV NZ and MenACWY vaccines when concomitantly 
administered to healthy subjects 16-18 years of age. 
• 
Rationale for the study design 
The purpose of this study is to assess the safety and demonstrate the non-inferiority of the 
antibody responses of rMenB+OMV NZ and MenACWY vaccines when concomitantly 
administered compared to either alone in healthy subjects 16-18 years of age. The 
subjects will be randomized to one of the 3 parallel treatment arms in a 1:1:1 ratio to 
receive the concomitant rMenB+OMV NZ and MenACWY vaccines (Group 
MenB+MenACWY) or rMenB+OMV NZ vaccine + placebo (Group MenB) or 
MenACWY vaccine+ placebo (Group MenACWY) in 2 different arms. 
• 
Rationale for the use of placebo 
In order to ensure proper blinding, placebo will be administered to subjects in all groups 
in a staggered fashion. Subjects in Group MenB and Group MenACWY will be 
administered Placebo at Visit 1 and for subjects in Group MenB+MenACWY, placebo 
will be administered at Visit 4 (study Day 91). 

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Objectives and Endpoints (Amended 11 October 2022): 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of rMenB+OMV 
NZ and MenACWY, when administered 
concomitantly or alone, in healthy subjects 16-18 
years of age. 
• 
The frequencies and percentages of subjects with 
solicited local (i.e., injection site pain, erythema, 
swelling, induration) and systemic (i.e., fever 
[temperature ≥ 38.0°C/100.4°F], nausea, fatigue, 
myalgia, arthralgia, headache) adverse events 
(AEs) during the 7 days (including the day of 
vaccination) following the first (Visit 1, Day 1/Month 
0), the second (Visit 3, Month 2) and the third (Visit 
4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
any unsolicited AEs (including all SAEs), AEs 
leading to withdrawal and medically attended AEs 
during the 30 days (including the day of 
vaccination) following the first (Visit 1, Day 1/Month 
0), the second (Visit 3, Month 2) and the third (Visit 
4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
SAEs, AEs leading to withdrawal, and medically 
attended AEs, throughout the study period (Day 
1/Month 0 to Month 9). 
• 
The frequencies and percentages of subjects (who 
received rMenB+OMV NZ) with AESI throughout 
the study period (Day 1/Month 0 to Month 9). 
• 
Among subjects who are followed for 12 
months after their last dose: 
o 
The frequencies and percentages of 
subjects with SAEs, AEs leading to 
withdrawal, between SFU 5/Month 9 and 
SFU 7/Month 15.  
o 
The frequencies and percentages of 
subjects (who received rMenB+OMV 
NZ) with AESI between SFU 5/Month 9 
and SFU 7/Month 15. 
 
To demonstrate the non-inferiority of the antibody 
response to rMenB+OMV NZ given concomitantly 
with MenACWY to healthy subjects 16-18 years of 
age compared to rMenB+OMV NZ administered 
alone, as measured by serum bactericidal assay 
using human complement (hSBA) Geometric Mean 
Titers (GMTs) against N. meningitidis serogroup B 
indicator strains M14459 (fHbp), 96217 (NadA), 
NZ98/254 (PorA) and M07-0241084* (NHBA), at one 
month after the second vaccination with rMenB+OMV 
NZ. 
Criterion: Non-inferiority will be demonstrated if for 
each of the four serogroup B test strains, the lower 
limit of the 2-sided 95% confidence interval of the 
between-group ratio of hSBA GMTs (rMenB+OMV 
NZ with MenACWY versus rMenB+OMV NZ alone) is 
>0.5. 
• 
Co-primary endpoints for Group MenB+MenACWY 
and Group MenB are the hSBA GMTs for 
rMenB+OMV NZ against each of the four serogroup 
B test strains (M14459, 96217, NZ98/254 and M07-
0241084) at one month after the second 
vaccination with rMenB+OMV NZ (Visit 4, Month 3). 

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Objectives 
Endpoints 
To demonstrate the non-inferiority of the antibody 
response to MenACWY given concomitantly with 
rMenB+OMV NZ to healthy subjects 16-18 years of 
age compared to MenACWY administered alone, as 
measured by hSBA GMTs against each of the N. 
meningitidis serogroups A, C, W and Y, at one month 
after the (study) vaccination with MenACWY. 
Criterion: Non-inferiority will be demonstrated if for 
each of the four serogroups A, C, W and Y, the lower 
limit of the 2-sided 95% confidence interval of the 
between-group ratio of hSBA GMTs (rMenB+OMV 
NZ with MenACWY versus MenACWY alone) is >0.5. 
• 
Co-primary endpoints for Group MenB+MenACWY 
and Group MenACWY are the hSBA GMTs against 
each of the four serogroups A, C, W and Y with 
MenACWY at one month after the study vaccination 
of MenACWY (Visit 2, Month 1). 
Secondary 
To assess the non-inferiority of the responses to 
MenACWY when given concomitantly with 
rMenB+OMV NZ to healthy subjects 16-18 years of 
age compared to MenACWY administered alone as 
measured by Enzyme-Linked Immunosorbent Assay 
(ELISA) Geometric Mean Concentrations (GMCs) 
against each of the serogroups A, C, W and Y, at one 
month after the (study) vaccination with MenACWY. 
Criterion: Non-inferiority will be demonstrated if for 
each of the four A, C, W and Y strains, the lower limit 
of the 2-sided 95% confidence interval of the 
between-group ratio of ELISA GMCs (MenACWY 
with rMenB+OMV NZ versus MenACWY alone) is 
>0.5. 
Immune response to MenACWY 
The immune response to MenACWY when administered 
with/without rMenB+OMV NZ at one month after the first 
vaccination (Visit 2, Month 1; Groups MenB+MenACWY 
and MenACWY) will be assessed for the serogroups A, 
C, W and Y as ELISA GMCs. 
To assess the immune response to rMenB+OMV NZ 
in healthy subjects 16-18 years of age against N. 
meningitidis serogroup B test strains M14459 (fHbp), 
96217 (NadA), NZ98/254 (PorA) and M07-0241084* 
(NHBA), at one month after the first and the second 
vaccination with rMenB+OMV NZ. 
Immune response to rMenB+OMV NZ 
The immune response to rMenB+OMV NZ when 
administered with/without MenACWY will be evaluated by 
measuring bactericidal activity against N. meningitidis 
serogroup B test strains M14459, 96217, NZ98/254 and 
M07-0241084 in both MenB+MenACWY and MenB 
Groups as following: 
• 
GMTs at one month after first and second 
vaccination with rMenB+OMV NZ and Geometric 
Mean Ratio (GMRs) at one month after the first 
(Visit 2, Month 1) and the second (Visit 4, Month 3) 
rMenB+OMV NZ vaccination compared to the 
baseline at Visit 1, Day 1/Month 0. 
• 
The percentage of subjects with hSBA titers ≥ 
Lower Limit of Quantitation (LLOQ) for each and all 
serogroup B test strains, one month after the first 
(Visit 2, Month 1) and second (Visit 4, Month 3) 
vaccination. 
• 
The percentage of subjects with fourfold increase in 
hSBA titers relative to baseline (Visit 1, Day 
1/Month 0) is defined as: 
− 
For a pre-vaccination titer < limit of detection 
(LOD), a post-vaccination titer (Visit 2, Month 
1 and Visit 4, Month 3) of ≥ fourfold the LOD 
or ≥ LLOQ, whichever is greater, 
− 
For a pre-vaccination titer ≥LOD but <LLOQ, 
a post vaccination titer (Visit 2, Month 1 and 
Visit 4, Month 3) of at least fourfold the LLOQ,  

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Objectives 
Endpoints 
− 
For a pre-vaccination titer ≥ LLOQ, a post 
vaccination titer (Visit 2, Month 1 and Visit 4, 
Month 3) of at least fourfold the pre-
vaccination titer (for Groups 
MenB+MenACWY and MenB). 
• 
The ratio of GMTs (rMenB+OMV NZ when 
administered with MenACWY [Group 
MenB+MenACWY] versus rMenB+OMV NZ when 
administered alone [Group MenB]), one month after 
the first vaccination (Visit 2, Month 1). 
To assess the immune response to MenACWY in 
healthy subjects 16-18 years of age against each of 
the serogroups A, C, W and Y, at one month after the 
(study) vaccination with MenACWY. 
Immune response to MenACWY 
The immune response to MenACWY when administered 
with/without rMenB+OMV NZ at baseline (i.e. pre-
vaccination, Visit 1, Day 1/Month 0) and at one month 
after the first vaccination (Visit 2, Month 1; Groups 
MenB+MenACWY and MenACWY) will be assessed for 
the serogroups A, C, W and Y as: 
• 
The percentage of subjects with hSBA titers 
≥LLOQ, for each serogroup. 
• 
GMRs at one month after first vaccination 
compared to baseline 
• 
The percentage of subjects with fourfold increase in 
hSBA titers relative to baseline (Visit 1, Day 
1/Month 0) is defined as: 
− 
For a pre-vaccination titer < LOD, a post-
vaccination titer (Visit 2, Month 1) of ≥ 
fourfold the LOD or ≥ LLOQ, whichever is 
greater, 
− 
For a pre-vaccination titer ≥LOD but <LLOQ, 
a post vaccination titer (Visit 2, Month 1) of at 
least fourfold the LLOQ,  
− 
For a pre-vaccination titer ≥ LLOQ, a post 
vaccination titer (Visit 2, Month 1) of at least 
fourfold the pre-vaccination titer (for Groups 
MenB+MenACWY and MenACWY). 
*The NHBA indicator strain M07-0241084 may be subject to change during the study before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
CCI

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The study will be deemed successful if both: 
1. the non-inferiority of rMenB+OMV NZ when given concomitantly with MenACWY 
versus rMenB+OMV NZ alone and 
2. the non-inferiority of MenACWY when given concomitantly with rMenB+OMV NZ 
versus MenACWY alone are demonstrated. 

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Overall Design (Amended 11 October 2022): 
  
Approximately 945 subjects will be screened to achieve 750 evaluable subjects for an 
estimated total of 250 evaluable subjects per treatment group. Withdrawals will not be 
replaced. 
• 
Experimental design: Phase IIIB, observer-blind, randomized, controlled, multi-
centric, study with 3 parallel groups. 
• 
Study groups: 
− 
Group MenB+MenACWY: rMenB+OMV NZ given concomitantly with 
MenACWY at study Day 1; rMenB+OMV NZ at study Day 61; Placebo at 
study Day 91. 
− 
Group MenB: rMenB+OMV NZ given concomitantly with Placebo at study 
Day 1 and rMenB+OMV NZ at study Day 61; MenACWY at study Day 91. 
− 
Group MenACWY: MenACWY given concomitantly with Placebo at study 
Day 1; rMenB+OMV NZ at study Day 61 and at study Day 91. 
• 
Duration of the study: 
− 
Epoch 001: Primary starting at Visit 1 (Day 1) and ending at Visit 4 (Day 91) 
− 
Epoch 002: Safety follow-up period starting at Visit 4 (Day 91) and ending at 
Study termination-call (Day 451 [Month 15]) or (Day 271 [Month 9]) for 
subjects who have not reached Day 271 at the time this amendment takes 
effect 

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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Table 3 
Schedule of Activities (Amended 11 October 2022) 
Age (years) 
16-18 at study start 
Notes 
Epoch 
Epoch 001 
Epoch 002 
Type of contact¥ 
Visit 1 SFU 1 Visit 2  Visit 3 SFU 2 Visit 4 SFU 3 Visit 5 SFU 4 SFU 
5¥ 
SFU 6 SFU 7 
 
Timepoint (s) [refer to Table 4 
and Table 5 for visit windows] 
Day 1 Day 15 Day 31 Day 61 Day 75 Day 91 
Day 
105 
Day 
121 
Day 
181 
Day 
271 
Day 
361 
Day 
451 
 
Sampling timepoints 
Pre-
Vacc I 
  
Post-
Vacc I 
 
 
Pre- 
Vacc III 
 
 
 
 
 
 
 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Activities that can be performed at a separate 
visit before Visit 1 (approximately 2 weeks 
before the Visit 1). AEs / SAEs related to 
study participation or to a concurrent GSK 
medication/vaccine should also be recorded 
starting from this separate visit. 
Inclusion/exclusion criteria should be re-
checked prior to vaccination at visit 1. 
See Section 12.4.3 for details. 
Check inclusion/exclusion 
criteria 
● 
 
 
● 
 
● 
 
 
 
 
 
 
See Section 6.1 and 6.2 for Inclusion and 
Exclusion criteria. 
Collect demographic data 
● 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.2 for more information. 
Medical history 
● 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.3 for more information. 
Medical history-directed 
Physical examination 
O 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.3 and 8.2.4 for more 
information. 
Symptom-directed physical 
examination 
 
 
 
O 
 
O 
 
 
 
 
 
 
See Section 8.2.4 for more information. 
Urine pregnancy test (pre-
vaccination) 
● 
 
 
● 
 
● 
 
 
 
 
 
 
Only for women of childbearing potential. 
A pregnancy test is mandatory on Visit 1, Visit 
3, and Visit 4 even if performed during a prior 
separate visit 
See Section 8.2.5 for more information. 

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Age (years) 
16-18 at study start 
Notes 
Epoch 
Epoch 001 
Epoch 002 
Type of contact¥ 
Visit 1 SFU 1 Visit 2  Visit 3 SFU 2 Visit 4 SFU 3 Visit 5 SFU 4 SFU 
5¥ 
SFU 6 SFU 7 
 
Timepoint (s) [refer to Table 4 
and Table 5 for visit windows] 
Day 1 Day 15 Day 31 Day 61 Day 75 Day 91 
Day 
105 
Day 
121 
Day 
181 
Day 
271 
Day 
361 
Day 
451 
 
Sampling timepoints 
Pre-
Vacc I 
  
Post-
Vacc I 
 
 
Pre- 
Vacc III 
 
 
 
 
 
 
 
Check contraindications and 
warnings and precautions to 
vaccination 
● 
 
 
● 
 
● 
 
 
 
 
 
 
See Section 7.7 and 7.8 for more information. 
Pre-vaccination body 
temperature 
● 
 
 
● 
 
● 
 
 
 
 
 
 
See Section 8.2.6 for more information. 
Vaccines 
 
 
 
 
 
 
Study group and treatment 
number allocation 
O 
 
 
 
 
 
 
 
 
 
 
 
See Section 7.2.2.2.1 for more information. 
Treatment number allocation for 
subsequent doses 
 
 
 
O 
 
O 
 
 
 
 
 
 
See Section 7.2.2.2.2 for more information. 
Recording of administered 
treatment number 
● 
 
 
● 
 
● 
 
 
 
 
 
 
See Section 7.2.2 for more information. 
Vaccines administration 
● 
 
 
● 
 
● 
 
 
 
 
 
 
See Section 7.1 for more information. 
Laboratory Assays 
 
 
 
 
 
 
Blood sampling for antibody 
determination (20 mL, at each 
visit) 
● 
 
● 
 
 
● 
 
 
 
 
 
 
Blood sample collection on Visit 1 and Visit 4 
will be performed before vaccine 
administration. 
See Section 8.3.4.1 for more information. 
Safety assessments 
 
 
 
 
 
 
Record any concomitant 
medications/vaccinations¥ 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 7.5 for more information. 
Record any intercurrent medical 
conditions¥ 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 7.6 for more information. 
Distribution of eDiary 
O 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eDiary 
 
 
O 
 
 
O 
 
O 
 
 
 
 
 

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Age (years) 
16-18 at study start 
Notes 
Epoch 
Epoch 001 
Epoch 002 
Type of contact¥ 
Visit 1 SFU 1 Visit 2  Visit 3 SFU 2 Visit 4 SFU 3 Visit 5 SFU 4 SFU 
5¥ 
SFU 6 SFU 7 
 
Timepoint (s) [refer to Table 4 
and Table 5 for visit windows] 
Day 1 Day 15 Day 31 Day 61 Day 75 Day 91 
Day 
105 
Day 
121 
Day 
181 
Day 
271 
Day 
361 
Day 
451 
 
Sampling timepoints 
Pre-
Vacc I 
  
Post-
Vacc I 
 
 
Pre- 
Vacc III 
 
 
 
 
 
 
 
Return of eDiary 
 
 
 
 
 
 
 
O 
 
 
 
 
 
30 minutes post-injection 
assessment 
● 
 
 
● 
 
● 
 
 
 
 
 
 
 
Recording of solicited adverse 
events (Days 1–7 post 
vaccination) in eDiary 
O 
 
 
O 
 
O 
 
 
 
 
 
 
 
Recording of unsolicited 
adverse events within 30 days 
post-vaccination 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
Recording of unsolicited AEs 
leading to vaccine/study 
withdrawal, medically attended 
AEs, SAEs, pregnancies and 
AESIs*¥ 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 12.5.8 for more information. 
Recording of SAEs related to 
study participation, or to a 
concurrent GSK 
medication/vaccine**¥ 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
  
Study Conclusion¥ 
 
 
 
 
 
 
 
 
 
● 
 
● 
See Section 5.4 for more information. 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
*COVID-19 infection-related AEs and SAEs should also be recorded on a separate eCRF page. 
**Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins from the time a parent(s)/LAR(s) or participant signs the consent form to the end 
of the study  
¥ Safety follow up and contact will terminate at SFU 5 for subjects who have not reached SFU 5 at the time this amendment takes effect. Please note that for these 
subjects, the termination call would be performed at SFU 5.  
 

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Whenever possible, the investigator should arrange study visits within the intervals 
described in Table 4. For safety follow-up calls, the windows in Table 5 will apply. 
Table 4 
Intervals between study visits (Amended 11 October 2022) 
Interval 
Length of interval 
Allowed interval 
Visit 1 → Visit 2 
30 days  
23 - 58 days  
Visit 1 → Visit 3 
60 days 
53 - 88 days 
Visit 3 → Visit 4 
30 days 
23 - 58 days 
Visit 4 → Visit 5 
30 days 
23 - 58 days 
Table 5 
Intervals between study visits and safety follow-up calls (Amended 
11 October 2022) 
Interval 
Length of interval 
Allowed interval 
Visit 1 → SFU 1 
14 days  
11 - 17 days  
Visit 3 → SFU 2 
14 days 
11 - 17 days 
Visit 4 → SFU 3 
14 days 
11 - 17 days 
Visit 4 → SFU 4 
90 days 
83 - 111 days 
Visit 4 → SFU 5* 
180 days 
173 - 201 days 
Visit 4 → SFU 6 
270 days 
263 - 291 days 
Visit 4 → SFU 7 
360 days 
353 – 381 days 
*Safety follow up will terminate at SFU 5 for subjects who have not reached SFU 5 at the time this amendment 
takes effect. 
3. 
INTRODUCTION 
3.1. 
Study rationale 
Data from clinical studies conducted in several age groups show that rMenB+OMV NZ 
and MenACWY are well tolerated and immunogenic when administered with a number 
of other vaccine antigens, including DTPa. Data from an infant study showed that both 
rMenB+OMV NZ and MenACWY were well tolerated and immunogenic when 
administered concomitantly in healthy infants (aged 3 to 13 months). No data is currently 
available on the concomitant use of rMenB+OMV NZ and MenACWY in adolescents. 
The purpose of this clinical study is to evaluate the immunogenicity, the safety and the 
tolerability of rMenB+OMV NZ and MenACWY vaccines when concomitantly 
administered to healthy subjects 16-18 years of age. 
3.2. 
Background 
Invasive meningococcal disease (IMD) occurs when the normally asymptomatically 
carried bacterium Neisseria meningitidis (N. meningitidis) enters the bloodstream, 
multiplies and causes sepsis. If the bacteria cross the blood–brain barrier, meningitis 
occurs [Khatami, 2010]. 
IMD 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 

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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 IMD, 
approximately 9% of European patients die, with case-fatality rates generally increasing 
with age [ECDC, 2016]. In the 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 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 disease in 
industrialized nations, showing potential for broader control with A, C, W and Y 
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, 2015]. In Europe, the incidence of 
disease due to serogroup B is particularly high in Ireland, the United Kingdom, 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 to 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 3 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]. 
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 serogroup B is poorly immunogenic in humans, 
possibly due to antigenic 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 

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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’s 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]. 
 
 
 
 
 
 
 
On 23 January 2015, the US Food and Drug Administration 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. 
Data from clinical studies conducted in several age groups show that both rMenB+OMV 
NZ and MenACWY are well tolerated and immunogenic when administered with a 
number of other vaccine antigens, including DTPa. Data from an infant study showed 
that both rMenB+OMV NZ and MenACWY were well tolerated and immunogenic when 
administered concomitantly in healthy infants [Clinicaltrials.gov]. However, no data is 
currently available on the concomitant use of rMenB+OMV NZ and MenACWY in 
adolescents. 
Please refer to the current Investigator Brochure (IB) for information regarding the pre-
clinical and clinical studies and the epidemiological information of Bexsero 
(rMenB+OMV NZ). 
3.3. 
Benefit/Risk assessment 
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of Bexsero (rMenB+OMV NZ) and Menveo (MenACWY). 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
CCI

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3.3.1. 
Risk assessment 
Important Potential/Identified Risk 
Data/Rationale for Risk  
Mitigation Strategy 
Investigational vaccine: rMenB+OMV NZ (Bexsero) 
 
 
 
Important potential risk: Guillain-Barre 
Syndrome (GBS) 
GBS has been observed with other vaccines. No cases have been 
identified in 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) and SAE 
collection (see Section 12.5.5.2). 
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 can occur is mentioned in the ICF. ADEM will 
be monitored through the pIMD and SAE collection (see 
Section 12.5.5.2). 
Important potential risk: Anaphylaxis and 
anaphylactic shock 
No cases of anaphylaxis to be related to Bexsero have been 
reported in the Bexsero clinical development program. However, 
one case of anaphylaxis within 30 minutes following vaccination was 
reported in a third party expanded access program (V72_70TP).  
Allergic reaction (including anaphylactic reaction) is listed in the 
Bexsero US PI. 
Anaphylaxis following the administration of Bexsero 
constitutes a contraindication (see section 7.7). 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 8.2.1). 
Hypersensitivity, including allergy to any component of 
vaccines, are exclusion criteria in this study (see Section 
6.2). 
Important potential risk: 
Arthritis 
This potential risk is based on a signal observed for Bexsero. 
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 
Bexsero and 6 spontaneous reports considered to have a possible 
causal relationship have been observed. 
Arthritis will be monitored through the AESI collection (see 
Section 12.5.5.1). 

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Important Potential/Identified Risk 
Data/Rationale for Risk  
Mitigation Strategy 
Investigational vaccine: MenACWY (Menveo) 
Important Identified risk: 
Reconstitution errors 
Cases describing medication errors due to administration of the 
MenCWY conjugate liquid component only without reconstitution 
with the MenA conjugate lyophilized component, or due to 
administration of the MenA conjugate lyophilized component only 
after reconstitution with a different solvent, have been reported 
during the MenACWY clinical development program. 
In several sections of the protocol (e.g., Section 7.1. 
“Description of study vaccines”) it is clarified that the 2 
vaccine components have to be reconstituted before 
vaccine injection. 
Important potential risk: 
GBS 
GBS has been observed with other vaccines. No cases have been 
reported during the MenACWY clinical development program. 
The potential risk of events of possible autoimmune 
aetiology that might occur is mentioned in ICF. GBS will be 
monitored through the pIMDs and SAE collection (see 
Section 12.5.5.2). 
Important potential risk: 
ADEM 
ADEM has been observed with other vaccines. Two serious cases 
from clinical trials were retrieved from the GSK’s global safety 
database for MenACWY. None of them has provided sufficient 
evidence of a causal association between ADEM and MenACWY. 
The potential risk of events of possible autoimmune 
aetiology that can occur is mentioned in the ICF. ADEM will 
be monitored through the pIMD and SAE collection (see 
Section 12.5.5.2). 
Important potential risk: 
Thrombocytopenia 
Immune thrombocytopenic purpura has been reported in association 
with several licensed vaccines. One serious case related to 
MenACWY has been reported during the clinical development 
program. This case didn’t provide sufficient evidence of a causal 
association between thrombocytopenia and MenACWY vaccine. 
Immune thrombocytopenic purpura will be monitored 
through SAE collection (see Section 12.5.5.2). 
Important potential risk: 
Facial paresis 
Facial paresis was recognized as an important potential risk 
following the results of a sponsored observational study 
(V59_34OB) which found an imbalance of cases of facial paresis 
following vaccination with MenACWY, mainly when administered 
concomitantly with other vaccines. No cases of facial paresis were 
reported from interventional clinical trials. 
Paralysis of the face is mentioned in the list of side effects 
in the ICF. Facial paresis will be monitored through SAE 
collection. 
Study Procedures 
Risk of blood sampling 
Blood sampling is associated with a risk of syncope, dizziness, 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 feeling faint, 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 will not be harmful to the health of the subject. 
 

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3.3.2. 
Benefit assessment 
• 
Receiving GSK’s meningococcal vaccines Bexsero and Menveo during the study 
duration may protect against meningococcal IMDs caused by N. meningitidis 
serogroups A, B, C, W, Y.  
• 
Medical monitoring and evaluations/assessments associated with this study. 
3.3.3. 
Overall Benefit: Risk conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks identified in association with rMenB+OMV NZ 
and MenACWY are justified by the potential benefits (prevention) that may be afforded 
to subjects receiving rMenB+OMV NZ and MenACWY. 
4. 
OBJECTIVE(S) AND ENDPOINT(S) 
Table 6 
Study objectives and endpoints (Amended 11 October 2022)  
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of rMenB+OMV NZ and 
MenACWY, when administered concomitantly or alone, in 
healthy subjects 16-18 years of age. 
• 
The frequencies and percentages of 
subjects with solicited local (i.e., 
injection site pain, erythema, swelling, 
induration) and systemic (i.e., fever 
[temperature ≥ 38.0°C/100.4°F], 
nausea, fatigue, myalgia, arthralgia, 
headache) adverse events (AEs) during 
the 7 days (including the day of 
vaccination) following the first (Visit 1, 
Day 1/Month 0), the second (Visit 3, 
Month 2) and the third (Visit 4, Month 3) 
vaccination for all groups. 
• 
The frequencies and percentages of 
subjects with any unsolicited AEs 
(including all SAEs), AEs leading to 
withdrawal and medically attended AEs 
during the 30 days (including the day of 
vaccination) following the first (Visit 1, 
Day 1/Month 0), the second (Visit 3, 
Month 2) and the third (Visit 4, Month 3) 
vaccination for all groups.  
• 
The frequencies and percentages of 
subjects with SAEs, AEs leading to 
withdrawal, and medically attended 
AEs, throughout the study period (Day 
1/Month 0 to Month 9). 
• 
The frequencies and percentages of 
subjects (who received rMenB+OMV 
NZ) with AESI throughout the study 
period (Day 1/Month 0 to Month 9).  
• 
Among subjects who are followed for 
12 months after their last dose: 
o 
The frequencies and 
percentages of subjects with 

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Objectives 
Endpoints 
SAEs, AEs leading to 
withdrawal, between SFU 5 
(Month 9) and SFU 7 (Month 15).  
The frequencies and 
percentages of subjects 
(who received rMenB+OMV 
NZ) with AESI between SFU 
5 (Month 9) and SFU 7 
(Month 15). 
To demonstrate the non-inferiority of the antibody response to 
rMenB+OMV NZ given concomitantly with MenACWY to 
healthy subjects 16-18 years of age compared to rMenB+OMV 
NZ administered alone, as measured by serum bactericidal 
assay using human complement (hSBA) Geometric Mean 
Titers (GMTs) against N. meningitidis serogroup B indicator 
strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA) and 
M07-0241084* (NHBA), at one month after the second 
vaccination with rMenB+OMV NZ.  
Criterion: Non-inferiority will be demonstrated if for each of the 
four serogroup B test strains, the lower limit of the 2-sided 
95% confidence interval of the between-group ratio of hSBA 
GMTs (rMenB+OMV NZ with MenACWY versus rMenB+OMV 
NZ alone) is >0.5.  
Co-primary endpoints for Group 
MenB+MenACWY and Group MenB are the 
hSBA GMTs for rMenB+OMV NZ against each of 
the four serogroup B test strains (M14459, 96217, 
NZ98/254 and M07-0241084) at one month after 
the second vaccination with rMenB+OMV NZ 
(Visit 4, Month 3). 
To demonstrate the non-inferiority of the antibody response to 
MenACWY given concomitantly with rMenB+OMV NZ to 
healthy subjects 16-18 years of age compared to MenACWY 
administered alone, as measured by hSBA GMTs against 
each of the N.  meningitidis serogroups A, C, W and Y, at one 
month after the (study) vaccination with MenACWY.  
Criterion: Non-inferiority will be demonstrated if for each of the 
four serogroups A, C, W and Y, the lower limit of the 2-sided 
95% confidence interval of the between-group ratio of hSBA 
GMTs (rMenB+OMV NZ with MenACWY versus MenACWY 
alone) is >0.5.  
Co-primary endpoints for Group 
MenB+MenACWY and Group MenACWY are the 
hSBA GMTs against each of the four serogroups 
A, C, W and Y with MenACWY at one month after 
the study vaccination of MenACWY (Visit 2, 
Month 1).  
Secondary 
To assess the non-inferiority of the responses to MenACWY 
when given concomitantly with rMenB+OMV NZ to healthy 
subjects 16-18 years of age compared to MenACWY 
administered alone as measured by Enzyme-Linked 
Immunosorbent Assay (ELISA) Geometric Mean 
Concentration (GMCs) against each of the serogroups A, C, 
W and Y, at one month after the (study) vaccination with 
MenACWY.  
Criterion: Non-inferiority will be demonstrated if for each of the 
four A, C, W and Y strains, the lower limit of the 2-sided 95% 
confidence interval of the between-group ratio of ELISA GMCs 
(MenACWY with rMenB+OMV NZ versus MenACWY alone) is 
>0.5.  
Immune response to MenACWY 
The immune response to MenACWY when 
administered with/without rMenB+OMV NZ one 
month after the first vaccination (Visit 2, Month 1, 
Groups MenB+MenACWY and MenACWY) will 
be assessed for the serogroups A, C, W and Y as 
ELISA GMCs.  
To assess the immune response to rMenB+OMV NZ in 
healthy subjects 16-18 years of age against  
N. meningitidis serogroup B test strains M14459 (fHbp), 96217 
(NadA), NZ98/254 (PorA) and M07-0241084 (NHBA), at one 
month after the first and the second vaccination with 
rMenB+OMV NZ.  
Immune response to rMenB+OMV NZ 
The immune response to rMenB+OMV NZ when 
administered with/without MenACWY will be 
evaluated by measuring bactericidal activity 
against N.  meningitidis serogroup B test strains 
M14459, 96217, NZ98/254 and M07-0241084 in 
both MenB+MenACWY and MenB Groups as 
following: 

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Objectives 
Endpoints 
• 
GMTs at one month after first (Visit 2, 
Month 1) and second (Visit 4, Month 3) 
vaccination with rMenB+OMV NZ and 
Geometric Mean Ratio (GMRs) at one 
month after the first and the second 
rMenB+OMV NZ vaccination compared to 
the baseline at Visit 1, Day 1/Month 0.  
• 
The percentage of subjects with hSBA titers 
≥ Lower Limit of Quantitation (LLOQ) for 
each and all serogroup B test strains, one 
month after the first (Visit 2, Month 1) and 
second (Visit 4, Month 3) vaccination. 
• 
The percentage of subjects with fourfold 
increase in hSBA titers relative to baseline 
(Visit 1, Day 1/Month 0) defined as: 
− 
For a pre-vaccination titer < limit of 
detection (LOD), a post-vaccination 
titer (Visit 2, Month 1 and Visit 4, 
Month 3) of ≥ fourfold the LOD or ≥ 
LLOQ, whichever is greater, 
− 
For a pre-vaccination titer ≥LOD but 
<LLOQ, a post vaccination titer (Visit 
2, Month 1 and Visit 4, Month 3) of at 
least fourfold the LLOQ,  
− 
For a pre-vaccination titer ≥ LLOQ, a 
post vaccination titer (Visit 2, Month 1 
and Visit 4, Month 3) of at least 
fourfold the pre-vaccination titer (for 
Groups MenB+MenACWY and 
MenB). 
• 
The ratio of GMTs (rMenB+OMV NZ when 
administered with MenACWY [Group 
MenB+MenACWY] versus rMenB+OMV NZ 
when administered alone [Group MenB]), 
one month after the first vaccination (Visit 2, 
Month 1).  
To assess the immune response to MenACWY in healthy 
subjects 16-18 years of age against each of the serogroups A, 
C, W and Y, at one month after the (study) vaccination with 
MenACWY.  
Immune response to MenACWY 
The immune response to MenACWY when 
administered with/without rMenB+OMV NZ at 
baseline (i.e. pre-vaccination, Visit 1, Day 1/Month 
0) and at one month after the first vaccination 
(Visit 2, Month 1; Groups MenB+MenACWY and 
MenACWY) will be assessed for the serogroups 
A, C, W and Y as:  
• 
The percentage of subjects with hSBA titers 
≥LLOQ, for each serogroup.  
• 
GMRs at one month after first vaccination 
compared to baseline 
• 
The percentage of subjects with fourfold 
increase in hSBA titers relative to baseline 
(Visit 1, Day 1/Month 0) is defined as: 
− 
For a pre-vaccination titer < LOD, a 
post-vaccination titer (Visit 2, Month 
1) of ≥ fourfold the LOD or ≥ LLOQ, 
whichever is greater, 

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Objectives 
Endpoints 
− 
For a pre-vaccination titer ≥LOD but 
<LLOQ, a post vaccination titer (Visit 
2, Month 1) of at least fourfold the 
LLOQ,  
− 
For a pre-vaccination titer ≥ LLOQ, a 
post vaccination titer (Visit 2, Month 1) 
of at least fourfold the pre-vaccination 
titer (for Groups MenB+MenACWY 
and MenACWY). 
*The NHBA indicator strain M07-0241084 may be subject to change during the study, before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
The study will be deemed successful if both: 
1. the non-inferiority of the antibody response to rMenB+OMV NZ when given 
concomitantly with MenACWY versus rMenB+OMV NZ alone and  
2. the non-inferiority of the antibody response to MenACWY when given 
concomitantly with rMenB+OMV NZ versus MenACWY alone are demonstrated. 
5. 
STUDY DESIGN 
5.1. 
Scientific rationale for study design 
The purpose of this study is to demonstrate the non-inferiority of the antibody response in 
terms of Human Serum Bactericidal Assay (hSBA) using human complement GMTs 
against N. meningitidis test strains indicative of serogroups A, C, W, Y, and B, after 
concomitant rMenB+OMV NZ and MenACWY vaccine administration to either vaccine 
alone in healthy subjects 16-18 years of age. 
The selection of the study population is based on ACIP recommendations for use of 
meningococcal vaccines [ACIP, 2011]. Routine administration of a MenACWY vaccine 
for all persons aged 11 through 18 years is recommended. A single dose of vaccine 
should be administered at 11 or 12 years of age, and a booster dose should be 
administered at 16 years of age. Adolescents who receive their first dose at 13 through 15 
years of age should receive a booster dose at 16 through 18 years of age. In Europe, 
Menveo has been approved by EMA for active immunization of children (from 2 years of 
age), adolescents and adults at risk of exposure to N. meningitidis groups A, C, W and Y, 
CCI

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to prevent invasive disease. The use of this vaccine should be in accordance with official 
recommendations. 
To be eligible for this study design, all subjects must have received a previous 
vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY; Menveo 
or Menactra) at least 4 years prior to study start. The available data support 
interchangeability of the 2 licensed meningococcal conjugate vaccines [ACIP, 2013]. 
Consequently, a booster dose of Menveo can be administered, regardless of the vaccine 
brand used for the previous dose. 
Data collected from this study may support the concomitant use of rMenB+OMV NZ and 
MenACWY in healthy subjects 16-18 years of age. 
5.1.1. 
Rationale for the use of placebo 
In order to ensure proper blinding and uniformity, placebo will be administered at Visit 1 
(study Day 1) to subjects in Groups MenB and MenACWY. In addition, at Visit 4 (study 
Day 91), placebo will be administered to subjects in Group MenB+MenACWY while 
subjects in Groups MenB and MenACWY will receive MenACWY and rMenB+OMV 
NZ respectively. 
5.2. 
Overall design (Amended 11 October 2022) 
Figure 1 
Study design overview (Amended 11 October 2022) 
 
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 schedule of activities (Section 2), are essential and 

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required for study conduct.  
• 
Type of study: self-contained 
• 
Experimental design: Phase IIIB, observer-blind, randomized, controlled, multi-
centric, study with 3 parallel groups. 
• 
Duration of the study: 
− 
Epoch 001: Primary starting at Visit 1 (Day 1) and ending at Visit 4 (Day 91) 
− 
Epoch 002: Safety follow-up period starting at Visit 4 (Day 91) and ending at 
Study termination-call (Day 451 [Month 15]) or (Day 271 [Month 9]) for 
subjects who have not reached Day 271 at the time this amendment takes 
effect. 
− 
Primary completion Date (PCD): Study termination-call (Day 451) or (Day 271 
[Month 9]) for subjects who have not reached Day 271 at the time this 
amendment takes effect.  
Refer to section 12.1.2 for the definition of PCD. 
− 
End of Study (EoS): Last subject last visit (LSLV) [last concluding contact on 
Day 451 (Month 15) or Day 271 (Month 9) for subjects who have not reached 
Day 271 at the time this amendment takes effect or Date of the last 
testing/reading released of the Human Biological Samples or imaging data, 
related to primary and secondary endpoints, whichever occurs later. EoS must 
be achieved no later than 8 months after LSLV. EoS cannot be before LSLV. 
Refer to section 12.1.2 for the definition of EoS. 
• 
Study groups: 
− 
Group MenB+MenACWY: rMenB+OMV NZ given concomitantly with 
MenACWY at study Day 1; rMenB+OMV NZ at study Day 61; Placebo at 
study Day 91. 
− 
Group MenB: rMenB+OMV NZ given concomitantly with Placebo at study 
Day 1 and rMenB+OMV NZ at study Day 61; MenACWY at study Day 91. 
− 
Group MenACWY: MenACWY given concomitantly with Placebo at study 
Day 1; rMenB+OMV NZ at study Day 61 and at study Day 91. 

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Table 7 
Study groups, treatment and epochs foreseen in the study 
Study Groups 
Number 
of 
subjects 
Age 
(Min-Max) 
Treatment 
name 
Vaccine/Product 
name 
Epochs 
(Blinding) 
Epoch 001 
(observer-
blind) 
Epoch 002 
(observer-
blind) 
MenB+MenACWY 
315 
16 years – 
18 years 
Bexsero 
rMenB+OMV NZ 
x 
x 
Menveo 
MenACWY (MenA 
lyo+MenCWY liquid 
Placebo 
NaCl 
MenB 
315 
16 years – 
18 years 
Bexsero 
rMenB+OMV NZ 
x 
x 
Menveo 
MenACWY (MenA 
lyo+MenCWY liquid 
Placebo 
NaCl 
MenACWY 
315 
16 years – 
18 years 
Bexsero 
rMenB+OMV NZ 
x 
x 
Menveo 
MenACWY (MenA 
lyo+MenCWY liquid 
Placebo 
NaCl 
Table 8 
Overview of study design: Vaccination and Blood Draw Schedule 
Visits 
Study Day 
Visit 1 
Day 1 
Visit 2 
Day 31 
Visit 3 
Day 61 
Visit 4 
Day 91 
Group 
MenB+MenACWY 
N=315 
Blood Draw 
rMenB+OMV NZ 
MenACWY 
Blood Draw 
rMenB+OMV NZ 
Blood Draw 
Placebo 
Group MenB 
N=315 
Blood Draw 
rMenB+OMV NZ 
Placebo 
Blood Draw  
MenACWY 
Group MenACWY 
N=315 
Blood Draw 
MenACWY 
Placebo 
Blood Draw  
rMenB+OMV NZ 
• 
Control: active control. 
• 
Vaccination schedules: Day 1 (Visit 1), Day 61 (Visit 3) and Day 91 (Visit 4) 
• 
Treatment allocation: Subjects to be randomized in a 1:1:1 ratio at Visit 1 (Day 1) to 
Groups MenB+MenACWY, MenB and MenACWY. 
• 
Blinding: observer-blind. 
• 
Sampling schedule: 
− 
Blood sampling: For all the 3 groups (i.e., Group MenB+MenACWY, Group 
MenB, and Group MenACWY), approximately 20 mL sample of blood will be 
drawn at Visit 1 (Day 1) before the first vaccination, at Visit 2 (Day 31) and at 
Visit 4 before vaccination (Day 91). 
− 
Urine sampling: Urine samples for pregnancy testing will be collected from 
female subjects at Visit 1, Visit 3 and Visit 4 prior to the vaccinations. 
• 
Data collection: Electronic Case Report Form (eCRF). Solicited symptoms will be 
collected using a subject Diary (electronic Diary [eDiary]). 

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5.3. 
Number of subjects  
A maximum of 945 subjects will be randomized such that approximately 750 evaluable 
subjects complete the study.  
Refer to Section 10.1 for a detailed description of the criteria used in the determination of 
sample size. 
Withdrawals will not be replaced. 
5.4. 
Subject and study completion 
A subject is considered to have completed the study if he/she is available for the 
concluding contact (Day 271/451 safety follow-up contact) as described in the protocol. 
Global completion of the study is required in order to provide sufficient subjects as 
defined in Section 10.1 Sample Size Determination. 

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6. 
STUDY POPULATION 
6.1. 
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 who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits) or/and 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 diary cards, return for follow-up visits). 
• 
Previous vaccination with one dose of quadrivalent meningococcal conjugate 
vaccine (MenACWY, Menveo or Menactra) at least 4 years prior to informed 
consent and assent as applicable (according to the subject’s age). 
• 
Written or /witnessed/thumb printed informed consent obtained from the 
subject/parent(s)/LAR(s) of the subject prior to performance of any study specific 
procedure. 
• 
Written informed assent obtained from the subject (if applicable) along with 
informed consent from the subject's parent(s)/LAR(s) prior to performing any study 
specific procedure. 
• 
A male or female between, and including, 16 and 18 years of age at the time of the 
first vaccination. 
• 
Healthy subjects as established by medical history and clinical examination before 
entering into the study. 
• 
Female subjects of non-childbearing potential may be enrolled in the study. Non-
childbearing potential is defined as pre-menarche, current bilateral tubal ligation or 
occlusion, hysterectomy, bilateral ovariectomy or post-menopause (please refer to 
Section 12.6.1 for definitions of menarche and menopause). 
• 
Female subjects of childbearing potential may be enrolled in the study, if the subject 
(refer to Section 12.6.1 for definitions of woman of childbearing potential and 
adequate contraception): 
− 
has practiced adequate contraception for 30 days prior to vaccination, and 
− 
has a negative pregnancy test on the day of vaccination, and 
− 
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Prior to receipt of second and third study vaccination, subjects must be evaluated to 
confirm that they are eligible for subsequent vaccination. If subjects do not meet any of 
the original inclusion criteria listed above, they should not receive additional 
vaccinations. 

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6.2. 
Exclusion criteria for enrolment 
6.2.1. 
Medical conditions 
• 
Progressive, unstable, or uncontrolled clinical conditions. 
• 
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 within 90 days prior to study vaccination. This will mean 
prednisone 20 mg/day (for adult subjects) or 0.5 mg/kg/day or 20 mg/day 
whichever is the maximum dose for paediatric subjects, or equivalent. Inhaled 
and topical steroids are allowed. 
− 
Administration of antineoplastic or immunomodulating agents or radiotherapy 
within 90 days prior to informed consent. 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any medicinal 
products or medical equipment whose use is foreseen in this study. 
• 
Current or previous, confirmed or suspected disease caused by N. meningitidis. 
• 
Known contact to an individual with any laboratory-confirmed N. meningitidis 
infection within 60 days, prior to enrolment. 
• 
History of neuroinflammatory or autoimmune condition. 
• 
Recurrent history or un-controlled neurological disorders or seizures. 
6.2.2. 
Prior/Concomitant therapy 
• 
Use of any investigational or non-registered product (drug, vaccine or medical 
device) other than the study vaccine(s) during the period starting 30 days before the 
informed consent or planned use during the study period. 
• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 180 days before the informed consent or planned 
administration during the study period. 
• 
Previous vaccination with any group B meningococcal vaccine at any time prior to 
informed consent and assent as applicable (according to the subject’s age). 
• 
Previous vaccination with two doses of quadrivalent meningococcal conjugate 
vaccine (MenACWY, Menveo, Menactra or MenQuadfi). 

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6.2.3. 
Prior/Concurrent clinical study experience 
• 
Subject concurrently participating in another clinical study, at any time during the 
study period, in which the subject has been or will be exposed to an investigational 
or a non-investigational vaccine/product (drug or medical device), will not be 
enrolled. 
6.2.4. 
Other exclusions 
• 
Child in care 
Please refer to section 12.1.2 for the definition of child in care. 
• 
Pregnant or lactating female. 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions. 
• 
Any study personnel or immediate dependants, family, or household member. 
Prior to receipt of second and third 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, they should not receive additional study 
vaccinations. Eligibility to each study vaccination should be documented in the source 
documents. 
6.3. 
Criteria for temporary delay for vaccination 
Vaccination may be postponed within the allowed time interval until transient 
circumstances cited below have been resolved: 
• 
Acute disease and/or fever at the time of vaccination. 
− 
Fever is defined as body temperature  38.0°C (100.4°F). The preferred location 
for measuring temperature in this study will be the oral cavity. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
• 
Use of antipyretics and/or analgesic medications within 6 hours prior to vaccination. 
• 
Significant acute illness within the previous 7 days. 
• 
Administration of any other vaccine 14 days (for inactivated vaccines) or 28 days 
(for live vaccines) prior to and after each vaccination*. 
*In case emergency mass vaccination for an unforeseen public health threat (e.g. a 
pandemic) is organised by public health authorities outside the routine immunisation 
programme, the time period described above can be reduced if, necessary for that 
vaccine, provided it is licensed and used according to its Product Information. 
• 
A positive test for active COVID-19 within the previous 14 days. The testing should 
be done using a molecular assay (polymerase chain reaction [PCR]) or antigen test 
approved by the country regulatory authorities. 

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• 
Subjects with known COVID-19 positive contacts in the past 14 days. 
Under such circumstances, a subject may be considered eligible for study vaccination 
after the appropriate window for delay has passed and inclusion/exclusion criteria have 
been re-checked, and if the subject is confirmed to be eligible. 
6.4. 
Screen and baseline failures 
In the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. If the individual is determined to be eligible for the study, 
he/she will be enrolled into the study. 
7. 
TREATMENTS 
Study treatment is defined as a set of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
7.1. 
Treatments administered 
The candidate vaccine to be used has been developed and manufactured by GSK. 
The study vaccines specific to this study are described below.  
• 
rMenB+OMV NZ (GSK Meningococcal Group B Vaccine, Bexsero). 
• 
MenACWY (GSK Meningococcal Groups A, C, W, and Y conjugate Vaccine, 
Menveo) 
• 
Placebo 
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 currently approved dossier. 

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Table 9 
Treatments administered  
Study Treatment Name: 
Bexsero 
Menveo*** 
Placebo 
Vaccine(s)/Product(s) name 
rMenB+OMV NZ  
MenA lyo 
MenCWY liquid  
Placebo  
(NaCl) 
Presentation 
Suspension for injection_Suspension for 
suspension for injection in a syringe 
Powder for solution 
for injection in a vial 
Solution for solution for 
injection in a vial 
Solution for injection 
in a syringe 
Vaccines formulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium chloride 
(NaCl) (0.9%); Water 
for injections  
Product Category 
Combination Product 
Biological Product 
Combination Product 
Route of Administration 
Intramuscular use 
Intramuscular use 
Intramuscular use 
Administration site: 
Location 
Deltoid 
Deltoid 
Deltoid 
Laterality* 
Left/Right**** 
 
 
Number of doses to be administered: 
2 
1 
1 
Volume to be administered** 
0.5 mL 
0.5 mL  
0.65 mL*****  
Packaging and Labelling 
Do not include a sample of the label text 
or details of pack design in the 
protocol. It will be specified in the SPM 
Refer to SPM for more details 
Refer to SPM for more details 
Refer to SPM for 
more details 
Manufacturer 
GSK 
GSK 
GSK 
* The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-dominant arm, an injection in the dominant arm may be 
performed. 
** Refer to the SPM for the volume after reconstitution, if applicable. 
*** 
 
 
 
 
**** Laterality information per visit/ group/treatment is provided in Table 10.  
***** The volume of the saline pre-filled syringe may be between 0.6mL and 0.8 mL. The full volume is to be injected. 
CCI
CCI

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Table 10 
Administration and Laterality 
Type of contact and timepoint 
Study group 
Treatment name 
Laterality* 
Visit 1 
(Day 1) 
MenB+MenACWY 
rMenB+OMV NZ 
Left 
MenACWY 
Right 
MenB 
rMenB+OMV NZ 
Left 
Placebo 
Right 
MenACWY 
MenACWY 
Left 
Placebo 
Right 
Visit 3 
(Day 61) 
MenB+MenACWY 
rMenB+OMV NZ 
Left 
MenB 
rMenB+OMV NZ 
Left 
MenACWY 
rMenB+OMV NZ 
Left 
Visit 4 
(Day 91) 
MenB+MenACWY 
Placebo 
Left 
MenB 
MenACWY 
Left 
MenACWY 
rMenB+OMV NZ 
Left 
*Laterality is defined due to multiple vaccinations at different visits; non-dominant arm is the preferred arm for injection, when applicable. In case it is not possible to administer the 
vaccine in the non-dominant arm, an injection in the dominant arm may be performed. 

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• 
Study vaccination will be performed on Day 1 (Visit 1), Day 61 (Visit 3) and Day 91 
(Visit 4). 
• 
All subjects will undergo a physical exam and safety related assessments at each 
Visit (5 clinic visits on study days 1, 31, 61, 91 and 121, respectively). 
• 
After completing all prerequisite procedures prior to vaccination, vaccines should be 
administered by unblinded study personnel as a deep intramuscular (IM) injection, 
preferably into the deltoid area of the arm. To be able to efficiently distinguish local 
AEs after the concomitant vaccination at study Day 1 (Visit 1), the 2 injections will 
be separately administered into both arms. The second and third study vaccination 
occurring at study Day 61 (Visit 3) and study Day 91 (Visit 4) will be preferably 
administered into the deltoid area of the non-dominant arm. The exact anatomic 
location of each injection must be carefully recorded in the Medical Chart and in the 
eCRF (refer to Section 7.1 for detailed description of the vaccines administration 
procedure). 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccines administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 4). 
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 and syncope. 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available. 
In the event of any foreign particulate matter and/or variation of physical aspect being 
observed, do not administer the vaccine and report the issue to the manufacturer. For 
rMenB+OMV NZ and MenACWY vaccines the issue should be reported as a 
Pharmaceutical Technical Complaint. The vaccine should not be discarded until 
authorized by GSK. Any unused medicinal product or waste material should be disposed 
of in accordance with local requirements. 
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the Clinical Trials Supply Manual prior to study start. 
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 study vaccine rMenB+OMV NZ and MenACWY. 
An overdose would also occur if 2 doses of the study vaccine are administered within 
half the time of the recommended interval between doses, as defined in the protocol. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an AE, and if the vaccine administration error or overdose is 
associated with a serious AE, it must be reported as such within 24 hours to the Sponsor. 

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7.2. 
Method of treatment assignment 
7.2.1. 
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. 
7.2.2. 
Randomization of treatment 
7.2.2.1. 
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 Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers /warehouse(s). 
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.  
7.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by component. 
7.2.2.2.1. Study group and treatment number allocation 
The target will be to enroll approximately 945 eligible subjects who will be randomly 
assigned to 3 study groups in a 1: 1: 1 ratio (approximately 315 subjects in each group). 
Subjects will be randomized in the source data base for internet randomization system 
(SBIR) system to one of the 3 parallel treatment arms in a 1:1:1 ratio to receive: 
• 
Group MenB+MenACWY: rMenB+OMV NZ given concomitantly with 
MenACWY at study Day 1; rMenB+OMV NZ at study Day 61; Placebo at study 
Day 91. 
• 
Group MenB: rMenB+OMV NZ given concomitantly with Placebo at study Day 1; 
rMenB+OMV NZ at study Day 61; MenACWY at study Day 91.  
• 
Group MenACWY: MenACWY given concomitantly with Placebo at study Day 1; 
rMenB+OMV NZ at study Day 61 and at study Day 91. 
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. 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR). The randomization algorithm will use a 
minimization procedure accounting for center. 

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After obtaining the signed/witnessed/thumb printed and dated ICF/IAF from the subject/ 
subject’s parent/ LAR and having checked the eligibility of the subject, the site staff in 
charge of the vaccine administration 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 component. 
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. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure and the 
early termination study procedures must be applied. The reason for all randomization 
failures should be recorded in the Screening and Enrolment Log and in the source 
document as specified in the Source Documentation Agreement Form (SDA). The 
information on subjects who are randomization failures should be kept distinct from 
subjects who are screen failures, as described in section 6.4. 
If for any reason, after randomization the subject fails to undergo treatment, this is an 
Early Termination and the reason should be recorded in source document as specified in 
the Source Data Agreement. The information on these Early Termination subjects should 
be kept distinct in the source documentation from randomization failures. 
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. 
7.2.2.2.2. 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. 
The number of each administered treatment must be recorded in the eCRF the Vaccine 
Administration screen. 
7.3. 
Blinding and unblinding 
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 qualified healthcare professional who will not participate in any of the study 
clinical evaluations. 

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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). 
7.3.1. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency when knowledge of the treatment is essential for the clinical 
management or welfare of the subject. 
The emergency unblinding process consists of the automated Internet-based system 
(SBIR) that allows the investigator to have unrestricted, immediate and direct access to 
the subject’s individual study treatment. 
As back up process, the investigator has the option of contacting a GSK Helpdesk (refer 
to Table 11) if he/she needs support to perform the unblinding (i.e., he/she cannot access 
the automated Internet-based system). 
Non-investigator physician (e.g., physician from emergency room) or subject/care 
giver/family member can also request emergency unblinding either via the investigator 
(preferred option) or via the GSK Helpdesk (back up process). Contact details of 
investigator and GSK Helpdesk are reported in the patient/subject card. 
Table 11 
Contact information for emergency unblinding 
GSK Helpdesk 
24/24 hour and 7/7 day availability 
The Helpdesk is available by phone, fax and email 
Phone: +32.2.656.68.04 
For US only Toll Free: + 1 844 446 3133 
Italy Toll Free: 800 879 197 
For Canada, US and Puerto Rico 
Alternate Toll-free number: 877.870.0019 
Fax: +32.2.401.25.75 
email: rix.ugrdehelpdesk@gsk.com 
GSK Vaccines Clinical Safety and Pharmacovigilance (VCSP) staff may unblind the 
treatment assignment for any subject in case of Suspected Unexpected Serious Adverse 
Reaction (SUSAR) as well as in case of fatal or life-threatening cases. If the SAE 
requires that an expedited regulatory report be sent to 1 or more regulatory agencies, a 
copy of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy. 

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7.4. 
Handling, storage and replacement of study 
vaccine(s)/product(s) 
7.4.1. 
Storage and handling of study vaccines 
The study vaccine 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. 
A temperature excursion is any temperature that is not in range of the label storage 
temperature conditions. Temperatures outside the range of label storage temperature 
conditions must be reported and/or documented. Temperature excursion impacting study 
vaccines must be reported and/or documented. 
In the frame of the reporting, the lack/absence of temperature monitoring documentation 
from a device, meeting GSK requirements has to be considered as a temperature 
excursion. 
Study vaccines that are impacted by a temperature excursion may not be used and must 
be quarantined at label storage conditions until usage approval has been obtained 
from/via the local study contact (e.g., Site Monitor). 
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. 
The Sponsor will ensure the following: 
• 
Supply the study vaccines. 
• 
Appropriate labelling of all 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 study vaccines by a designated staff member at the site, 
including: 
− 
Confirmation that the vaccines were received in good condition 
• 
Appropriate use of the study vaccines, including: 
− 
Use only in accordance with the approved protocol. 
− 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 

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− 
Appropriate documentation of administration of vaccines to study subjects 
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. 
Monitoring of vaccine 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 vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 
7.4.2. 
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 20% additional vaccine doses will be 
supplied to replace those that are unusable.  

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7.5. 
Concomitant medication(s)/product(s) and concomitant 
vaccinations 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations (Amended 11 October 2022) 
At each study visit/contact, the investigator or delegate should question the subject and/or 
the subject’s parent(s)/LAR(s) about any medications/products taken and vaccinations 
received by the subject. 
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 period of 30 days post-vaccination. 
• 
Relevant medications/products administered during the period (Day 1 to Day 451) or 
(Day 1 to Day 271) for subjects who have not reached Day 271 at the time this 
amendment takes effect.  
• 
Any concomitant vaccination administered in the period starting 14 days before the 
first dose of study vaccines and ending at the last study contact (Day -14 to Day 451) 
or (Day 1 to Day 271) for subjects who have not reached Day 271 at the time this 
amendment takes effect. 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
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 oral cavity. 
• 
Any concomitant medications/products/vaccines leading to the withdrawal or non-
eligibility of the subject from the study. Please refer to the section 7.5.2 for further 
details. 
• 
Any concomitant medications/products/vaccines relevant to an SAE/Adverse Event 
of Special interest (AESI) to be reported as per protocol or administered at any time 
during the study period for the treatment of an SAE/AESI. In addition, concomitant 
medications relevant to SAEs and AESI’s 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. 
• 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 

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7.5.2. 
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 10.2 for populations to be analysed. 
• 
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 defined as follows: 
− 
Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed. This will mean prednisone 
20 mg/day (for adult subjects) or 0.5 mg/kg/day or 20 mg/day whichever is 
the maximum dose for paediatric subjects, or equivalent. Inhaled and topical 
steroids are allowed. 
− 
Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent. 
• 
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. 
• 
Investigational or non-registered medicinal products within 30 days prior to 
informed consent/assent. 
• 
Drug and/or alcohol abuse. 
7.6. 
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 that may lead to elimination from per protocol analysis. If it is the case, the 
condition(s) must be recorded in the eCRF. 
7.7. 
Contraindications to subsequent vaccine(s) administration 
Prior to receipt of additional study vaccination, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects meet any of the original exclusion 
criteria or the criteria listed below, they should not receive additional vaccinations. 
However, these subjects should be encouraged to continue study participation. 
• 
Anaphylaxis following the administration of vaccines 
• 
Pregnancy (see Section 12.5.7.1) 
• 
Any condition that in the judgment of the investigator would make IM injection 
unsafe. 

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• 
Any occurrence of an event listed in the exclusion criteria which must be always re- 
assessed by the investigator before administration of the second dose of study 
vaccine. 
• 
Subjects who experience any serious adverse event (SAE) judged to be possibly or 
probably related to study vaccine or non-study vaccines, including hypersensitivity 
reactions. 
• 
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.  
• 
Occurrence of a new AESI or the exacerbation of an existing AESI. Refer to Section 
12.5.5 for the definition of AESIs. 
7.8. 
Warnings and precautions 
Warnings and precautions to vaccination must be checked at the beginning of each 
vaccination visit. Refer to the approved product label/package insert. 
7.9. 
Treatment after completion of the study  
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 care 
needed as per local/regional practices (such as re-vaccination of the subject(s)). 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 2).  
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns.  
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject(s) should discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (e.g. blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 

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8.1. 
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. 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems in a uniform fashion and sites will be 
monitored to ensure consistency in study execution across all centers. 
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 8.7 for further details. 
8.2. 
Pre-vaccination procedures 
8.2.1. 
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
• 
Demographic Information. 
• 
Medical history (any significant past diagnoses including allergies, hospitalizations, 
surgeries requiring in-patient hospitalization, any other medical conditions which 
may impair the assessment of safety of the rMenB+OMV NZ and MenACWY 
vaccines). 
• 
Vaccination history as confirmed by vaccination records, if accessible. 
• 
Pre-vaccination body temperature. 
• 
Post-vaccination immediate reactions observed for at least 30 minutes after injection: 
signs or symptoms of anaphylaxis, allergic phenomena (such as rashes, itching, or 
other allergic manifestations). Local and systemic solicited data (including e.g., use 
of medication to treat or prevent fever, and/or pain). 
• 
Post-vaccination solicited local and systemic AEs collected at home by subject 
and/or subject’s parent(s)/LAR(s) and recorded on Subject Diary (eDiary) for 7 days 
following each vaccination visit. 
• 
Adverse Events. 
− 
Unsolicited AEs occurring within 30 days after each vaccination will be 
collected for all subjects by interviewing the subject and/or subject’s 
parent(s)/LAR(s) (as applicable) during the site visits or Safety Follow-up Calls 
and by reviewing of available medical records.  
− 
SAEs occurring during the entire study period 

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− 
Medically attended AEs occurring during the entire study period 
− 
AEs leading to premature withdrawal from the vaccination/study occurring 
during the entire study period 
− 
AESI occurring during the entire study period (for subjects who received 
rMenB+OMV NZ) 
• 
Prior and concomitant medication as defined in Section 7.5. 
All data collected must only be identified using the GSK Subject ID, as described in 
Section 7.2, documented in the source documents and entered in the eCRF*. 
*Only the solicited local and systemic AEs 30 minutes post vaccination are entered in the 
eCRF. The solicited local and systemic AEs during 7-day post-vaccination period are not 
entered in the eCRF and are documented only in eDiary. 
8.2.2. 
Collection of demographic data 
Record demographic data such as date of birth, sex, height and weight, race and ethnicity 
in the subject’s eCRF. 
8.2.3. 
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, 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 7.5.2), 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 subject/subjects’ 
parent(s)/LAR(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. 
8.2.4. 
Physical examination 
Physical examination is to be performed by a qualified health care professional. 
“Qualified health care professional” refers to a licensed or certified health care 
professional with documented training and experience, as determined by the Principal 
Investigator (PI), and who is permitted by institutional policy to perform protocol 
required procedures, and who is identified on the Study Staff Signature Log. 

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The physical examination of the subject will include assessment of body temperature 
(preferably oral) and resting vital signs: systolic/diastolic blood pressure and heart rate 
after at least 10 minutes of rest. 
Medical history-directed physical examination to assess eligibility will be performed 
during Visit 1. 
Physical examination at each study visit subsequent to the first vaccination visit, will be 
performed only if the subject/subject’s parent(s)/LAR(s) indicates during questioning that 
there might be some underlying pathology(ies) or if deemed necessary by the Investigator 
or delegate (symptom-directed physical examination). 
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. 
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled. 
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
8.2.5. 
Pregnancy test 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccines may only be administered if the 
pregnancy test is negative. 
Urine will be collected for pregnancy testing in females of child-bearing potential, before 
vaccination at Visits 1, 3, and 4, and the results recorded in the source document and the 
eCRF. 
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit. 
8.2.6. 
Pre-vaccination body temperature 
The body temperature (preferably oral) of each subject needs to be measured prior to any 
study vaccines administration. If the subject has fever [fever is defined as 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 4 
and Section 6.3). 

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8.3. 
Efficacy assessments 
Please refer to the SPM and central laboratory manual for details on biospecimen 
management (handling, storage and shipment). 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
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. 
It is also possible that further findings may make it desirable to use the samples acquired 
in this study for further research, not described in this protocol. Therefore, all 
subjects/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 further research. Further research will be 
subject to the laws and regulations in the respective countries and will only be performed 
once an independent Ethics Committee or Review Board has approved this research. 
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/subject’s parent(s)/LAR(s). 
Refer also to the 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 8.3.4 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. 
8.3.1. 
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 
CCI

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exclusion of the subject from the per-protocol analysis (See Section 10.2 for the 
definition of populations for analyses). 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 or the central laboratory manual. 
The above applies to any external partners designated by GSK as well. 
8.3.2. 
Biological samples 
Blood samples will be collected from all subjects for serology evaluation. Refer to the 
Module on Biospecimen Management in the SPM or central laboratory manual for 
detailed instructions for the collection, handling and processing of the samples. 
8.3.2.1. 
Blood sampling for immunogenicity response assessments 
Blood samples will be taken during certain study visits as specified in Section 2. 
• 
Before vaccination a blood sample will be obtained at Visit 1 and Visit 4 for 
serologic evaluation. 
• 
A volume of approximately 20 mL of whole blood should be drawn from all subjects 
before first vaccination (Visit 1, study Day 1), 1 month after the first vaccination 
(Visit 2, study Day 31) and 1 month after the second vaccination and before the third 
vaccination (Visit 4, study Day 91) for immunogenicity evaluation. After 
centrifugation, serum samples should be kept at –20°C/ –4°F or below until 
shipment. Refer to the SPM and the central laboratory manual for more details on 
sample management and storage conditions. 
• 
The total amount of blood collected over the study period per subject will be 
approximately 60 mL. 
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 processed, identified and stored according to the Central Laboratory 
manual. 
In clinic visits where a blood draw and a vaccination are planned, ensure that all samples 
collected for immunogenicity assessments are taken prior to any 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 at Visit 1, Visit 2 and Visit 4. 
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 and 

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vaccination may be delayed as appropriate to ensure sample collection prior to 
vaccination. 
Table 12 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Subject/Group 
Day 
Blood 
Approximately 20 
mL 
Visit 1 (Pre-Vacc I) 
All 
1 
Visit 2 (Post Vacc1) 
31 
Visit 4 (Post Vacc2) 
91 
8.3.2.2. 
Other biological samples 
Urine sampling: Urine test is the preferable method to test pregnancy. Urine will be 
collected for pregnancy testing in females of child-bearing potential, before each 
vaccination at Visits 1, 3, and 4, and the results recorded in the source document and 
eCRF. 
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit. 
8.3.3. 
Laboratory assays 
The measures of immunogenicity used in this study are standard, i.e., widely accepted 
and generally recognized as reliable, accurate, and relevant (able to describe the quality 
and extent of the immune response). 
The immunogenicity of the rMenB+OMV NZ and of MenACWY vaccines will be 
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.  
The induction of antibodies directed against serogroup A, C, W, and Y meningococci 
following MenACWY vaccination will also be measured by Enzyme-Linked 
Immunosorbant Assay (ELISA). The ELISA procedure is used to detect the amount of 
sera immunoglobulin G (IgG) antibody in response to N. meningitidis polysaccharide 
antigens. 
Please refer to Appendix 2 for a detailed description of the assays performed in the study.  
Please refer to Appendix 3 for the address of the clinical laboratories used for sample 
analysis. 
Serological testing for immunogenicity to rMenB+OMV NZ and to MenACWY vaccines 
will be performed at GSK Biologicals’ laboratories or in a laboratory designated by GSK 
Biologicals using standardized and validated procedures (refer to Table 13). 

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Table 13 
Humoral Immunity (Antibody determination)  
System 
Component 
Method 
Kit/Manuf
acturer 
Unit* 
LOD* 
LLOQ
* 
Laboratory** 
SER 
Neisseria meningitidis B 
M14459 (fHbp) Ab 
hSBA 
In house 
1/DIL 
3 
5 
GSK*** or 
laboratory 
designated by 
GSK 
Biologicals 
Neisseria meningitidis B 
96217 (NadA) Ab 
6 
15 
Neisseria meningitidis B 
NZ98/254 (PorA) Ab 
4 
6 
Neisseria meningitidis B M07-
0241084+ (NHBA) Ab 
4 
4 
SER 
Neisseria meningitidis 
Serogroup A 3125 Ab 
hSBA 
In house 
1/DIL 
4 
5 
Neisseria meningitidis 
Serogroup C C11 Ab 
4 
6 
Neisseria meningitidis 
Serogroup W 240070 Ab 
4 
7 
Neisseria meningitidis 
Serogroup Y 860800 Ab 
4 
6 
SER 
N men Serogroup A Ab.IgG 
ELISA 
TBD 
µg/m
L 
TBD 
TBD 
N men Serogroup C Ab.IgG 
TBD 
TBD 
N men Serogroup W Ab.IgG 
TBD 
TBD 
N men Serogroup Y Ab.IgG 
TBD 
TBD 
Ab: Antibody; IgG: Immunoglobin G; µg: Microgram, ml: Milliliter, DIL: Dilution, SER: Serum, 1/dilution: reciprocal of the 
dilution; LOD: Limit of detection; LLOQ: Lower limit of quantitation, ELISA: enzyme-linked immunosorbent assay; TBD 
= to be determined. 
*Strain, assay cut-off(s) and unit(s) might be subject to change during the course of the study (e.g. in case of 
requalification, revalidation or standardization). In this case, this will be documented either in a protocol amendment or 
in the clinical report. 
**Refer to Appendix 3 to for the laboratory addresses. 
***GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart Belgium or Wavre, 
Belgium. CLS may delegate testing to GSK Research laboratories in Siena, Italy or to an external laboratory. 
+ The NHBA indicator strain, M07-0241084 may be subject to change during the study, before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
For each of the MenACWY serogroups, ELISA assay cut-offs will be determined following validation of the assay. 
This will be documented in the clinical report. 
Additional testing on the vaccine and/or on the disease under study may be performed 
within the framework of the study 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. 

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8.3.4. 
Biological samples evaluation 
8.3.4.1. 
Immunological read-outs 
Table 14 
Immunological read-outs (Amended 11 October 2022) 
Blood sampling timepoint 
Subset/Sub-
cohort Name 
No. of 
subjects Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-Vacc 
Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
Visit 2 (Day 31) 
Post Vacc1 
Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
ELISA IgG anti meningococcal A, C, W, Y 
Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
ELISA IgG anti meningococcal A, C, W, Y 
Visit 4 (Day 91) 
Post Vacc2 
Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
*The NHBA indicator strain M07-0241084 may be subject to change during the study before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
 

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In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 14.  
8.3.5. 
Immunological correlates of protection 
For the N. meningitidis serogroup C antigen in the MenACWY vaccine, an 
immunological Correlate of Protection (CoP) has been established as ≥ 1:4 hSBA. 
No generally accepted immunological CoP has been demonstrated so far for the other 
antigen(s) used in the candidate vaccine(s). 
The immunological assay results will be communicated to the investigator when ready 
and available. 
Refer to the section 7.9 for details regarding treatment for non-responders. 
8.4. 
Safety Assessments 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and any 
designees remain responsible for following up AEs that are serious, considered related to 
the study treatment or the study, or that caused the subject to discontinue the study 
treatment or study. 
The measures of safety used in this study are routine clinical procedures. They include a 
close vigilance for, and stringent reporting of, selected local and systemic AEs routinely 
monitored in vaccine clinical studies as indicators of reactogenicity. 
8.4.1. 
Safety definitions 
Please refer to Section 12.5 for safety definitions. 
8.4.2. 
Follow-up Clinic Visit 
Follow-up clinic visits will be performed on study Days 31 (Visit 2), 91 (Visit 4) and 121 
(Visit 5). 
During the follow-up clinic visit on study Days 31 (Visit 2), 91 (Visit 4) and 121 (Visit 
5), the eDiary will be reviewed by the staff. Study-specific requirements are described in 
the SPM. At last Follow-Up clinic visit (Day 121), the eDiary should be returned to the 
study site and collected. For details on the eDiary see Section 12.5.8. 
The subject and/or parent(s)/LAR(s) will be interviewed to determine if any unsolicited 
AEs occurred and if any concomitant medications associated with those events or 
vaccines were taken/received in the time since the last clinic visit. The 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. AEs 
reported by the subject and/or parent(s)/LAR(s) at this follow-up clinic visit must be 

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recorded in the subject's source document and on an Adverse Events eCRF, as specified 
in Section 8.4. 
Perform a brief symptom-directed physical examination if necessary according to 
symptoms the subject has reported. 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 
measurement of vital signs, body temperature (preferably oral) 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 (when deemed abnormal) resulting from the 
symptom-directed physical examination should be documented in the subject’s source 
document and eCRF(s). 
Approximately 20 mL of blood will be drawn from all subjects for immunological 
evaluation at Visit 1 (Day 1), Visits 2 (Day 31) and Visit 4 (Day 91). Refer to Section 
8.3.2. 
The site should schedule the next study visit with the subject and/or parent(s)/LAR(s). 
The subject and/or 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. 
8.4.3. 
Safety Follow-up calls (Amended 11 October 2022) 
A total of seven safety follow-up calls will be performed. Safety follow-up calls will be 
performed on Day 15, Day 75, Day 105, Day 181, Day 271, Day 361 and Day 451 (study 
termination). For subjects who have not reached Day 271 at the time this amendment 
takes effect, a total of five safety follow-up calls will be performed. Safety follow-up 
calls will be performed on Day 15, Day 75, Day 105, Day 181, and Day 271 (study 
termination). 
Safety follow-up calls are calls made to the subject 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/subject’s parent(s)/LAR(s) will be 
interviewed according to the script, and information relating to unsolicited adverse events 
[including SAEs, adverse events of special interest (AESIs), medically attended adverse 
events, and/or AEs leading to withdrawal] and concomitant medications or vaccinations 
associated with those events. All safety information described by the subject 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/ safety call) with the 
subject/subject’s parent(s)/LAR(s). 

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The subject/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. 
8.4.4. 
Time period and frequency for collecting AE and serious adverse 
event (SAE) information 
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in is given in Table 15. Refer to the Section 12.5.8.2 for details on the time 
period for recording safety information. 

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Table 15 
Reporting periods for collecting safety information in subjects who 
have crossed D271 (Amended 11 October 2022) 
Event 
V1 
 
V2 
 
V3 
 
 
V4 
 
V5 
 
 
 
Study 
Conclusion 
 
D1 D15 D31 
D61 D75 
D 91 D105 D121 
D181 
D271 
D361 
D451 
Solicited local 
and systemic 
AEs* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
within 30 days 
post-vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically 
attended AEs, 
AEs/SAEs 
leading to 
withdrawal from 
the study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
the study 
vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation  
or concurrent GSK 
medication/vaccine¥ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs/pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: Adverse event, AESI: adverse event of special interest, D: Day, SAE: Serious adverse event, V: Visit. 
*Solicited AEs to be collected for 7 days following each vaccination, with ongoing solicited AEs collected until 
resolution or day 30, whichever occurs first.  
** Including COVID-19 infection related AEs. 
¥Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins from the time a 
parent(s)/LAR(s) or participant signs the consent form to the end of the study 

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Table 16 
Reporting periods for collecting safety information in subjects who 
have not reached D271 (Amended 11 October 2022) 
Event 
V1 
 
V2 
 
V3 
 
 
V4 
 
V5 
 
Study 
Conclusion
 
D1 D15 D31 
D61 D75 
D 91 D105 D121 
D181 
D271 
Solicited local 
and systemic 
AEs* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
within 30 days 
post-vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically 
attended AEs, 
AEs/SAEs 
leading to 
withdrawal from 
the study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
the study 
vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine
¥ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs/pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: Adverse event, AESI: adverse event of special interest, D: Day, SAE: Serious adverse event, V: Visit. 
*Solicited AEs to be collected for 7 days following each vaccination, with ongoing solicited AEs collected until 
resolution or day 30, whichever occurs first.  
** Including COVID-19 infection related AEs. 
¥Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins from the 
time a parent(s)/LAR(s) or participant signs the consent form to the end of the study 
All SAEs will be recorded and reported via Expedited AE Reporting Form to the sponsor 
or designee immediately and under no circumstance should this exceed 24 hours after the 
investigator became aware of it, as indicated in Appendix 5. The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available. 

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A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 15. Investigators are not obligated to actively seek AEs 
or SAEs in former study subjects. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event to be reasonably related to the study vaccines, the investigator 
will promptly notify the Study Contact for Reporting SAEs. 
For further details, please see Section 12.5.11.1.2. 
8.4.5. 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing intensity, causality and outcome of 
AEs and SAEs and the procedures for completing and transmitting SAE reports are 
provided in Section 12.5.8. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence.  
8.4.6. 
Reporting of serious adverse events, pregnancies, and other 
events 
Table 17 
Timeframes for submitting serious adverse event, pregnancy 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 
Pregnancies 
24 hours* 
electronic pregnancy report 
24 hours* 
paper pregnancy follow-up 
report/electronic pregnancy 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. 

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8.4.6.1. 
Contact information for reporting of serious adverse events (SAEs), 
AESIs, pregnancies and study holding rules 
Table 18 
Contact information for reporting of serious adverse events (SAEs), 
AESIs, and pregnancies 
Study contact for questions regarding SAEs, AESIs, and pregnancies 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs, AESIs, and pregnancies 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
US sites Fax: 1-610-787-7053 
Canadian sites only Fax: 1-866-903-4718 
8.4.6.2. 
Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential for meeting 
legal obligations and ethical responsibilities for the safety of subjects and the safety of a 
study treatment under clinical investigation.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
All SAEs must be reported by the investigator to his/her corresponding EC/ IRB or 
applicable regulatory authorities in accordance with institutional policy/regulatory 
requirements and adequate documentation of this notification must be provided to the 
Sponsor. 
8.4.7. 
Medical device deficiencies  
Per Section 201(h) of the Food, Drug, and Cosmetic Act, a device is: 
An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or 
other similar or related article, including a component part, or accessory which is: 
1. recognized in the official National Formulary, or the United States Pharmacopoeia, 
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2. intended for use in the diagnosis of disease or other conditions, or in the cure, 
mitigation, treatment, or prevention of disease, in man or other animals, or 
3. intended to affect the structure or any function of the body of man or other animals, 
and which does not achieve its primary intended purposes through chemical action 
within or on the body of man or other animals and which does not achieve its 
primary intended purposes through chemical action within or on the body of man or 
other animals and which is not dependent upon being metabolized for the 
achievement of its primary intended purposes. The term "device" does not include 
software functions excluded pursuant to section 520(o). 
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. 
8.4.7.1. 
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 12.7 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. 
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 12.7.3 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. 

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8.4.8. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 12.5.5), will be followed until the event is resolved, stabilized, 
otherwise explained, or the subject is lost to follow-up. Further information on follow-up 
procedures is given in Section 12.5.11. 
8.4.9. 
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 7.5). 
8.4.10. 
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/subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their 
possession at all times during the study duration. 
8.5. 
Genetic Research (Pharmacogenetics) 
Genetics are not evaluated in this study. 
8.6. 
Study conclusion 
• The study termination call will occur on study Day 451 (after safety follow up call 7) 
or (Day 271 [Month 9]) for subjects who have not reached Day 271 [Month 9] at 
the time this amendment takes effect. The termination visit will be a phone call 
(Amended 11 October 2022).  
• 
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. 

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• 
At the Termination visit, the following procedures will be performed: interview of 
subject and/or parent(s)/LAR(s) to collect any medically attended AEs, AEs leading 
to withdrawal, AESI, SAEs, and/or concomitant medications/vaccinations. 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 and/or 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, treatment assignments). 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 and/or parent(s)/LAR(s) chooses 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. 
8.6.1. 
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. 
During the telephone call, the following procedures will be performed:  
• 
review of Subject eDiary (if applicable). 
• 
interview of subject and/or parent(s)/LAR(s) to collect unsolicited AEs, medically 
attended AEs, AEs leading to withdrawal, SAEs, AESI. 
• 
interview of subject and/or parent(s)/LAR(s) to collect concomitant 
medications/vaccinations administered to treat AEs collected in the study. 
Additionally, the following 2 procedures will be performed at the clinic visit: 
• 
perform a symptom-directed physical assessment (including e.g., measurement of 
vital signs, body temperature [preferably oral] and a check of general appearance). 
• 
blood sampling to test immunogenicity (if withdrawal occur at or prior to Visit 4 
[study Day 91]). 
If the Early Termination Visit is a telephone call, collect as much information as possible. 
Early Termination Visits include subjects who were randomized but not treated. 
The site will review with the subject and/or 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, treatment assignments). 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 and/or parent(s)/LAR(s) chooses to share this information. 

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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. 
8.7. 
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 subjects:  
• 
If the eDiary device was provided to the subject, it may be returned to the site by 
conventional mail after the end of the relevant data collection period (Visit 5). 
• 
Biological samples may be collected at a different location* other than the study site 
or at subject’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use.  
*It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as adequate 
facilities to perform study procedures, appropriate training of the staff and documented 
delegation of responsibilities in this location. This alternate location should be covered by 
proper insurance for the conduct of study on subjects by investigator and staff at a site other 
than the designated study site. Refer to local regulatory guidance on conduct of clinical 
trials during COVID-19. 
Impact on the Per Protocol Set (PPS) for immunogenicity will be determined on a case by 
case basis. 
9. 
DISCONTINUATION CRITERIA 
9.1. 
Discontinuation from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol.  
All data and samples 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. 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Primary reason for study withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 

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the subject himself/herself, 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: 
• 
SAEs requiring expedited reporting (please refer to section 12.5.9.2 for the details) 
• 
Unsolicited non-serious AE 
• 
Solicited adverse event 
• 
Protocol deviation 
• 
Withdrawal by subject, not due to an adverse event* 
• 
Migrated/Moved from the study area 
• 
Lost to follow-up 
• 
Sponsor study termination 
• 
Other (specify) 
*In case a subject is withdrawn from the study because he/she/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 12.5.11). 
The reasons for premature withdrawal from the study include adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event: 
For any subject withdrawn from study participation prior to the planned Study 
Termination Call, 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 resolution or stabilization. 
Subjects who develop a SAE judged to be possibly 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. 

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Withdrawal of consent: 
The subject and/or 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 and/or 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. 
If the subject requests complete withdrawal from the study, no further study interventions 
will be performed with the subject. 
If a subject and/or parent(s)/LAR(s) withdraw(s) consent but does not revoke the HIPAA 
(The Health Insurance Portability and Accountability Act) authorization, the Sponsor will 
have full access to the subject’s medical records, including termination visit information. 
If a subject and/or 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: 
For subjects who are not accessible through call for final visit (study Day 451), or for 2 
consecutive visits, study staff are encouraged to make at least 3 documented attempts to 
contact the subject by telephone and at least one documented written attempt to contact 
the subject and/or 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. Please refer to Section 9.3 for further details. 
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 until resolution/stabilization. 
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. 

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Protocol 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. 
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.  
Any subject who becomes pregnant during the study, despite the protocol requirement for 
highly effective method of contraception, will not receive further vaccinations but should 
be encouraged to continue participating in the study for safety follow-up. The site must 
complete a Pregnancy Report eCRF (initial report) as soon as possible after learning of 
pregnancy occurrence (see Section 12.5.8 for further details). If the subject withdraws 
from the study for any of the above categories except death, the site will obtain 
permission from the subject to continue to remain in contact with her until the outcome of 
the pregnancy is known, even if the outcome is not known until after the subject reaches 
the end of follow-up period. 
9.2. 
Discontinuation of 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 continue further study 
procedures (safety or immunogenicity) if planned in the study protocol, as deemed 
appropriate by the investigator.  
Primary reason 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 himself/herself, 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: 
• 
Adverse event requiring expedited reporting 
• 
Non-serious AE (specify) 
• 
Unsolicited non-serious AE 
• 
Solicited adverse event 
• 
Not willing to be vaccinated 
• 
Other (specify). 

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9.3. 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample size determination 
The target sample size is 750 subjects evaluable for immunogenicity (250 subjects per 
study group). Evaluable subjects mean all subjects included in the set for the primary 
statistical analysis defined in Section 10.2) Considering that approximately 20% of the 
enrolled subjects might withdraw or not be evaluable for immunogenicity, the target 
sample size to be enrolled is 945 subjects (315 subjects per study group). These sample 
sizes were calculated based on the standard deviations from corresponding treatments in 
the mentioned studies, the non-inferiority margin of 0.5 and the expected ratio GMR of 
the GMTs (or GMCs) of 0.9. 
10.1.1. 
Hypotheses related to primary and secondary objectives 
10.1.1.1. 
Primary Immunogenicity Objectives 
The statistical hypotheses and analyses are based on the common assumption that the 
logarithmically (base of 10) transformed hSBA titers are normally distributed. 
Non-inferiority of concomitant rMenB+OMV NZ with MenACWY to rMenB+OMV NZ  
The null (not non-inferiority) and the alternative (non-inferiority) hypotheses are: 
 
versus  
, 

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where i=1,…,4 is an index over the four serogroup B strains M14459, 96217, NZ98/254 
and M07-0241084, and 
 and 
are the population means of the 
logarithmically (base of 10) transformed hSBA titers for the ith serogroup B strain at one 
month after the second vaccination in Groups MenB+MenACWY and MenB 
respectively. 
Non-inferiority of concomitant rMenB+OMV NZ with MenACWY to MenACWY 
The null (inferiority) and the alternative (non-inferiority) hypotheses are: 
versus  
, 
where j=1,…,4 is an index over the four serogroups A, C, W and Y, and 
j
MenACWY
A
,
,

 and 
j
MenACWY
C
,
,

are the population means of the logarithmically (base of 10) transformed 
hSBA titers for the jth MenACWY serogroup at one month after the first vaccination in 
Groups MenB+MenACWY and MenACWY respectively. 
The threshold of 
3.0
2
log
)5.0(
log
10
10
−

−
=
 is the non-inferiority margin. 
The choice of non-inferiority margin of 0.5 for the assessment of GMT ratios for the four 
serogroup B test strains is based on previous clinical study results (post-vaccination 
GMTs) showing that individual titers would, on average, remain protective for all 4 
strains if individual titers were reduced to half (see section 10.1). 
The non-inferiority margin of 0.5 for the assessment of GMT ratios for the MenACWY 
serogroups was found appropriate in view of the Center for Biologics Evaluation & 
Research (CBER) concurrence with the 2-fold equivalence margin (for a lot-to-lot 
consistency study) at the End-of-Phase II meeting in 2006. 
The 8 hypotheses associated with the primary objective will be tested simultaneously, to 
control for the type I error rate. The testing of the hypotheses will be done simultaneously 
on all the strains and serogroups . 
10.1.1.2. 
Secondary Immunogenicity Objectives 
There is a non-inferiority test associated with the concomitant rMenB+OMV NZ with 
MenACWY to MenACWY using ELISA GMCs.  
Non-inferiority of concomitant rMenB+OMV NZ with MenACWY to MenACWY 
The null (inferiority) and the alternative (non-inferiority) hypotheses are: 
)
5.0
(
log
:
10
,
,
,
,
,0

−
j
MenACWY
C
j
MenACWY
A
MenACWY
j
H


 versus 

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)
5.0
(
log
:
10
,
,
,
,
,0

−
j
MenACWY
C
j
MenACWY
A
MenACWY
j
H


, 
where j=1,…,4 is an index over the four serogroups A, C, W and Y, and 
j
MenACWY
A
,
,

 and 
j
MenACWY
C
,
,

are the population means of the logarithmically (base of 10) transformed 
hSBA titers for the jth MenACWY serogroups at one month after the first vaccination in 
Groups MenB+MenACWY and MenACWY respectively. 
Non-inferiority of concomitant rMenB+OMV NZ with MenACWY versus MenACWY 
alone will be claimed if the null hypotheses are rejected for all four serogroups A, C, W 
and Y, as measured by ELISA GMCs. 

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10.1.2. 
Sample size calculation 
For the immune response to rMenB+OMV NZ, sample size calculations are based on 
hSBA titer data from the GSK V102_03 and V72_41 studies and for the immune 
response to MenACWY, data from GSK V59P13E1 study and V102_02 study (ELISA 
GMCs) is used. 
Sample size/power calculations are based on specific fixed values for the 
• 
non-inferiority margin, 
• 
standard deviations of (the distributions of) the logarithmically transformed (base of 
10) hSBA titers for the strains M14459, 96217, NZ98/254 and M07-0241084. 
• 
standard deviations of (the distributions of) the logarithmically transformed (base of 
10) hSBA titers for the serogroups A, C, W and Y, 
• 
ratios of the GMTs medians of (the distribution of) the hSBA titers for strains 
M14459, 96217, NZ98/254 and M07-0241084 when rMenB+OMV NZ is 
administered with MenACWY versus when rMenB+OMV NZ is administered alone 
(one ratio per strain),  
• 
ratios of the GMTs/GMCs of (the distribution of) the hSBA titers for the serogroups 
A, C, W and Y when MenACWY is administered with rMenB+OMV NZ vs when 
MenACWY is administered alone (one ratio per serogroup). 
Standard Deviations for hSBA Titer: 
In Table 19 the standard deviations are listed that were used in the power calculation, 
along with the 80% upper limit of the confidence interval (CI) for standard deviation. 
For the primary objective 1, hypothesis 1, testing of rMenB+OMV NZ when given 
concomitantly with MenACWY to rMenB+OMV NZ given alone, test of treatment 
Group MenB+MenACWY versus treatment Group MenB, the standard deviations from 
studies V102_03 and V72_41 were used. 
For the primary objective 2, hypothesis 2, testing of MenACWY when given 
concomitantly with rMenB+OMV NZ to MenACWY given alone, test of treatment 
Group MenB+MenACWY versus treatment Group MenACWY, the standard deviations 
from study V59P13E1 GrIV_V were used. 
For the secondary objective, hypothesis 3, testing of MenACWY when given 
concomitantly with rMenB+OMV NZ to MenACWY given alone based on ELISA 
GMCs, test of treatment Group MenB+MenACWY versus treatment Group MenACWY, 
the standard deviations from study V102_02 were used. 

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Table 19 
Observed SDs with the Upper Limits of the Two-Sided 80% CI for the 
Logarithmically (base of 10) Transformed hSBA Titers 
Hypothesis 
study 
strain 
sd 
N 
alpha 
df 
Est_sd 
1 
V102_03 
M14459 
0.65413 
92 
0.2 
91 
0.72443 
1 
V72_41 
96217 
0.25408 
30 
0.2 
29 
0.30774 
1 
V102_03 
NZ98/254 
0.56100 
92 
0.2 
91 
0.62129 
1 
V102_03 
M07-0241084 
0.55235 
92 
0.2 
91 
0.61171 
2 
V59P13E1GrIV_V 
MenA 
0.46542 
119 
0.2 
118 0.50866 
2 
V59P13E1GrIV_V 
MenC 
0.54356 
117 
0.2 
116 0.59455 
2 
V59P13E1GrIV_V 
MenW 
0.57507 
118 
0.2 
117 0.62875 
2 
V59P13E1GrIV_V 
MenY 
0.59519 
118 
0.2 
117 0.65075 
3 
V102_02 
MenA 
0.67891 
59 
0.2 
58 
0.77338 
3 
V102_02 
MenC 
0.56615 
59 
0.2 
58 
0.64493 
3 
V102_02 
MenW 
0.50023 
57 
0.2 
56 
0.57128 
3 
V102_02 
MenY 
0.53432 
58 
0.2 
57 
0.60943 
The testing of the hypotheses will be done simultaneously on all the strains and 
serogroups. 
Power Calculation and Sample Size Results of the Non-inferiority Testing of 
rMenB+OMV NZ, First Primary Objective, Referred to as Hypothesis 1 
In Table 20 the results are presented of the power calculation (in %) with T1 MenB 
strains M14459, 96217, NZ98/254 and M07-0241084 with sample size raising from 200 
to 300 per treatment group. The individual power calculations are presented along with 
the power for all serogroup B strains. The power for rMenB+OMV NZ is the 
multiplication of the power for all 4 individual strains. A non-inferiority margin of 0.5 
and a GMT ratio between treatments of 0.9 was used. 
Table 20 
Power (in %) for the Individual and for the Overall MenB Strains 
Hypothesis 
N 
Power 
M14459 
Power 
96217 
Power 
NZ98_254 
Power 
M07_0241084 
Power 
MenB 
1 
200 
94.01 
100 
98.38 
98.62 
91.21 
1 
210 
94.98 
100 
98.75 
98.95 
92.80 
1 
220 
95.80 
100 
99.04 
99.20 
94.11 
1 
230 
96.49 
100 
99.26 
99.39 
95.19 
1 
240 
97.08 
100 
99.43 
99.54 
96.08 
1 
250 
97.57 
100 
99.57 
99.65 
96.81 
1 
260 
97.98 
100 
99.67 
99.74 
97.40 
1 
270 
98.33 
100 
99.75 
99.80 
97.89 
1 
280 
98.62 
100 
99.81 
99.85 
98.28 
1 
290 
98.86 
100 
99.86 
99.89 
98.60 
1 
300 
99.06 
100 
99.89 
99.92 
98.87 
Power Calculation and Sample Size Results of the Non-inferiority Testing of 
MenACWY, Second Primary Objective, Referred to as Hypothesis 2 
In Table 21 the results are presented of the power calculation (in %) with MenACWY 
with sample size raising from 200 to 300 per treatment group. The individual power 
calculations are presented along with the power for all MenACWY serogroups combined. 
The power for MenACWY is the multiplication of the power of all 4 individual 

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serogroups. A non-inferiority margin of 0.5 and a GMT ratio between treatments of 0.9 
was used. 
Table 21 
Power (in %) for the Individual Serogroups and for the Overall 
MenACWY Serogroups 
Hypothesis 
N 
Power 
MenA 
Power 
MenC 
Power 
MenW 
Power 
MenY 
Power 
MenACWY 
2 
200 
99.88 
98.99 
98.17 
97.46 
94.60 
2 
210 
99.92 
99.24 
98.58 
97.98 
95.79 
2 
220 
99.95 
99.43 
98.90 
98.40 
96.72 
2 
230 
99.97 
99.58 
99.15 
98.74 
97.45 
2 
240 
99.98 
99.69 
99.34 
99.01 
98.02 
2 
250 
99.99 
99.77 
99.49 
99.22 
98.47 
2 
260 
99.99 
99.83 
99.61 
99.39 
98.82 
2 
270 
99.99 
99.87 
99.70 
99.52 
99.09 
2 
280 
100.00 
99.91 
99.77 
99.62 
99.30 
2 
290 
100.00 
99.93 
99.83 
99.71 
99.46 
2 
300 
100.00 
99.95 
99.87 
99.77 
99.59 
Power Calculation and Sample Size Results of the Non-inferiority Testing of 
MenACWY, Secondary Objective, Referred to as Hypothesis 3 
In Table 22 the results are presented of the power calculation (in %) with MenACWY 
using ELISA GMCs with sample size raising from 200 to 300 per treatment group. The 
individual power calculations are presented along with the power for all MenACWY 
serogroups combined. The power for MenACWY is the multiplication of the power of all 
4 individual serogroups. A non-inferiority margin of 0.5 and a GMT ratio between 
treatments of 0.9 was used. 
Table 22 
Power (in %) for the Individual and for the Overall MenACWY 
Serogroups Using ELISA GMCs 
Hypothesis 
N 
Power 
MenA 
Power 
MenC 
Power 
MenW 
Power 
MenY 
Power 
MenACWY 
3 
200 
90.87 
97.66 
99.37 
98.67 
87.02 
3 
210 
92.14 
98.15 
99.55 
98.99 
89.12 
3 
220 
93.24 
98.55 
99.67 
99.23 
90.88 
3 
230 
94.21 
98.86 
99.76 
99.42 
92.37 
3 
240 
95.04 
99.10 
99.83 
99.56 
93.61 
3 
250 
95.76 
99.30 
99.88 
99.67 
94.65 
3 
260 
96.38 
99.45 
99.91 
99.75 
95.53 
3 
270 
96.91 
99.57 
99.94 
99.81 
96.26 
3 
280 
97.37 
99.67 
99.95 
99.86 
96.87 
3 
290 
97.77 
99.74 
99.97 
99.89 
97.38 
3 
300 
98.11 
99.80 
99.98 
99.92 
97.81 
Power Calculation and Sample Size Results for all 3 Hypotheses Combined 
In Table 23 the results are presented of the overall power (in %) when combining all, 3 
hypotheses, consisting of 4 tests each. The overall power is the multiplication of the 
power of all 3 hypotheses as presented in Table 20, Table 21 and Table 22. 

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Table 23 
Overall Power (in %) for the 3 Hypothesis Combined 
N 
Power 
Hypothesis 1 
Power 
Hypothesis 2 
Power 
Hypothesis 3 
Power 
Overall 
200 
91.21 
94.60 
87.02 
75.08 
210 
92.80 
95.79 
89.12 
79.22 
220 
94.11 
96.72 
90.88 
82.72 
230 
95.19 
97.45 
92.37 
85.68 
240 
96.08 
98.02 
93.61 
88.16 
250 
96.81 
98.47 
94.65 
90.23 
260 
97.40 
98.82 
95.53 
91.95 
270 
97.89 
99.09 
96.26 
93.37 
280 
98.28 
99.30 
96.87 
94.54 
290 
98.60 
99.46 
97.38 
95.50 
300 
98.87 
99.59 
97.81 
96.31 
In summary to have an overall power of 90% or more, the minimum sample size need to 
be N=250 subjects per group. To account for a 20% drop out rate, N=315 subjects per 
group need to be enrolled. For the study, with 3 treatment groups, N=945 subjects need to 
be enrolled to have 750 eligible subjects. 
10.2. 
Populations for analyses 
For purposes of analysis, the following analysis sets are defined: 
Analysis Set 
Description 
Enrolled  
All subjects who sign informed consent  
Exposed 
All subjects who received at least 1 dose of the study treatment. The allocation in a group is done 
in function of the administered treatment. 
Full Analysis 
All subjects who received at least 1 dose of the study treatment and have post-vaccination 
immunogenicity data  
Per Protocol  
All subjects who received at least 1 dose of the study treatment to which they are randomized and 
have post-vaccination data (Full Analysis Set) minus subjects with protocol deviations that lead to 
exclusion 
10.3. 
Statistical analyses 
10.3.1. 
Subjects disposition 
Number of subjects enrolled, vaccinated subjects and completed will be described by 
group. Reason for early withdraw will be described by group. Full analysis and per-
protocol analysis population set will be described by group. 
10.3.2. 
Demography and baseline characteristics analyses 
Descriptive statistics (mean, standard deviation [SD], median, minimum and maximum) 
for age, height, weight and body mass index (BMI) at enrolment will be calculated 
overall and by Group. 
Distributions of subjects by sex, race, ethnic origin, geographical locations (US sites, 
non-US sites, if applicable) and according to the pre-vaccination hSBA titer (per strain, 
<LLOQ or ≥LLOQ) will be summarized overall and by Group. 

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10.3.3. 
Immunogenicity analyses 
The primary analysis will be based on the Per Protocol Set of immunogenicity for the 
primary and secondary (non-inferiority) immunogenicity objective. If, in any study 
group, the percentage of enrolled or vaccinated subjects with serological results excluded 
from the per-protocol set for analysis of immunogenicity is 5% or more, a second 
analysis based on the Full Analysis Set (FAS) will be performed to complement the per-
protocol analysis. Supportive analyses using the FAS will also be performed for the 
primary immunogenicity endpoints.  
Endpoint 
Statistical Analysis Methods 
Primary 
Within group assessment 
• 
For Group MenB+MenACWY and Group MenB: hSBA GMTs for rMenB+OMV NZ against each 
of the four serogroup B test strains (M14459, 96217, NZ98/254 and M07-0241084*) at one 
month after the second vaccination for rMenB+OMV NZ (Visit 4) will be calculated. 
• 
For Group MenB+MenACWY and Group MenACWY: hSBA GMTs against each of the four 
serogroups A, C, W and Y for MenACWY at one month after the study vaccination of 
MenACWY (Visit 2) will be calculated. 
Between group assessment 
• 
The ratio of hSBA GMTs between Group MenB+MenACWY versus Group MenB when 
administered alone [Group MenB], at one month after the second vaccination of MenB will be 
calculated. 
• 
The ratio of hSBA GMTs between Group MenB+MenACWY versus Group MenACWY when 
administered alone [Group MenACWY], at one month after the (study) vaccination of 
MenACWY will be calculated. 
Secondary 
Within groups assessment 
• 
ELISA GMCs against each of the four serogroups A, C, W and Y at one month after the (study) 
vaccination of MenACWY for Groups MenB+MenACWY and MenACWY. The percentage of 
subjects (and 2-sided 95% Clopper-Pearson CIs) with hSBA titers ≥LLOQ for each and all 
serogroup B test strains at one month after the first and second vaccination for Groups 
MenB+MenACWY and MenB; and for serogroups A, C, W and Y at one month after the (study) 
vaccination for Groups MenB+MenACWY and MenACWY. 
• 
hSBA GMTs against each of the four serogroup B test strains at baseline and one month after 
first vaccination with rMenB+OMV NZ for Groups MenB+MenACWY and MenB. 
• 
hSBA GMRs (compared to baseline) against each serogroup B test strains at one month after 
the first and second vaccination for Groups MenB+MenACWY and MenB; and against 
serogroups A, C, W and Y at one month after the (study) vaccination for Groups 
MenB+MenACWY and MenACWY. 
• 
The percentage of subjects (and 2-sided 95% Clopper-Pearson CIs) with fourfold increase in 
hSBA titers relative to baseline for each serogroup B test strains at one month after the first 
and second vaccination for Groups MenB+MenACWY and MenB; and for serogroups A, C, W 
and Y at one month after the (study) vaccination for Groups MenB+MenACWY and MenACWY. 
Between group assessment 
• 
For all four serogroups A, C, W and Y, non-inferiority of the responses to MenACWY when 
given with rMenB+OMV NZ compared to MenACWY administered alone will be assessed in 
terms of ELISA GMCs. 
• 
The ratio of hSBA GMTs between Group MenB+MenACWY versus Group MenB when 
administered alone at one month after the first vaccination, will be calculated. 
• 
Between group differences (Group MenB+MenACWY vs Group MenB; and Group 
MenB+MenACWY vs Group MenACWY), at one month after the first and the second 
vaccination (as applicable) will be calculated, as well as their associated 95% CIs. 
*The NHBA indicator strain M07-0241084 may be subject to change during the study, before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
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10.3.4. 
Safety analyses 
All safety analyses will be performed on the exposed set. 
Endpoint 
Statistical Analysis Methods 
Primary 
Analysis of Solicited Adverse events 
• 
Frequencies and percentages of subjects 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 AEs reported from Day 1 (of vaccination) to Day 7 will be 
summarized for the intervals Day 1-3, Day 4-7, Day 1-7 by maximal severity and by group, 
excluding the 30-minute measurement, which will be summarized separately. The severity of 
solicited local AEs, including injection-site erythema, induration, and swelling will be 
summarized according to categories based on linear measurements as presented in Table 
29. 
• 
Injection site pain and systemic AEs (including fever) occurring up to 7 days after each 
vaccination will be summarized according to “mild”, “moderate” or “severe”. 
• 
Each solicited local and systemic AE will also be further summarized as “none” versus “any”. 
Use of antipyretics and analgesics will be summarized by frequency by type of use (prophylactic 
versus treatment) and percentage of subjects reporting use.  
• 
Body temperature will be summarized by 0.5 °C increments from 38.0 °C/100.4°F up to ≥40 
°C/104.0°F and will be broken down accordingly by route of measurement. 
Analysis of Unsolicited Adverse Events 
This analysis applies to all AEs occurring during the study, judged either as 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 AEs 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 Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The AEs will then 
be grouped by MedDRA preferred terms into frequency tables according to system organ class. 
All reported AEs, as well as AEs judged by the investigator as possibly 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 vaccination 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 group will be counted. 
Separate summaries will be produced for the following categories: 
• 
Serious adverse events (SAEs) 
• 
Adverse Events of Special Interest (AESIs) for subjects who received rMenB+OMV NZ 
• 
Adverse events that are possibly related to vaccine. 
• 
Adverse event leading to withdrawal. 
• 
Adverse events leading to a medically attended visit. 
• 
Data listings of all AEs will be provided by subject. In addition, AEs in the categories above 
will be provided as listed data. 
Between groups assessment 
No statistical tests for between-group comparisons will be performed. 
• 
The percentages of subjects with solicited local and systemic AEs during the 7 days 
(including the day of vaccination) following the first (Visit 1), the second (Visit 3) and the third 
(Visit 4) vaccination for all groups will be calculated. 
• 
The percentages of subjects with any unsolicited AEs (including all SAEs) during the 30 days 
(including the day of vaccination) following the first (Visit 1), the second (Visit 3) and the third 
(Visit 4) vaccination for all groups will be calculated. 
• 
The percentages of subjects with SAEs, AEs leading to withdrawal, and medically attended 
AEs, throughout the study period will be calculated. 
• 
The percentages of subjects with AESI throughout the study period will be calculated (for 
subjects who received rMenB+OMV NZ). 

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10.3.5. 
Other analyses  
Primary immunogenicity endpoints may be repeated using another panel of strains, if 
requested. 
10.3.6. 
Interim analyses 
All analyses will be conducted on final data and therefore no interim analyses are 
planned. 
10.4. 
Sequence of analyses 
The final study report will contain at least the final analyses of all primary and secondary 
endpoints. 
 
 
. 
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11. 
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. 
Centers for Disease Control and Prevention (CDC). Active Bacterial Core Surveillance 
Report, Emerging Infections Program Network, Neisseria meningitidis, 2015. 
Centers for Disease Control and Prevention Advisory Committee on Immunization 
Practices (ACIP). Licensure of a meningococcal conjugate vaccine for children aged 2 
through 10 years and updated booster dose guidance for adolescents and other persons at 
increased risk for meningococcal disease. MMWR. 2011; 60 (30):1018-1019. 
Centers for Disease Control and Prevention Advisory Committee on Immunization 
Practices (ACIP). Prevention and Control of Meningococcal Disease: Recommendations 
of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2013; 62 
(RR02):1-22. 
Clinicaltrials.gov [NCT02106390]. Safety and Immunogenicity of Novartis 
Meningococcal Group B Vaccine When Administered Concomitantly With Novartis 
MenACWY Conjugate Vaccine to Healthy Infants. Available at: 
https://www.clinicaltrials.gov/ct2/show/NCT02106390?term=v72_56&rank=1 (Accessed 
on: 23 Jan 2020). 
Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. 
Prevention and Control of Meningococcal Disease. Morbidity and Mortality Weekly 
Report. 2013; 62(2): 1-22. 
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
in May 2006); 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf  
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  
Harrison OB, Claus H, Jiang Y, et al. Description and nomenclature of N. meningitidis 
capsule locus. Emer Inf Dis. 2013; 19 (4):566-573. 
IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. 2011. 
Washington, DC: The National Academies Press. 
Khatami A and Pollard AJ. The epidemiology of meningococcal disease and the impact 
of vaccines. Expert Rev. Vaccines. 2010; 9(3): 285–298.  

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Metropolitan Atlanta Congenital Defects Program (MACDP) 
http://www.cdc.gov/ncbddd/birthdefects/documents/macdpcode0807.pdf  
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. 
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 
immunization. Ann Rheum Dis. 1986 Feb;45(2):110-4. 
World Health Organization (WHO). Meningococcal vaccines: WHO position paper, 
Weekly epidemiological record. No. 47, 2011, 86, 521–540. 

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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations, glossary of terms and 
trademarks 
12.1.1. 
List of abbreviations (Amended 11 October 2022)  
AE: 
Adverse Event 
AESI: 
Adverse Event of Special Interest 
CDC: 
Centers for Disease Control 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
CoP: 
Correlate of Protection 
COVID-19: 
Coronavirus disease 2019 
CSR: 
Clinical Study Report 
DTPa: 
Diphtheria, Tetanus and acellular Pertussis 
eCRF: 
electronic Case Report Form 
ELISA: 
Enzyme-Linked Immunosorbent Assay 
EoS: 
End of Study 
FAS: 
Full Analysis Set 
fHbp: 
Factor H binding protein 
GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration 
GMR: 
Geometric Mean Ratio 
GMT: 
Geometric Mean Titer 
GSK: 
GlaxoSmithKline 
hSBA: 
Human Serum Bactericidal Assay 
IAF: 
Informed Assent Form 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council on Harmonization 
IEC: 
Independent Ethics Committee 
IM: 
Intramuscular 
IMD: 
Invasive meningococcal disease 
IRB: 
Institutional Review Board 

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LAR: 
Legally Acceptable Representative 
LLOQ: 
Lower Limit of Quantitation 
LOD: 
Limit of Detection 
LSLV: 
Last Subject Last Visit 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MenACWY: 
Meningococcal serogroups A, C, W, and Y vaccine 
(Menveo) 
NadA: 
Neisseria Adhesin A 
NHBA: 
Neisserial Heparin Binding Antigen 
OMV: 
Outer Membrane Vesicles 
PCD: 
Primary Completion Date 
PI: 
Principal Investigator 
pIMD: 
Potential Immune-Mediated Disease 
PorA: 
Porin A 
rMenB+OMV NZ: 
Recombinant Meningococcal B with Outer Membrane 
Vesicle derived from Neisseria meningitidis serogroup B 
strain NZ98/254 (New Zealand strain) Vaccine (Bexsero) 
SAE: 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBIR: 
Source data Base for Internet Randomization  
SFU: 
Safety Follow-up 
SMP: 
Study Management Plan 
SmPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 

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12.1.2. 
Glossary of terms  
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 unfavourable 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. 
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. 
Blinding: 
A procedure in which 1 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 7.3 for details on observer-blinded studies). 
Certified copy: 
A copy (irrespective of the type of media used) of the original 
record that has been verified (i.e. by a dated signature or by 
generation through a validated process) to have the same 
information, including data that describe the context, content, 
and structure, as the original. 
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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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. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study (EoS)  
(Synonym of End of 
Trial) 
Last subject last visit (LSLV) (Visit X) or Date of the last 
testing/reading released of the Human Biological Samples or 
imaging data, related to primary and secondary endpoints, 
whichever occurs later. EoS must be achieved no later than 8 
months after LSLV. EoS cannot be before LSLV. 
Epoch: 
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, 
treatment, follow-up), which applies across all arms of a 
study. NOTE: Epoch is intended as a standardized term to 
replace: period, cycle, phase, stage. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the data 
produced 
eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the per-
protocol analysis (see Section 10.2 for details on criteria for 
evaluability). 
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 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.  

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Investigator: 
A person responsible for the conduct of the clinical trial at a 
trial site. If a trial is conducted by a team of individuals at a 
trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.  
The investigator can delegate trial-related duties and functions 
conducted at the trial site to qualified individual or party to 
perform those trial-related duties and functions 
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. 
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. 
Medically attended 
adverse events: 
Symptoms or illnesses requiring hospitalization, or emergency 
room visit, or visit to/by a health care provider. 
Menarche: 
Menarche is the onset of menses for the first time in a young 
female and is preceded by several changes associated with 
puberty including breast development and pubic hair growth. 
Menarche usually occurs within 1-2 years of breast 
development, thelarche. However, a young female can 
become pregnant before her first menses. Thus, a conservative 
definition of non-childbearing potential in a pre-menarcheal 
female is a young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable glandular 
breast tissue). 
Menopause: 
Menopause is the age associated with complete cessation of 
menstrual cycles, menses, and implies the loss of reproductive 
potential by ovarian failure. A practical definition accepts 
menopause after 1 year without menses with an appropriate 
clinical profile at the appropriate age e.g. > 45 years. 

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Pharmacogenomics: 
The International Council on Harmonization (ICH) E15 
Guidance for Industry defines pharmacogenomics as Study of 
variation of DNA and RNA characteristics as related to drug 
or treatment response. Pharmacogenetics, which is a subset of 
pharmacogenomics, is “the study of variations in DNA 
sequence as related to drug response.” Pharmacogenomic 
biomarkers include germline (host) DNA and RNA as well as 
somatic changes (e.g. mutations) that occur in cells or tissues. 
Pharmacogenomic biomarkers are not limited to human 
samples but include samples from viruses and infectious 
agents as well as animal samples. The term pharmacogenomic 
experiment includes both the generation of new genetic or 
genomic (DNA and/or RNA) data with subsequent analysis as 
well as the analysis of existing genetic or genomic data to 
understand drug or treatment response (pharmacokinetics, 
safety, efficacy or effectiveness, mode of action). Proteomic 
and metabolomic biomarker research are not 
pharmacogenomics. 
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 
amendment: 
The 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 
administrative 
change: 
A protocol administrative change addresses changes to only 
logistical or administrative aspects of the study.  
Qualified health care 
professional: 
A licensed or certified health care professional who is 
permitted by institutional policy to perform protocol required 
procedures, and who is identified on the Study Staff Signature 
Log. 
Randomization: 
Process of random attribution of treatment to subjects in order 
to reduce bias of selection. 

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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 1 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. 
Source data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
Source documents: 
Original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories and at medico-technical 
departments involved in the clinical trial). 
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. 
Sub-cohort: 
A group of subjects for whom specific study procedures are 
planned as compared to other subjects or a group of subjects 
who share a common characteristic (e.g. ages, vaccination 
schedule…) at the time of enrolment. 
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 vaccine(s) or 
as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Subset  
(Synonym of 
Immunosubset): 
Selection of blood samples among all blood sample collected 
at given time point(s) for testing by specific assay 

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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. 
Treatment number: 
A number identifying a treatment to a subject, according to 
treatment allocation. 
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. 
12.1.3. 
Trademarks 
Trademark Information 
Trademarks of the GSK group of 
companies 
 
Generic description 
Bexsero 
 
Meningococcal group B vaccine (rMenB 
proteins + OMV component, adsorbed on alum) 
Menveo 
 
Meningococcal Groups A, C, W-135 and Y 
Oligosaccharide Diphtheria CRM197 Conjugate 
Vaccine, MenACWY 
12.2. 
Appendix 2: Clinical laboratory assays 
MenB serum bactericidal assays using human complement (hSBA) - Bexsero: 
Serum bactericidal activity against rMenB+OMV NZ will be determined by using a 
validated manual (Tilt-based) hSBA against a standard panel consisting of 4 
meningococcal B indicator strains M14459, 96217, NZ98/254 and M07-0241084*. 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; strain NZ98/254 measures hSBA 
against PorA P1.4, the immunodominant antigen in the OMV NZ vaccine component; 
strain M07-0241084 measures hSBA against the 287 part of the 287-953 antigen, also 
known as NHBA. 
*The NHBA indicator strain M07-0241084 may be subject to change during the study, 
before clinical testing starts. In this case, this change will be documented in the clinical 
report. 
CCI

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MenACWY serum bactericidal assays using human complement (hSBA) - Menveo: 
• 
The induction of functional anti-meningococcal activity by bactericidal antibodies 
directed against N. meningitidis serogroups A, C, W and Y will be also determined 
by a validated hSBA with a new format, so-called agar overlay hSBA, using a higher 
throughput colony counting method compared to the manual hSBA based on the Tilt 
method. 
This new hSBA that has been validated for the 4 MenACWY serogroups is also based on 
the measurement of human complement-dependent bactericidal killing of meningococci. 
As with all functional hSBAs, the assay includes a first step of heat inactivation of the 
human serum samples to inactivate the endogenous complement, followed by serial 
dilution of the serum samples in which a fixed amount of bacteria and of human 
exogenous complement are added. The reactions are incubated to allow the association of 
meningococcal specific antibodies and their target antigen. The antibody-antigen 
complex activates the classical pathway of complement which ultimately results in 
bacterial lysis. 
As a measure of the meningococcal specific antibody titer of each serum sample, the 
MenACWY agar-overlay hSBA follows the principle of detecting and counting the 
surviving meningococcal bacteria after bacterial growth within solid agar media, using an 
automatic colony counter. 
MenACWY IgG ELISA 
• 
The anti-MenACWY total IgG antibody (Ab) concentrations will be measured by 
using a validated Enzyme-Linked Immunosorbent Assay (ELISA) to evaluate the 
immunogenicity of the capsular polysaccharides of serogroups A, C, W and Y in 
MenACWY vaccine. 
• 
As per recent recommendation from Authorities, this MenACWY IgG ELISA is 
under re-validation for the 4 serogroups in alignment with the most recent guidelines 
and accepted practices on assay validation. 
• 
The assay characteristics (e.g. validated assay cut-offs and units) for each of the 
serogroup will be determined during the course of the study at the time of the 
generation of new validated data. Any of these changes will be documented in a 
protocol amendment or in the clinical study report. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 6 of the protocol. 
The investigator is not allowed to do extra testing on samples outside of what has been 
agreed upon by the ethic committees. 

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12.3. 
Appendix 3: Clinical laboratories 
Table 24 
GSK Biologicals laboratories  
Laboratory 
Address 
GSK Biological’s Clinical Laboratory Sciences, 
Rixensart  
Biospecimen Reception-B7/44 
Rue de l'Institut, 89-B-1330 Rixensart-Belgium  
GSK Biological’s Clinical Laboratory Sciences, 
Wavre-Nord Noir Epine 
Avenue Fleming, 20-B-1300 Wavre-Belgium 
Table 25 
Outsourced laboratories (potential)  
Laboratory 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.4. 
Appendix 4: Study governance considerations 
12.4.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, Informed Consent Form (ICF) or Informed 
Assent Form (IAF), IB, and other relevant documents (e.g. advertisements) must be 
submitted, to an IRB/IEC by the investigator for review and approval. These 
documents will be signed and dated by the investigator before the study is initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects.  
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
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− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
12.4.1.1. 
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 (AE) 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 qualified 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/favourable 
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/favourable opinion. As soon as possible, the implemented deviation or change, 

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the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
• 
to the IRB/IEC for review and approval/favourable opinion, 
• 
to the Sponsor for agreement and, if required, 
• 
to the regulatory authority(ies). 
12.4.1.2. 
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. In cases when the amendment is required in order to protect 
the subject safety, the amendment can be implemented prior to IRB/EC approval. 
Notwithstanding, the need for formal approval of a protocol amendment, the investigator 
is expected to take any immediate action required for the safety of any subject included in 
this study, even if this action represents a deviation from the protocol. In such cases, GSK 
should be notified of this action, the IRB/EC at the study site, and, if required by local 
regulations, the relevant health authority) should be informed within 10 working days. 
12.4.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study.  
12.4.3. 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study.  
Subjects must be informed that their participation is voluntary.  
Eligible subjects may only be included in the study after providing written informed 
consent or assent. Before the start of the study, the investigator will have the informed 
consent and any other materials that will be provided to the subjects reviewed and 
approved by the IRB/EC. This review and approval will be documented and stored with 
other study documents. The investigator or designee must fully inform the subject or 
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 subject or the designee. The subject/designee must 

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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 and/or 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 
approximately 2 weeks prior to vaccination on day 1. If the subject and/or LAR(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. 
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject and/or each subject’s parent(s)/LAR(s) and subject informed assent, as 
appropriate, prior to participation in the study. 
The content of Informed Consent Form (ICF) must meet the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
GSK will prepare a model ICF which will embody the ICH GCP and GSK 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.  
In accordance with the ICH Harmonized Tripartite Guidelines for GCP, those subjects 
who can only be enrolled in the study with the consent of the subject’s legally acceptable 
representative (e.g. minors), should be informed about the study to the extent compatible 
with the subject’s understanding and, if capable, the subject should sign and personally 
date a written IAF. It is required that the assent be signed by each subject, if capable, in 
addition to the informed consent that is to be signed by his/her legal representative. It 
should be assessed whether an assent is required depending of the age of the study 
population and the local requirements. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
For subjects who become legally emancipated during the course of the study, e.g. become 
of the legal age of consent, re-consent is sought in accordance with local laws and 
regulations. The subject can provide consent by signing an ICF, similar to that provided 
to the parent(s)/LAR(s) at the study start, which summarizes the study and includes a 
consent statement and documents that the subject agrees to continue participating in the 
study. 
Subjects must be re-consented to the most current version of the ICF(s) or an ICF 
addendum during their participation in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s parent(s)/LAR(s).  
Subjects who are rescreened are required to sign a new ICF. 

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The study investigator is encouraged to obtain assent from the minor in addition to the 
consent provided by the LAR(s) when a minor is able to give assent to decisions about 
his/her participation in a study. The investigator is also accountable for determining a 
minor's capacity to assent to participation in a research study according to the local laws 
and regulations. 
12.4.4. 
Data protection 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
12.4.5. 
Publication policy 
GSK aims to publish the results of this study in searchable, peer reviewed scientific 
literature. GSK will target to submit within 18 months from LSLV for interventional 
studies and from the completion of the analysis for non-interventional studies and follows 
the guidance from the International Committee of Medical Journal Editors. 
12.4.6. 
Dissemination of clinical study data 
The key design elements of this protocol will be posted on the GSK Clinical Study 
Register and on publicly accessible registers including Clinicaltrials.gov. Where required, 
protocol summaries will also be posted on national or regional clinical trial registers or 
databases (e.g. EudraCT database) in compliance with the applicable regulations. 
GSK also assures that results will be submitted to Clinicaltrials.gov within the required 
time-frame, in compliance with the current regulations mentioned in the table below.  
At the time of study results posting, the full study protocol and SAP will also be posted 
on Clinicaltrials.gov.  
In addition, for studies that are in scope of the EU Clinical Trial Regulation, summaries 
of the results of GSK interventional studies (phase I-IV) in paediatric/adult population 
will be posted within defined timelines on the publicly EU Clinical Trial Register.  
If it is not possible to submit a summary of the results within the required timelines 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.  

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Clinicaltrial.gov 
EU 
Protocol summary 
Before enrolment of subjects 
As per CTA submission/Before 
enrolment of subjects 
Results summary 
Within 12 months of PCD (Primary and safety 
endpoint results)/Within 12 months of LSLV* (for 
secondary endpoint results) 
Within 6 months (for paediatric 
population studies)/Within 12 months 
(for adult population studies) of EoS*. 
* As defined in the study protocol. 
Under the framework of the SHARE initiative, anonymized patient-level data from GSK 
sponsored interventional studies that evaluate products will be made available within 6 
months of this publication to independent researchers whose research proposals have 
been approved by an independent panel. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, provided reasonable access to statistical 
tables, figures, and relevant reports. 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. 
12.4.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the trial and for 
archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
Essential documents for the trial may be added or reduced where justified (in advance of 
trial initiation) based on the importance and relevance to the trial. When a copy is used to 
replace an original document (e.g. source documents, eCRF), the copy should fulfil the 
requirements for certified copies. 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.  
The investigator must maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial subjects that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not 

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obscure the original entry, and should be explained if necessary (e.g. via an audit trail). 
Safety and rights of subjects must be protected and study be conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
Quality tolerance limits (QTLs) will be pre-defined in the Study Management Plan 
(SMP) to identify systematic issues that can impact participant safety and/or the 
reliability of study results. These pre-defined parameters will be monitored during the 
study. Important deviations from the QTLs and remedial actions taken will be 
summarized in the Clinical Study Report (CSR). 
Trial records and source documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 25 years from the issue of the final 
CSR/equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
12.4.8. 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Investigator should maintain a record of the location(s) of 
their source documents.  
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
Definition of what constitutes source data and source documents can be found in the 
section 12.1.2. 
12.4.9. 
Study and site closure 
GSK Biologicals or its designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of GSK Biologicals, provided there 
is sufficient notice given to account for patient’s safe exit from study participation. Study 
sites regular closure will be upon study completion. A study site is considered closed 
when all required data/documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 

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• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study treatment development 
At study conclusion, the investigator will: 
• 
Review data collected to ensure accuracy and completeness 
• 
Complete the Study Conclusion screen in the eCRF. 
12.5. 
Appendix 5: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting 
12.5.1. 
Definition of AE 
12.5.1.1. 
AE Definition 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
12.5.1.2. 
Events Meeting the AE Definition 
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
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, or the clinical sequelae of a suspected overdose of either study 
vaccines or a concurrent medication (overdose per se should not be reported as an 
AE/SAE). 
• 
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). 
• 
Medically attended visits related to adverse events (e.g. Hospital stays, physician 
visits and emergency room visits). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 12.5.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
Solicited AEs are derived from organized data collection systems, such as Subject Diaries 
or interview. 

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The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE.  
12.5.1.3. 
Events NOT Meeting the AE Definition  
• 
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. 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
12.5.2. 
Definition of SAE 
An 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, OR 
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, diarrhoea, 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. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 

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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 a SAE need not, 
by definition, be severe. 
SAEs will be captured both on the Vaccines Serious Adverse Event (VSAE) form as well 
as on the AE eCRF. All SAEs will be evaluated by the investigator for relationship of the 
event to study vaccine. 
12.5.3. 
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 
subjects/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 . 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported in parentheses below:  
The collected data will be entered into the Subject eDiary. Please see Section 12.5.8 for 
more detail.  
a. Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 26 
Solicited local adverse events* 
All age groups 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
Induration at injection site 
* Solicited local AEs occurring within 30 minutes after vaccination. 
b. Solicited systemic adverse events 
The following systemic AEs will be solicited: 

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Table 27 
Solicited systemic adverse events 
Adolescents (from 11 years of age) and adults 
Fatigue 
Fever (body temperature ≥ 38.0°C/100.4°F) 
Nausea 
Headache 
Myalgia 
Arthralgia 
Note: Subjects/parent(s)/LAR(s) will be instructed to measure and record the body 
temperature (preferably oral) in the evening. Should additional temperature 
measurements be performed at other times of day, subjects/parent(s)/LAR(s) will be 
instructed to record the highest temperature in the eDiary. 
The study staff must review the data entered into the Subject Diary as described in 
Section 12.5.8. 
12.5.3.1. 
Other Solicited Adverse Events 
The use of analgesics/antipyretics for either prophylactic or treatment purposes will be 
recorded as other solicited events in the Subject Diary (eDiary) and subsequently 
recorded onto the eCRFs and subject medical records. 
The study staff must review the data entered into the Subject Diary as described in 
Section 12.5.8. 
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 12.5.8) 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 12.5.8.3.3). 
• 
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 12.5.2). 
12.5.4. 
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 subjects/parent(s)/LAR(s) who has 
signed the informed consent. Please see Section 12.5.3.1 for more detail, where the 
criteria are listed. 
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 subjects/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. 

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Unsolicited AEs will be collected during interview with the subjects/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. 
All unsolicited AEs will be collected during the first 30 days after the first (Visit 1), 
second (Visit 3) and third (Visit 4) injection. Unsolicited AEs leading to vaccine/study 
withdrawal, medically attended AEs, AESI and SAEs will be collected during the entire 
study period starting from signature of informed consent until study termination. 
12.5.5. 
Adverse events of special interest (AESIs) 
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. 
12.5.5.1. 
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 signs/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. 
12.5.5.2. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AESIs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in the Table 28. Please refer to section 12.5.9.2 for 
reporting details. 
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. 

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Table 28 
List of potential immune-mediated diseases (pIMDs) 
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. 
• 
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. 
• 
Systemic lupus erythematosus and associated 
conditions 
• 
Systemic scleroderma (Systemic sclerosis), 
including: 
− 
Diffuse Scleroderma 
− 
CREST syndrome 
• 
Idiopathic inflammatory myopathies, including: 
− 
Dermatomyositis  
− 
Polymyositis  
• 
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. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin diseases (including 
pemphigus, pemphigoid and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localised Scleroderma (Morphoea). 

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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),  
− 
Churg–Strauss syndrome (allergic 
granulomatous angiitis or eosinophilic 
granulomatosis with polyangiitis),  
− 
Buerger’s disease (thromboangiitis obliterans),  
− 
Necrotising vasculitis (cutaneous or systemic),  
− 
anti-neutrophil cytoplasmic antibody (ANCA) 
positive vasculitis (type unspecified), 
− 
Henoch-Schonlein purpura (IgA vasculitis),  
− 
Behcet's syndrome, 
− 
Leukocytoclastic vasculitis. 
• 
Autoimmune haemolytic 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. 
• 
Ocular autoimmune diseases including: 
− 
Autoimmune uveitis  
− 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson syndrome. 
• 
Sjögren’s syndrome. 
• 
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. 
 

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When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as AESI 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. 
12.5.6. 
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, 
haematology, 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 12.5.1 and 12.5.2). 
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. However, clinically significant abnormal laboratory findings 
or other abnormal assessments that are associated with the disease being studied, unless 
judged by the investigator as more severe than expected for the subject’s condition, or 
that are present or detected at the start of the study and do not worsen, will not 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. 
12.5.7. 
Events or outcomes not qualifying as adverse events or serious 
adverse events 
12.5.7.1. 
Pregnancy 
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccines but may continue other study procedures at the 
discretion of the investigator. 
While pregnancy is not considered an AE or SAE, any adverse pregnancy outcome or 
complication or elective termination of a pregnancy for medical reasons will be recorded 
and reported as an AE or a SAE. 
Note: The pregnancy should always be recorded on an electronic pregnancy report. 
The following should always be considered as SAE and will be reported as described in 
Sections 12.5.9.1 and 12.5.9.4: 
• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 

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− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks’ cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).  
• 
Any congenital anomaly or birth defect identified in the offspring of a study subject 
(either during pregnancy, at birth or later) regardless of whether the foetus is 
delivered dead or alive. This includes anomalies identified by prenatal ultrasound, 
amniocentesis or examination of the products of conception after elective or 
spontaneous abortion. 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccines will be reported to GSK 
Biologicals as described in Section 12.5.9. While the investigator is not obligated to 
actively seek this information from former subjects, he/she may learn of a pregnancy 
through spontaneous reporting. 
12.5.8. 
Detecting and recording adverse events, serious adverse events 
and pregnancies 
An Electronic Diary (eDiary) hereafter referred to as Subject Diary will be used in this 
study to capture solicited and unsolicited adverse events. The subject or subject’s 
parent/LAR should be trained on how and when to complete each field of the Subject 
Diary. 
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. 
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/subject’s parent(s)/LAR(s), but if a person 
other than the subject/subject’s parent(s)/LAR(s) 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 eDiary throughout the 
relevant reporting period. 
The subject/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 adverse events is to be performed using the ruler 
provided by the site. 

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Subjects/parent(s)/LAR(s) will be instructed to measure and record the body temperature 
(preferably oral) in the evening. Should additional temperature measurements be 
performed at other times of day, subjects/parent(s)/LAR(s) will be instructed to record 
the highest temperature in the Subject eDiary. 
Subject eDiary assignment and use: 
• 
Each subject/subject’s parent(s)/LAR(s) will be assigned a Subject eDiary 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/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 eDiary throughout the reporting period (Visit 1-Visit 5). 
• 
The subject/subject’s parent(s)/LAR(s) will select an alarm time that suits their daily 
routines whilst ensuring compliance with protocol requirements. 
Subject eDiary instructions must ensure that the subject/subject’s parent(s)/LAR(s) 
understands the following: 
• 
Timely completion of the Subject eDiary on a daily basis is a critical component to 
study participation. 
• 
The Subject eDiary will allow certain time windows for completion of each day’s 
observations. 
• 
The Subject eDiary employs the use of audio-visual alarms to ensure timely 
completion of data entry. 
• 
The trained and assigned user of the Subject eDiary must not share access codes with 
anyone. 
• 
A helpdesk will be provisioned for users of Subject eDiary 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 eDiary itself must never be considered a substitute for direct medical 
care and any concerns must be communicated to site staff as soon as possible. 
− 
The subject/parent(s)/LAR(s) will be contacted by the site staff on Days 15, 75, 
105, 181, 271, 361, and 451 (or Days 15, 75, 105, 181, and 271 for subjects 
who have not reached Day 271 at the time this amendment takes effect via a 
scripted safety follow-up phone call. At, or in advance of each phone call the 
site will review the eDiary web-portal for responses entered by the 
subject/subject’s parent/LARs in order to solicit additional information during 
the phone call e.g. related to unsolicited adverse events, concomitant 
vaccinations/medication and medically attended events (Amended 11 October 
2022). 
• 
Any new safety information reported during the safety follow-up phone call or site 
visits (including a solicited adverse event) cannot be entered into the Subject eDiary. 
Such information must be described in the source documents as a verbally-reported 
event. Any adverse event reported in this fashion must be described as an unsolicited 
adverse event and therefore entered into the eCRF. 

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• 
The subject and/or subject’s parent(s)/LAR(s) will bring the eDiary at each visit. The 
eDiary will be collected by site staff at Day 121 (Visit 5). 
Subject Diaries will be the only source document allowed for solicited local 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 and systemic adverse events that were of 
concern to the subject. 
• 
No corrections or additions of data recorded by the subjects/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. Subjects/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. At the end of the study it is necessary for the 
investigator to acknowledge in the eCRF that the review of Subject Diary data has 
been performed for each subject. 
• 
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. 
12.5.8.1. 
Post-vaccination reminders 
Reminder calls or alerts are not intended to be an interview for collection of safety data. 
If the subject/subject’s parent(s)/LAR(s) wishes to describe safety information, this 
information should only be collected by a healthcare professional at the site, and the 
safety data described must be written down in the subject’s medical chart. 
12.5.8.1.1. Subject Diary Alerts 
The subject/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 though Day 7, after each vaccination visit. 
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: 

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• 
Non-compliance (i.e. failing to enter or transmit diary data), 
• 
Reporting of any severe solicited reactions, 
• 
Subject experienced an unsolicited adverse event 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 5.3 on the premature withdrawals from the study and Section 12.5.8.3 on 
the evaluation of Adverse Events for guidance on necessary action in the event of one of 
these alerts. 
12.5.8.2. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
All AEs during 30 days following administration of each dose of study vaccines must be 
recorded into the appropriate section of the eCRF, irrespective of intensity or whether or 
not they are considered vaccination-related.  
Any solicited AE that has not resolved within 30 days post vaccination and is reported 
during clinic visits or safety follow-up calls will be entered into the subject’s eCRF as an 
unsolicited AE. It will also be included in the subject’s source documents at the site by 
the investigator/site staff as a verbally reported event. It will not be included in the 
Subject eDiary. These AEs will be analysed as unsolicited AEs (i.e. in the Unsolicited 
Safety Set). 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccines and will end 12 months following administration of the last dose of study 
vaccines for each subject. See Section 12.5.9 for instructions on reporting of SAEs. 
However, any SAEs assessed as related to study participation (e.g. study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK Biologicals product will be recorded from the time a subject consent to participate 
in the study. 
All AEs occurring after the ICF is signed but prior to receiving study vaccine will be 
documented as an AE and recorded within source document and eCRF. However, any 
AEs occurring prior to receipt of any study vaccine will be analyzed separately from 
“treatment emergent” AEs (AEs occurring after administration of the first study vaccine). 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccines until 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 Biologicals 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. 

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The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccines and will end 12 months following administration of the last dose of study 
vaccines. See section 12.5.9 for instructions on reporting of pregnancies. 
The time period for collecting and recording of AESIs will begin at the first receipt of 
study vaccines and will end 12 months following administration of the last dose of study 
vaccines. See section 12.5.9.5 for instructions on reporting of AESIs. 
12.5.8.3. 
Evaluation of adverse events and serious adverse events 
12.5.8.3.1. Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject or the subject’s parent(s)/LAR(s) 
should be asked a non-leading question such as: 
‘Have you felt different in any way since receiving the vaccines or since the previous 
visit?’ (for subjects above 18 years of age) 
OR 
‘Has your child acted differently or felt different in any way since receiving the vaccines 
or since the last visit?’ (for subjects below 18 years of age) 
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. 
12.5.8.3.2. Assessment of adverse events 
1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 

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Table 29 
Intensity scales for solicited symptoms in adults and children of 6 
years of age or more  
Adolescents (from 11 years of age) and adults 
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing 
normal every day activities. 
 
2 
Moderate: Painful when limb is moved and interferes with 
every day activities. 
 
3 
Severe: Significant pain at rest. Prevents normal every 
day activities. 
Injection Site Induration, 
Swelling, Erythema 
0 
1 – 24 mm 
1 
25 - 50 mm 
2 
51 - 100 mm 
3 
>100 mm 
Temperature* 
0 
< 38.0°C (100.4°F) 
 
1 
≥ 38.0 - 38.9°C (100.4 – 102.02°F) 
 
2 
≥ 39.0 - 39.9°C (102.2 – 103.82°F) 
 
3 
≥ 40.0°C (104.0°F) 
Headache 
0 
Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Nausea  
0 
Normal 
 
1 
Mild: Nausea that is easily tolerated 
 
2 
Moderate: Nausea that interferes with normal activity 
 
3 
Severe: Nausea that prevents normal activity 
Generalized Myalgia 
0 
Normal 
 
1 
Mild: Myalgia that is easily tolerated 
 
2 
Moderate Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Generalized Arthralgia 
0 
Normal 
 
1 
Mild: Arthralgia that is easily tolerated 
 
2 
Moderate: Arthralgia that interferes with normal activity 
 
3 
Severe: Arthralgia that prevents normal activity 
*Fever is defined as temperature 38.0°C/100.4°F. The preferred location for measuring temperature in this study will 
be the oral cavity for subjects. 
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 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 intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
(In adults/adolescents, such an AE would, for example, prevent 
attendance at work/school and would necessitate the 
administration of corrective therapy.) 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets 1 of the pre-defined 
outcomes as described in Section 12.5.2. 
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) 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 Summary of Product Characteristics (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 1 of the criteria 
used when determining regulatory reporting requirements. 
All solicited local (injection site) reactions 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 vaccines 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. 

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If an event meets the criteria to be determined as ‘serious’ (see Section 12.5.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
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). 
AEs will also be evaluated by the investigator for the co-existence of any of the other 
following conditions: 
“Medically attended AEs”: an AE that leads to a visit to a healthcare provider.  
AEs leading to withdrawal: AEs leading to study or vaccine withdrawal. 
If solicited or unsolicited AEs have been reported and the subject and/or 
parent(s)/LAR(s) indicated that the symptoms required medical attendance or were of 
concern, the subject and/or parent(s)/LAR(s) must be contacted for further information. 
When the subject and/or parent(s)/LAR(s) is contacted for any of these reasons, the 
contact must be documented in the subject’s source documentation. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. 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.  
The end date of AEs ongoing at the time of each subject’s last visit and judged by the 
investigator as not chronic or stable should be documented in the source documents. 
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. 

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• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
12.5.8.3.3. Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject/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. 
12.5.8.4. 
Recording of AEs related to COVID-19 
For COVID-19 infection-related AEs, sites should follow routine AE/SAE processes as 
outlined in the protocol, using the following terms according to the latest COVID-19 case 
definitions criteria in effect at the institution: 
• 
Suspected COVID-19 case 
• 
Probable COVID-19 case 
• 
Confirmed COVID-19 case  
If subject is diagnosed with COVID-19 as above, report each occurrence in the COVID-
19 Coronavirus Infection Assessment form. In addition, complete for each occurrence as 
AE on the Non-Serious Adverse form or as SAE on the Expedited Adverse Event Report 
form (depending on the level of seriousness as assessed by the Principal Investigator or 
delegate). Please also report the relevant medications related to this event. Follow the 
guidelines applicable for those forms on how to record COVID-19. 
12.5.9. 
Reporting of serious adverse events, pregnancies, and other 
events 
12.5.9.1. 
Prompt reporting of serious adverse events, pregnancies, and other 
events to GSK Biologicals  
SAEs that occur in the time period defined in Section 12.5.8 will be reported promptly to 
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 12.5.8 will be reported 
promptly to GSK within the timeframes described in Table 17, once the investigator 
becomes aware of the pregnancy.  
AESIs that occur in the time period defined in Section 12.5.8 will be reported promptly to 
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a AESIs. 

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12.5.9.2. 
SAEs requiring expedited reporting 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. 
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 SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
12.5.9.3. 
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.  
12.5.9.4. 
Completion and transmission of pregnancy reports to GSK Biologicals  
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
within 24 hours. 
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
12.5.9.5. 
Reporting of AESI’s 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. The report 
allows 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, in accordance with the AESIs 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. 

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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 12.5.9.3 for back-up system in case the electronic reporting system does 
not work. 
12.5.10. 
Updating of SAE, pregnancy, and AESI information after removal 
of write access to the subject’s eCRF 
When additional SAE, pregnancy, 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 17. 
12.5.11. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
12.5.11.1. Follow-up of adverse events and serious adverse events  
12.5.11.1.1. 
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 17). 
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/contact 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 the 
last visit/contact of the subject. 
12.5.11.1.2. 
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.  
• 
with other non-serious AEs, until one year after LSLV or if the subject is lost to 
follow-up. 

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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 and/or pregnancy 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. 
12.5.11.2. Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the paper pregnancy follow-up 
report/electronic pregnancy report and the Expedited Adverse Events Report if 
applicable. Generally, the follow-up period doesn’t need to be longer than 6 to 8 weeks 
after the estimated date of delivery. 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE. 
The following should always be considered as SAE. 
• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of fetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure. It is recognized that national regulations 
might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect [as per Metropolitan Atlanta Congenital 
Defects Program [MACDP] guidelines] identified in the offspring of a study subject 
(either during pregnancy, at birth or later) regardless of whether the foetus is 
delivered dead or alive. This includes anomalies identified by prenatal ultrasound, 
amniocentesis or examination of the products of conception after elective or 
spontaneous abortion. 

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12.6. 
Appendix 6: Contraceptive guidance and collection of 
pregnancy information 
12.6.1. 
Definitions 
12.6.1.1. 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
12.6.1.1.1. Women in the following categories are not considered WOCBP 
• 
Premenarchal 
Menarche is the onset of menses for the first time in a young female and is preceded by 
several changes associated with puberty including breast development and pubic hair 
growth. Menarche usually occurs within 1-2 years of breast development, thelarche. 
However, a young female can become pregnant before her first menses. Thus, a 
conservative definition of non-childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as evidenced by lack of breast 
development (palpable glandular breast tissue). 
• 
Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of subject’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use 1 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 

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12.6.2. 
Contraception guidance 
• 
Female subjects of childbearing potential are eligible to participate if they agree to 
use an adequate contraception consistently and correctly according to the methods 
listed in GSK list of highly effective contraceptive methods as described in Table 30. 
Table 30 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
• 
oral 
• 
intravaginal  
• 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.)  
Male partner sterilization prior to the female subject’s entry into the study, and this male is the sole 
partner for that subject, 
(The information on the male sterility can come from the site personnel’s review of the subject’s 
medical records; medical examination and/or semen analysis, or medical history interview provided 
by her or her partner). 
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.)  
NOTES:  
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects in clinical studies.  
b. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilised during the 
treatment period and for at least 2 months after the last dose of study treatment.  

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12.6.3. 
Collection of pregnancy information 
12.6.3.1. 
Female Subjects who become pregnant 
• 
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a subject's pregnancy.  
• 
Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on subject and neonate, which will be 
forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in 12.5.9. While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting.  
Any female subject who becomes pregnant while participating will discontinue study 
treatment. 
12.7. 
Appendix 7: Definition of medical device AE, adverse device 
effect (ADE), serious adverse device effect (SADE) and 
unanticipated SADE (USADE) 
12.7.1. 
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 or not considered related to a medical device. 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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12.7.2. 
Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
c. 
Led to death  
d. 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 hospitalisation. Planned hospitalisation 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 
e. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
f. 
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, intervention had not occurred, 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 risk analysis report (see Section 
3.3). 
12.7.3. 
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 8.4.6.1. 
• GSK will review all device deficiencies and 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. 

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12.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 7 
11 October 2022 
Amendment 6 
21 June 2022 
Amendment 5 
13 April 2021 
Amendment 4 
26 November 2020 
Amendment 3 
29 September 2020 
Amendment 2 
23 January 2020 
Amendment 1 
14 August 2019 
Original Protocol 
28 June 2016 
Overall Rationale for the Amendments: 
Section # and Name 
Description of Change 
Brief Rationale 
Amendment 7: 
Contributing authors 
Updated job titles 
Internal update in name of job titles 
Sponsor signatory page  Updated job title 
Internal update in name of job title 
Section 1 
Updated objectives and endpoints table 
Updated overall design figure 
Updated text 
To incorporate 2 additional primary 
endpoints 
To incorporate a shortened safety follow-up 
into the overall design figure 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
safety follow-up (SFU) 5 (Day 271) at the 
time this amendment takes effect 
Table 3 
Added a bullet mark for study conclusion 
also under SFU 5 and added a footnote 
with details 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 4 
Updated 
To extend the visit window to 28 days post 
reference day 
Table 5 
Addition of footnote 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 6 
Updated 
To incorporate 2 additional primary 
endpoints 
Figure 1 
Updated 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2 
Section 5.4 
Section 7.5.1 
Section 8.4.3 
Section 8.6 
Section 12.5.8 
Addition of text 
To introduce a shortened safety follow-up 
period in subjects who have not reached 
SFU 5 (Day 271) at the time this 
amendment takes effect 
Table 14 
Table revised 
To provide clarity on what assay to be 
performed at which visit. 
Table 15 
Table title edited 
To clarify that study conclusion at Day 451 
is applicable in subjects who have crossed 
Day 271 
Table 16 
New table created 
 
To clarify that study conclusion at Day 271 
is applicable in subjects who have not 
reached Day 271 
Amendment 6: 
Contributing authors 
Names of CEPL, CRDL, SDL, LDL, 
ODM, CTSM, Safety Scientist, 
Statistician, Lead Statistician, GRA and 
Global patent representative updated. 
Change in study team members. 
Sponsor signatory page  Name of sponsor signatory updated 
Change in study team members. 
Table 3 
Addition of footnote 
To clarify that the recording of SAEs related 
to study participation starts from the 
signature of the ICF. 
Section 5.2 
Section 12.1.2 
Definition of End of Study updated. 
This update in definition accounts for 
instances where LSLV precedes the last 
date of testing/reading released of the 
human biological samples or imaging data. 
Section 6.2.1 
Deletion of the exclusion criterion about 
obesity. 
Both Bexsero and Menveo are already 
licensed in both the US and Italy, neither 
product labels list individuals with obesity 
as a contraindication. 
Section 6.2.2 
Addition of MenQuadfi to the list of 
quadrivalent Meningococcal vaccines 
MenQuadfi was approved in the US in 2021 
Section 8.3.2.1 
Addition of the word ‘any’ in from of 
vaccination. 
To clarify that sample collection for 
immunogenicity assessments should be 
done prior to any vaccination. 
Table 15 
Addition of medically attended AEs 
 
 
Addition of footnote 
To clarify that safety information on 
medically attended AEs is also collected. 
 
To clarify that the recording of SAEs related 
to study participation starts from the 
signature of the ICF. 
Section 11 
References updated 
Alignment of COVID-19 reporting 
requirement to the local guidelines 
Table 16 
Section 12.5.9.4 
Section 12.6.3.1 
 
Modification of timeframe to report 
pregnancies 2 weeks to 24 hours 
To align with industry standards for 
reporting pregnancies. 
Section 12.1.1: 
Addition of LSLV 
LSLV features in the body of the document 
Section 12.5.8.4 
Addition of wording on recording of AEs 
related to COVID-19 
Alignment of COVID-19 reporting 
requirement to the local guidelines 
Section 12.5.8.4.1 
Deletion of WHO Case Definition 
Alignment of COVID-19 reporting 
requirement to the local guidelines 
Amendment 5: 
Co-ordinating author(s) 
Name of science writers updated. 
Change in study team members. 

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Section # and Name 
Description of Change 
Brief Rationale 
Contributing authors 
Name of LDL updated. 
Change in study team members 
Sponsor signatory page 
and investigator 
agreement page 
Addition of note on alternative signature 
process. 
Addition of bullet point. 
Update in the protocol template 
instructions. 
Section 1 
Table 6 
Table 13 
Table 14 
Section 10.3.3 
Section 12.2 
Footnote and text updated. 
Clarification that reporting of changes to the 
NHBA strain during the study will be 
documented in the clinical study report. 
Table 3 
Modification of ICF signature window.  
Team agreement to provide a wider window 
to increase operational feasibility. 
Section 6.3 
Addition of wording on emergency mass 
vaccination. 
Update in the protocol template wording. 
Table 9 
Addition of new row “Product Category’. 
Update in the protocol template instructions 
to define the product category of each study 
intervention administered in the study: 
Section 7.3.1 
Explanatory text added to provide the 
criteria for emergency unblinding. 
Text included to follow-up on a specific 
question raised by AIFA Health Authority on 
08 January 2021 
Table 13 
 
 
 
 
Table 14 
Deletion of column: Components priority 
rank. 
Simplification of the serological section. 
Table 15 
Addition of footnote 
Clarification on how solicited AEs that 
continue beyond day 7 after vaccination will 
be handled. 
Section 8.4.7 
Addition of new section on medical 
device deficiencies. 
Update in the protocol template wording. 
Section 10.1.1.1 
Removal of order of statistical testing of 
the strains. 
Simplification of the statistical strategy. 
Section 10.1.2 
Removal of order of statistical testing of 
the strains. 
Simplification of the statistical strategy. 
Section 12.1.2 
Addition of two new terms in glossary of 
terms. 
Update in the protocol template wording. 
Section 12.2 
Removal of reference to Axiolab Image 
analysis System 
Use of alternative equipment planned 
Table 23 
 
 
 
Table 24 
  
 
 
Section 12.4.3 
Modification of ICF signature window.  
Team agreement to provide a wider window 
to increase operational feasibility. 
Section 12.5.3 
Addition of text.  
Clarification on how solicited AEs that 
continue beyond day 7 after vaccination will 
be handled. 
Section 12.5.3.1 
Deletion of bullet point.  
The deleted bullet point was incorrect. 
Section 12.5.5.1 
Additional text added to ‘threshold of 
duration of 6 weeks.  
This is to clarify that threshold of duration 
pertains to signs/symptoms of arthritis.   
Section 12.5.8.2 
Addition of paragraph. 
Clarification on how solicited AEs that 
continue beyond day 7 after vaccination will 
be handled. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.7 
Addition of new appendix. 
Update in the protocol template to cover 
FDA requirement for medical device 
deficiencies reporting. 
Amendment 4: 
Contributing authors 
Name of CRDL 
Name of CTSM 
Change in study team members 
Sponsor signatory page 
and investigator 
agreement page 
Short title replaced by Title. 
No change in the wording 
Change in the protocol template 
instructions 
A note in Table 3 under 
laboratory assay 
Deletion of Visit 2 from the note 
Incorrect sentence, no vaccine 
administration on Visit 2. 
Section 8.3.2.1 
Additional text added to clarify the clinical 
circumstances that may warrant delay in 
blood sample collection for 
immunogenicity assessments 
Use of antibiotics may alter the 
immunogenicity assessments 
Section 10.1.2 
Correction of treatment group names for 
the secondary objective, hypothesis 3, 
under the standard deviations for hSBA 
titer paragraph 
Typographical error 
Section 12.1.1 
Addition of 2 abbreviations 
Additional texts in the body of document 
Section 12.2 
Updated text under clinical laboratory 
assays for new hSBA for Menveo 
Update in the status of the laboratory assay 
Section 12.4.2 
Updated text for the financial disclosure 
description 
Update in the protocol template wording 
Section 12.4.7 
Text on quality tolerance limits (QTL) was 
added 
Update in the protocol template wording 
Amendment 3: 
Co-ordinating author(s) 
Name of science writer updated 
Change in study team members 
Contributing authors 
Names of CEPL, ODM, CTSM, CLS and 
Safety representatives updated. 
Change in study team members 
Table 3 Schedule of 
Activities 
Reference section updated for symptom-
directed physical examination. 
Footnote * added regarding recording of 
COVID-19 infection related AEs and 
SAEs. 
Symptom-directed physical examination is 
now described only in Section 8.2.4. 
COVID-19 infection-related AEs/SAEs to be 
also recorded in a separate eCRF page. 
Table 3 Schedule of 
Activities 
Visit window row deleted and reference 
to Table 4 and Table 5 included. 
A separate table for intervals between visits 
and telephone contacts has been added. 
Table 5 Intervals 
between study visits 
and safety follow-up 
calls 
A separate table for intervals between 
visits and telephone contacts has been 
added. 
Table added to clarify the windows for 
safety follow-up (SFU) calls are in relation 
to previous visit.. 
Section 5.2 Overall 
design 
Primary Completed Date updated 
Data collected at Month 15 (Day 451) is 
part of the primary outcome. Hence PCD 
date was updated as Study termination-call 
Day 451. 
Section 6.3 Criteria for 
temporary delay for 
enrolment, vaccination 
and/or blood sampling 
Criteria for temporary delay for 
enrolment, vaccination and/or blood 
sampling due to COVID-19 were added 
Criteria added to clarify temporary delay for 
enrolment, vaccination and/or blood 
sampling procedures due to COVID-19 
Table 9 Treatments 
administered 
Entry for Menveo and Bexsero was 
updated and a footnote was added. 
Change in the formulation description and 
presentation description was done to align 
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Section # and Name 
Description of Change 
Brief Rationale 
Entry for placebo volume was updated 
and a footnote was added. 
with the internal vaccine database 
dictionary. 
 
 
 
Change in placebo volume from 0.5 mL to 
0.65 mL to be aligned with the certificate of 
analysis. A footnote was added in order to 
avoid future amendments if the placebo 
volume were to vary in different batches 
and also to clarify that the volume of the 
pre-filled syringe administered will be within 
a range and the full volume should be 
injected. 
Table 10 Administration 
and Laterality 
A footnote was added. 
Laterality defined due to multiple 
vaccinations at different visits. 
Section 7.3.1 
Emergency unblinding 
– Table 11 Contact 
information for 
emergency unblinding 
US and Italy toll-free numbers updated. 
Reference added to SPM for individual 
country numbers. 
Helpdesk numbers have been updated. 
Section 8.1 
Section updated 
Paragraph added for special circumstances 
such as COVID-19. 
Section 8.2.3 Medical 
history 
Section updated 
Description on physical examination was 
deleted 
Section 8.2.4 Physical 
examination 
Section updated 
Description on physical examination in 
Section 8.2.3 was moved to Section 8.2.4 
Section 8.3 Efficacy 
assessments 
Section updated 
The wording “future research” was updated 
as “further research” to align to the most 
recent GSK protocol and ICF template 
wording. 
Table 15 Reporting 
periods for collecting 
safety information 
Footnote added 
A footnote was added to clarify including 
COVID-19 infection related AEs will be 
collected. 
Section 8.7 Study 
procedures during 
special circumstances 
Section added. 
Certain study procedures can be adapted 
during special circumstances such as 
COVID-19 pandemic. 
Section 11 References 
Section updated 
2 new references were added 
Section 12.1.1 List of 
abbreviations 
List updated 
List was updated to include COVID-19 
expansion. 
Section 12.5.8 
Detecting and recording 
adverse events, serious 
adverse events and 
pregnancies 
When a person other than the 
subject/subject’s parent(s)/LAR(s) helps 
in the completion of the eDiary, their 
identity must be documented in the 
subject’s source record and not in the 
subject diary. 
As there is no option available to enter a 
name in eDiary, it was agreed to include the 
instruction for training and capturing 
individual’s information in source document. 
Section 12.5.8.4 
Section added 
Section added to include recording of AEs 
related to COVID-19. 
Section 12.5.8.4.1 
Section added 
Section added to describe WHO case 
definitions for COVID-19. 
Amendment 2: 
Scientific rationale for 
Inclusion criteria 
(Section 6.1) 
Modified the inclusion criteria for subject 
selection. Subjects enrolled will be 
required to have received a priming dose 
of MenACWY, Menveo or Menactra at 
The inclusion of a booster recommendation 
in Menveo’s US Prescription Insert, with the 
recommendation to administer the booster 
at least 4 years after the priming dose, has 
only been approved by US FDA in 
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Section # and Name 
Description of Change 
Brief Rationale 
least 4 years prior to informed consent, 
instead of 3 years prior. 
December 2019. As a result, the company 
intends to align the inclusion criterion in the 
V72_79 study with the recently introduced 
booster recommendation in the US, and 
amend the protocol accordingly to allow 
inclusion of subjects who have received a 
meningococcal ACWY vaccine 4 years or 
greater in the past. 
Amendment 1 
Across the document 
Assay validations have been updated: 
• 
Develop, validate, and use a new 
“agar overlay” serum bactericidal 
assay using human complement 
(hSBA) and automated colony 
counting method in order to 
quantify serogroup-specific 
immunogenicity of the MenACWY 
vaccine against N. meningitidis 
serogroups A, C, W and Y 
(MenACWY agar-overlay hSBA); 
• 
Validate the MenB manual (Tilt) 
hSBA for the use of the M14459 
(fHbp), 96217(NadA) NZ98/254 
(PorA) and M07-0241084 (NHBA) 
indicator strains to measure 
immunogenicity of Bexsero against 
N. meningitidis serogroup B. 
• 
Modification of the 4-fold increase 
in post-vaccination hSBA titer 
definition when the pre-vaccination 
titer is below the limit of detection. 
• 
Modification of the population set 
to be used for safety analysis; 
exposed set is to be used for all 
safety analyses. 
To support the primary endpoint analyses 
of this study and based on the most recent 
expectations set by Center for Biologics 
Evaluation & Research (CBER) 
recommendation. 
Detailed description of Protocol Amendment 7: 
Additional texts are presented in bold italics and deleted texts are presented in 
strikethrough. 
• 
Title page: Contributing authors  
− 
 Clinical Sciences Lead 
Clinical Research and Development Lead 
− 
, 
Local Delivery Lead 
− 
 SERM Safety Scientist 
− 
 
− 
, SERM Principal Scientist 
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− 
, Clinical Project Lead Clinical and 
Epidemiology Project Leader (CEPL)from Protocol Amendment 3 onwards and 
, Associate Clinical Project Lead  Associate Clinical and 
Epidemiology Project Leader (CEPL) from Protocol Amendment 6 onwards 
• 
Protocol amendment & Sponsor signatory page: Sponsor signatory – Alessandro Ble, 
Director, Associate Clinical Project Lead Associate Clinical and Epidemiology 
Project Lead 
• 
Section 1: Synopsis 
 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of rMenB+OMV 
NZ and MenACWY, when administered concomitantly 
or alone, in healthy subjects 16-18 years of age. 
• 
The frequencies and percentages of subjects with 
solicited local (i.e., injection site pain, erythema, 
swelling, induration) and systemic (i.e., fever 
[temperature ≥ 38.0°C/100.4°F], nausea, fatigue, 
myalgia, arthralgia, headache) adverse events 
(AEs) during the 7 days (including the day of 
vaccination) following the first (Visit 1, Day 
1/Month 0), the second (Visit 3, Month 2) and the 
third (Visit 4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
any unsolicited AEs (including all SAEs), AEs 
leading to withdrawal and medically attended AEs 
during the 30 days (including the day of 
vaccination) following the first (Visit 1, Day 
1/Month 0), the second (Visit 3, Month 2) and the 
third (Visit 4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
SAEs, AEs leading to withdrawal, and medically 
attended AEs, throughout the study period (Day 
1/Month 0 to Month 915). 
• 
The frequencies and percentages of subjects 
(who received rMenB+OMV NZ) with AESI 
throughout the study period (Day 1/Month 0 to 
Month 915). 
• 
Among subjects who are followed for 12 
months after their last dose: 
o 
The frequencies and percentages of 
subjects with SAEs, AEs leading to 
withdrawal, between SFU 5/Month 9 
and SFU 7/Month 15.  
o 
The frequencies and percentages of 
subjects (who received rMenB+OMV 
NZ) with AESI between SFU 5/Month 9 
and SFU 7/Month 15. 
 
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Overall design:  
 
Duration of the study: 
Epoch 002: Safety follow-up period starting at Visit 4 (Day 91) and ending at Study 
termination-call (Day 451 [Month 15]) or (Day 271 [Month 9]) for subjects who have 
not reached Day 271 at the time this amendment takes effect. 

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• 
Table 3: Schedule of Activities 
Study Conclusion¥ 
 
 
 
 
 
 
 
 
 
● 
 
● See Section 5.4 for more 
information. 
Footnote: ¥ Safety follow up and contact will terminate at SFU 5 for subjects who have not reached SFU 5 at the 
time this amendment takes effect. Please note that for these subjects, the termination call would be performed 
at SFU 5.  
• Table 4: Intervals between study visits 
Interval 
Length of interval 
Allowed interval 
Visit 1 → Visit 2 
30 days  
23 - 58 51days  
Visit 1 → Visit 3 
60 days 
53 - 88 81days 
Visit 3 → Visit 4 
30 days 
23 - 58 51days 
Visit 4 → Visit 5 
30 days 
23 - 58 51days 
• Table 5: Intervals between study visits and safety follow-up calls 
Footnote: *Safety follow up will terminate at SFU 5 for subjects who have not reached SFU 5 at the time 
this amendment takes effect. 
 
• Table 6: Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of rMenB+OMV 
NZ and MenACWY, when administered concomitantly 
or alone, in healthy subjects 16-18 years of age. 
• 
The frequencies and percentages of subjects with 
solicited local (i.e., injection site pain, erythema, 
swelling, induration) and systemic (i.e., fever 
[temperature ≥ 38.0°C/100.4°F], nausea, fatigue, 
myalgia, arthralgia, headache) adverse events 
(AEs) during the 7 days (including the day of 
vaccination) following the first (Visit 1, Day 
1/Month 0), the second (Visit 3, Month 2) and the 
third (Visit 4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
any unsolicited AEs (including all SAEs), AEs 
leading to withdrawal and medically attended AEs 
during the 30 days (including the day of 
vaccination) following the first (Visit 1, Day 
1/Month 0), the second (Visit 3, Month 2) and the 
third (Visit 4, Month 3) vaccination for all groups. 
• 
The frequencies and percentages of subjects with 
SAEs, AEs leading to withdrawal, and medically 
attended AEs, throughout the study period (Day 
1/Month 0 to Month 915). 
• 
The frequencies and percentages of subjects 
(who received rMenB+OMV NZ) with AESI 
throughout the study period (Day 1/Month 0 to 
Month 915). 
• 
Among subjects who are followed for 12 
months after their last dose: 
o 
The frequencies and percentages of 
subjects with SAEs, AEs leading to 

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Objectives 
Endpoints 
withdrawal, between SFU 5/Month 9 
and SFU 7/Month 15.  
o 
The frequencies and percentages of 
subjects (who received rMenB+OMV 
NZ) with AESI between SFU 5/Month 9 
and SFU 7/Month 15. 
 
• Figure 1: Study design overview 
 
 
• Section 5.2.1: Overall design  
− Epoch 002: Safety follow-up period starting at Visit 4 (Day 91) and ending at 
Study termination-call (Day 451 [Month 15]) or (Day 271 [Month 9]) for 
subjects who have not reached Day 271 at the time this amendment takes effect. 

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− Primary completion Date (PCD): Study termination-call (Day 451) or (Day 271 
[Month 9]) for subjects who have not reached Day 271 at the time this 
amendment takes effect.  
− 
End of Study (EoS): Last subject last visit (LSLV) [last concluding contact on 
Day 451 (Month 15) or Day 271 (Month 9) for subjects who have not reached 
Day 271 at the time this amendment takes effect or Date of the last 
testing/reading released of the Human Biological Samples or imaging data, 
related to primary and secondary endpoints, whichever occurs later. EoS must 
be achieved no later than 8 months after LSLV. EoS cannot be before LSLV 
• Section 7.5.1: Recording of concomitant medications/products and concomitant 
vaccinations 
Relevant medications/products administered during the period (Day 1 to Day 451) or 
(Day 271) for subjects who have not reached Day 271 at the time this amendment 
takes effect.  
Any concomitant vaccination administered in the period starting 14 days before the 
first dose of study vaccines and ending at the last study contact (Day -14 to Day 451) 
or (Day 271) for subjects who have not reached Day 271 at the time this 
amendment takes effect. 
• Table 14: Immunological read-outs 
Blood sampling timepoint 
Subset/Sub-
cohort Name 
No. of 
subjects Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-Vacc 
Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
Visit 2 (Day 31) 
Post Vacc1 Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
ELISA IgG anti meningococcal A, C, W, Y 

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Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
ELISA IgG anti meningococcal A, C, W, Y 
Visit 4 (Day 91) 
Post Vacc2 
Group 
MenB+MenACWY  315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
Group MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
*The NHBA indicator strain M07-0241084 may be subject to change during the study before clinical testing starts. In 
this case, this change will be documented in the clinical report. 
• Section 8.4.3: Safety Follow-up calls 
A total of seven safety follow-up calls will be performed. Safety follow-up calls will 
be performed on Day 15, Day 75, Day 105, Day 181, Day 271, Day 361 and Day 451 
(study termination). For subjects who have not reached Day 271 at the time this 
amendment takes effect, a total of 5 safety follow-up calls will be performed. Safety 
follow-up calls will be performed on Day 15, Day 75, Day 105, Day 181, and Day 
271 (study termination). 
• Table 15: Reporting periods for collecting safety information in subjects who have 
crossed D271 
• Table 16: Reporting periods for collecting safety information in subjects who have 
crossed D271 
• 
Event 
V1 
 
V2 
 
V3 
 
 V4 
 
V5 
 
Study 
Conclusion 
 
D1 D15 D31 
D61 D75 
D 
91 
D105 D121 D181 
D271 
Solicited local and 
systemic AEs* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
within 30 days 
post-vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended 
AEs, AEs/SAEs 
leading to 
withdrawal from 
the study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
the study vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation  
or concurrent GSK 
medication/vaccine¥ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs/pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: Adverse event, AESI: adverse event of special interest, D: Day, SAE: Serious adverse event, V: Visit. 
*Solicited AEs to be collected for 7 days following each vaccination, with ongoing solicited AEs collected until 
resolution or day 30, whichever occurs first.  
** Including COVID-19 infection related AEs. 
¥Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins from the 
time a parent(s)/LAR(s) or participant signs the consent form to the end of the study 
• Section 8.6: Study conclusion 
The study termination call will occur on study Day 451 (after safety follow up call 7) 
or (Day 271 [Month 9]) for subjects who have not reached Day 271 [Month 9] at 
the time this amendment takes effect. The termination visit will be a phone call.  
• 
Section 12.1.1: List of abbreviations 
SFU 
Safety Follow-up 
• Section 12.5.8: Detecting and recording adverse events, serious adverse events and 
pregnancies 
The subject/parent(s)/LAR(s) will be contacted by the site staff on Days 15, 75, 105, 
181, 271, 361, and 451 (or (Day 271) for subjects who have not reached Day 271 at 
the time this amendment takes effect via a scripted safety follow-up phone call. 
Detailed description of Protocol Amendment 6: 
Additional texts are presented in bold italics and deleted texts are presented in 
strikethrough. 
• 
Title page: Contributing authors  

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− 
, Clinical Research and 
Development Lead 
− 
, Study Delivery Lead 
− 
, Local Delivery 
Lead 
− 
, Oversight Data Manager 
− 
, Clinical 
Trials Supply Manager  
− 
, SERM Safety Scientist 
− 
, Global Regulatory Affairs 
− 
, Global Patent 
− 
, Study Statistician 
− 
, Lead Statistician 
− 
, Clinical and Epidemiology Project Leader (CEPL) from 
Protocol Amendment 3 onwards and 
, Associate Clinical and 
Epidemiology Project Leader (CEPL) from Protocol Amendment 6 onwards. 
• 
Protocol amendment 6 Sponsor signatory page: Sponsor signatory – Alessandro Ble,  
Associate Clinical and Epidemiology Project Lead 
• 
Table 3: Schedule of Activities 
Footnote: **Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins 
from the time a parent(s)/LAR(s) or participant signs the consent form to the end of the study 
• 
Section 5.2: Overall design 
End of Study (EoS): Last subject last visit (LSLV) (last concluding contact on Day 
451) or Date of the last testing/reading released of the Human Biological Samples 
or imaging data, related to primary and secondary endpoints, whichever occurs 
later. EoS must be achieved no later than 8 months after LSLV. EoS cannot be 
before LSLV the date of release of the last testing results, to be achieved not later 
than 8 months after LSLV. 
• 
Section 6.2.1: Medical conditions 
Are obese at screening (obesity is defined as a BMI of  95th percentile for age and 
gender). 
• 
Section 6.2.2: Prior/Concomitant therapy 
Previous vaccination with two doses of quadrivalent meningococcal conjugate 
vaccine (MenACWY, Menveo, Menactra or MenQuadfi) 
• 
Section 8.3.2.1: Blood sampling for immunogenicity response assessments 
In clinic visits where a blood draw and a vaccination are planned, ensure that all 
samples collected for immunogenicity assessments are taken prior to any vaccination 
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• 
Table 15: Reporting periods for collecting safety information 
Medically 
attended AEs, 
AEs/SAEs 
leading to 
withdrawal from 
the study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote: ¥Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine 
begins from the time a parent(s)/LAR(s) or participant signs the consent form to the end of the study 
• Table16 
Timeframes for submitting serious adverse event, pregnancy and other 
events reports to GSK Biologicals  
Pregnancies 
24 hours2 
weeks* 
electronic pregnancy report 
24 hours2 
weeks * 
paper pregnancy follow-up 
report/electronic pregnancy report 
• 
Section 11: References 
World Health Organization (WHO). Laboratory testing for 2019 novel coronavirus 
(2019-nCoV) in suspected human cases. Interim guidance. WHO, 2019 [cited 11-
SEP-2019] Available from: https://www.who.int/publications/i/item/10665-331501 
World Health Organization (WHO). WHO COVID-19 Case Definition. WHO, 2020 
[cited 11-SEP-2019] Available from: https://www.who.int/publications/i/item/WHO-
2019-nCoV-Surveillance_Case_Definition-2020.1 
• 
Section 12.1.1: List of abbreviations 
LSLV 
Last Subject Last Visit 
 
• 
Section 12.1.2: Glossary of terms 
End of Study (EoS)  
(Synonym of End of 
Trial): 
Last subject last visit (LSLV) (Visit X) or Date of the last 
testing/reading released of the Human Biological Samples 
or imaging data, related to primary and secondary 
endpoints, whichever occurs later. EoS must be achieved no 
later than 8 months after LSLV. EoS cannot be before 
LSLV. For studies with collection of human biological 
samples and/or imaging data, the End of Study is defined as 
follows: Last subject last visit (last concluding contact on Day 
451) or Last testing results released of samples collected at 
Visit 4*  
* In this case EoS must be achieved no later than 8 months 
after LSLV (last concluding contact). 
• 
Section 12.5.8.4: Recording of AEs related to COVID-19 
For COVID-19 infection-related AEs, sites should follow routine AE/SAE processes 
as outlined in the protocol, using the following terms according to the latest COVID-
19 WHO defined case definitions criteria in effect at the institution 
• 
Suspected COVID-19 case 

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• 
Probable COVID-19 case 
• 
Confirmed COVID-19 case [WHO, 2020] 
• 
Section 12.5.8.4.1: WHO Case Definition 
Suspected COVID-19 case 
A. A person who meets the clinical AND epidemiological criteria 
Clinical criteria: 
Acute onset of fever AND cough OR acute onset of ANY THREE OR MORE of the 
following signs or symptoms: fever, cough, general weakness/fatigue, headache, 
myalgia, sore throat, coryza, dyspnoea, anorexia/nausea/vomiting, diarrhoea, altered 
mental status  
AND 
Epidemiological criteria: 
Residing or working in an area with high risk of transmission of virus: closed 
residential settings, humanitarian settings such as camp and camp-like settings for 
displaced persons; anytime within the 14 days prior to symptom onset OR residing to 
travel to an area with community transmission anytime within the 14 days prior to 
symptom onset OR working in any health care setting, including within health 
facilities or within the community; anytime within the 14 days prior to symptom 
onset 
OR 
B. A patient with severe acute respiratory illness (SARI: acute respiratory infection 
with history of fever or measured fever of ≥38.0°C, and cough; with onset within the 
last 10 days; and requires hospitalization) 
• 
Probable COVID-19 case  
A. A patient who meets clinical criteria above AND is a contact of a probable or 
confirmed case, or epidemiologically linked to a cluster with at least one confirmed 
case 
OR 
B. A suspect case with chest imaging showing findings suggestive of COVID-19 
disease* 
* Typical chest imaging findings suggestive of COVID-19 include the following: 
Chest radiography: hazy opacities, often rounded in morphology, with peripheral and 
lower lung distribution 
Chest computed tomography (CT): multiple bilateral ground glass opacities, often 
rounded in morphology, with peripheral and lower lung distribution 
Lung ultrasound: thickened pleural lines, B lines (multifocal, discrete, or confluent), 
consolidative patterns with or without air bronchograms 
OR 

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C. A person with recent anosmia (loss of smell) or ageusia (loss of taste) in the 
absence of any other identified cause.  
OR 
D. Death, not otherwise explained, in an adult with respiratory distress preceding 
death AND was a contact of a probable or confirmed case or epidemiologically 
linked to a cluster with at least one confirmed case. 
• 
Confirmed COVID-19 case  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms. See “Laboratory testing for 2019 novel coronavirus 
(2019-nCoV) in suspected human cases” [WHO, 2019] for details. 
• 
Section 12.5.9.4: Completion and transmission of pregnancy reports to GSK 
Biologicals  
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKSwithin 24 hours. 
Section 12.6.3.1: Female subjects who become pregnant 
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks24 hours of learning of a subject's pregnancy 
 

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Detailed description of Protocol Amendment 5: 
Additional texts are presented in bold italics and deleted texts are presented in 
strikethrough. 
• 
Title page: Contributing author –
 
, Scientific Writing 
• 
Title page: Contributing authors – 
, Local 
Delivery Lead 
• 
Protocol amendment 5 Sponsor signatory page: 
Note: Not applicable if an alternative signature process (e.g. electronic signature 
or email approval) is used to get the sponsor approval. 
• 
Protocol amendment 5 Investigator agreement: 
That I will comply with the terms of the site agreement. 
• 
Section 1: Synopsis 
Footnote: *The NHBA indicator strain M07-0241084 may be subject to change 
during the study, before clinical testing starts. In this case, this change will be 
documented in the clinical report. 
• Table 3: Schedule of Activities 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Activities that can be 
performed at a separate visit 
before Visit 1 (approximately 
2 weeks maximum 5 days 
before the Visit 1). AEs / SAEs 
related to study participation or 
to a concurrent GSK 
medication/vaccine should also 
be recorded starting from this 
separate visit. 
Inclusion/exclusion criteria 
should be re-checked prior to 
vaccination at visit 1. 
See Section 12.4.3 for details. 
• 
Table 6: Study objectives and endpoints 
Footnote: *The NHBA indicator strain M07-0241084 may be subject to change 
during the study, before clinical testing starts. In this case, this change will be 
documented in the clinical report. 
• 
Table 9: Treatments administered 
Product Category 
Combination Product 
Biological Product 
Combination Product 
• 
Section 6.3: Criteria for temporary delay for vaccination 
Administration of any other vaccine 14 days (for inactivated vaccines) or 28 days 
(for live vaccines) prior to and after each vaccination*. 
PPD
PPD

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* In case emergency mass vaccination for an unforeseen public health threat (e.g. a 
pandemic) is organised by public health authorities outside the routine immunisation 
programme, the time period described above can be reduced if, necessary for that 
vaccine, provided it is licensed and used according to its Product Information. 
• 
Section 7.3.1: Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case 
of a medical emergency when knowledge of the treatment is essential for the 
clinical management or welfare of the subject. 
• 
Table 13: Humoral Immunity (Antibody determination) 
Footnote: 
***GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in 
Rixensart Belgium or Wavre, Belgium; Marburg, Germany. CLS may delegate 
testing to GSK Research laboratories in Siena, Italy or to an external laboratory. 
+ The NHBA indicator strain, M07-0241084 may be subject to change during the 
study, before clinical testing starts. In this case, this change will be documented in 
the clinical report. 
• 
Table 14: Immunological read-outs 
Blood sampling timepoint 
Subset/Sub-cohort 
Name 
No. of 
subjects/Group 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-Vacc 
Groups 
MenB+MenACWY and 
MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
1.1 M14459 
1.2 96217 
1.3 NZ98/254 
1.4 M07-0241084* 
Groups 
MenB+MenACWY and 
MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
2.1 MenY 
2.2 MenW 
2.3 MenA 
2.4 MenC 
Visit 2 (Day 31) 
Post Vacc1 
Groups 
MenB+MenACWY and 
MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
1.1 M14459 
1.2 96217 
1.3 NZ98/254 
1.4 M07-0241084* 
Groups 
MenB+MenACWY and 
MenACWY 
315 
hSBA-MenA 
hSBA-MenC 
hSBA-MenW 
hSBA-MenY 
2.1 MenY 
2.2 MenW 
2.3 MenA 
2.4 MenC 
Groups 
MenB+MenACWY and 
MenACWY 
315 
ELISA IgG anti 
meningococcal 
serogroups A, C, W, 
Y 
3 MenA 
3 MenC 
3 MenW 
3 MenY 
Visit 4 (Day 91) 
Post Vacc2 
Groups 
MenB+MenACWY and 
MenB 
315 
hSBA-M14459 
hSBA-96217 
hSBA-NZ98/254 
hSBA-M07-0241084* 
1.1 M14459 
1.2 96217 
1.3 NZ98/254 
1.4 M07-0241084* 
Footnote: *The NHBA indicator strain M07-0241084 may be subject to change 
during the study, before clinical testing starts. In this case, this change will be 
documented in the clinical report. 

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• 
Table 15: Reporting periods for collecting safety information 
Footnote: *Solicited AEs to be collected for 7 days following each vaccination, 
with ongoing solicited AEs collected until resolution or day 30, whichever occurs 
first.  
• 
Section 8.4.7: Medical device deficiencies 
Per Section 201(h) of the Food, Drug, and Cosmetic Act, a device is: 
An instrument, apparatus, implement, machine, contrivance, implant, in vitro 
reagent, or other similar or related article, including a component part, or 
accessory which is: 
4. recognized in the official National Formulary, or the United States 
Pharmacopoeia, or any supplement to them, 
5. intended for use in the diagnosis of disease or other conditions, or in the cure, 
mitigation, treatment, or prevention of disease, in man or other animals, or 
6. intended to affect the structure or any function of the body of man or other 
animals, and which does not achieve its primary intended purposes through 
chemical action within or on the body of man or other animals and 
which does not achieve its primary intended purposes through chemical action 
within or on the body of man or other animals and which is not dependent upon 
being metabolized for the achievement of its primary intended purposes. The term 
"device" does not include software functions excluded pursuant to section 520(o). 
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. 
8.4.7.1 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 12.7 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. 
8.4.7.2 Regulatory reporting of medical device deficiency when used as combination 
product  

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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 10.1.1.1: Primary Immunogenicity Objectives 
For the testing of theThe 8 hypotheses associated with the primary objective will be 
tested simultaneously, to control for the type I error rate. The testing of the 
hypotheses will be done simultaneously on all the strains and serogroups. a 
stepwise approach will be used. To control for the type I error rate of α=0.05 (2-
sided), the testing of the hypotheses will be done in a predefined order. The approach 
will start with the first hypothesis and, if rejected, will continue with the same 
α=0.05 to the next hypothesis in order and will stop at the first hypothesis not 
rejected. The testing will be done in the following order of the strains: A, C, W, Y, 
M14459, 96217, NZ98/254 and M07-0241084. 
• 
Section 10.1.2: Sample size calculation 
To control for the type I error rate of α=0.05 (2-sided), the testing of the hypotheses 
will be done in a predefined order. The approach will start with the first hypothesis 
and, if rejected, will continue with the same α=0.05 to the next hypothesis in order 
and will stop at the first hypothesis not rejected. The testing of the hypotheses will 
be done simultaneously on all the strains and serogroups. will be done in the 
following order of the strains: A, C, W, Y, M14459, 96217, NZ98/254 and M07-
0241084. 
For the testing of the hypotheses associated with the primary objective a stepwise 
approach will be used. 
• 
Section 10.3.3: Immunogenicity analyses 
Footnote: *The NHBA indicator strain M07-0241084 may be subject to change 
during the study, before clinical testing starts. In this case, this change will be 
documented in the clinical report. 
• 
Section 12.1.2: Glossary of terms 
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. 

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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. 
• 
Section 12.2: Appendix 2: Clinical laboratory assays 
*The NHBA indicator strain M07-0241084 may be subject to change during the 
study, before clinical testing starts. In this case, this change will be documented in 
the clinical report. 
As a measure of the meningococcal specific antibody titer of each serum sample, the 
MenACWY agar-overlay hSBA follows the principle of detecting and counting the 
surviving meningococcal bacteria after bacterial growth within solid agar media, 
using an automatic colony counter (AxioLab Image Analysis System – detection of 
colony forming units, CFU).  
• 
Table 23: GSK Biologicals laboratories 
GSK Vaccines GmbH 
Clinical Laboratory Sciences, Marburg, Germany 
Emil-von-Behring-Str. 76, 35041 Marburg, Germany 
• 
Table 24: Outsourced laboratories (potential) 
 
 
 
• 
Section 12.4.3: Informed consent process 
The informed consent process may be conducted approximately 2 weeks up to 5 
days prior to vaccination on day 1. 
• 
Section 12.5.3: 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 subjects/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. 
• 
Section 12.5.3.1: Other Solicited Adverse Events 
Solicited local or systemic adverse event that continues beyond day 7 after 
vaccination. 
• 
Section 12.5.5.1: Arthritis 
Due to the heterogeneity of the presentation of arthritis which can be either acute or 
chronic, the threshold of duration of signs/symptoms of 6 weeks is to be considered. 
• 
Section 12.5.8.2: Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
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Any solicited AE that has not resolved within 30 days post vaccination and is 
reported during clinic visits or safety follow-up calls will be entered into the 
subject’s eCRF as an unsolicited AE. It will also be included in the subject’s 
source documents at the site by the investigator/site staff as a verbally reported 
event. It will not be included in the Subject eDiary. These AEs will be analysed as 
unsolicited AEs (i.e. in the Unsolicited Safety Set). 
• 
Section 12.7: Appendix 7: Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and unanticipated SADE (USADE) 
12.7.1 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 or not considered related to a medical device. 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. 
12.7.2 Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
g. Led to death  
h. 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 hospitalisation. Planned hospitalisation 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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i. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
j. 
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, intervention had not occurred, 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 risk analysis report (see 
Section 3.3). 
12.7.3 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 8.4.6.1. 
• 
GSK will review all device deficiencies and 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. 

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Detailed description of Protocol Amendment 4: 
Additional texts are presented in bold italics and deleted texts are presented in 
strikethrough. 
• 
Title page: Contributing authors – 
, Clinical Research and 
Development Lead 
, Clinical Trials Supply 
Manager 
• 
Protocol amendment 4 Sponsor signatory page – Short title was replaced with Title. 
• 
Protocol amendment 4 Investigator agreement – Short title was replaced with Title. 
• 
Note for the laboratory assay in Table 3 was updated 
Blood sample collection on Visit 1, Visit 2 and Visit 4 will be performed before 
vaccine administration. 
• 
Section 8.3.2.1: Blood sampling for immunogenicity response assessments 
In clinic visits where a blood draw and a vaccination are planned, ensure that all 
samples collected for immunogenicity assessments 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 at Visit 1, Visit 2 and Visit 4. 
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 and vaccination may be delayed as appropriate to ensure sample collection 
prior to vaccination. 
• 
Section 10.1.2: Sample size calculation 
Standard deviations for hSBA Titer 
For the secondary objective, hypothesis 3, testing of MenACWY when given 
concomitantly with rMenB+OMV NZ to MenACWYrMenB+OMV NZ when given 
PPD
PPD
CCI

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concomitantly with MenACWY to rMenB+OMV NZ given alone based on ELISA 
GMCs, test of treatment Group MenB+MenACWY versus treatment Group 
MenACWYMenB, the standard deviations from study V102_02 were used. 
• 
Section 12.1.1: List of abbreviations 
CSR – Clinical study report; SMP – Study management plan 
• 
Section 12.2: Appendix 2: Clinical laboratory assays 
MenACWY serum bactericidal assays using human complement (hSBA) – 
Menveo 
This new hSBA that has been fully validated for the 4 MenACWY serogroupsunder 
development is also based on the measurement of human complement-dependent 
bactericidal killing of meningococci. 
• 
Section 12.4.2: Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial 
interests during the prior initiation of the center and at the end of the study. 
Investigators are responsible for providing an update of financial disclosure if their 
financial interest changes at any point during their participation in a study and for 1 
year after completion of the study. 
• 
Section 12.4.7: Data quality assurance 
Quality tolerance limits (QTLs) will be pre-defined in the Study Management Plan 
(SMP) to identify systematic issues that can impact participant safety and/or the 
reliability of study results. These pre-defined parameters will be monitored during 
the study. Important deviations from the QTLs and remedial actions taken will be 
summarized in the Clinical Study Report (CSR). 

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Detailed description of Protocol Amendment 3: 
Additional texts are presented in bold italics and deleted texts are presented in 
strikethrough. 
• 
Title page: Co-ordinating author – 
 
• 
Title page: Contributing authors – 
, Oversight Data Manager; 
 
 Clinical Trials Supply Manager; 
, Clinical Laboratory 
Sciences Study Manager; 
 SERM Safety Scientist; 
 
 Clinical and Epidemiology Project Leader (CEPL) from Protocol 
Amendment 3 
• 
Sponsor signatory page: Daniela Toneatto Pavitra Keshavan,  
Clinical and Epidemiology Project Lead 
• 
Table 3: Schedule of Activities 
Medical History-directed 
Physical examination 
O 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.3 and 8.2.4 
for more information. 
Symptom-directed physical 
examination 
 
 
 
O 
 
O 
 
 
 
 
 
 
See Section 8.2.3 and 8.2.4 
for more information. 
COVID-19 infection-related AEs and SAEs should also be recorded on a separate eCRF page. 
• 
Table 5 
Intervals between study visits and safety follow-up calls included 
Interval 
Length of interval 
Allowed interval 
Visit 1 → SFU 1 
14 days  
11 - 17 days  
Visit 3 → SFU 2 
14 days 
11 - 17 days 
Visit 4 → SFU 3 
14 days 
11 - 17 days 
Visit 4 → SFU 4 
90 days 
83 - 111 days 
Visit 4 → SFU 5 
180 days 
173 - 201 days 
Visit 4 → SFU 6 
270 days 
263 - 291 days 
Visit 4 → SFU 7 
360 days 
353 – 381 days 
• 
Section 5.2 –  Primary completion Date (PCD): Study termination-call Visit 4 (Day 
91Day 451). 
• 
Section 6.3 – Criteria for temporary delay for vaccination 
A positive test for active COVID-19 within the previous 14 days. The testing should 
be done using a molecular assay (polymerase chain reaction [PCR]) or antigen test 
approved by the country regulatory authorities. 
Subjects with known COVID-19 positive contacts in the past 14 days. 
• 
Table 9: Treatments administered 
Study Treatment Name: 
Bexsero 
Menveo*** 
Placebo 
Vaccine(s)/Product(s) 
name 
rMenB+OMV NZ  
MenA lyo 
MenCWY liquid  
Placebo  
(NaCl) 
Presentation 
Suspension for 
injection_Suspension for 
suspension for injection 
in a syringe 
Suspension for injection 
in a syringe 
Powder for 
solution for 
injection in a 
vial 
Powder for 
solution for 
injection in a vial 
Solution for 
solution for 
injection in a vial 
Solution for injection 
in a vial 
Solution for 
injection in a 
syringe 
PPD
PPD
PPD
PPD
PPD
PPD

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Study Treatment Name: 
Bexsero 
Menveo*** 
Placebo 
Vaccines formulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium 
chloride 
(NaCl) 
(0.9%); 
Water for 
injections 
q.s. 0.5 mL 
Volume to be 
administered** 
0.5 mL 
0.5 mL  
0.5 0.65 
mL*****  
** Refer to the SPM for the volume after reconstitution, if applicable. 
*** 
 
 
 
 
 
 
 
***** The volume of the saline pre-filled syringe may be between 0.6mL and 0.8 mL. The full volume is to be 
injected. 
CCI
CCI
CCI
CCI

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• 
Table 10: Administration and laterality 
*Laterality is defined due to multiple vaccinations at different visits; non-dominant 
arm is the preferred arm for injection, when applicable. In case it is not possible to 
administer the vaccine in the non-dominant arm, an injection in the dominant arm 
may be performed. 
• 
Table 11: Contact information for emergency unblinding 
GSK Helpdesk 
24/24 hour and 7/7 day availability 
The Helpdesk is available by phone, fax and email 
Phone: +32.2.656.68.04 
For US only Toll Free: + 1 844 446 3133 
Italy Toll Free: 800 879 197 
For Canada, US and  Puerto Rico  
Alternate Toll-free number: 877.870.0019 
Fax: +32.2.401.25.75 
email: rix.ugrdehelpdesk@gsk.com 
• 
Section 8.1 – General study aspects 
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 8.7 for further details 
• 
Section 8.2.3 – Medical history 
A general physical examination is to be performed by a qualified health care 
professional. “Qualified health care professional” refers to a licensed or certified 
health care professional with documented training and experience, as determined by 
the Principal Investigator (PI), and who is permitted by institutional policy to 
perform protocol required procedures, and who is identified on the Study Staff 
Signature Log. The physical examination will include a check of general appearance, 
the measurement of vital signs (body temperature [preferably oral] 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. 
• 
Section 8.2.4 – Physical examination 
A general p Physical examination is to be performed by a qualified health care 
professional. “Qualified health care professional” refers to a licensed or certified 
health care professional with documented training and experience, as determined 
by the Principal Investigator (PI), and who is permitted by institutional policy to 
perform protocol required procedures, and who is identified on the Study Staff 
Signature Log. The physical examination will include a check of general 
appearance, the measurement of vital signs (body temperature [preferably oral] and 
heart rate), auscultation of heart and lungs, measurement of length and weight. 
Perform aThe physical examination of the subject will include, including assessment 
of body temperature (preferably oral) and resting vital signs: systolic/diastolic blood 
pressure, and heart rate and respiratory rate after at least 10 minutes of rest. 
Medical history-directed physical examination to assess eligibility will be 
performed during Visit 1. 

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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. 
Physical examination at each study visit subsequent to the first vaccination visit, will 
be performed only if the subject/subject’s parent(s)/LAR(s) indicates during 
questioning that there might be some underlying pathology(ies) or if deemed 
necessary by the Investigator or delegate (symptom-directed physical examination). 
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. 
• 
Section 8.3 – Efficacy assessments 
It is also possible that futurefurther findings may make it desirable to use the 
samples acquired in this study for furtherfuture research, not described in this 
protocol. Therefore, all subjects/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 
furtherfuture research. FurtherFuture research will be subject to the laws and 
regulations in the respective countries and will only be performed once an 
independent Ethics Committee or Review Board has approved this research. 
• 
Table 15: Reporting periods for collecting safety information 
Footnote: *Including COVID-19 infection related AEs. 
• 
Section 8.7: 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 subjects:  
• 
If the eDiary device was provided to the subject, it may be returned to the site by 
conventional mail after the end of the relevant data collection period (Visit 5). 
• 
Biological samples may be collected at a different location* other than the study 
site or at subject’s home. Biological samples should not be collected if they cannot 
be processed in a timely manner or appropriately stored until the intended use.  
* It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on subjects by 
investigator and staff at a site other than the designated study site. Refer to local 
regulatory guidance on conduct of clinical trials during COVID-19. 
Impact on the Per Protocol Set (PPS) for immunogenicity will be determined on a case 
by case basis. 

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• 
Section 11 – References 
World Health Organization (WHO). Laboratory testing for 2019 novel coronavirus 
(2019-nCoV) in suspected human cases. Interim guidance. WHO, 2019 [cited 11-SEP-
2019] Available from: https://www.who.int/publications/i/item/10665-331501 
World Health Organization (WHO). WHO COVID-19 Case Definition. WHO, 2020 
[cited 11-SEP-2019] Available from: https://www.who.int/publications/i/item/WHO-
2019-nCoV-Surveillance_Case_Definition-2020.1 
• 
Section 12.1.1 – List of abbreviations 
COVID-19 – Coronavirus disease 2019. 
• 
Section 12.5.8 – Detecting and recording adverse events, serious adverse events and 
pregnancies 
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/subject’s parent(s)/LAR(s), but if a 
person other than the subject/subject’s parent(s)/LAR(s) enters information into the 
Subject Diary, this person’s identity must be documented in the Subject Diary 
subject’s source record. 
• 
Section 12.5.8.4 - Recording of AEs related to COVID-19 
For COVID-19 infection-related AEs, sites should follow routine AE/SAE 
processes as outlined in the protocol, using the following terms according to WHO 
defined case definitions: 
Suspected COVID-19 case 
Probable COVID-19 case 
Confirmed COVID-19 case [WHO, 2020] 
• 
Section 12.5.8.4.1 - WHO Case Definition 
Suspected COVID-19 case 
A. A person who meets the clinical AND epidemiological criteria. 
Clinical criteria: 
Acute onset of fever AND cough OR acute onset of ANY THREE OR MORE of 
the following signs or symptoms: fever, cough, general weakness/fatigue, 
headache, myalgia, sore throat, coryza, dyspnoea, anorexia/nausea/vomiting, 
diarrhoea, altered mental status. 
AND 
Epidemiological criteria: 
Residing or working in an area with high risk of transmission of virus: closed 
residential settings, humanitarian settings such as camp and camp-like settings for 
displaced persons; anytime within the 14 days prior to symptom onset OR residing 
to travel to an area with community transmission anytime within the 14 days prior 
to symptom onset OR working in any health care setting, including within health 
facilities or within the community; anytime within the 14 days prior to symptom 
onset. 

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OR 
B. A patient with severe acute respiratory illness (SARI: acute respiratory infection 
with history of fever or measured fever of ≥38.0°C, and cough; with onset within 
the last 10 days; and requires hospitalization). 
Probable COVID-19 case 
A. A patient who meets clinical criteria above AND is a contact of a probable or 
confirmed case, or epidemiologically linked to a cluster with at least one confirmed 
case. 
OR 
B. A suspect case with chest imaging showing findings suggestive of COVID-19 
disease* 
* Typical chest imaging findings suggestive of COVID-19 include the following: 
Chest radiography: hazy opacities, often rounded in morphology, with peripheral 
and lower lung distribution. 
Chest computed tomography (CT): multiple bilateral ground glass opacities, often 
rounded in morphology, with peripheral and lower lung distribution. 
Lung ultrasound: thickened pleural lines, B lines (multifocal, discrete, or 
confluent), consolidative patterns with or without air bronchograms. 
OR 
C. A person with recent anosmia (loss of smell) or ageusia (loss of taste) in the 
absence of any other identified cause. 
OR 
D. Death, not otherwise explained, in an adult with respiratory distress preceding 
death AND was a contact of a probable or confirmed case or epidemiologically 
linked to a cluster with at least one confirmed case. 
Confirmed COVID-19 case 
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms. See “Laboratory testing for 2019 novel coronavirus 
(2019-nCoV) in suspected human cases” [WHO, 2019] for details. 

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Detailed description of Protocol Amendment 2: 
• 
Inclusion criteria has been updated (Section 6.1): Previous vaccination with one dose 
of quadrivalent meningococcal conjugate vaccine (MenACWY, Menveo or 
Menactra) at least 4 3years prior to informed consent and assent as applicable 
(according to the subject’s age). 
• 
Exclusion criteria has been updated (Section 6.2.1): Systemic administration of 
corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior 
to study vaccination. This will mean prednisone 205 mg/day (for adult subjects) or  
0.5 mg/kg/day or 20 mg/day whichever is the maximum dose for (paediatric 
subjects), or equivalent. Inhaled and topical steroids are allowed. 
• 
The End of Study definition (Section 12.1.2) has been updated to adapt to the study 
design: For studies with collection of human biological samples and/or imaging data, 
the End of Study is defined as follows: Last subject last visit (last concluding 
contact on Day 451 Visit 4) or Last testing results released of samples collected at 
Visit 4*. 
* In this case EoS must be achieved no later than 8 months after LSLV (last 
concluding contact). 
• 
Sentence referring to implausible measurements in Section 10.3.4 has been deleted 
as this has been explained in Section 12.5.8 of the protocol: Implausible 
measurements (for further definition see SAP) will be left out of the analysis. 
• 
Treatments administered table (Section 7.1; Table 8) has been updated to reflect the 
correct concentration for rp961c antigen in the Bexsero formulation. Additional 
editorial changes have been included in Table 8, that do not impact the vaccine 
formulation. As the study will be conducted in the US, EU specifications for the 
vaccines from the footnote has been deleted.  
Study Treatment 
Name: 
Bexsero 
Menveo*** 
Placebo 
Vaccine(s)/Product(s) 
name 
rMenB+OMV NZ  
MenA lyo 
MenCWY liquid  
Placebo  
(NaCl) 
Presentation 
Suspension for injection 
in a syringe Prefilled 
syringe (liquid) 
Powder for 
solution for 
injection in 
a vial 
Lyophilized 
component 
in a vial 
Solution for injection 
in a vial Liquid 
component in a vial 
Solution for 
injection in a 
syringe 
Prefilled 
syringe 
(liquid) 
Vaccines formulation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium 
chloride 
(NaCl) 
(0.9%); 
Water for 
injections 
q.s. 0.5 mL 
CCI

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Study Treatment 
Name: 
Bexsero 
Menveo*** 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccines formulation 
(in the US)**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NaCl=150mM 
Route of 
Administration 
Intramuscular use IM 
injection 
Intramuscular use IM injection 
Intramuscul
ar use IM 
injection 
*** Menveo commercial formulation consisting of a MenA lyophilized component and of a MenCWY liquid component, 
to be reconstituted together before administration (0.5 mL). 
 
 
**** 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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Detailed description of Protocol Amendment 1: 
The major changes made to this amendment were with regard to transferring the protocol 
to the GSK protocol template (DS-BIO-CLIN-1000 v16.0) 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. 
Throughout the protocol, the study group names were changed as follows: 
• 
Vaccine Group A to Group MenB+MenACWY 
• 
Vaccine Group B to Group MenB 
• 
Vaccine Group C to Group MenACWY 
The introduction section and rationale for the study were updated to include the following 
data from V72_56 infant study, as follows: 
Data from an infant study showed that both rMenB+OMV NZ and MenACWY were 
well tolerated and immunogenic when administered concomitantly in healthy infants. 
However, no data is currently available on the concomitant use of rMenB+OMV NZ and 
MenACWY in adolescents. 
The success criterion for primary and secondary immunogenicity objectives were re-
written for clarity as follows (Synopsis and Section 4): 
Primary Immunogenicity objectives: 
• 
To demonstrate the non-inferiority of the antibody response to rMenB+OMV NZ 
given concomitantly with MenACWY to healthy subjects 16-18 years of age 
compared to rMenB+OMV NZ administered without MenACWY, as measured by 
serum bactericidal assay using human complement (hSBA) Geometric Mean Titers 
(GMTs) against N. meningitidis serogroup B test strains M14459 (fHbp), 96217 
(NadA), NZ98/254(PorA) and M07-0241084 (NHBA), at one month after the second 
vaccination with rMenB+OMV NZ. 
Criterion: Non-inferiority will be demonstrated if for each of the four serogroup B 
test strains, the lower limit of the 2-sided 95% confidence interval of the between-
group ratio of hSBA GMTs null hypothesis that the difference in the population 
means (of the logarithmically [base of 10] transformed hSBA titers) of 
(rMenB+OMV NZ with MenACWY versus rMenB+OMV NZ alone) is >less than 
or equal to log10(0.5) is rejected. 
• 
To demonstrate the non-inferiority of the antibody response to MenACWY given 
concomitantly with rMenB+OMV NZ to healthy subjects 16-18 years of age 
compared to MenACWY administered alone, as measured by hSBA GMTs against 
each of the serogroups A, C, W and Y, at one month after the (study) vaccination 
with MenACWY. 

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Criterion: Non-inferiority will be demonstrated if for each of the four serogroups A, 
C, W and Y, the lower limit of the 2-sided 95% CI of the between-group ratio of 
hSBA GMTs (null hypothesis that the difference in the population means (of the 
logarithmically [base of 10] transformed hSBA titers) of rMenB+OMV NZ with 
MenACWY versus MenACWY alone) is >less than or equal to log10 (0.5) is 
rejected. 
Secondary objectives: 
• 
To assess the non-inferiority of the responses to MenACWY when given 
concomitantly with rMenB+OMV NZ to healthy subjects 16-18 years of age 
compared to MenACWY administered alone as measured by ELISA Geometric 
Mean Concentrations (GMCs) against each of the serogroups A, C, W and Y, at one 
month after the (study) vaccination with MenACWY. 
Criterion: Non-inferiority will be demonstrated if for each of the four A, C, W and Y 
strains, the lower limit of the 2-sided 95% CI of the between-group ratio of ELISA 
GMCs (null hypothesis that the difference in the population means (of the 
logarithmically [base of 10] transformed hSBA titers) of MenACWY with 
rMenB+OMV NZ versus MenACWY alone) is >less than or equal to log10 (0.5) is 
rejected. 
Details regarding the blinding process to the lab personnel performing clinical testing are 
updated. Following the integration of the two legacy blinding processes with regards to 
lab personnel, a duly assessment confirmed that the laboratory in charge of the clinical 
testing can be blinded to the treatment as well as to the subject number.  Moreover, in 
order to prevent the laboratory from linking the consecutive visits to a specific subject, a 
different subject code will be used for each timepoint tested. 
• 
The 4-fold increase in post-vaccination hSBA titer definition when the pre-
vaccination titer is below the LOD, has been modified to: For a pre-vaccination titer 
< LOD, a post-vaccination titer of ≥ fourfold the LOD or ≥ LLOQ, whichever is 
greater. 
Section 7.5.1, Recording of concomitant medication/products and concomitant 
vaccinations, the following criteria was added: 
• 
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. 
In Section 8.2.1 Data collected from subjects, the following change was made: 
• 
Vaccination history as confirmed by vaccination records, if accessible. 
• 
In Section 8.2.3, Medical history, text on qualified healthcare professional was added 
as follows: 
A general physical examination is to be performed by a qualified health care 
professional. “Qualified health care professional” refers to a licensed or certified 
health care professional with documented training and experience, as determined by 
the Principal Investigator, and who is permitted by institutional policy to perform 
protocol required procedures, and who is identified on the Study Staff Signature Log. 

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The physical examination will include a check of general appearance, the 
measurement of vital signs (body temperature [preferably oral] 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. 
In Section 8.2.4, Physical examination, changes were made to clarify that only 
abnormal findings from physical examination will be documented in the eCRF. The text 
was modified as follows: 
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. Collected information needs to be recorded in the eCRF. 
In Section 8.3.3, Laboratory assays, the humoral immunity table (Table 12) has been 
updated to capture the hSBA assay cut-off values (LOD and LLOQ) for MenB and 
MenACWY. 
In Section 12.5.3.1, Other solicited adverse events, the following changes were made: 
The use of analgesics/antipyretics for either prophylactic or treatment purposes will be 
recorded as other solicited events in the Subject Diary (eDiary) and subsequently 
recorded onto the eCRFs and subject medical records. 
The following criteria was added for solicited AEs which need to be entered into 
subject’s source documents and also as an AE on AE eCRF: 
• 
Solicited local or systemic adverse event that continues beyond day 7 after 
vaccination. 
In Section 12.5.5, Adverse events of special interest, Arthritis was added as an AESI 
and following related text was added under Section 12.4.5.1: 
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 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. 

Signature Page for  205419 TMF-15023006 v1.0
Signature Page for TMF-15023006 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 14-Oct-2022 06:39:47 GMT+0000
PPD