A Phase III, Randomized, Controlled, Observer-blind Study to Demonstrate Effectiveness, Immunogenicity and Safety of GSK's Meningococcal Group B and Combined ABCWY Vaccines When Administered to Healthy Adolescents and Young Adults
Phase: PHASE3
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

Protocol 
Study ID:  205416 
Official Title of Study: A phase III, randomized, controlled, observer-blind study to 
demonstrate effectiveness, immunogenicity and safety of GSK's meningococcal Group B 
and combined ABCWY vaccines when administered to healthy adolescents and young 
adults. 
Date of Document: 12 May 2021

CONFIDENTIAL 
205416 [MENB REC 2ND GEN-038 (V72_72)] 
Protocol Amendment 4 Final 
9 May 2021 
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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
Primary Study vaccine 
GlaxoSmithKline Biologicals S.A (GSK)’s 
Meningococcal Group B Vaccine (Bexsero 
GSK3536829A) 
GSK’s Combined Meningococcal Groups A, B, C, W 
and Y Vaccine (GSK3536819A) 
Other Study vaccine/ 
product 
• 
GSK’s combined Meningococcal Groups A, C, Y 
and W-135 Conjugate Vaccine (Menveo, 
GSK3536820A) 
• 
Placebo 
eTrack study number and 
abbreviated title 
205416 [MENB REC 2ND GEN-038 (V72_72)]  
Investigational New Drug 
(IND) numbers 
BB-IND-11561 
BB-IND-14605 
EudraCT number 
2019-001666-15  
Date of protocol 
Final Version 1: 29 January 2015  
Date of protocol amendment 
Amendment 1 Final: 23 May 2019 
Amendment 2 Final: 18 March 2020 
Amendment 3 Final: 23 September 2020 
Amendment 4 Final: 9 May 2021 
Short title 
Effectiveness of GlaxoSmithKline Biologicals S.A’s 
Meningococcal Group B and Combined ABCWY 
Vaccines in Healthy Adolescents and Young Adults.  
Title 
A phase III, randomized, controlled, observer-blind 
study to demonstrate effectiveness, immunogenicity 
and safety of GSK's meningococcal Group B and 
combined ABCWY vaccines when administered to 
healthy adolescents and young adults.  
Co-ordinating author 
(Amended: 9 May 2021) 
, Scientific Writer 
Contributing authors  
(Amended: 9 May 2021) 
• 
, Clinical Research and 
Development Lead 
• 
, Clinical and Epidemiology 
Project Leader  
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Protocol Amendment 4 Final 
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eTrack study number and 
abbreviated title 
205416 [MENB REC 2ND GEN-038 (V72_72)]  
IND number 
BB-IND-11561 
BB-IND-14605 
EudraCT number 
2019-001666-15  
Title  
A phase III, randomized, controlled, observer-blind 
study to demonstrate effectiveness, immunogenicity 
and safety of GSK's meningococcal Group B and 
combined ABCWY vaccines when administered to 
healthy adolescents and young adults. 
Contributing authors 
(continued) 
(Amended: 9 May 2021) 
• 
 and 
, Study Delivery 
Leads 
• 
, Study Statistician for GSK  
• 
, Lead Statistician 
• 
 - 
, Oversight Data 
Manager 
• 
, Clinical Trials Supply Manager 
• 
, Clinical Laboratory Sciences 
Read-Out Team Lead 
• 
, Clinical Laboratory Sciences 
Study Manager 
• 
, SERM Safety Scientist 
• 
, Global Regulatory Affairs 
• 
, Across Country Expert, Local 
Delivery Lead 
• 
, US Agent – Global Regulatory 
Affairs 
• 
 and 
, US Medical 
Affairs Leads 
• 
 and 
, Global 
Patents 
GSK Protocol WS v 16.0.1  
©2015 GSK group of companies or its licensor.  
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PPD
PPD
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PPD
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PPD
PPD
PPD
PPD

CONFIDENTIAL 
205416 [MENB REC 2ND GEN-038 (V72_72)] 
Protocol Amendment 4 Final 
9 May 2021 
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Protocol Amendment 4 Sponsor Signatory Approval 
(Amended 9 May 2021) 
eTrack study number and 
Abbreviated Title 
205416 [MENB REC 2ND GEN-038 (V72_72)]  
IND numbers 
BB-IND-11561  
BB-IND-14605 
EudraCT number 
2019-001666-15  
Date of protocol amendment 
Amendment 4 Final: 9 May 2021 
Title 
A phase III, randomized, controlled, observer-blind 
study to demonstrate effectiveness, immunogenicity 
and safety of GSK's meningococcal Group B and 
combined ABCWY vaccines when administered to 
healthy adolescents and young adults.  
Sponsor signatory 
Daniela Toneatto,  
Clinical and Epidemiology 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 4 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 SA. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study vaccine(s)/product(s) 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 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 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(s)/product(s), and more generally about 
his/her financial ties with the sponsor. GSK will use and disclose the information 
solely for the purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply GSK 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 may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK 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 
205416 [MENB REC 2ND GEN-038 (V72_72)]  
IND numbers 
BB-IND-11561  
BB-IND-14605 
EudraCT number 
2019-001666-15  
Date of protocol amendment 
Amendment 4 Final: 9 May 2021  
Title 
A phase III, randomized, controlled, observer-blind 
study to demonstrate effectiveness, immunogenicity 
and safety of GSK’s meningococcal Group B and 
combined ABCWY vaccines when administered to 
healthy adolescents and young adults.  
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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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 Central Back-up Study Contact for Reporting SAEs: refer to protocol Section 
12.5.10.3  
Study Contact for Reporting SAEs: refer to the local study contact information 
document. 
5. GSK Central Safety Physician On-Call Contact information for Emergency 
Unblinding 
GSK Central Safety Physician and Back-up Phone contact: refer to protocol Section 
8.5.6.1. 
Refer to the protocol section 7.3.1 for details on emergency unblinding. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document history 
Document 
Date 
Protocol amendment 4 
9 May 2021 
Protocol Amendment 3 
23 September 2020 
Protocol Amendment 2 
18 March 2020 
Protocol Amendment 1 
23 May 2019 
Protocol Final Version 1 
29 January 2015 
Amendment 4 [9 May 2021] 
Overall Rationale for the Amendment change: The protocol is being amended to 
document the increase in blood volumes drawn at certain visits (Visit 2 and Visit 6) to 
improve the serum yield which is critical to evaluate the study endpoints. The allowed 
windows for study visits during special circumstances have also been widened to 
maintain subject visit compliance during the COVID-19 pandemic. Additionally, 
considering that some of the study interventions are combination products constituted of 
a device and biologic product (pre-filled syringes), the amended protocol provides 
instructions for collection of safety information related to the use of medical devices. The 
reporting period for pregnancies has also been updated in line with the current guidelines.  
The list of main changes in the protocol with rationale is presented in Table 2 and all 
changes made to this amendment (including correction of typos) are presented in the 
amendment history (Refer to Section 12.10.1). 
Table 2 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Overall design 
Section 5.1: Scientific rationale 
for study design 
Section 5.2: Overall design 
Section 8.4.2.1: Blood sampling 
for effectiveness and 
immunogenicity response 
assessments 
 
 
The blood volume collected at Visit 2 
and Visit 6 has been increased from 
25mL to 30 mL. 
This change has been made to 
increase serum yield which is 
critical to evaluate study endpoints. 
Section 8.9: Study procedures 
during special circumstances 
The allowed windows for study visits 
during special circumstances (Table 17) 
has been changed from +21 days to 
+28 days. 
To allow for subject visit 
compliance during the global 
COVID-19 pandemic. 
Section 7.1: Treatments 
administered 
Section 8.5.10: Medical device 
deficiencies 
Section 12.8: Appendix 8: 
Definition of medical device AE, 
Product category and Type included 
 
Implementation of wording on medical 
device deficiency for combination 
products for Post Marketing Safety 
Reporting  
In line with the FDA Combination 
Product Post Marketing Safety 
Reporting guidance. 
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Section # and Name 
Description of Change 
Brief Rationale 
adverse device effect (ADE), 
serious adverse device effect 
(SADE) and unanticipated SADE 
(USADE) 
Synopsis Table 1: Objectives and 
endpoints 
Section 4, Table 6: Objectives 
and endpoints 
Section 8.4.3: Laboratory assays 
Section 8.4.4.1: Immunological 
read-outs 
Section 10.1: Sample size 
determination 
Section 10.1.2.12: Non inferiority 
of MenABCWY vs rMenB+OMV 
NZ measured by percentage of 
subjects with 4-fold rise in hSBA 
titres against MenB component 
indicator strains post 2nd dose 
Section 10.3.4.1: Immunological 
non-inferiority: MenABCWY vs. 
rMenB+OMV NZ 
Section 10.3.4.4: Immune 
response of MenABCWY, 
rMenB+OMV NZ and MenACWY 
Section 12.2.2: MenB serum 
bactericidal assays using 
exogenous human complement 
(hSBA) – rMenB + OMV NZ 
 
The NHBA strain has been changed 
from M07-0241084 to M13520. 
The new strain has been approved 
for use in this study by competent 
authority. 
Section 8.5.6: Reporting of 
serious adverse events, 
pregnancies and other events 
Section 12.5.10.4: Completion 
and transmission of pregnancy 
reports to GSK 
Section 12.6.3: Collection of 
pregnancy information 
The timeframe for submitting pregnancy 
report to GSK is now 24 hours (changed 
from 2 weeks) 
In line with the pregnancy reporting 
guidelines 
Synopsis: Overall design 
Section 2: Schedule of activities 
Section 5.2: Overall design 
Section 8.10: Decentralised study 
procedures 
Home/ remote visits (subject to 
allowance by local regulations and 
quality maintenance of study 
procedures) can be offered to subjects 
for the collection of biological samples 
and/or study intervention administration. 
In alignment to the decentralised 
study procedures. 
Section 8.4.3, Laboratory assays 
(Table 12) 
Section 12.3 Appendix 3 – 
Clinical laboratories 
The laboratory at Marburg is removed 
from the list of GSK laboratories. 
The laboratory at Marburg has 
become an external laboratory. 
 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
1. 
SYNOPSIS ............................................................................................................. 19 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 31 
3. 
INTRODUCTION .................................................................................................... 34 
3.1. 
Study rationale ............................................................................................ 34 
3.2. 
Background ................................................................................................ 36 
3.3. 
Benefit/Risk assessment ............................................................................. 37 
3.3.1. 
Risk assessment .......................................................................... 38 
3.3.2. 
Benefit assessment ..................................................................... 41 
3.3.3. 
Overall Benefit: Risk conclusion ................................................... 41 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 41 
5. 
STUDY DESIGN .................................................................................................... 47 
5.1. 
Scientific rationale for study design ............................................................. 47 
5.1.1. 
Rationale for the use of placebo .................................................. 49 
5.2. 
Overall design ............................................................................................. 49 
5.3. 
Number of subjects ..................................................................................... 53 
5.4. 
Subject and study completion ..................................................................... 53 
6. 
STUDY POPULATION ........................................................................................... 54 
6.1. 
Inclusion criteria for enrolment .................................................................... 54 
6.2. 
Exclusion criteria for enrolment ................................................................... 55 
6.2.1. 
Medical conditions ....................................................................... 55 
6.2.2. 
Prior/Concomitant therapy ........................................................... 56 
6.2.3. 
Prior/Concurrent clinical study experience ................................... 56 
6.2.4. 
Other exclusions .......................................................................... 56 
6.3. 
Criteria for temporary delay for enrolment and vaccination and/or 
blood sampling ........................................................................................... 57 
6.4. 
Screen and baseline failures ....................................................................... 57 
7. 
TREATMENTS ....................................................................................................... 58 
7.1. 
Treatments administered ............................................................................ 58 
7.1.1. 
Precautions to be observed in administering study vaccine ......... 61 
7.1.2. 
Vaccine Administration Error or Overdose of Vaccine .................. 61 
7.2. 
Method of treatment assignment ................................................................. 62 
7.2.1. 
Subject identification .................................................................... 62 
7.2.2. 
Randomisation of treatment ......................................................... 62 
7.2.2.1. 
Randomisation of supplies .......................................... 62 
7.2.2.2. 
Treatment allocation to the subject ............................. 62 
7.2.2.2.1. 
Study group and treatment 
number allocation ................................... 62 
7.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 63 
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7.2.3. 
Allocation of subjects to assay subsets ........................................ 63 
7.2.3.1. 
Randomisation to strains for enc-hSBA testing ........... 64 
7.3. 
Blinding and unblinding ............................................................................... 64 
7.3.1. 
Emergency unblinding ................................................................. 64 
7.4. 
Handling, storage and replacement of study vaccine(s)/product(s) ............. 65 
7.4.1. 
Storage and handling of study vaccine(s)/product(s) ................... 65 
7.4.2. 
Replacement of unusable vaccine(s)/product(s) doses ................ 66 
7.5. 
Concomitant medication(s)/product(s) and concomitant vaccinations ......... 66 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 66 
7.5.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 67 
7.6. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 68 
7.7. 
Contraindications to subsequent vaccine(s) administration ......................... 68 
7.8. 
Warnings and precautions .......................................................................... 69 
7.9. 
Treatment after completion of the study ...................................................... 69 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 69 
8.1. 
General study aspects ................................................................................ 70 
8.2. 
Data Collected from Subjects ...................................................................... 70 
8.3. 
Pre-vaccination procedures ........................................................................ 71 
8.3.1. 
Screening/ Eligibility criteria ......................................................... 71 
8.3.2. 
Collection of demographic data .................................................... 71 
8.3.3. 
Medical history ............................................................................. 71 
8.3.4. 
General and symptom-directed physical examination .................. 72 
8.3.5. 
Pregnancy test ............................................................................. 72 
8.3.6. 
Pre-vaccination body temperature ............................................... 72 
8.4. 
Effectiveness and/or immunogenicity assessments .................................... 73 
8.4.1. 
Use of specified study materials .................................................. 73 
8.4.2. 
Biological samples ....................................................................... 74 
8.4.2.1. 
Blood sampling for effectiveness and 
immunogenicity response assessments ..................... 74 
8.4.2.2. 
Other biological samples ............................................ 75 
8.4.3. 
Laboratory assays ....................................................................... 75 
8.4.4. 
Biological samples evaluation ...................................................... 77 
8.4.4.1. 
Immunological read-outs ............................................ 77 
8.4.5. 
Immunological correlates of protection ......................................... 78 
8.5. 
Safety Assessments ................................................................................... 78 
8.5.1. 
Safety definitions ......................................................................... 78 
8.5.2. 
Follow-up Clinic Visit(s) ................................................................ 78 
8.5.3. 
Safety Follow-up Calls ................................................................. 79 
8.5.4. 
Time period and frequency for collecting AE and serious 
adverse event (SAE) information ................................................. 80 
8.5.5. 
Method of detecting AEs and SAEs ............................................. 82 
8.5.6. 
Reporting of serious adverse events, pregnancies, and 
other events ................................................................................. 82 
8.5.6.1. 
Contact information for reporting of serious 
adverse events, AESIs and pregnancies .................... 82 
8.5.6.2. 
Regulatory reporting requirements for SAEs .............. 83 
8.5.7. 
Follow-up of AEs and SAEs ......................................................... 83 
8.5.8. 
Treatment of adverse events ....................................................... 83 
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8.5.9. 
Subject card ................................................................................. 83 
8.5.10. 
Medical device deficiencies ......................................................... 84 
8.5.10.1. Detection, follow-up and prompt reporting of 
medical device deficiency ........................................... 84 
8.5.10.2. Regulatory reporting of medical device 
deficiency when used as combination product ............ 84 
8.6. 
Holding rules and safety monitoring ............................................................ 84 
8.7. 
Biomarkers and pharmacogenomics ........................................................... 84 
8.8. 
Study Termination Visit/ Study Conclusion .................................................. 85 
8.8.1. 
Early Termination Visit ................................................................. 85 
8.9. 
Study procedures during special circumstances ......................................... 86 
8.10. 
Decentralised study procedures .................................................................. 87 
9. 
DISCONTINUATION FROM THE STUDY .............................................................. 87 
9.1. 
Discontinuation of study vaccine(s)/product(s) ............................................ 90 
9.2. 
Lost to follow-up.......................................................................................... 91 
10. STATISTICAL CONSIDERATIONS ........................................................................ 91 
10.1. 
Sample size determination .......................................................................... 91 
10.1.1. 
Hypothesis testing strategy .......................................................... 92 
10.1.1.1. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................... 93 
10.1.1.2. Effectiveness (Responder-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................... 93 
10.1.1.3. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................... 94 
10.1.1.4. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................... 94 
10.1.1.5. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................... 94 
10.1.1.6. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................... 94 
10.1.1.7. Lot-to-lot consistency: MenABCWY - ACWY 
component ................................................................. 94 
10.1.1.8. Immunological non-inferiority: MenABCWY vs. 
MenACWY ................................................................. 95 
10.1.1.9. Vaccine effectiveness (Test-based): 
MenABCWY ............................................................... 95 
10.1.1.10. Effectiveness non-inferiority: MenABCWY vs. 
rMenB+OMV NZ ......................................................... 95 
10.1.1.11. Effectiveness (Responder-based): MenABCWY ......... 96 
10.1.2. 
Sample size justification ............................................................... 96 
10.1.2.1. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................... 96 
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10.1.2.2. Effectiveness (Responder-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................... 97 
10.1.2.3. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................... 97 
10.1.2.4. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................... 97 
10.1.2.5. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................... 97 
10.1.2.6. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................... 98 
10.1.2.7. Lot-to-lot consistency: MenABCWY - ACWY 
component ................................................................. 98 
10.1.2.8. Immunological non-inferiority: MenABCWY vs. 
MenACWY in subjects without a previous 
MenACWY vaccination (unprimed) ............................. 98 
10.1.2.9. Vaccine effectiveness (Test-based): 
MenABCWY ............................................................... 99 
10.1.2.10. Effectiveness non-inferiority: MenABCWY vs. 
rMenB+OMV NZ ......................................................... 99 
10.1.2.11. Effectiveness (Responder-based): MenABCWY ......... 99 
10.1.2.12. Non inferiority of MenABCWY vs rMenB+OMV 
NZ measured by percentage of subjects with 4-
fold rise in hSBA titres against MenB 
component indicator strains post 2nd dose ............... 100 
10.2. 
Populations for analyses ........................................................................... 100 
10.3. 
Statistical analyses ................................................................................... 101 
10.3.1. 
Subjects disposition ................................................................... 101 
10.3.2. 
Demography and baseline characteristics analyses ................... 101 
10.3.3. 
Primary effectiveness and immunogenicity analyses ................. 101 
10.3.3.1. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................. 101 
10.3.3.2. Effectiveness (Responder-based): 
rMenB+OMV NZ - 3 doses (0,2,6-months 
schedule) .................................................................. 102 
10.3.3.3. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................. 102 
10.3.3.4. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,6-months 
schedule) .................................................................. 102 
10.3.3.5. Vaccine effectiveness (Test-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................. 102 
10.3.3.6. Effectiveness (Responder-based): 
rMenB+OMV NZ - 2 doses (0,2-months 
schedule) .................................................................. 102 
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10.3.3.7. Lot-to-lot consistency: MenABCWY - ACWY 
component ............................................................... 103 
10.3.3.8. Immunological non-inferiority: MenABCWY vs. 
MenACWY in subjects without a previous 
MenACWY vaccination (unprimed) ........................... 103 
10.3.3.9. Vaccine effectiveness (Test-based): 
MenABCWY ............................................................. 103 
10.3.3.10. Effectiveness non-inferiority: MenABCWY vs. 
rMenB+OMV NZ ....................................................... 103 
10.3.3.11. Effectiveness (Responder-based): MenABCWY ....... 104 
10.3.4. 
Secondary effectiveness and immunogenicity analyses ............. 104 
10.3.4.1. Immunological non-inferiority: MenABCWY vs. 
rMenB+OMV NZ ....................................................... 104 
10.3.4.2. Effectiveness by each of the endemic US N. 
meningitidis serogroup B strains ............................... 104 
10.3.4.3. Distribution of percentages of serogroup B 
invasive disease strains killed ................................... 105 
10.3.4.4. Immune response of MenABCWY, 
rMenB+OMV NZ and MenACWY ............................. 105 
10.3.5. 
Safety analyses ......................................................................... 106 
10.3.6. 
Other analyses .......................................................................... 107 
10.3.7. 
Interim analyses ......................................................................... 107 
10.4. 
Sequence of analyses............................................................................... 107 
11. REFERENCES ..................................................................................................... 108 
12. APPENDICES ...................................................................................................... 110 
12.1. 
Appendix 1: Abbreviations, glossary of terms and trademarks .................. 110 
12.1.1. 
List of abbreviations ................................................................... 110 
12.1.2. 
Glossary of terms ....................................................................... 113 
12.1.3. 
Trademarks ............................................................................... 119 
12.2. 
Appendix 2: Clinical laboratory tests ......................................................... 119 
12.2.1. 
Effectiveness Assessment: Endogenous complement 
serum bactericidal assay – rMenB + OMV NZ ........................... 119 
12.2.2. 
MenB serum bactericidal assays using exogenous human 
complement (hSBA) – rMenB + OMV NZ ................................... 120 
12.2.3. 
MenACWY serum bactericidal assays using human 
complement (hSBA): .................................................................. 120 
12.2.4. 
MenACWY IgG ELISA ............................................................... 121 
12.3. 
Appendix 3: Clinical laboratories ............................................................... 121 
12.4. 
Appendix 4: Study governance considerations ......................................... 121 
12.4.1. 
Regulatory and ethical considerations ....................................... 121 
12.4.2. 
Financial disclosure ................................................................... 122 
12.4.3. 
Informed consent process .......................................................... 122 
12.4.4. 
Data protection .......................................................................... 123 
12.4.5. 
Committees structure ................................................................. 124 
12.4.5.1. Responsibilities of the Investigator and IRB/EC ........ 124 
12.4.6. 
Protocol Amendments................................................................ 125 
12.4.7. 
Publication policy ....................................................................... 125 
12.4.8. 
Dissemination of clinical study data ........................................... 125 
12.4.9. 
Data quality assurance .............................................................. 126 
12.4.10. Source documents ..................................................................... 127 
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12.4.11. Study and site closure................................................................ 128 
12.5. 
Appendix 5: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting .......................................... 128 
12.5.1. 
Definition of AE .......................................................................... 128 
12.5.1.1. AE Definition............................................................. 128 
12.5.1.2. Examples of events Meeting the AE Definition ......... 128 
12.5.1.3. Examples of events NOT Meeting the AE 
Definition .................................................................. 129 
12.5.2. 
Definition of SAE ........................................................................ 129 
12.5.3. 
Solicited adverse events ............................................................ 130 
12.5.4. 
Other solicited adverse events ................................................... 131 
12.5.5. 
Unsolicited adverse events ........................................................ 131 
12.5.6. 
Adverse events of special interest (AESIs) ................................ 132 
12.5.6.1. Arthritis ..................................................................... 132 
12.5.6.2. Potential immune-mediated diseases ....................... 132 
12.5.7. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events .......................................................................... 135 
12.5.8. 
Events or outcomes not qualifying as adverse events or 
serious adverse events .............................................................. 135 
12.5.8.1. Pregnancy ................................................................ 135 
12.5.9. 
Detecting and recording adverse events, serious adverse 
events and pregnancies ............................................................. 136 
12.5.9.1. Post-vaccination reminders ...................................... 138 
12.5.9.2. Time period for detecting and recording 
adverse events, serious adverse events and 
pregnancies .............................................................. 138 
12.5.9.3. Evaluation of adverse events and serious 
adverse events ......................................................... 139 
12.5.9.3.1. Active questioning to detect 
adverse events and serious 
adverse events ..................................... 139 
12.5.9.3.2. Assessment of adverse events ............. 139 
12.5.9.3.3. Medically attended visits ....................... 143 
12.5.9.4. Recording of AEs related to COVID-19 ..................... 143 
12.5.9.4.1. WHO Case Definition ............................ 143 
12.5.10. Reporting of serious adverse events, pregnancies, and 
other events ............................................................................... 144 
12.5.10.1. Prompt reporting of serious adverse events, 
pregnancies, and other events to GSK ..................... 144 
12.5.10.2. SAEs requiring expedited reporting to GSK .............. 145 
12.5.10.3. Back-up system in case the electronic 
reporting system does not work ................................ 145 
12.5.10.4. Completion and transmission of pregnancy 
reports to GSK .......................................................... 145 
12.5.10.5. Reporting of AESI’s to GSK ...................................... 145 
12.5.11. Updating of SAE, pregnancy, and AESI information after 
removal of write access to the subject’s eCRF ........................... 146 
12.5.12. Follow-up of adverse events, serious adverse events, and 
pregnancies ............................................................................... 146 
12.5.12.1. Post-vaccination Procedures .................................... 146 
12.5.12.2. Post-vaccination Visit(s) ........................................... 146 
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12.5.12.3. Unscheduled Visits ................................................... 147 
12.5.12.4. Follow-up of adverse events and serious 
adverse events ......................................................... 147 
12.5.12.4.1. Follow-up during the study .................... 147 
12.5.12.4.2. Follow-up after the subject is 
discharged from the study .................... 147 
12.5.12.4.3. Follow-up of pregnancies ...................... 147 
12.6. 
Appendix 6: Contraceptive guidance and collection of pregnancy 
information ................................................................................................ 148 
12.6.1. 
Definitions .................................................................................. 148 
12.6.1.1. Woman of Childbearing Potential (WOCBP) ............. 148 
12.6.1.1.1. Women in the following categories 
are not considered WOCBP .................. 148 
12.6.2. 
Contraception guidance ............................................................. 148 
12.6.3. 
Collection of pregnancy information ........................................... 149 
12.6.3.1. Female Subjects who become pregnant ................... 149 
12.7. 
Appendix 7: Genetics ................................................................................ 150 
12.8. 
Appendix 8: Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and unanticipated 
SADE (USADE) ........................................................................................ 150 
12.8.1. 
Definition of medical device AE and adverse device effect 
(ADE) ......................................................................................... 150 
12.8.2. 
Definition of medical device SAE, SADE and USADE ................ 151 
12.8.3. 
Recording and reporting of medical device AE, ADEs, 
SADEs and USADE ................................................................... 151 
12.9. 
Appendix 9: Country-specific requirements ............................................... 152 
12.10. Appendix 9: Protocol Amendment/Administrative change History ............. 153 
12.10.1. Protocol amendment 4 ............................................................... 153 
12.10.2. Protocol amendment 3 ............................................................... 166 
 
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LIST OF TABLES 
PAGE 
Table 1 
Document history ..................................................................................... 7 
Table 2 
List of main changes in the protocol and their rationale ............................ 7 
Table 3 
Schedule of Activities ............................................................................. 31 
Table 4 
Intervals between study visits ................................................................. 34 
Table 5 
Intervals between study visits and phone calls ....................................... 34 
Table 6 
Study objectives and endpoints .............................................................. 41 
Table 7 
Study groups and treatment foreseen in the study ................................. 51 
Table 8 
Overview of study design: Vaccination and Blood Draw Schedule ......... 52 
Table 9 
Treatments administered ........................................................................ 59 
Table 10 
Contact information for emergency unblinding ....................................... 65 
Table 11 
Biological samples ................................................................................. 75 
Table 12 
Laboratory assays .................................................................................. 76 
Table 13 
Immunological read-outs ........................................................................ 77 
Table 14 
Reporting periods for collecting safety information ................................. 80 
Table 15 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK ................................................................... 82 
Table 16 
Contact information for reporting of serious adverse events, 
AESIs and pregnancies .......................................................................... 82 
Table 17 
Intervals between study visits during special circumstances .................. 87 
Table 18 
Power for VE 65% against all 110 strains combined, any 
schedule ................................................................................................ 97 
Table 19 
Power for rMenB+OMV NZ Responder-based analysis 3 dose 
(0,2,6-months schedule) ......................................................................... 97 
Table 20 
Power calculation to demonstrate lot-to-lot consistency ......................... 98 
Table 21 
Power calculation to demonstrate non-inferiority for serogroups 
A, C, W and Y of MenABCWY compared to MenACWY in 
subjects without a previous MenACWY vaccination (unprimed), 
at 1 month after the second dose vs 1 month after a single dose ........... 99 
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Table 22 
Power calculation to demonstrate NI of MenABCWY to MenB ............... 99 
Table 23 
Power of Non inferiority of MenABCWY vs rMenB+OMV NZ ................ 100 
Table 24 
GSK laboratories* ................................................................................ 121 
Table 25 
Solicited local adverse events .............................................................. 130 
Table 26 
Solicited systemic adverse events ........................................................ 131 
Table 27 
List of potential immune-mediated diseases (pIMDs) ........................... 133 
Table 28 
Intensity scales for solicited symptoms in adults and children of 
10 years of age or more ....................................................................... 140 
Table 29 
Highly Effective Contraceptive Methods ............................................... 149 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 49 
Figure 2 
Hierarchical testing of hypothesis ........................................................... 92 
 
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1. 
SYNOPSIS 
Rationale: 
In 2013, the US Food and Drug Administration (FDA) agreed with the Company 
proposal to evaluate meningococcal B vaccine effectiveness against a large panel of US 
epidemiologically relevant invasive disease strains of N. meningitidis serogroup B in 
adolescents using serum bactericidal assays with endogenous human complement (enc-
hSBA). This panel includes 110 serogroup B strains randomly selected from the original 
panel of 442 endemic strains identified as appropriately representative of invasive 
meningococcal serogroup B strains detected in the US by the Centers for Disease Control 
and Prevention (CDC) [Welsch, 2018].  
Following licensure of Bexsero (rMenB+OMV NZ) in the US in 2015, as required under 
accelerated approval regulations, GSK was requested to demonstrate effectiveness of 
Bexsero via a post-approval confirmatory trial in US adolescents and adults. To date, 
there has not been an evaluation completed to assess the vaccine effectiveness of the 
rMenB+OMV NZ vaccine against the panel (as described above) of the US 
epidemiologically relevant invasive disease strains of N. meningitidis serogroup B. 
The investigational MenABCWY combination vaccine is based upon two established 
GSK vaccines, the quadrivalent meningococcal ACWY conjugate vaccine (Menveo) and 
the multi-component recombinant meningococcal B vaccine (Bexsero), for which 
significant nonclinical and clinical data have been generated and used to support 
marketing authorisations in US, European Union (EU) and several other countries. The 
MenABCWY investigational vaccine will be reconstituted from the following two 
components before administration: 
• 
the MenACWY component lyophilised in vial; 
• 
the MenB liquid component in prefilled syringe. 
The MenACWY component contains the same antigens in the same amounts as the 
commercial Menveo, in a lyophilised form. The MenB liquid component is the same 
formulation as the commercial Bexsero. 
The primary purpose of this study is hence to demonstrate the vaccine effectiveness using 
enc-hSBA against a panel of 110 randomly selected endemic US N. meningitidis 
serogroup B invasive disease strains, when administered in a 3-dose (0,2,6-months) or a 
2-dose (0,6-months; 0,2-months) schedule as a meningococcal group B vaccine (Bexsero) 
and when administered in a 2-dose (0,6-months) schedule as a combined MenABCWY 
vaccine. 
In addition, the other main objectives of this study are: 
• 
to demonstrate the consistency of immune responses from 3 production lots of the 
MenACWY component of the MenABCWY vaccine,  
• 
to demonstrate the non-inferiority of a 2-dose series of MenABCWY vaccine versus 
a single dose of Menveo (MenACWY) in terms of immune response to 
meningococcal serogroups A, C, W and Y, 
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• 
to demonstrate the non-inferiority of the effectiveness of the MenABCWY vaccine 
versus Bexsero (rMenB+OMV NZ) against a randomly selected panel of endemic 
US N. meningitidis serogroup B invasive disease strains, 
• 
to assess the safety of all study vaccines administered as per their vaccination 
schedule to healthy subjects aged 10-25 years. 
Objectives and Endpoints: 
Synopsis Table 1 
Study objectives and endpoints 
(Amended: 9 May 2021) 
Objectives 
Endpoints 
Primary 
Vaccine effectiveness (Test-based): rMenB+OMV NZ 
To demonstrate the effectiveness of the rMenB+OMV NZ 
vaccine against a randomly selected panel of endemic US N. 
meningitidis serogroup B invasive disease strains as 
measured by bactericidal activity using enc-hSBA at 1 month 
after the 3-dose (0,2,6-months) and 2-dose (0,6-months; 0,2-
months) vaccination series when compared to 1 month after 
the MenACWY vaccination. 
Criterion 
Lower limit (LL) of the two-sided 97.5% confidence interval 
(CI) for vaccine effectiveness is above 65% against a 
randomly selected strain panel between the: 
• 
MenB_0_2_6 and ACWY groups (for 0,2,6-months 
schedule) 
• 
MenB_0_6 and ACWY groups (for 0,6-months schedule),  
• 
MenB_0_2_6 and ACWY groups (for 0,2-months 
schedule)  
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains, at 1 month after the: 
• 
3-dose vaccination series in MenB_0_2_6 
group (Day 211, Month 7) 
• 
2-dose vaccination series in MenB_0_6 
group (Day 211, Month 7), and 
• 
2-dose vaccination series in MenB_0_2_6 
group (Day 91, Month 3) 
• 
1 month after the MenACWY vaccination in 
ACWY group (Day 31, Month 1). 
Effectiveness (Responder-based): rMenB+OMV NZ 
To demonstrate the effectiveness of the rMenB+OMV NZ 
vaccine by assessing the percentages of subjects whose sera 
kill ≥70% of strains tested using enc-hSBA at 1 month after 
the 3-dose (0,2,6-months) and 2-dose (0,6-months; 0,2-
months) vaccination series of the rMenB+OMV NZ. 
Criterion: 
LL of the two-sided 97.5% CI for the percentages of subjects 
whose sera kill ≥70% of strains is above 65%, tested for: 
• 
MenB_0_2_6 group (for 0,2,6-months schedule) 
• 
MenB_0_6 group (for 0,6-months schedule),  
• 
MenB_0_2_6 group (for 0,2-months schedule)  
The percentages of subjects whose sera kill 
≥70% of the strains tested using enc-hSBA, at 1 
month after the: 
• 
3-dose vaccination series (Day 211, Month 7 
in MenB_0_2_6 group)  
• 
2-dose vaccination series (Day 211, Month 7 
in MenB_0_6 group),  
• 
2-dose vaccination series (Day 91, Month 3 
in MenB_0_2_6 group)  
The 3 vaccine schedules will be tested for both, test-based and responder-based, in a hierarchical way (starting 
from 0-2-6, to 0-6 and 0-2). Refer to Section 10.1 for details on continuing the evaluation. 
Lot-to-lot consistency: MenABCWY vaccine 
To demonstrate lot-to-lot consistency of the immune 
responses of 3 lots of the MenACWY component of the 
MenABCWY vaccine, as measured by hSBA GMTs directed 
GMTs directed against serogroups A, C, W and Y 
for each lot (ABCWY-1 group, ABCWY-2 group, 
ABCWY-3 group) at 1 month after the last 
vaccination (Day 211, Month 7) 
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Objectives 
Endpoints 
against serogroups A, C, W and Y at 1 month after last 
vaccination (0,6-months). 
Criterion: 
The two-sided 97.5% CIs^ for the ratio of hSBA GMTs of 
antibodies against serogroups A, C, W and Y are within the 
[0.5;2.0] equivalence interval for each pair of lots. 
Immunological non-inferiority: MenABCWY vaccine vs. 
MenACWY vaccine*** 
To demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the MenACWY vaccine as 
measured by the percentages of subjects achieving a 4-fold 
rise in hSBA titres against N. meningitidis serogroups A, C, W 
and Y at 1 month after the last MenABCWY vaccination (0,6-
months) and 1 month after the MenACWY vaccination. 
Criterion: 
LL of the two-sided 97.5% CI^ for the group difference in 
percentages of subjects achieving a 4-fold rise* in hSBA titres 
is above -10%. 
The percentages of subjects with 4-fold rise* in 
hSBA titres against N. meningitidis serogroups A, 
C, W and Y at 1 month after the: 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7), and 
• 
1 month after the MenACWY vaccination for 
the ACWY group (Day 31, Month 1) 
relative to baseline (Day 1, Month 0). 
Vaccine effectiveness (Test-based): MenABCWY vaccine 
To demonstrate the effectiveness of the MenABCWY vaccine 
against a randomly selected panel of endemic US N. 
meningitidis serogroup B invasive disease strains as 
measured by enc-hSBA at 1 month after the last MenABCWY 
vaccination (0,6-months) when compared to 1 month after the 
MenACWY vaccination. 
Criterion: 
LL of the two-sided 97.5% CI^ for vaccine effectiveness is 
above 65% against a randomly selected strain panel between 
the ABCWY group (pooled lots) and the ACWY group. 
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains, at 1 month after the: 
• 
last vaccination for the ABCWY group 
(pooled) (Day 211, Month 7), and  
• 
1 month after the MenACWY vaccination in 
the ACWY group (Day 31, Month 1).  
Effectiveness non-inferiority: MenABCWY vaccine vs. 
rMenB+OMV NZ vaccine 
To demonstrate the non-inferiority of the effectiveness of the 
MenABCWY vaccine (0,6-months schedule) compared to the 
rMenB+OMV NZ vaccine (0,2,6-months or 0,6-months or 0,2-
months)† in terms of percentage of samples with bactericidal 
serum activity using enc-hSBA against a randomly selected 
panel of endemic US N. meningitidis serogroup B invasive 
disease strains. 
Criterion: 
LL of the two-sided 97.5% CI^ for the difference in 
percentages of samples with bactericidal serum activity using 
enc-hSBA against a randomly selected panel of endemic US 
N. meningitidis serogroup B invasive disease strains is above 
-5% at 1 month after: 
• 
 the last vaccination in ABCWY group (pooled lots) (for 
0,6 months schedule), and 
• 
The last vaccination in MenB_0_2_6 group (for 0,2,6-
months schedule) or the last vaccination in MenB_0_6 
group (for 0,6-months schedule) or the second 
The percentages of samples with bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains at 1 month after the: 
• 
last MenABCWY vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots), 
and 
• 
3-dose vaccination series of rMenB+OMV 
vaccine (Day 211, Month 7 in MenB_0_2_6 
group) or 2-dose vaccination series (Day 
211, Month 7 in MenB_0_6 group) or 2-dose 
vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
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Objectives 
Endpoints 
vaccination in MenB_0_2_6 group (for 0,2-months 
schedule  
Effectiveness (Responder-based): MenABCWY vaccine 
To demonstrate the effectiveness of MenABCWY vaccine by 
assessing the percentages of subjects whose sera kill ≥70% 
of strains tested using enc-hSBA at 1 month after the last 
vaccination of MenABCWY (0,6-months). 
Criterion: 
LL of the two-sided 97.5% CI^ for the percentages of subjects 
whose sera kill ≥70% of strains tested for MenABCWY is 
above 65%. 
The percentages of subjects whose sera kill 
≥70% of the strains tested using enc-hSBA, at 1 
month after the last vaccination for the ABCWY 
group (pooled lots) (Day 211, Month 7). 
Safety 
To evaluate the safety and reactogenicity of the MenB, 
MenABCWY, and the MenACWY vaccines  
• 
The frequencies and percentages of 
subjects with solicited local (i.e., injection 
site pain, erythema, swelling, induration) 
and systemic (i.e., fever [body temperature 
≥ 38.0°C], nausea, fatigue, myalgia, 
arthralgia, headache) adverse events (AEs) 
during the 7 days (including the day of 
vaccination) following each vaccination at 
Day 1, Day 61 and Day 181. 
• 
The frequencies and percentages of 
subjects with any unsolicited AEs (including 
all SAEs, AEs leading to withdrawal, AESIs 
and medically attended AEs) during the 30 
days (including the day of vaccination) 
following each vaccination at Day 1, Day 61 
and Day 181. 
• 
The percentages of subjects with SAEs, 
AEs leading to withdrawal, AESIs and 
medically attended AEs throughout the 
study period [Month 0 to Month 12]. 
Secondary 
To demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the rMenB+OMV NZ 
vaccine as measured by the percentages of subjects 
achieving a 4-fold rise in hSBA titres against N. meningitidis 
serogroup B indicator strains at 1 month after the last 
MenABCWY vaccination (0,6-months schedule) and 1 month 
after the rMenB+OMV NZ vaccination (0,2,6-months or 0,6-
months or 0,2-months)† 
Criterion: 
Non-inferiority will be demonstrated if the LL of the 2-sided 
95% CI for the group difference in percentage of subjects 
achieving a 4-fold rise** in hSBA titres against N. meningitidis 
serogroup B indicator strains is above 
 -10%. 
The percentages of subjects with 4-fold rise** in 
hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the: 
• 
last MenABCWY vaccination for the 
ABCWY group (pooled lots) (Day 211, 
Month 7), and 
• 
3-dose vaccination series of rMenB+OMV 
vaccine(Day 211, Month 7 in MenB_0_2_6 
group) or 2-dose vaccination series (Day 
211, Month 7 in MenB_0_6 group) or 2-
dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
 relative to baseline (Day 1, Month 0). 
To assess the effectiveness of the rMenB+OMV NZ and 
MenABCWY vaccines against each of the randomly selected 
endemic US N. meningitidis serogroup B invasive disease 
strains as measured by bactericidal activity using enc-hSBA at 
1 month after the 3-dose (0,2,6-months in MenB_0_2_6 
group) and 2-dose (0,6-months in MenB_0_6 group, 0,2-
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains at 1 month after the:  
• 
3-dose vaccination series (Day 211, Month 
7 in MenB_0_2_6 group) 
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Objectives 
Endpoints 
months in MenB_0_2_6 group and 0,6-months in the ABCWY 
(pooled) group) vaccination series when compared to 1 month 
after the MenACWY vaccination. 
• 
2-dose vaccination series (Day 211, Month 
7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 
in MenB_0_2_6 group) 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7), and 
• 
MenACWY vaccination (Day 31, Month 1 in 
ACWY group). 
To describe the distribution of subjects by percentages of 
serogroup B invasive disease strains killed using enc-hSBA at 
1 month after the 3-dose (0,2,6-months in MenB_0_2_6 
group) and 2-dose (0,6-months in MenB_0_6 group, 0,2-
months in MenB_0_2_6 group and 0,6-months in the ABCWY 
(pooled) group) vaccination series of rMenB+OMV NZ and 
MenABCWY vaccines. 
The percentages of serogroup B invasive disease 
strains killed using enc-hSBA in each subject at 1 
month after the: 
• 
3-dose vaccination series (Day 211, Month 
7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 
7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 
in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
To assess the immune response to the rMenB+OMV NZ 
(0,2,6-months, 0,6-months and 0,2-months) and MenABCWY 
(0,6-months) vaccines against N. meningitidis serogroup B 
indicator strains at pre-vaccination (Day 1, Month 0) and at 1 
month after the last MenABCWY vaccination and at 1 month 
after the second and third vaccination of rMenB+OMV NZ. 
The immune response to the rMenB+OMV NZ 
and ABCWY vaccines will be evaluated by 
measuring bactericidal activity against N. 
meningitidis serogroup B indicator strains as 
following: 
1. The percentages of subjects with hSBA titres  
≥ lower limit of quantitation (LLOQ) for each 
(individual response) and all (composite 
response) serogroup B indicator strains at 
baseline (Day 1, Month 0) and at 1 month after 
the: 
• 
3-dose vaccination series (Day 211, Month 
7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 
7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 
in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
2. The percentages of subjects with 4-fold rise** in 
hSBA titres at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 90, 
Month 3 in MenB_0_2_6 group), and 
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Objectives 
Endpoints 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
relative to baseline (Day 1, Month 0). 
3. hSBA GMTs at baseline (Day 1, Month 0) and 
at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, 
Month 3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
4. hSBA GMRs at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, 
Month 3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
relative to the baseline (Day 1, Month 0). 
To assess the immune response to MenABCWY (0,6-months 
schedule) and MenACWY (single dose) vaccines against N. 
meningitidis serogroups A, C, W and Y, at pre-vaccination 
(Day 1, Month 0) and at 1 month after the first and the last 
MenABCWY vaccination and 1 month after the MenACWY 
vaccination. 
1. The percentage of subjects with hSBA titres 
≥ LLOQ for serogroups A, C, W and Y at baseline 
(Day 1, Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) 
and the last MenABCWY vaccination (Day 
211, Month 7) for the ABCWY group 
(pooled lots), and 
• 
at 1 month after the MenACWY vaccination 
in the ACWY group (Day 31, Month 1). 
2. The percentage of subjects with 4-fold rise* in 
hSBA titres at 1 month after the: 
• 
first vaccination (Day 31, Month 1) for the 
ABCWY group (pooled lots) compared to 
the MenACWY vaccination in the ACWY 
group (Day 31, Month 1)  
relative to baseline (Day 1, Month 0). 
3. hSBA GMTs against N. meningitidis 
serogroups A, C, W and Y at baseline (Day 1, 
Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) 
and the last MenABCWY vaccination (Day 
211, Month 7) for the ABCWY group 
(pooled lots), and  
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Objectives 
Endpoints 
• 
at 1 month after the MenACWY vaccination 
in the ACWY group (Day 31, Month 1). 
4. hSBA GMRs against N. meningitidis 
serogroups A, C, W and Y at: 
• 
1 month after the first (Day 31, Month 1) 
and the last MenABCWY vaccination (Day 
211, Month 7) for the ABCWY group 
(pooled lots) as compared to baseline (Day 
1, Month 0), and  
• 
1 month after the single MenACWY 
vaccination in the ACWY group (Day 31, 
Month 1) as compared to baseline (Day 1, 
Month 0). 
5.The total IgG as measured by ELISA GMCs 
against serogroups A, C, W and Y at baseline 
(Day 1, Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) 
and the last MenABCWY vaccination (Day 
211, Month 7) for the ABCWY group 
(pooled lots), and  
• 
at 1 month after the MenACWY vaccination 
in the ACWY group (Day 31, Month 1). 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; Enc-hSBA = endogenous complement human serum 
bactericidal assay; GMC = geometric mean concentrations; GMT = geometric mean titre; GMR = geometric mean 
ratio; CI = confidence interval; hSBA = human serum bactericidal assay; LOD: limit of detection; LLOQ = lower limit of 
quantitation; LL = lower limit; AE = Adverse event; SAE = Serious adverse event; AESI = Adverse event of special 
interest 
N. meningitidis serogroup B indicator strains = M14459, 96217, M13520 and NZ98/254 for fHbp, NadA, NHBA and 
PorA P1.4 antigens, respectively.  
Refer to Section 10 for details on evaluation of objectives and sample size justification. Refer to Glossary of terms for 
definitions of test-based and responder-based effectiveness 
^ If the co-primary effectiveness objectives for rMenB+OMV NZ are met, then all objectives for MenABCWY will be 
evaluated at 95% CI. Refer to Section 10.1 for details 
† If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 0,6-
months is also not met, then the 0,2,6-months schedule will be the comparator. 
*For the Men A, C, W, Y evaluation, the 4-fold rise is defined as: 
a post-vaccination hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD but <LLOQ, 
and 
a post-vaccination hSBA titre ≥4 times the pre-vaccination titre for subjects with a pre-vaccination hSBA titre 
≥LLOQ.  
**For the MenB evaluation, the 4-fold rise per each indicator strain is defined as: 
a post-vaccination‡ hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination‡ hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD and 
<LLOQ, and 
a post-vaccination‡ hSBA titre ≥4 times the pre-vaccination hSBA titre for subjects with a pre-vaccination hSBA 
titre ≥ LLOQ 
‡ = post-2nd vaccination for 0,6 and 0,2 schedule and post-3rd vaccination for 0,2,6 schedule). 
***The primary objective of immunological NI of the MenABCWY vaccine to MenACWY will be evaluated only in 
subjects without a previous MenACWY vaccination (unprimed). All other primary and secondary objectives will be 
evaluated in subjects with and without previous MenACWY vaccination (primed/unprimed). 
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Overall Design: 
(Amended: 9 May 2021) 
Synopsis Figure 1 
Study design overview 
 
 
N = number of subjects; d = dose; V = visit; D = day; T = telephone call; 
Refer to Table 3 for details on all visits 
# subjects will receive 2 doses of MenABCWY vaccine with Lot 1 or Lot 2 or Lot 3 of the MenACWY lyophilised vial 
component of the vaccine. Refer to the study groups description below the figure for details and Figure 1 for the 
detailed study design overview 
Notes:  
If local regulations allow and if quality of study procedures can be maintained, participant(s) can be offered 
remote visits (e.g. home visits) for the collection of biological samples and/or study intervention 
administration. These remote visits must be performed by qualified study staff/healthcare professionals 
(HCPs). Refer to Section 8.10 (decentralised study procedures) for details 
Refer to Section 8.9 for information on study procedures during special circumstances 
This is a phase III, randomised, controlled, observer-blind, multi-centre study to evaluate 
effectiveness, immunogenicity and safety of rMenB+OMV NZ and MenABCWY 
vaccines. 
A total of 3651 healthy adolescents and young adults aged 10-25 years will be enrolled 
and randomised (5:5:3:3:3:1 ratio) to one of the six parallel study groups: 
• 
MenB_0_2_6 group: subjects will receive 3 doses of rMenB+OMV NZ at Day 1, 
Day 61 and Day 181 (0,2,6-months schedule). These subjects will receive 1 dose of 
the MenACWY at Day 211*. Data from this group will be used to assess both the 
0,2-months and 0,2,6-months schedules; the 0,2-months schedule will be assessed 1 
month after the second rMenB+OMV NZ vaccination administered at Day 61 (Visit 
3), and the 0,2,6-months schedule will be assessed 1 month after the third 
rMenB+OMV NZ vaccination at Day 181 (Visit 5), in the same group. 
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• 
MenB_0_6 group: subjects will receive 2 doses of rMenB+OMV NZ at Day 1and 
Day 181 and 1 dose of MenACWY vaccine at Day 61 (0,6-months schedule). These 
subjects will receive 1 dose of the placebo at Day 211*. 
• 
ABCWY-1**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 1 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211*.  
• 
ABCWY-2**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 2 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211*. 
• 
ABCWY-3**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 3 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211*. 
• 
ACWY group: subjects will receive 1 dose of MenACWY at Day 1, 1 dose of 
placebo at Day 61 and 2 doses of rMenB+OMV NZ at Day 181 and Day 211*. 
* In order to let the subjects in MenB_0_2_6 group receive a dose of MenACWY 
vaccine and for subjects in ACWY group to receive the second dose of 
rMenB+OMV NZ in line with the vaccine as standard of care (also in line with the 
Advisory Committee on Immunization Practices (ACIP) recommendations in the US 
[ACIP, 2011]), the subjects in these groups will receive a vaccination of MenACWY 
and rMenB+OMV NZ vaccines, respectively, on Day 211 (Visit 6) after completion 
of the post-vaccination 3 blood sampling. To maintain the blinding of the study, 
subjects in the rest of the groups (MenB_0_6, ABCWY-1, ABCWY-2 and ABCWY-
3) will receive a dose of Placebo. All these vaccines/ products administered at Day 
211 are not associated with any study objectives/ endpoints (safety assessment 
conducted after 1 dose of rMenB+OMV NZ in the ACWY group at Day 181 is to 
maintain the blind of the study). 
** (1) A single MenB lot will be used for the pre-filled syringe component of the 
MenABCWY vaccine; (2) The groups ABCWY-1, ABCWY-2, ABCWY-3 will be 
pooled into a single group, ABCWY (pooled lots) (except for analysis of lot-to-lot 
consistency).  
Duration of the study: The study duration is approximately 12 months for each 
subject. 
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Synopsis Table 2 
Study groups and treatment foreseen in the study 
Study Groups 
Number of 
subjects 
Age 
(Min-Max) 
Treatment name 
 
Vaccine/Product name 
MenB_0_2_6  
912 
10 – 25 y 
Bexsero (Injection) 
rMenB+OMV NZ 
Menveo (Injection) 
MenACWY 
MenB_0_6  
912  
Bexsero (Injection) 
rMenB+OMV NZ 
Menveo (Injection) 
MenACWY 
Placebo (Injection) 
NaCl 
ABCWY-1 
548 
MenABCWY (with Lot 1 
of ACWY) (Injection) 
MenABCWY-1 
Placebo (Injection) 
NaCl 
ABCWY-2 
548 
MenABCWY (with Lot 2 
of ACWY) (Injection) 
MenABCWY-2 
Placebo (Injection) 
NaCl 
ABCWY-3 
548 
MenABCWY (with Lot 3 
of ACWY) (Injection) 
MenABCWY-3 
Placebo (Injection) 
NaCl 
ACWY  
183  
Menveo (Injection) 
MenACWY 
Placebo (Injection) 
NaCl 
Bexsero (Injection) 
rMenB+OMV NZ 
 
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Synopsis Table 3 
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 
Visit 5 
Day 181 
Visit 6 
Day 211 
Group  
MenB_0_2_6 
N=912 
Pre-vacc  
Blood sample 
 
rMenB+OMV NZ 
Post-vacc1 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 2 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
MenACWY 
Group  
MenB_0_6 
N=912 
Pre-vacc  
Blood sample 
 
rMenB+OMV NZ 
Post-vacc 1 Blood 
sample 
MenACWY 
Post-vacc 2 Blood 
sample  
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-1 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-1 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-1 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-2 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-2 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-2 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-3 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-3 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-3 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group  
ACWY 
N=150 
Pre-vacc  
Blood sample 
 
MenACWY 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
rMenB+OMV NZ 
N = number of subjects; Pre-vacc = pre-vaccination; post-vacc = post-vaccination 
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• 
Sampling schedule:  
− 
A total of 4 blood samples* will be collected from each subject at Day 1 (pre-
vaccination blood sample; approximately 20 mL), at Day 31 (post-vaccination 1 
blood sample; approximately 30 mL), at Day 91 (post-vaccination 2 blood 
sample; approximately 25 mL) and at Day 211 (post-vaccination 3 blood 
sample; approximately 30 mL). 
− 
Urine sampling: Urine samples for pregnancy testing will be collected from 
female subjects of child-bearing potential at Visit 1 (Day 1), Visit 3 (Day 61), 
Visit 5 (Day 181) and Visit 6 (Day 211), prior to the vaccination. 
* Insufficient blood volume may lead to test cancellation and jeopardise the 
statistical power. Hence, every effort must be done to collect blood volume as per 
protocol requirements. 
• 
Data collection: standardised Electronic Case Report Form (eCRF). Solicited 
symptoms will be collected using a subject Diary (electronic Diary [eDiary]). 
• 
Safety follow-up: Regular safety follow-up will be done through telephone calls (T). 
There will also be an extended safety follow-up (ESFU) phone call 6 months post-
vaccination 3 (Day 181; Visit 5). This ESFU phone call (Day 361; T7) will also 
mark the study conclusion. Refer to Table 3 and Section 8.5.3 for details on the 
safety follow-up.  
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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Table 3 
Schedule of Activities  
(Amended 9 May 2021) 
Age  
10 through 25 years of age at study start 
Type of contact 
Visit  
PC  
Visit 
Visit 
PC 
Visit 
PC 
Visit  
PC 
Visit  
PC 
PC 
PC 
Visit/Phone call no. 
V19 
T1  
V29 
V39 
T2 
V49 
T3  
V59 
T4  
V69 
T5  
T6  
T7  
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 121 
Day 181 Day 195 Day 211 
Day 241 
Day 301 
Day 361 
(ESFU) 
Informed consent2 
●1 
 
 
 
 
 
 
 
 
 
 
 
 
Informed assent, if applicable2 
○1 
 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
●1 
 
 
○1, 3 
 
 
 
○1, 3 
 
○1, 3 
 
 
 
Collect demographic data 
●1 
 
 
 
 
 
 
 
 
 
 
 
 
Study group and treatment number 
allocation (randomisation) 
●1 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
●1 
 
 
 
 
 
 
 
 
 
 
 
 
General Physical examination4 
○1 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
○ 
○1 
 
○ 
 
○1 
 
○1 
 
 
 
Urine Pregnancy test for females of 
child-bearing potential 
●1 
 
 
●1 
 
 
 
●1 
 
●1 
 
 
 
Check contraindications and warnings 
and precautions to vaccination 
○1 
 
 
○1 
 
 
 
○1 
 
○1 
 
 
 
Check criteria for temporary delay for 
enrolment and/ or vaccination and/or 
blood sampling  
○1 
 
○ 
○1 
 
○ 
 
○1 
 
○1 
 
 
 
Pre-vaccination body temperature 
●1, 5 
 
 
●1, 5 
 
 
 
●1, 5 
 
○1, 5 
 
 
 
Blood sampling 
●1 
 
● 
 
 
● 
 
 
 
●1 
 
 
 
Vaccines administration 
● 
 
 
● 
 
 
 
● 
 
●6 
 
 
 
Recording of administered treatment 
number 
● 
 
 
● 
 
 
 
● 
 
● 
 
 
 
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Age  
10 through 25 years of age at study start 
Type of contact 
Visit  
PC  
Visit 
Visit 
PC 
Visit 
PC 
Visit  
PC 
Visit  
PC 
PC 
PC 
Visit/Phone call no. 
V19 
T1  
V29 
V39 
T2 
V49 
T3  
V59 
T4  
V69 
T5  
T6  
T7  
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 121 
Day 181 Day 195 Day 211 
Day 241 
Day 301 
Day 361 
(ESFU) 
Post Injection Assessment (30 
minutes) 
● 
 
 
● 
 
 
 
● 
 
○ 
 
 
 
Treatment number allocation for 
subsequent doses 
 
 
 
○ 
 
 
 
○ 
 
○ 
 
 
 
Distribution of eDiary 
○ 
 
 
○ 
 
 
 
○ 
 
 
 
 
 
Review and return of eDiary 
 
 
● 
 
 
● 
 
 
 
● 
 
 
 
Recording of solicited AEs (Days 1–7 
post vaccination) in eDiary 
×5 
 
 
×5 
 
 
 
×5 
 
 
 
 
 
Recording of unsolicited AEs within 
30 days post-vaccination 
● 
● 
● 
● 
● 
● 
 
● 
● 
● 
 
 
 
Record any concomitant 
medications/vaccinations 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Record any intercurrent medical 
conditions 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of any AEs leading to 
vaccine/study withdrawal, medically 
attended AEs, SAEs, pregnancies 
and AESIs10 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
●7 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study Conclusion8 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 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. Documentation will be required in the source documents. 
× is used to indicate a study procedure that will be documented in eDiary.  
PC = Phone contact; V = Visit; T=Telephone call; ESFU = Extended safety follow-up; pre-vacc = pre-vaccination; post-vacc = post-vaccination; AE = adverse event; SAE = serious 
adverse event; AESI = Adverse events of special interest 
1 Procedure to be performed prior to vaccination. 
2 Confirm consent form(s) and informed assent form (if applicable) signed prior to any procedures. 
3 Prior to each vaccination investigator must check eligibility criteria for subsequent vaccination and criteria for vaccination delay as specified in Section 6.3 
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4  Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated within the Delegation of 
Responsibility Log 
5 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 route. In case any other route (other than 
oral) is used for measurement of body temperature/ fever, this also needs to be recorded in the subject’s eCRF 
6 Note 3: In order to let the subjects in MenB_0_2_6 group receive a dose of MenACWY vaccine and for subjects in ACWY group to receive the second dose of rMenB+OMV NZ in line 
with the standard of care (also in line with the ACIP recommendations in the US), the subjects in these groups will receive a vaccination of MenACWY and rMenB+OMV NZ vaccines, 
respectively, on Day 211 (Visit 6) after completion of the post-vaccination 3 blood sampling. To maintain the blinding of the study, subjects in the rest of the groups (MenB_0_6, 
ABCWY-1, ABCWY-2 and ABCWY-3) will receive a dose of Placebo. All these vaccines/ products administered at Day 211 are not associated with any study objectives/ endpoints 
(Safety assessment conducted after 1 dose of rMenB+OMV NZ in the ACWY group at Day 181 is to maintain the blind of the study). 
7 Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine begins from the time a subject/parent(s)/LAR(s) signs the consent form/ assent form (if 
applicable) to the end of the study 
8 Subjects who terminate the study early are recommended to complete certain study-related procedures (refer to Section 8.8.1) 
9 If local regulations allow and if quality of study procedures can be maintained, participant(s) can be offered remote visits (e.g. home visits) for the collection of biological 
samples and/or study intervention administration. These remote visits must be performed by qualified study staff/healthcare professionals (HCPs). Refer to Section 8.10 
(decentralised study procedures) for details 
10 Diagnosis of coronavirus 2019 (COVID-19) should be made in accordance with the World Health Organization case definitions. Cases should be reported as AEs or SAEs (refer to 
Section 12.5 for the definitions), and routine procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance with the protocol-defined 
time periods (refer to Table 14). In addition, separate COVID-19 specific eCRF form(s) should be completed. Refer to Section 8.9 for information related to study procedures 
during special circumstances 
 
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Whenever possible, the investigator should arrange study visits within the intervals 
described in Table 4 and Table 5. 
Table 4 
Intervals between study visits 
(Amended: 9 May 2021) 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1 → Visit 2 
30 days 
25 to 44 days after vaccination at V11  
(from -5 to +14 days) 
Visit 1→Visit 3 
60 days 
55 to 74 days after vaccination at V11  
(from -5 to +14 days) 
Visit 3→Visit 4 
30 days 
25 to 44 days after vaccination at V31  
(from -5 to +14 days) 
Visit 3→Visit 5 
120 days 
115 to 134 days after vaccination at V31  
(from -5 to +14 days) 
Visit 5→Visit 6 
30 days 
25 to 44 days after vaccination at V51  
(from -5 to +14 days) 
1 Subjects will not be eligible for inclusion in the Per-Protocol Set (PPS) for analysis of immunogenicity if the study visit 
is performed outside this interval  
Refer to Table 17 for intervals between study visits during special circumstances 
Table 5 
Intervals between study visits and phone calls 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1→T1 
15 days 
12 to 18 days after vaccination at V1  
(from -3 to +3 days) 
Visit 3→T2 
15 days 
12 to 18 days after vaccination at V3  
(from -3 to +3 days) 
Visit 3→T3 
60 days 
57 to 63 days after vaccination at V3 
 (from -3 to +3 days) 
Visit 5→T4 
15 days 
12 to 18 days after vaccination at V5  
(from -3 to +3 days) 
Visit 5→T5  
60 days 
53 to 74 days after vaccination at V5  
(from -7 to +14 days) 
Visit 5→T6 
120 days 
113 to 134 days after vaccination at V5  
(from -7 to +14 days) 
Visit 5→T7 (ESFU; study end) 
180 days 
173 to 194 days after vaccination at V5 
(from -7 to +14 days) 
3. 
INTRODUCTION 
3.1. 
Study rationale 
In 2013, the United States (US) Food and Drug Administration (FDA) agreed with the 
Company proposal to evaluate meningococcal B vaccine effectiveness against a large 
panel of the US epidemiologically relevant invasive disease strains of Neisseria 
meningitidis (N. meningitidis) serogroup B in adolescents using serum bactericidal assay 
with endogenous human complement (enc-hSBA). This panel includes 110 serogroup B 
strains selected from the original panel of 442 endemic strains identified as appropriately 
representative of invasive meningococcal serogroup B strains detected in the US by the 
US Centers for Disease Control (CDC) [Welsch, 2018]. Following licensure of Bexsero 
(rMenB+OMV NZ) in the US in 2015, under accelerated approval regulations, GSK was 
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requested to demonstrate effectiveness of Bexsero via a post-approval confirmatory trial 
in US adolescents and young adults. 
The first effectiveness study with GSK’s MenB-containing vaccine (investigational 
MenABCWY vaccine; V102_16) was initiated in 2014 and showed a vaccine 
effectiveness (test-based) of 67% after 2 doses against the panel of strains described 
above, as measured by serum bactericidal activity at 1:4 dilution one month post-
vaccination [Welsch, 2018]. The V102_16E1 extension study showed a vaccine 
effectiveness of 71% after 3 doses. To date there has not been an evaluation to assess the 
vaccine effectiveness of the rMenB+OMV NZ vaccine (Bexsero) against this same panel 
of the US epidemiologically relevant invasive disease strains of N. meningitidis 
serogroup B.  
GSK investigational MenABCWY vaccine intended to protect against 5 of the most 
prevalent serogroups of N. meningitidis (A, B, C, W, Y) in humans. This combination 
vaccine is based upon two established GSK vaccines, the quadrivalent meningococcal 
ACWY conjugate vaccine (Menveo) and the multi-component recombinant 
meningococcal B vaccine (Bexsero), for which significant nonclinical and clinical data 
have been generated and used to support marketing authorisations in US, European 
Union (EU) and several other countries. The MenABCWY investigational vaccine will 
be reconstituted from the following two components before administration: 
• 
the MenACWY component lyophilised in vial; 
• 
the MenB liquid component in prefilled syringe. 
The MenACWY component contains the same antigens in the same amounts as the 
commercial Menveo, in a lyophilised form. The MenB liquid component is the same 
formulation as the commercial Bexsero. 
The primary purpose of this study is to hence demonstrate the vaccine effectiveness using 
enc-hSBA against a randomly selected panel of endemic US N. meningitidis serogroup B 
invasive disease strains, when administered in a 3-dose (0,2,6-months) or a 2-dose (0,6-
months; 0,2-months) schedule as a meningococcal group B vaccine (Bexsero) and when 
administered in a 2-dose (0,6-months) schedule as a combined MenABCWY vaccine. 
In addition, the other main objectives of this study are: 
• 
to demonstrate the consistency of immune responses from 3 production lots of the 
MenACWY component of the MenABCWY vaccine,  
• 
to demonstrate the non-inferiority of a 2-dose series of MenABCWY vaccine versus 
a single dose of Menveo (MenACWY) in terms of immune response to 
meningococcal serogroups A, C, W and Y, 
• 
to demonstrate the non-inferiority of the effectiveness of the MenABCWY vaccine 
versus Bexsero (rMenB+OMV) against a randomly selected panel of endemic US N. 
meningitidis serogroup B invasive disease strains, 
• 
to assess the safety of all study vaccines administered as per their vaccination 
schedule to healthy subjects aged 10-25 years. 
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3.2. 
Background 
(Amended 9 May 2021) 
N. meningitidis is a leading cause of bacterial meningitis and sepsis worldwide, capable 
of causing outbreaks and epidemics of invasive disease. N. meningitidis infections 
causing invasive meningococcal disease (IMD) are an important public health concern 
worldwide due to the substantial morbidity and mortality they cause, as well as the 
transmissibility of these infections. In healthy individuals, IMD can rapidly progress to 
serious clinical disease and may be associated with poor outcomes, including fatality in 
~10% of cases. While the greatest IMD burden is in infants, there is a second peak of 
disease in adolescents and young adults. 
IMD occurs when the normally asymptomatically carried encapsulated gram-negative 
bacterium N. meningitidis enters the bloodstream, multiplies and causes sepsis. Once the 
blood-brain barrier is compromised, development of acute bacterial meningitis represents 
a neurological emergency and necessitates immediate diagnosis and treatment 
[Heckenberg, 2014]. Although IMD occurs worldwide, incidence varies in different 
geographic regions, with the highest disease burden observed in low-income countries. 
Reliable estimates of the global burden of disease are currently not available, as case 
definitions differ and surveillance data from many regions are incomplete [Gossger, 
2012]. The overall incidence of IMD in European countries ranges from approximately 
0.1 to 2.4 cases per 100 000 populations [ECDC, 2016]. In the US, incidence was 0.1 
cases per 100 000 population [CDC, 2018]. 
Ninety percent of meningococcal meningitis and septicaemia are caused by only five N. 
meningitidis serogroups: A, B, C, W and Y. The distribution of serogroups varies 
geographically and over time. While the disease burden of IMD in higher-income 
regions, such as Europe and Australia, is largely attributable to serogroup B, in the 
‘meningitis belt’ of sub-Saharan Africa, IMD is predominantly caused by serogroups A 
and W. In the US, serogroups B, C and Y account for most IMD.  
The best option for the control of meningococcal disease is the use of effective vaccines 
that would include all five of the most common serogroups responsible for invasive 
disease. 
GSK’s Meningococcal Groups A, C, Y and W-135 Conjugate Vaccine (Menveo) is a 
meningococcal oligosaccharide conjugate vaccine licensed for active immunisation to 
prevent IMD caused by N. meningitidis serogroups A, C, W-135, and Y. It contains a 
nontoxic mutant of diphtheria toxin (Corynebacterium diphtheriae Cross Reacting 
Material-197, CRM197) as the carrier protein and has been demonstrated to be highly 
immunogenic against serogroups ACWY and is well tolerated in all age groups. It has 
been licensed in more than 60 countries; many of these countries have also approved its 
use in children. In the EU, the vaccine is indicated for use in individuals 2 years of age 
and older, and in the US, in individuals 2 months to 55 years of age. 
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In contrast to the meningococcal serogroups A, C, W and Y, the capsular polysaccharide 
of serogroup B is poorly immunogenic in humans, possibly due to antigenic similarities 
in serogroup B carbohydrate moieties to carbohydrates widely expressed on various 
human cell types. As a result, research has focused on proteins in the outer membrane of 
meningococci with potential for broad protection against serogroup B as potential 
antigens for candidate vaccines.  
The Meningococcal Group B Vaccine (Bexsero, rMenB+OMV NZ) contains three 
recombinant proteins [factor H binding protein (fHbp), Neisseria adhesin A (NadA), and 
Neisserial Heparin Binding Antigen (NHBA)], combined with Outer Membrane Vesicles 
(OMV) components from the New Zealand outbreak strain NZ98/254. rMenB+OMV NZ 
is immunogenic against the majority of circulating meningococcal serogroup B strains 
and has acceptable reactogenicity and safety profiles when administered to individuals 
across age groups.  
In January 2013 European marketing authorisation had been granted for Bexsero for use 
in individuals over 2 months of age. In January 2015, based on accelerated approval 
regulations, FDA licensed Bexsero for active immunisation to prevent invasive disease 
caused by N. meningitidis serogroup B in adolescents and young adults 10 through 25 
years of age. The vaccine is currently approved in 42 countries worldwide.   
Bexsero is indicated for active immunisation against invasive disease caused by N. 
meningitidis serogroup B. 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. 
With evidence of meningococcal epidemiology changing over time and across 
geographies [Cohn, 2015; Halperin, 2012; Harrison, 2009], a vaccine with the broadest 
possible coverage is an important step toward a definitive and global solution for 
meningococcal disease prevention. 
GSK is currently developing a combination vaccine intended to protect against five of the 
most prevalent serogroups of N. meningitidis (A, B, C, W, Y) in humans. The availability 
of a pentavalent meningococcal vaccine in a single administration would reduce the 
number of injections and could increase coverage for meningococcal disease caused by 
N. meningitidis serogroups A, B, C, W, and Y worldwide. 
Please refer to the current Investigator Brochures for information regarding the pre-
clinical and clinical studies of Bexsero, Menveo and MenABCWY vaccine. 
3.3. 
Benefit/Risk assessment 
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of MenABCWY vaccine. 
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. 
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3.3.1. 
Risk assessment 
Important/Potential/Identified/Risk of Clinical 
Significance 
Summary of 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 (pIMD) and SAE 
collection 
(See Section 12.5.6.2) 
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 12.5.6.2) 
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). 
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 
rMenB+OMV NZ has been observed. 
Arthritis will be monitored through the AESI collection 
(See Section 12.5.6.1). 
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Important/Potential/Identified/Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational vaccine: MenABCWY 
Important potential risk: Anaphylaxis, anaphylactic 
shock 
Anaphylaxis and anaphylactic shock have been observed 
with other vaccines. No serious cases of anaphylaxis 
related to MenABCWY have been reported in the 
MenABCWY clinical development program. Allergic 
reaction (including anaphylactic reaction) is reported in the 
MenABCWY IB section “Warning and Precaution". 
Anaphylaxis following the administration of MenABCWY 
constitutes an absolute contraindication to subsequent 
vaccination (see Section 7.7. 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.  
Hypersensitivity, including allergy, to any component of 
vaccines, are exclusion criteria in this study (see Section 
6.2). 
MenACWY vaccine (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 lyophilised 
component, or due to administration of the MenA 
conjugate lyophilised component only after reconstitution 
with a different solvent, have been reported during the 
MenACWY clinical development program. 
In Section 7.1. of the protocol (“Treatment administered”) 
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 serious 
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 the ICF. GBS 
will be monitored through the pIMD and SAE collection 
(See Section 12.5.6.2) 
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 12.5.6.2) 
Important potential risk: 
Thrombocytopenia 
Immune thrombocytopenic purpura has been reported in 
association with several licensed vaccines. One serious 
case has been reported during the MenACWY 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 12.5.6.2). 
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Important/Potential/Identified/Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Important potential risk: 
Facial paresis 
Facial paresis was recognised 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 (See Section 12.5.6.2) 
Important potential risk: 
Vaccination failure (lack of efficacy) 
It is known that a protective immune response may not be 
generated in every recipient. The number of reports 
suggestive of vaccination failure reported cumulatively 
does not suggest a significantly or unexpectedly high rate 
of vaccine failure.  
No specific risk mitigation in place in this study. 
Study Procedures 
Risk of blood sampling 
Blood sampling is associated with a risk of syncope, 
dizziness, local reactions and infection after or during 
venepuncture. 
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. Appropriate medical treatment will 
be readily available.  
 
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3.3.2. 
Benefit assessment 
• 
Receiving GSK’s meningococcal vaccines rMenB+OMV NZ, MenABCWY or 
MenACWY during the study duration may protect against meningococcal IMDs 
caused by N. meningitidis serogroups A, C, W, Y and/or B.  
• 
Medical monitoring and evaluations/assessments associated with this study. 
• 
Contributing to the process of developing new therapies.  
3.3.3. 
Overall Benefit: Risk conclusion 
Considering the measures taken to minimise risk to subjects participating in this study, 
the potential or identified risks in association with rMenB+OMV NZ, MenABCWY and 
MenACWY are justified by the potential benefits (prevention/treatment) that may be 
afforded to subject(s) receiving rMenB+OMV NZ and MenACWY or MenABCWY. 
4. 
OBJECTIVE(S) AND ENDPOINT(S) 
Table 6 
Study objectives and endpoints 
(Amended: 9 May 2021) 
Objectives 
Endpoints 
Primary 
Vaccine effectiveness (Test-based): 
rMenB+OMV NZ 
To demonstrate the effectiveness of the 
rMenB+OMV NZ vaccine against a randomly 
selected panel of endemic US N. meningitidis 
serogroup B invasive disease strains as 
measured by bactericidal activity using enc-
hSBA at 1 month after the 3-dose (0,2,6-months) 
and 2-dose (0,6-months; 0,2-months) 
vaccination series when compared to 1 month 
after the MenACWY vaccination. 
Criterion 
Lower limit (LL) of the two-sided 97.5% 
confidence interval (CI) for vaccine effectiveness 
is above 65% against a randomly selected strain 
panel between the: 
• 
MenB_0_2_6 and ACWY groups (for 
0,2,6-months schedule) 
• 
MenB_0_6 and ACWY groups (for 0,6-
months schedule),  
• 
MenB_0_2_6 and ACWY groups (for 0,2-
months schedule)  
The percentages of samples without bactericidal serum activity 
using enc-hSBA against each of the endemic US N. 
meningitidis serogroup B strains, at 1 month after the: 
• 
3-dose vaccination series in MenB_0_2_6 group (Day 
211, Month 7) 
• 
2-dose vaccination series in MenB_0_6 group (Day 211, 
Month 7), and 
• 
2-dose vaccination series in MenB_0_2_6 group (Day 91, 
Month 3) 
• 
1 month after the MenACWY vaccination in ACWY group 
(Day 31, Month 1). 
Effectiveness (Responder-based): 
rMenB+OMV NZ 
To demonstrate the effectiveness of the 
rMenB+OMV NZ vaccine by assessing the 
percentages of subjects whose sera kill ≥70% of 
strains tested using enc-hSBA at 1 month after 
the 3-dose (0,2,6-months) and 2-dose (0,6-
The percentages of subjects whose sera kill ≥70% of the 
strains tested using enc-hSBA, at 1 month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group)  
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Objectives 
Endpoints 
months; 0,2-months) vaccination series of the 
rMenB+OMV NZ. 
Criterion: 
LL of the two-sided 97.5% CI for the 
percentages of subjects whose sera kill ≥70% of 
strains is above 65%, tested for: 
• 
MenB_0_2_6 group (for 0,2,6-months 
schedule) 
• 
MenB_0_6 group (for 0,6-months 
schedule),  
• 
MenB_0_2_6 group (for 0,2-months 
schedule)  
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group),  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group)  
The 3 vaccine schedules will be tested for both, test-based and responder-based, in a hierarchical way (starting 
from 0-2-6, to 0-6 and 0-2). Refer to Section 10.1 for details on continuing the evaluation. 
Lot-to-lot consistency: MenABCWY vaccine 
To demonstrate lot-to-lot consistency of the 
immune responses of 3 lots of the MenACWY 
component of the MenABCWY vaccine, as 
measured by hSBA GMTs directed against 
serogroups A, C, W and Y at 1 month after last 
vaccination (0,6-months). 
Criterion: 
The two-sided 97.5% CIs^ for the ratio of hSBA 
GMTs of antibodies against serogroups A, C, W 
and Y are within the [0.5;2.0] equivalence 
interval for each pair of lots. 
GMTs directed against serogroups A, C, W and Y for each lot 
(ABCWY-1 group, ABCWY-2 group, ABCWY-3 group) at 1 
month after the last vaccination (Day 211, Month 7) 
Immunological non-inferiority: MenABCWY 
vaccine vs. MenACWY vaccine*** 
To demonstrate the immunological non-inferiority 
of the MenABCWY vaccine compared to the 
MenACWY vaccine as measured by the 
percentages of subjects achieving a 4-fold rise in 
hSBA titres against N. meningitidis serogroups 
A, C, W and Y at 1 month after the last 
MenABCWY vaccination (0,6-months) and 1 
month after the MenACWY vaccination. 
Criterion: 
LL of the two-sided 97.5% CI^ for the group 
difference in percentages of subjects achieving a 
4-fold rise* in hSBA titres is above -10%. 
The percentages of subjects with 4-fold rise* in hSBA titres 
against N. meningitidis serogroups A, C, W and Y at 1 month 
after the: 
• 
last vaccination for the ABCWY group (pooled lots) (Day 
211, Month 7), and 
• 
1 month after the MenACWY vaccination for the ACWY 
group (Day 31, Month 1) 
relative to baseline (Day 1, Month 0). 
Vaccine effectiveness (Test-based): 
MenABCWY vaccine 
To demonstrate the effectiveness of the 
MenABCWY vaccine against a randomly 
selected panel of endemic US N. meningitidis 
serogroup B invasive disease strains as 
measured by enc-hSBA at 1 month after the last 
MenABCWY vaccination (0,6-months) when 
compared to 1 month after the MenACWY 
vaccination. 
The percentages of samples without bactericidal serum activity 
using enc-hSBA against each of the endemic US N. 
meningitidis serogroup B strains, at 1 month after the: 
• 
last vaccination for the ABCWY group (pooled) (Day 211, 
Month 7), and  
• 
1 month after the MenACWY vaccination in the ACWY 
group (Day 31, Month 1).  
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Objectives 
Endpoints 
Criterion: 
LL of the two-sided 97.5% CI^ for vaccine 
effectiveness is above 65% against a randomly 
selected strain panel between the ABCWY group 
(pooled lots) and the ACWY group. 
Effectiveness non-inferiority: MenABCWY 
vaccine vs. rMenB+OMV NZ vaccine 
To demonstrate the non-inferiority of the 
effectiveness of the MenABCWY vaccine (0,6-
months schedule) compared to the rMenB+OMV 
NZ vaccine (0,2,6-months or 0,6-months or 0,2-
months)† in terms of percentage of samples with 
bactericidal serum activity using enc-hSBA 
against a randomly selected panel of endemic 
US N. meningitidis serogroup B invasive disease 
strains. 
Criterion: 
LL of the two-sided 97.5% CI^ for the difference 
in percentages of samples with bactericidal 
serum activity using enc-hSBA against a 
randomly selected panel of endemic US N. 
meningitidis serogroup B invasive disease 
strains is above -5% at 1 month after: 
• 
the last vaccination in ABCWY group 
(pooled lots) (for 0,6 months schedule), 
and 
• 
The last vaccination in MenB_0_2_6 group 
(for 0,2,6-months schedule) or the last 
vaccination in MenB_0_6 group (for 0,6-
months schedule) or the second 
vaccination in MenB_0_2_6 group (for 0,2-
months schedule  
The percentages of samples with bactericidal serum activity 
using enc-hSBA against each of the endemic US N. 
meningitidis serogroup B strains at 1 month after the: 
• 
last MenABCWY vaccination (Day 211, Month 7) for the 
ABCWY group (pooled lots), and 
• 
3-dose vaccination series of rMenB+OMV vaccine (Day 
211, Month 7 in MenB_0_2_6 group) or 2-dose 
vaccination series (Day 211, Month 7 in MenB_0_6 
group) or 2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
Effectiveness (Responder-based): 
MenABCWY vaccine 
To demonstrate the effectiveness of 
MenABCWY vaccine by assessing the 
percentages of subjects whose sera kill ≥70% of 
strains tested using enc-hSBA at 1 month after 
the last vaccination of MenABCWY (0,6-
months). 
Criterion: 
LL of the two-sided 97.5% CI^ for the 
percentages of subjects whose sera kill ≥70% of 
strains tested for MenABCWY is above 65%. 
The percentages of subjects whose sera kill ≥70% of the 
strains tested using enc-hSBA, at 1 month after the last 
vaccination for the ABCWY group (pooled lots) (Day 211, 
Month 7). 
Safety 
To evaluate the safety and reactogenicity of the 
MenB, MenABCWY, and the MenACWY 
vaccines  
• 
The frequencies and percentages of subjects with 
solicited local (i.e., injection site pain, erythema, swelling, 
induration) and systemic (i.e., fever [body temperature ≥ 
38.0°C], nausea, fatigue, myalgia, arthralgia, headache) 
adverse events (AEs) during the 7 days (including the day 
of vaccination) following each vaccination at Day 1, Day 
61 and Day 181. 
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Objectives 
Endpoints 
• 
The frequencies and percentages of subjects with any 
unsolicited AEs (including all SAEs, AEs leading to 
withdrawal, AESIs and medically attended AEs) during 
the 30 days (including the day of vaccination) following 
each vaccination at Day 1, Day 61 and Day 181. 
• 
The percentages of subjects with SAEs, AEs leading to 
withdrawal, AESIs and medically attended AEs 
throughout the study period [Month 0 to Month 12]. 
Secondary 
To demonstrate the immunological non-inferiority 
of the MenABCWY vaccine compared to the 
rMenB+OMV NZ vaccine as measured by the 
percentages of subjects achieving a 4-fold rise in 
hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the last 
MenABCWY vaccination (0,6-months schedule) 
and 1 month after the rMenB+OMV NZ 
vaccination (0,2,6-months or 0,6-months or 0,2-
months ) † 
Criterion: 
Non-inferiority will be demonstrated if the LL of 
the 2-sided 95% CI for the group difference in 
percentage of subjects achieving a 4-fold rise** 
in hSBA titres against N. meningitidis serogroup 
B indicator strains is above 
 -10%. 
The percentages of subjects with 4-fold rise** in hSBA titres 
against N. meningitidis serogroup B indicator strains at 1 month 
after the: 
• 
last MenABCWY vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7), and 
• 
3-dose vaccination series of rMenB+OMV vaccine(Day 
211, Month 7 in MenB_0_2_6 group) or 2-dose 
vaccination series (Day 211, Month 7 in MenB_0_6 
group) or 2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
 relative to baseline (Day 1, Month 0). 
To assess the effectiveness of the rMenB+OMV 
NZ and MenABCWY vaccines against each of 
the randomly selected endemic US N. 
meningitidis serogroup B invasive disease 
strains as measured by bactericidal activity using 
enc-hSBA at 1 month after the 3-dose (0,2,6-
months in MenB_0_2_6 group) and 2-dose (0,6-
months in MenB_0_6 group, 0,2-months in 
MenB_0_2_6 group and 0,6-months in the 
ABCWY (pooled) group) vaccination series when 
compared to 1 month after the MenACWY 
vaccination. 
The percentages of samples without bactericidal serum activity 
using enc-hSBA against each of the endemic US N. 
meningitidis serogroup B strains at 1 month after the:  
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) 
• 
last vaccination for the ABCWY group (pooled lots) (Day 
211, Month 7), and 
• 
MenACWY vaccination (Day 31, Month 1 in ACWY 
group). 
To describe the distribution of subjects by 
percentages of serogroup B invasive disease 
strains killed using enc-hSBA at 1 month after 
the 3-dose (0,2,6-months in MenB_0_2_6 group) 
and 2-dose (0,6-months in MenB_0_6 group, 
0,2-months in MenB_0_2_6 group and 0,6-
months in the ABCWY (pooled) group) 
vaccination series of rMenB+OMV NZ and 
MenABCWY vaccines. 
The percentages of serogroup B invasive disease strains killed 
using enc-hSBA in each subject at 1 month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled lots) (Day 
211, Month 7) 
To assess the immune response to the 
rMenB+OMV NZ (0,2,6-months, 0,6-months and 
0,2-months) and MenABCWY (0,6-months) 
vaccines against N. meningitidis serogroup B 
The immune response to the rMenB+OMV NZ and ABCWY 
vaccines will be evaluated by measuring bactericidal activity 
against N. meningitidis serogroup B indicator strains as 
following: 
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Objectives 
Endpoints 
indicator strains at pre-vaccination (Day 1, 
Month 0) and at 1 month after the last 
MenABCWY vaccination and at 1 month after 
the second and third vaccination of rMenB+OMV 
NZ. 
1. 
The percentages of subjects with hSBA titres  
≥ lower limit of quantitation (LLOQ) for each (individual 
response) and all (composite response) serogroup B 
indicator strains at baseline (Day 1, Month 0) and at 1 
month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled lots) 
(Day 211, Month 7) 
2. 
The percentages of subjects with 4-fold rise** in hSBA 
titres at 1 month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 90, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled lots) 
(Day 211, Month 7) 
relative to baseline (Day 1, Month 0). 
3. 
hSBA GMTs at baseline (Day 1, Month 0) and at 1 month 
after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled lots) 
(Day 211, Month 7) 
4. 
hSBA GMRs at 1 month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled lots) 
(Day 211, Month 7) 
relative to the baseline (Day 1, Month 0). 
To assess the immune response to MenABCWY 
(0,6-months schedule) and MenACWY (single 
dose) vaccines against N. meningitidis 
serogroups A, C, W and Y, at pre-vaccination 
(Day 1, Month 0) and at 1 month after the first 
and the last MenABCWY vaccination and 1 
month after the MenACWY vaccination. 
1. 
The percentage of subjects with hSBA titres ≥ LLOQ for 
serogroups A, C, W and Y at baseline (Day 1, Month 0) 
and: 
• 
at 1 month after the first (Day 31, Month 1) and the 
last MenABCWY vaccination (Day 211, Month 7) for 
the ABCWY group (pooled lots), and 
• 
at 1 month after the MenACWY vaccination in the 
ACWY group (Day 31, Month 1). 
2. 
The percentage of subjects with 4-fold rise* in hSBA titres 
at 1 month after the: 
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Objectives 
Endpoints 
• 
first vaccination (Day 31, Month 1) for the ABCWY 
group (pooled lots) compared to the MenACWY 
vaccination in the ACWY group (Day 31, Month 1)  
relative to baseline (Day 1, Month 0). 
3. 
hSBA GMTs against N. meningitidis serogroups A, C, W 
and Y at baseline (Day 1, Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) and the 
last MenABCWY vaccination (Day 211, Month 7) for 
the ABCWY group (pooled lots), and  
• 
at 1 month after the MenACWY vaccination in the 
ACWY group (Day 31, Month 1). 
4. 
hSBA GMRs against N. meningitidis serogroups A, C, W 
and Y at: 
• 
1 month after the first (Day 31, Month 1) and the 
last MenABCWY vaccination (Day 211, Month 7) for 
the ABCWY group (pooled lots) as compared to 
baseline (Day 1, Month 0), and  
• 
1 month after the single MenACWY vaccination in 
the ACWY group (Day 31, Month 1) as compared to 
baseline (Day 1, Month 0). 
5. 
The total IgG as measured by ELISA GMCs against 
serogroups A, C, W and Y at baseline (Day 1, Month 0) 
and: 
• 
at 1 month after the first (Day 31, Month 1) and the 
last MenABCWY vaccination (Day 211, Month 7) for 
the ABCWY group (pooled lots), and  
• 
at 1 month after the MenACWY vaccination in the 
ACWY group (Day 31, Month 1). 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; Enc-hSBA = endogenous complement human serum 
bactericidal assay; GMC = geometric mean concentrations; GMT = geometric mean titre; GMR = geometric mean ratio; 
CI = confidence interval; hSBA = human serum bactericidal assay; LOD: limit of detection; LLOQ = lower limit of 
quantitation; LL = lower limit; AE = Adverse event; SAE = Serious adverse event; AESI = Adverse event of special 
interest. 
N. meningitidis serogroup B indicator strains = M14459, 96217, M13520 and NZ98/254 for fHbp, NadA, NHBA and 
PorA P1.4 antigens, respectively.  
Refer to Section 10 for details on evaluation of objectives and sample size justification. Refer to Glossary of terms for 
definitions of test-based and responder-based effectiveness 
^ If the co-primary effectiveness objectives for rMenB+OMV NZ are met, then all objectives for MenABCWY will be 
evaluated at 95% CI. Refer to Section 10.1 for details 
† If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 0,6-months 
is also not met, then the 0,2,6-months schedule will be the comparator. 
*For the Men A, C, W, Y evaluation, the 4-fold rise is defined as: 
a post-vaccination hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD but <LLOQ, 
and 
a post-vaccination hSBA titre ≥4 times the pre-vaccination titre for subjects with a pre-vaccination hSBA titre 
≥LLOQ.  
**For the MenB evaluation, the 4-fold rise per each indicator strain is defined as: 
a post-vaccination‡ hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination‡ hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD and 
<LLOQ, and 
a post-vaccination‡ hSBA titre ≥4 times the pre-vaccination hSBA titre for subjects with a pre-vaccination hSBA 
titre ≥ LLOQ 
‡ = post-2nd vaccination for 0,6 and 0,2 schedule and post-3rd vaccination for 0,2,6 schedule). 
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***The primary objective of immunological NI of the MenABCWY vaccine to MenACWY will be evaluated only in 
subjects without a previous MenACWY vaccination (unprimed). All other primary and secondary objectives will be 
evaluated in subjects with and without previous MenACWY vaccination (primed/unprimed). 
5. 
STUDY DESIGN 
5.1. 
Scientific rationale for study design 
(Amended 9 May 2021) 
As the rMenB+OMV NZ licensure in the US was issued through accelerated approval, 
the FDA has requested to demonstrate the effectiveness of the vaccine against an 
extended panel of serogroup B meningococcal strains (MenB) as a post-marketing 
commitment in US adolescents and young adults, thus confirming that the vaccine can 
protect against diverse meningococcal B strains prevalent in the US. 
The availability of a pentavalent meningococcal vaccine in a single administration would 
however reduce the number of injections and could increase coverage for meningococcal 
disease caused by N. meningitidis serogroups A, B, C, W, and Y worldwide. GSK’s 
investigational MenABCWY combination vaccine is intended to protect against 5 of the 
most prevalent serogroups of N. meningitidis (A, B, C, W, Y) in humans. 
Hence, along with the licensed MenB vaccine (Bexsero), this Phase III study will also 
assess the safety, effectiveness, and immunogenicity of the investigational MenABCWY 
vaccine. 
Rationale for effectiveness assessment 
As mentioned above, one of the primary purposes of this study is to evaluate the 
effectiveness of 2 or 3 doses of rMenB+OMV NZ and of 2 doses of the MenABCWY 
vaccines in healthy adolescents and young adults by measuring the bactericidal activity 
against 110 endemic US N. meningitidis serogroup B strains using an endogenous 
complement human Serum Bactericidal Assay (enc-hSBA), when compared to a control. 
Sera from the ACWY group receiving the MenACWY vaccine will also be tested against 
serogroup B meningococcal strains by enc-hSBA as a control for test-based effectiveness 
assessment. The overall vaccine effectiveness (VE) against all 110 strains combined will 
be computed by means of a generalised linear model. For additional details see statistical 
analysis section (Section 10). 
Rationale for lot-to-lot consistency assessment 
MenABCWY is a reconstituted vaccine with the lyophilised ‘ACWY component’ and 
liquid rMenB+OMV NZ. The MenB component has the same formulation as the 
commercial Bexsero. To demonstrate that the lots of the investigational MenABCWY 
vaccine are adequately representative of the formulation intended for marketing, 
equivalence will be assessed for 3 different lots of the ACWY component of the 
ABCWY vaccine. 
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Rationale for non-inferiority assessment of MenABCWY vs MenACWY and 
rMenB+OMV NZ 
The study aims to also demonstrate that the investigational combination MenABCWY 
vaccine is not inferior to a licensed MenACWY vaccine (Menveo) and a licensed MenB 
vaccine (Bexsero) which are part of the current standards of care in the US for prevention 
of invasive disease caused by N. meningitidis serogroups A, C, W, Y and by 
N. meningitidis serogroup B, respectively. 
Rationale for blood volume collected: 
In order to provide the necessary serum volume for the bactericidal assays (enc-hSBA 
and/ or hSBA(s)) and ELISA (or equivalent), approximately 30 mL whole blood will be 
collected at Visit 2 and Visit 6 and approximately 25 mL whole blood will be collected 
at Visit 4. At pre-vaccination (Visit 1), 20 mL whole blood will be collected to provide 
the necessary serum volume for the hSBA, and ELISA (or equivalent).  
Blood samples are taken from all subjects irrespective of the testing status in order to 
maintain the study blind. Refer to Section 8.4.2.1 for further details. 
Rationale for the selected vaccination schedules 
rMenB+OMV NZ: This study aims to demonstrate the VE of the rMenB+OMV NZ 
vaccine administered as 2-dose vaccine, either with a shorter interval (0,2-months) or a 
prolonged interval (0,6-months) between doses. A 3-dose schedule has also been added to 
better characterize the VE with an alternative dose regimen as a post approval 
requirement from the US FDA. 
Note: The rMenB+OMV NZ in the ACWY group is administered in a 0,1-months 
schedule. This interval is within the recommendations in the summary of product 
characteristics of Bexsero and helps in maintaining the blind. No objectives are 
associated with this schedule of rMenB+OMV NZ. 
MenABCWY: A number of different vaccine formulations were evaluated in 
MenABCWY Phase I and II clinical studies. The formulation with the same active 
ingredient composition as the rMenB+OMV NZ (Bexsero) and MenACWY (Menveo) 
vaccines was chosen as the final formulation of the investigational MenABCWY vaccine. 
Two doses administered 6 months apart (0,6-months) is considered the optimal dosing 
schedule, based on serogroup B immunogenicity results from MenABCWY Phase II 
clinical studies. 
MenACWY: As a comparator for serogroup A, C, W, and Y vaccine effectiveness and 
immune responses, a single dose of MenACWY vaccine is administered to subjects in the 
ACWY group. To conform with the standard of care (also in alignment with current 
ACIP routine immunisation recommendations in US), subjects in the MenB_0_2_6 and 
MenB_0_6 groups will also receive a dose of MenACWY at Day 211 and Day 61, 
respectively. 
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5.1.1. 
Rationale for the use of placebo 
For this study, a placebo (saline solution) will be administered as presented in Figure 1. A 
placebo is the only available option to minimize possible introduction of reporting bias in 
collecting information about AEs and to ensure the same number of vaccinations are 
administered to subjects assigned to either of the six study groups. 
5.2. 
Overall design 
(Amended 9 May 2021) 
Figure 1 
Study design overview 
 
 
N = number of subjects; d = dose; V = visit; D = day; T=Telephone call 
Refer to Table 3 for details on all visits 
Notes:  
If local regulations allow and if quality of study procedures can be maintained, participant(s) can be offered 
remote visits (e.g. home visits) for the collection of biological samples and/or study intervention 
administration. These remote visits must be performed by qualified study staff/healthcare professionals 
(HCPs). Refer to Section 8.10 (decentralised study procedures) for details 
Refer to Section 8.9 for information on study procedures during special circumstances 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the schedule of activities (Section 2), are essential and 
required for study conduct.  
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• 
Type of study: self-contained 
• 
Experimental design: This is a phase III, randomised, controlled, observer-blind, 
multi-centre study to evaluate effectiveness, immunogenicity and safety of 
rMenB+OMV NZ and MenABCWY vaccines. A total of 3651 healthy adolescents 
and young adults aged 10-25 years will be enrolled and randomised (5:5:3:3:3:1 
ratio) to one of the six parallel study groups:  
− 
MenB_0_2_6 group: subjects will receive 3 doses of rMenB+OMV NZ at Day 
1, Day 61 and Day 181 (0,2,6-months schedule). These subjects will receive 1 
dose of the MenACWY vaccine at Day 211*. Data from this group will be used 
to assess both the 0,2-months and 0,2,6-months schedules; the 0,2-months 
schedule will be assessed 1 month after the second rMenB+OMV NZ 
vaccination administered at Day 61 (Visit 3), and the 0,2,6-months schedule will 
be assessed 1 month after the third rMenB+OMV NZ vaccination at Day 181 
(Visit 5), in the same group. 
− 
MenB_0_6 group: subjects will receive 2 doses of rMenB+OMV NZ at Day 1 
and Day 181 and 1 dose of MenACWY vaccine at Day 61 (rMenB+OMV NZ, 
0,6-months schedule). These subjects will receive 1 dose of placebo at Day 
211*. 
− 
ABCWY-1**: subjects will receive 2 doses of MenABCWY vaccine 6 months 
apart (0,6-months schedule), at Day 1 and 181 with Lot 1 of the MenACWY 
lyophilised vial component of the vaccine. They will receive 1 dose of placebo 
at Day 61 and at Day 211*.  
− 
ABCWY-2**: subjects will receive 2 doses of MenABCWY vaccine 6 months 
apart (0,6-months schedule), at Day 1 and 181 with Lot 2 of the MenACWY 
lyophilised vial component of the vaccine. They will receive 1 dose of placebo 
at Day 61 and at Day 211*. 
− 
ABCWY-3**: subjects will receive 2 doses of MenABCWY vaccine 6 months 
apart (0,6-months schedule), at Day 1 and 181 with Lot 3 of the MenACWY 
lyophilised vial component of the vaccine. They will receive 1 dose of placebo 
at Day 61 and at Day 211*. 
− 
ACWY group: subjects will receive 1 dose of MenACWY vaccine at Day 1, 1 
dose of placebo at Day 61 and 2 doses of rMenB+OMV NZ at Day 181 and Day 
211*. 
* In order to let the subjects in MenB_0_2_6 group receive a dose of MenACWY 
vaccine and for subjects in ACWY group to receive the second dose of rMenB+OMV 
NZ in line with the vaccine as standard of care (also in line with the Advisory 
Committee on Immunization Practices (ACIP) recommendations in the US [ACIP, 
2011]), the subjects in these groups will receive a vaccination of MenACWY and 
rMenB+OMV NZ vaccines, respectively, on Day 211 (Visit 6) after completion of the 
post-vaccination 3 blood sampling. To maintain the blinding of the study, subjects in 
the rest of the groups (MenB_0_6, ABCWY-1, ABCWY-2 and ABCWY-3) will 
receive a dose of Placebo. All these vaccines/ products administered at Day 211 are 
not associated with any study objectives/ endpoints (safety assessment conducted 
after 1 dose of rMenB+OMV NZ in the ACWY group at Day 181 is to maintain the 
blind of the study). 
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** (1) A MenB lot will be used for the pre-filled syringe component of the 
MenABCWY vaccine; (2) The groups ABCWY-1, ABCWY-2, ABCWY-3 will be 
pooled into a single group, ABCWY (pooled lots) (except for analysis of lot-to-lot 
consistency). 
• 
Duration of the study: The study duration is approximately 12 months for each 
subject.  
• 
Primary completion Date (PCD): Day 361; T7.  
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): the date of release of the last testing results, to be achieved not 
later than 8 months after Last Subject Last Visit (LSLV) (LSLV = T7). If the 
completion of testing occurs prior the completion of the LSLV the latter date defines 
the end of study visit. 
Refer to glossary of terms for the definition of EoS. 
• 
Study groups: 
Table 7 
Study groups and treatment foreseen in the study 
Study Groups 
Number of 
subjects 
Age 
(Min-Max) 
Treatment name 
Vaccine/Product name 
MenB_0_2_6  
912 
10 – 25 y 
Bexsero (Injection) 
rMenB+OMV NZ 
Menveo (Injection) 
MenACWY 
MenB_0_6  
912  
Bexsero (Injection) 
rMenB+OMV NZ 
Menveo (Injection) 
MenACWY 
Placebo (Injection) 
NaCl 
ABCWY-1 
548 
MenABCWY (with Lot 1 
of ACWY) (Injection) 
MenABCWY-1 
Placebo (Injection) 
NaCl 
ABCWY-2 
548 
MenABCWY (with Lot 2 
of ACWY) (Injection) 
MenABCWY-2 
Placebo (Injection) 
NaCl 
ABCWY-3 
548 
MenABCWY (with Lot 3 
of ACWY) (Injection) 
MenABCWY-3 
Placebo (Injection) 
NaCl 
ACWY  
183  
Menveo (Injection) 
MenACWY 
Placebo (Injection) 
NaCl 
Bexsero (Injection) 
rMenB+OMV NZ 
 
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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 
Visit 5 
Day 181 
Visit 6 
Day 211 
Group  
MenB_0_2_6 
N=912 
Pre-vacc  
Blood sample 
 
rMenB+OMV NZ 
Post-vacc 1 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 2 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
MenACWY 
Group  
MenB_0_6 
N=912 
Pre-vacc  
Blood sample 
 
rMenB+OMV NZ 
Post-vacc 1 Blood 
sample 
MenACWY 
Post-vacc 2 Blood 
sample  
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-1 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-1 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-1 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-2 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-2 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-2 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group 
ABCWY-3 
N=548 
Pre-vacc  
Blood sample 
 
MenABCWY-3 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample  
MenABCWY-3 
Post-vacc 3 Blood 
sample 
 
Placebo 
Group  
ACWY 
N=150 
Pre-vacc  
Blood sample 
 
MenACWY 
Post-vacc 1 Blood 
sample 
Placebo 
Post-vacc 2 Blood 
sample 
rMenB+OMV NZ 
Post-vacc 3 Blood 
sample 
 
rMenB+OMV NZ 
N = number of subjects; Pre-vacc = pre-vaccination; Post-vacc = post-vaccination 
 
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• 
Treatment allocation: At Day 1, prior to the study vaccination, subjects will be 
randomised to 1 of the 6 study groups according to a 5:5:3:3:3:1 ratio.  
• 
Blinding: Observer-blind. Kindly refer to Section 7.3 for details on blinding and 
unblinding procedures. 
• 
Sampling schedule:  
− 
A total of 4 blood samples* will be collected from each subject at Day 1 (pre-
vaccination blood sample; approximately 20 mL), at Day 31 (post-vaccination 1 
blood sample; approximately 30 mL), at Day 91 (post-vaccination 2 blood 
sample; approximately 25 mL) and at Day 211 (post-vaccination-3 blood 
sample; approximately 30 mL). 
− 
Urine sampling: Urine samples for pregnancy testing will be collected from 
female subjects of child-bearing potential at Visit 1 (Day 1), Visit 3 (Day 61), 
Visit 5 (Day 181) and Visit 6 (Day 211) prior to the vaccination. 
*Insufficient blood volume may lead to test cancellation and jeopardise the statistical 
power. Hence, every effort must be done to collect blood volume as per protocol 
requirements. 
• 
Data collection: standardised Electronic Case Report Form (eCRF). Solicited 
symptoms will be collected using a subject Diary (electronic Diary [eDiary]). 
• 
Safety monitoring: Regular safety follow-up will be done through telephone calls 
(T). There will also be an extended safety follow-up (ESFU) phone call 6 months 
post-vaccination 3 (Day 181; Visit 5). This ESFU phone call (Day 361; T7) will also 
mark the study conclusion. Refer to Table 3 and Section 8.5.3 for details on the 
safety follow-up. 
5.3. 
Number of subjects 
A total of 3651 subjects will be randomised in a ratio of 5:5:3:3:3:1; 912 each in 
MenB_0_2_6 and MenB_0_6 groups, 548 in each ABCWY groups and 183 in ACWY 
group. Assuming a 25% drop-out rate, this should provide approximately 684 evaluable 
subjects in the MenB groups, 411 evaluable subjects in the ABCWY groups and 137 
evaluable subjects in the ACWY group.  
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 the subject is available for the 
concluding contact (Day 361; T7) as described in the protocol. 
Global completion of the study is required in order to provide enough 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 jeopardise 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
Note: Prior to receipt of each vaccination, subjects must be evaluated to confirm that they 
are eligible for subsequent vaccination. If subjects do not meet any of the applicable 
inclusion criteria listed below, they should not receive additional vaccinations. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects 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 eDiaries, return for follow-up visits and is 
available for telephone calls). 
• 
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) prior to performing 
any study specific procedure. 
• 
A male or female between, and including, 10 and 25 years of age (i.e. 25 years + 364 
days) at the time of the first vaccination. 
• 
Healthy subjects as established by medical history physical examination and clinical 
judgment of the investigator before entering into the study. 
• 
Subjects who are either unvaccinated with MenACWY vaccine or have received a 
single previous dose of MenACWY vaccine can participate in the study, if they have 
received it at least 4 years prior to informed consent and assent as applicable (with 
the exception of meningococcal C vaccination, if the last dose of MenC was received 
at ≤24 months of age). 
• 
Female subjects of non-childbearing potential may be enrolled in the study. 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 and 12.6.1.1 for definitions of woman of child-bearing 
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 until 30 days after completion of 
Visit 6.  
* A female is considered to be of non-childbearing potential prior to menarche and after 
natural or induced menopause. Natural menopause is recognised to have occurred after 
12 consecutive months of amenorrhea for which there is no other obvious pathological or 
physiological cause. Induced menopause is recognised to have occurred after 
hysterectomy, after bilateral oophorectomy, or iatrogenic ablation of ovarian function. 
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6.2. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Note: Prior to receipt of each study vaccination, subjects must be evaluated to confirm 
that they are eligible for subsequent vaccination. If subjects meet any of the applicable 
exclusion criteria listed below, they should not receive additional vaccinations. Eligibility 
to each study vaccination should be documented in the source documents. 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study. 
6.2.1. 
Medical conditions 
• 
Current or previous, confirmed or suspected disease caused by N. meningitidis. 
• 
Household contact with and/or intimate exposure to an individual with laboratory 
confirmed N. meningitidis infection within 60 days of enrolment. 
• 
Progressive, unstable or uncontrolled clinical conditions. 
• 
Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
• 
Any neuroinflammatory (including but not limited to: demyelinating disorders, 
encephalitis or myelitis of any origin), congenital neurological conditions, 
encephalopathies, seizures (including all subtypes such as: absence seizures, 
generalised tonic-clonic seizures, partial complex seizures, partial simple seizures). 
History of febrile convulsions should not lead to exclusion. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine(s)/product(s). 
− 
Hypersensitivity, including allergy, to any component of vaccines, including 
diphtheria toxoid (CRM 197) and latex medicinal products or medical equipment 
whose use is foreseen in this study.  
• 
Abnormal function or modification of the immune system resulting from: 
− 
Autoimmune disorders (including, but not limited to: blood, endocrine, hepatic, 
muscular, nervous system or skin autoimmune disorders; lupus erythematosus 
and associated conditions; rheumatoid arthritis and associated conditions; 
scleroderma and associated disorders) or immunodeficiency syndromes 
(including, but not limited to: acquired immunodeficiency syndromes and 
primary immunodeficiency syndromes). 
− 
Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to study vaccination until the post-
vaccination 3 blood sample (Visit 6). This will mean prednisone 20 mg/day 
(for adult subjects) or 0.5 mg/kg/day (for paediatric subjects), or equivalent. 
Inhaled and topical steroids are allowed. 
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− 
Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to study vaccination. 
− 
Administration of long-acting immune-modifying drugs at any time during the 
study period (e.g. infliximab). 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study. 
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)/product(s) during the period starting 30 days 
before the first dose of study vaccine(s)/product(s) (Day -29 to Day 1), or planned 
use during the study period. 
• 
Previous vaccination against any group B meningococcal vaccine at any time prior to 
informed consent and assent as applicable. 
• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 90 days before the first dose of study vaccine/ product or 
planned administration during the study period until the post-vaccination 3 blood 
sample (Visit 6). 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 90 
days prior to the vaccine/product dose(s) until the post-vaccination 3 blood sample 
(Visit 6). For corticosteroids, this will mean prednisone 20 mg/day (for adult 
subjects) or 0.5 mg/kg/day (for paediatric subjects), or equivalent. Inhaled and 
topical steroids are allowed. 
6.2.3. 
Prior/Concurrent clinical study experience 
• 
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). 
6.2.4. 
Other exclusions 
• 
Child in care 
Please refer to the glossary of terms for the definition of child in care.  
• 
Pregnant or lactating female. 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions. 
• 
History of /current chronic alcohol abuse and/or drug abuse as determined by the 
investigator. 
• 
Any study personnel or immediate dependants, family, or household member. 
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6.3. 
Criteria for temporary delay for enrolment and vaccination 
and/or blood sampling 
(Amended 9 May 2021) 
Enrolment/ vaccination/ blood sampling 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 route. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
• 
Significant acute illness within the previous 7 days. 
• 
Receipt of systemic antibiotics within 3 days prior to blood sampling visit (Visit 1, 
Visit 2, Visit 4 and Visit 6) (this will defer the blood draw). 
• 
A positive test for current infection with COVID-19. The testing should have been 
done using a molecular (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.  
• 
Individuals who have received any other vaccines within 7 days (for inactivated 
vaccines) or 14 days (for live vaccines) prior to and following each vaccination up to 
Visit 5*. 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to the local governmental 
recommendations and that the Sponsor is notified accordingly. 
In case of seasonal influenza vaccination, the time period described above can be 
reduced if necessary for that vaccine provided it is licensed and used according to its 
Prescribing Information and according to the local governmental recommendations. 
Under such circumstances, a subject may be considered eligible for study enrolment and 
vaccination and/or blood sampling 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. Screen failures are subjects who withdraw or are withdrawn 
from the study following informed consent, but before randomisation to study treatment. 
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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 
(Amended 9 May 2021) 
Refer to the section on Study Supplies in the SPM for more details on storage and 
handling of the study vaccine(s)/product(s). 
The study vaccines/ products specific to this study are described below. 
• 
rMenB+OMV NZ (GSK’s Meningococcal Group B Vaccine, Bexsero); 
• 
MenABCWY (GSK’s combined investigational Meningococcal Groups A, B, C, W 
and Y Vaccine); 
• 
MenACWY (GSK’s 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 Summary of Product Characteristics. 
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Table 9 
Treatments administered 
Study Treatment Name: 
Bexsero 
MenABCWY# 
Menveo*** 
Placebo 
Vaccine(s)/Product(s) name 
rMenB+OMV NZ 
MenACWY lyo 
rMenB+OMV NZ 
MenA 
MenCWY 
NaCl 
Presentation 
Syringe 
Vial 
Syringe 
Vial 
Vial 
Syringe 
Dose form 
Suspension for injection 
Powder for 
suspension for 
injection 
Suspension for injection 
Powder for 
solution for 
injection 
Solution for injection 
Solution for 
injection 
Vaccines/ product 
formulation†: 
NHBA fusion protein (50 µg) 
adsorbed on aluminium 
hydroxide; NadA protein (50 
µg) adsorbed on aluminium 
hydroxide; fHBP fusion protein 
(50 µg) adsorbed on 
aluminium hydroxide; OMV 
from N. meningitidis, 
serogroup B Strain NZ98/254 
(25 µg PorA P1.4) adsorbed 
on aluminium hydroxide; 
Aluminium hydroxide (0.5 mg 
Al³⁺); Water for injections q.s. 
0.5 mL 
MenA(10 µg)-
CRM197; MenC(5 
µg)-CRM197; 
MenW135(5 µg)-
CRM197; MenY(5 
µg)-CRM197 
NHBA fusion protein (50 
µg) adsorbed on 
aluminium hydroxide; 
NadA protein (50 µg) 
adsorbed on aluminium 
hydroxide; fHBP fusion 
protein (50 µg) adsorbed 
on aluminium hydroxide; 
OMV from N. 
meningitidis, serogroup B 
Strain NZ98/254 (25 µg 
PorA P1.4) adsorbed on 
aluminium hydroxide; 
Aluminium hydroxide (0.5 
mg Al³⁺); Water for 
injections q.s. 0.5 mL 
MenA(10 µg)-
CRM197 (16.7–
33.3 µg) 
MenC(5 µg)-CRM197 
(7.1–12.5 µg); 
MenW135(5 µg)-
CRM197(3.3–8.3 µg); 
MenY(5 µg)-CRM197 
(5.6–10 µg); water 
for injections q.s. 0.5 
mL 
Sodium chloride 
(NaCl) (0.9%); 
Water for 
injections  
Route of Administration 
Intramuscular use 
Intramuscular use 
Intramuscular use 
Intramuscular use 
Product category 
Combination 
Combination 
Biological 
Combination 
Type 
Study; 
Control 
Study 
Control 
Additional 
Administration site: 
Location 
Deltoid 
Deltoid 
Deltoid 
Deltoid 
Laterality* 
Non-dominant 
Non-dominant 
Non-dominant 
Non-dominant 
Number of doses to be 
administered: 
 
 
 
 
• 
MenB_0_2_6 group 
3 
- 
1 
- 
• 
MenB_0_6 group 
2 
- 
1 
1 
• 
ABCWY-1 group 
- 
2 
- 
2 
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Study Treatment Name: 
Bexsero 
MenABCWY# 
Menveo*** 
Placebo 
• 
ABCWY-2 group 
- 
2 
- 
2 
• 
ABCWY-3 group 
- 
2 
- 
2 
• 
ACWY group 
2 
- 
1 
1 
Volume to be 
administered** 
0.5 mL 
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 
Refer to SPM for 
more details 
Manufacturer 
GSK Biologicals SA 
GSK Biologicals SA 
GSK Biologicals SA 
GSK Biologicals 
SA  
OMV = Outer Membrane Vesicles; SPM = Study procedure manual; CRM 197 = Corynebacterium diphtheriae cross reacting material-197; fHbp = factor H binding protein; 
GSK = GlaxoSmithKline; NaCl = sodium chloride; NHBA = Neisserial heparin binding antigen; NZ = New Zealand 
† The composition per dose is presented here 
* 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. 
*** Menveo commercial formulation consisting of a MenA lyophilised component and of a MenCWY liquid component, to be reconstituted together before administration (0.5 mL) by a 
qualified healthcare professional. In the US, the approved specifications for Menveo are: MenA lyo: MenA=10 µg, CRM197=12.5 µg - 33 µg; potassium dihydrogen phosphate; sucrose 
and MenCWY liquid: MenC=5 µg, CRM197 6.25 µg –12.5 µg; MenW 135=5 µg, CRM197 3.3 µg –10 µg; MenY=5 µg, CRM197 3.3 µg– 10 µg; Sodium chloride; Sodium dihydrogen 
phosphate monohydrate; Disodium phosphate dihydrate; water for injections q.s. 0.5 mL.  
# MenABCWY formulation consisting of MenACWY lyo (lyophilised component) and of MenB liquid component, to be reconstituted together before administration (0.5 mL) by a 
qualified healthcare professional. Both the manufacture and the final composition of the MenB component of the MenABCWY are identical to that of the commercial Bexsero. 
However, to ensure a consistent reconstitution procedure and to reduce the risk of under-dosing the MenB component, the filling weight has been increased from a nominal 0.609 g 
presents in commercial Bexsero to 0.640g in the MenB component, used to reconstitute MenABCWY. Refer to SPM for details. 
**** The volume of the saline pre-filled syringe may be between 0.6ml and 0.8 mL. The full volume is to be injected. 
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The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the SPM prior to study start. The exact anatomic location of each 
injection must be carefully recorded in the Medical Chart and in the eCRF. 
After completing the pre-vaccination procedures on Day 1, Day 61, Day 181 and Day 
211, administer the vaccine to the subject. Observe the blinding procedures described in 
Section 7.3. 
7.1.1. 
Precautions to be observed in administering study vaccine 
Prior to each vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to each study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 6.1, Inclusion Criteria and 6.2, 
Exclusion Criteria and Section 7.7 regarding the contraindications to subsequent 
vaccination. 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine(s)/product(s) administration (Refer to 
Section 6.3), the visit will be rescheduled within the allowed interval for this visit (refer 
to Table 5). 
The subjects will be observed closely for at least 30 minutes following the administration 
of the vaccine(s)/product(s), with appropriate medical treatment readily available in case 
of anaphylaxis and/or syncope. 
7.1.2. 
Vaccine Administration Error or Overdose of Vaccine 
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, MenABCWY and/or MenACWY. 
An overdose would also occur if two doses of the study vaccine are administered within 2 
weeks of the recommended interval between doses. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
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7.2. 
Method of treatment assignment 
There are 2 randomisation processes for each subject in the study. 
• 
Randomisation to 1 of the 6 treatment groups (5:5:3:3:3:1 ratio). Refer to Section 
7.2.2. 
• 
Randomisation to strains for enc-hSBA testing (will be performed by the 
randomisation officer and a treatment blinded listing will be provided to GSK 
Laboratory or laboratory designated by GSK to schedule the enc-hSBA testing) 
(Refer Section 7.2.3) 
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 centre. The Subject ID will be documented in the 
Screening and Enrolment log. 
The eligibility of the subject will be determined based on the inclusion and exclusion 
criteria listed in Section 6 and evaluated during this screening procedure. The Subject ID 
will be the subject’s unique identification number for all eCRFs and associated study 
documentation that will be used for duration of the study. 
7.2.2. 
Randomisation of treatment 
7.2.2.1. 
Randomisation of supplies 
The randomisation of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in SAS (Cary, NC, USA) by GSK. 
Entire blocks will be shipped to the study centres/warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment in this multi-centre study 
and to thus reduce the overall study recruitment period, an over-randomisation 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 enrol a total of 3651 eligible subjects who will be randomly assigned 
to 6 study groups in a 5:5:3:3:3:1 ratio (912 each in MenB_0_2_6 and MenB_0_6 groups, 
548 in each ABCWY group and 183 in ACWY group). 
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Allocation of the subject to a study group/a treatment number at the investigator site will 
be performed using a randomisation system on internet (SBIR). The randomisation 
algorithm will use a minimisation procedure accounting for study, region (US and ex-US 
countries), previous MenACWY vaccination (primed)? (Yes and No)*, and age category 
(10-17 years of age and 18-25 years of age). Minimisation factors will have equal weight 
in the minimisation algorithm. 
To ensure adequate representation in the US in line with the post-marketing commitment 
(Section 3.1), a minimum of 30% of adolescents and young adults will be enrolled in the 
US. 
After obtaining the signed and dated ICF/IAF from the subject/subject’s parent/LAR and 
having checked the eligibility of the subject, blinded site staff will access SBIR. Upon 
providing the subject identification number, the subject’s age category and previous 
MenACWY vaccination? (Yes/ No)*, the randomisation system will determine the study 
group and will provide the treatment number to be used for each dose. 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 SPM for specific 
instructions. 
If for any reason, after randomisation the subject fails to undergo treatment, this is an 
early Termination and the reason should be recorded in source document as specified in 
the SDA.  
Note that enrolment will be frozen as soon as the target numbers (Table 7) are reached. 
Refer to the SPM for further details. 
Note: * Subjects with and without a previous MenACWY vaccination (primed and 
unprimed). 
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/product 
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 on the Vaccine 
Administration screen. 
7.2.3. 
Allocation of subjects to assay subsets 
Analysis of effectiveness and immunogenicity endpoints will be performed on different 
sub-sets of subjects, independent of allocation by study group. Refer to Section 10 for 
details. Blood samples will be collected from all subjects participating in the study.  
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7.2.3.1. 
Randomisation to strains for enc-hSBA testing 
The evaluation of the randomly selected panel of invasive serogroup B strains (110 
strains) for each vaccinated subject is not technically feasible with clinically acceptable 
blood volumes drawn from adolescents and young adults. For each applicable serum 
sample, 35 strains will be chosen completely at random from the 110 strains.  
• 
The target number of strains to be tested for each subject will be 35 strains. 
• 
The serum sample collected from each subject will be sent on an ongoing basis to 
GSK Clinical Laboratory Sciences or to laboratories delegated by GSK where the 
assays are available and qualified for the intended use. Aliquots for immunogenicity 
and enc-hSBA testing will be prepared depending on the serum volume available for 
a visit from one subject. A minimum amount of 5 mL of serum needs to be available 
to confirm eligibility to perform enc-hSBA testing. Additional instruction on the 
number of strains to be randomly assigned for enc-hSBA testing, according to the 
actual sample volume of serum provided to the laboratory, is provided in Section 
10.1.2. 
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 vaccine(s)/product(s) recipient and those responsible 
for the evaluation of any study endpoint (e.g. safety, reactogenicity, and effectiveness) 
will all be unaware of which vaccine/product was administered. To do so, 
vaccine/product preparation and administration will be done by qualified healthcare 
professional who will not participate in any of the study clinical evaluation. A minimum 
number of study site personnel responsible for preparing and / or delivering the injections 
will be unblinded. See Glossary of terms for definition of qualified healthcare 
professional and unblinded study staff. Site personnel responsible for delivering the 
injection must not be involved in study assessments. The study vaccine/placebo will be 
provided to the site as subjects’ kits, similar in appearance, identified with treatment 
information (either Meningococcal Group B Vaccine or Meningococcal Groups A, B, C, 
W and Y Vaccine or Meningococcal Groups A, C, Y and W Conjugate Vaccine or 
placebo). Refer to SPM for details. 
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.  
The serological data, which could 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 or analysis. 
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 
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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 10) 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 10 
Contact information for emergency unblinding 
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
Phone: +32 2 656 68 04 
Fax: +32 2 401 25 75 
Email: rix.ugrdehelpdesk@gsk.com 
Refer to SPM for other country-specific numbers. 
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 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. 
7.4. 
Handling, storage and replacement of study 
vaccine(s)/product(s) 
7.4.1. 
Storage and handling of study vaccine(s)/product(s)  
The study vaccine(s)/product(s) 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 
authorised 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 
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monitoring device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the 
SPM for more details on storage of the study vaccine(s)/product(s). 
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 
vaccine(s)/product(s) 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 vaccine(s)/product(s) 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 vaccine(s)/product(s). 
7.4.2. 
Replacement of unusable vaccine(s)/product(s) doses 
In addition to the vaccine/product doses provided for the planned number of subjects 
(including over-randomisation when applicable), at least 10% additional vaccine/product 
doses will be supplied to replace those that are unusable. 
7.5. 
Concomitant medication(s)/product(s) and concomitant 
vaccinations 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
Concomitant medications include all medications taken by/administered to the subject at 
and after enrolment to treat any AE collected in the eCRF and any vaccine administered 
to subjects. These medications/ vaccines must be documented on the Prior and 
Concomitant Medications and Vaccination eCRF.  
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. When recording concomitant medications/vaccines, they should 
be checked against the study entry and continuation criteria in Section 6, Selection of 
Study Population to ensure that the subject should be enrolled/continue in the study. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF. 
• 
Any concomitant medications/products administered for treatment of an AE to be 
recorded as per the protocol-specified reporting period (see Table 14). 
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• 
Any concomitant vaccination administered in the period starting 14 days before the 
first dose of study vaccine(s)/product(s) and ending at the last study contact (Day -14 
to Day 361).  
• 
Any concomitant medications/products/vaccines leading to the withdrawal or non-
eligibility of the subject from the study (Refer to 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’s. 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. 
Medications taken for prophylaxis are those intended to prevent the onset of 
symptoms. Medications taken for treatment are intended to reduce or eliminate the 
presence of symptoms that are present. 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 route.  
• 
The use of antipyretics and/or analgesic medications within 24 hours prior to 
vaccination must be identified and the reason for their use (prophylaxis versus 
treatment) must be described in the source document and Concomitant Medications 
eCRF.  
• 
The use of systemic antibiotics within 3 days prior to blood sampling visit is a reason 
to delay of blood sample withdrawal (see Section 6.3, Criteria for temporary Delay 
of Vaccination). 
• 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
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 
vaccine(s)/product(s) used during the study period.  
• 
Investigational or non-registered medicinal products within 30 days prior to 
informed consent. 
• 
Immunosuppressants or other immune-modifying drugs defined as follows: 
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− 
Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent until the post-
vaccination 3 blood sample (Visit 6). 
− 
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 or any blood products at any dose and for any duration from 90 
days prior to informed consent or until post vaccination 3 blood sample (Visit 6). 
7.6. 
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses  
If the subject meets one of the criteria mentioned in the Section 7.7, he/she may be 
eliminated from per protocol analysis. 
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, the subjects should be encouraged 
to continue other study procedures at the discretion of the investigator (Section 8.5.7). 
• 
Anaphylaxis following the administration of vaccines. 
• 
Pregnancy (see Section 12.5.8.1). 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Any occurrence of an event listed in the exclusion criteria which must be always re- 
assessed by the investigator before administration of the next dose of study vaccine. 
• 
Subjects who experience any serious adverse event 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 that, in the 
opinion of the investigator, exposes the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine(s)/product(s). Refer to Section 
12.5.6 for the definition of AESIs. 
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7.8. 
Warnings and precautions 
Warnings and precautions to vaccination must be checked at the beginning of each 
vaccination visit. Refer to the Investigator Brochure for MenABCWY and the approved 
product label/package insert of rMenB+OMV NZ and MenACWY vaccines. 
7.9. 
Treatment after completion of the study 
During the study conclusion contact, the investigator will ask each subject/subject’s 
parent(s)/LAR(s) if they are interested in participating/allowing the subject to participate 
in a booster study/long-term study. If a subject/subject’s parent(s)/LAR(s) is/are not 
interested in participating in the booster study/long-term study the reason for refusal will 
be documented, when available, in the subject’s CRF/eCRF. 
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)). 
Refer to Section 8.4.5 for details. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised 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 (i.e. eligibility criteria check) must be completed and results 
reviewed before confirming 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.  
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 3. 
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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. 
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 8.9 for further details. 
8.2. 
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, hospitalisations, 
surgeries requiring in-patient hospitalisation, any other medical conditions which 
may impair the assessment of safety of the rMenB+OMV NZ, MenABCWY and 
MenACWY vaccines). 
• 
Pre-vaccination body temperature. 
• 
Post-vaccination immediate reactions observed for at least 30 minutes after injection 
(on Day 1, Day 61, Day 181 and Day 211): 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).Refer to Section 12.5.12.1 for details. 
• 
Post-vaccination solicited local and systemic AEs collected at home by subject 
and/or subject’s parent(s)/LAR(s) and recorded in the Subject eDiary for 7 days 
following each vaccination visit (at Day 1, Day 61 and Day 181). Any ongoing event 
(beyond 7 days) may be followed up for 30 days or until resolution, whichever is 
earlier, in the eDiary. 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 
analyzed as unsolicited AEs (i.e. in the Unsolicited Safety Set).  
• 
Adverse Events. 
− 
Unsolicited AEs occurring within 30 days after each vaccination (at Day 1, Day 
61 and Day 181) 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 
− 
Medically attended AEs occurring during the entire study period 
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− 
AEs leading to premature withdrawal from the vaccination/study occurring 
during the entire study period 
− 
AESI occurring during the entire study period.  
• 
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 but are recorded in eDiary. 
8.3. 
Pre-vaccination procedures 
8.3.1. 
Screening/ Eligibility criteria 
After an individual or individual’s parent/LAR has consented participation in the study 
and informed consent/assent is signed, that individual will be given a unique Screening 
Number manually created by the investigator. The subject’s unique Screening Number 
will be documented in the Screening and Enrolment log. The eligibility of the subject 
will be determined based on the inclusion and exclusion criteria listed in Section 6 and 
evaluated during this screening procedure. 
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. 
8.3.2. 
Collection of demographic data 
Prior to study enrolment, demographic data will be collected from the subject, including 
date of birth (month and year), gender, race, ethnicity, weight, and height, and recorded 
in the subject’s eCRF. 
8.3.3. 
Medical history 
Medical history will also be collected, including but not limited to any medical history 
that may be relevant to subject eligibility for study participation such as prior 
vaccinations, concomitant medications, and previous and ongoing illnesses or injuries. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it represents 
an exacerbation of an underlying disease/pre-existing problem. 
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. 
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8.3.4. 
General and symptom-directed physical examination 
A general physical examination is to be performed by a qualified healthcare practitioner. 
“Qualified health care practitioner” refers to any licensed or certified healthcare 
professional who is permitted by institutional policy to perform protocol required 
procedures, and who is identified within the Delegation of Responsibility Log. The 
physical examination will include examination of organ systems that are relevant to the 
investigator based on medical history and review of systems and a measurement of heart 
rate, blood pressure, and temperature.  
These data will be written in the source document. Should the physical assessment reveal 
any abnormal values or events, these must be documented in the eCRF Adverse Events 
Form. 
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. 
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 this examination should be performed according to local 
medical practice outside this study or by referral to an appropriate health care provider. 
8.3.5. 
Pregnancy test 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine(s)/product(s) may only be administered 
if the pregnancy test is negative.  
Urine samples will be collected for pregnancy testing in females of child-bearing 
potential, before vaccinations at Visits 1, 3, 5 and 6, 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. 
8.3.6. 
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 body 
temperature 38.0°C/100.4°F regardless of the location of measurement] on the day of 
vaccination, the vaccination visit will be rescheduled within the allowed interval for this 
visit (see Section 6.3). 
Note: If the body temperature is measured by any other route (other than oral), this also 
needs to be recorded in the subject’s eCRF. 
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8.4. 
Effectiveness and/or immunogenicity assessments 
Please refer to the SPM and/or 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. 
Future findings may make it desirable to use the samples acquired in this study for further 
research, not described in this protocol. Additional serological testing may be performed 
in the future to further characterise the antibody response to the antigens included in the 
study vaccines or hSBA against an additional panel of strains of Neisseria species. 
Therefore, all subjects in countries where this is allowed 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 prior EC/IRB approval if required per local legislation. 
Information on further investigations and their rationale can be obtained from GSK.  
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 8.4.4 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.  
8.4.1. 
Use of specified study materials 
When materials are provided by GSK, it is MANDATORY that all clinical samples 
(including serum samples) be collected and stored exclusively using those materials in 
the appropriate manner. The use of other materials could result in the exclusion of the 
subject from the per-protocol analysis (See Section 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 does not 
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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. 
8.4.2. 
Biological samples 
Refer to the Module on Biospecimen Management in the SPM and/or Central Laboratory 
Manual for detailed instructions for the collection, handling and processing of the 
samples. 
8.4.2.1. 
Blood sampling for effectiveness and immunogenicity response 
assessments 
(Amended 9 May 2021) 
A minimum of approximately 20 mL of blood will be drawn from all subjects at visit 1 
before vaccination. Approximately 30 mL sample of blood will be drawn from all 
subjects 30 days after the first and third vaccination [at Visit 2 (Day 31) and Visit 6 
(Day 211)] and approximately 25 mL sample of blood will be drawn from all subjects 
30 days after the second vaccination (at Visit 4 (Day 91)). 
The blood samples should be collected before the study vaccination when applicable. The 
blood volume that is drawn as presented in Table 11 is needed in order to provide the 
necessary serum volume for the bactericidal assays (enc-hSBA and hSBA(s)). Refer to 
Section 5.1 and Section 7.2.3.1 for further details on the rationale for the requirement of 
this blood volume. 
Check criteria for blood draw delay as specified in Section 6.3. A topical anaesthetic (e.g. 
EMLA adhesives or cream) may be used at the site of blood sample draw, according to 
local practice in order to minimise pain. 
The blood will be processed as described in the SPM and/or Central Laboratory Manual. 
The serum will be stored at a temperature of -80°C (-70°C is accepted but -80°C is 
preferred). Each serum tube will be identified with a Central Laboratory label and sent to 
Central Laboratory per defined frequency. Complete instructions for labelling and storage of 
serum samples are included in the SPM and/or Central Laboratory Manual. 
The total amount of blood collected over the study period per subject will be 
approximately 105mL. 
Insufficient blood volume may lead to test cancellation and jeopardise the statistical 
power. Hence, every effort must be done to collect blood volume as per protocol 
requirements 
Note: Blood samples are taken from all subjects irrespective of the testing status to maintain 
the blind of the study. Refer to Section 8.4 for details on how the unused/ left-over samples 
will be used.  
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Table 11 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Subject/Group 
Day 
Blood 
Approximately 20 
mL 
Visit 1 (Pre-Vacc) 
All 
Day 1 
Approximately 30 
mL 
Visit 2 (Post-Vacc 1) 
All 
Day 31 
Approximately 25 
mL 
Visit 4 (Post-Vacc 2) 
All 
Day 91 
Approximately 30 
mL 
Visit 6 (Post-Vacc 3) 
All 
Day 211 
Note: in case of local regulations limiting the amount of blood to be taken in the younger population (e.g 10-
12 years of age and/or at the lower bound of the percentile of the growth chart), a reduced amount of blood 
volume could be drawn at Visit 2 and Visit 6. In this population every effort must be done to collect at least 
25ml of blood volume, samples will be analysed according to priority ranking provided in Table 13 
8.4.2.2. 
Other biological samples 
• 
Urine sampling 
Urine will be collected for pregnancy testing in females of child-bearing potential. Urine 
will be collected at Visit 1 before the first vaccination (Day 1), at Visit 3 before the 
second vaccination (Day 61), at Visit 5 before the third vaccination (Day 181) and at 
Visit 6 before vaccination (Day 211) and the results recorded in the source document 
and eCRF. 
8.4.3. 
Laboratory assays 
(Amended 9 May 2021) 
Serum bactericidal activity is a functional measure of the ability of antibodies, in 
conjunction with human complement, to kill meningococci, and it is widely accepted as 
the serological surrogate marker for protection.  
Effectiveness of the MenB component will be evaluated with serum bactericidal assays 
using endogenous source of human complement (enc-hSBA), on a panel of 110 US 
representative N. meningitidis serogroup B invasive disease strains. 
Immunogenicity of the vaccine against serogroups A, B, C, W and Y will be evaluated by 
serum bactericidal assays using exogenous source of human complement (hSBAs), using 
indicator strains representing serogroups A, B, C, W and Y. 
An Enzyme-Linked Immunosorbent Assay (ELISA), or equivalent, will be used to 
evaluate the serotype-specific IgG responses to A, C, W, and Y. The intent is to 
characterize whether the immunogenicity measured by hSBA using the MenA, C, W and 
Y indicator strains may be confounded by the contribution of the responses against the 
MenB antigens of the combination vaccine. The ELISA procedure is used to detect the 
amount of serum immunoglobulin G (IgG) antibodies in response to specific N. 
meningitidis polysaccharide antigens. 
Effectiveness testing by enc-hSBA and MenACWY immunogenicity testing by hSBA 
will be prioritised over any other assays using exogenous source of human complement, 
or ELISA (or equivalent), based on the volume of serum available for a visit from one 
subject. 
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Please refer to Section 12.2 for a detailed description of the assays performed in the 
study.  
All testing will be performed at GSK Biologicals’ laboratories or in a laboratory 
designated by GSK Biologicals (where the assays are available and qualified for the 
intended use) using standardised and validated procedures (refer to Section 12.2). Please 
refer to Section 12.3 for the address of the clinical laboratories used for sample analysis. 
Table 12 
Laboratory assays 
System 
N meningitidis Strains* 
Method 
Kit/Manufacturer 
Unit 
Laboratory 
Serum 
Panel of 110 strains [Welsch, 
2018] 
enc-hSBA 
In-house 
1/dilution 
GSK 
laboratory** or 
laboratory 
designated by 
GSK  
Serum 
N men A (3125) Ab  
hSBA 
In house 
1/dilution 
N men C (C11) Ab 
N men W (240070) Ab 
N men Y (860800) Ab 
Serum 
N men B fHbp (M14459) Ab 
hSBA 
In house 
1/dilution 
N men B NadA (96217) Ab 
N men B PorA (NZ98/254) Ab 
N men B NHBA (M13520) Ab 
Serum 
N men A Ab IgG 
ELISA# 
TBD 
µg/mL 
N men C Ab IgG 
N men W Ab IgG 
N men Y Ab IgG 
Abbreviations: enc-hSBA: serum bactericidal assay with endogenous human complement; hSBA: serum bactericidal 
assay using human complement; 1/dilution: reciprocal of the dilution; IgG: Immunoglobin G; µg: Microgram, ELISA = 
enzyme-linked immunosorbent assay; N men: Neisseria meningitidis; TBD: to be determined. 
* Strain(s) and/or assay cut-off(s) might be subject to change during the course of the study (e.g. in case of new 
qualification, (re-)validation or standardisation). In this case, this will be documented in the clinical report. 
** GSK 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 
#For each of the MenACWY serogroups, ELISA (or equivalent 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 clinical laboratories have established a Quality System supported by 
procedures. The activities of GSK clinical laboratories are audited regularly for quality 
assessment by an internal (sponsor-dependent) but laboratory-independent Quality 
Department. 
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8.4.4. 
Biological samples evaluation 
8.4.4.1. 
Immunological read-outs 
(Amended 9 May 2021) 
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 13. 
Table 13 
Immunological read-outs 
Blood sampling time 
point 
Group/ 
Subset 
name 
No. 
subjects Method1 
Component 
Components 
priority  
rank 
Type of 
contact and 
time point 
Sampling 
time point 
Visit 1  
(Day 1) 
Pre-Vacc 1  
For details on 
number of subjects 
and groups/ subsets 
please refer to 
Section 10.1.2 
hSBA 
N men A (3125) Ab  
1 
hSBA 
N men C (C11) Ab 
1 
hSBA 
N men W (240070) Ab  
1 
hSBA 
N men Y (860800) Ab 
1 
hSBA 
N men B fHbp (M14459) Ab 
2 
hSBA 
N men B NHBA (M13520) Ab 
2 
hSBA 
N men B NadA (96217) Ab 
2 
hSBA 
N men B PorA (NZ98/254) Ab 
2 
Visit 2  
(Day 31) 
Post-Vacc 1  
enc-hSBA 
110 random US MenB strains 
1 
hSBA 
N men A (3125) Ab  
2 
hSBA 
N men C (C11) Ab 
2 
hSBA 
N men W (240070) Ab  
2 
hSBA 
N men Y (860800) Ab 
2 
ELISA 
N men A Ab IgG 
3 
ELISA 
N men C Ab IgG 
3 
ELISA 
N men W Ab IgG 
3 
ELISA 
N men Y Ab IgG 
3 
Visit 4  
(Day 91) 
Post-Vacc 2 
enc-hSBA 
110 random US MenB strains 
1 
hSBA 
N men B fHbp (M14459) Ab 
2 
hSBA 
N men B NHBA (M13520) Ab 
2 
hSBA 
N men B NadA (96217) Ab 
2 
hSBA 
N men B PorA (NZ98/254) Ab 
2 
Visit 6  
(Day 211) 
Post_vacc 3 
enc-hSBA 
110 random US MenB strains 
1 
hSBA 
N men A (3125) Ab  
2 
hSBA 
N men C (C11) Ab 
2 
hSBA 
N men W (240070) Ab  
2 
hSBA 
N men Y (860800) Ab 
2 
hSBA 
N men B fHbp (M14459) Ab 
3 
hSBA 
N men B NHBA (M13520) Ab 
3 
hSBA 
N men B NadA (96217) Ab 
3 
hSBA 
N men B PorA (NZ98/254) Ab 
3 
ELISA 
N men A Ab IgG 
4 
ELISA 
N men C Ab IgG 
4 
ELISA 
N men W Ab IgG 
4 
ELISA 
N men Y Ab IgG 
4 
Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination  
1 For detail regarding the method refer to Table 12. 
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8.4.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far against N. meningitidis serogroups A, B, W, and Y. 
An hSBA titre ≥4 is a generally accepted correlate of protection against invasive 
meningococcal disease caused by N. meningitidis serogroup C. 
The immunological assay results will be communicated to the investigator when ready 
and available. 
8.5. 
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. 
8.5.1. 
Safety definitions 
Please refer to Section 12.5 for safety definitions. 
8.5.2. 
Follow-up Clinic Visit(s) 
A follow-up clinic visit will be performed on Day 31 (-5/+14 days, Visit 2), Day 91 (-5 / 
+14 days, Visit 4) and Day 211 (-5 / +14 days, Visit 6). 
The eDiary will be reviewed on Day 31 (Visit 2), Day 91 (Visit 4) and Day 211 (Visit 6).  
Study-specific requirements are described in the SPM. For details on the eDiary see 
Section 12.5.9. 
The subject and/or parent(s)/legal guardian(s) will be interviewed to determine if any 
unsolicited AEs occurred and if any concomitant medications or vaccines were 
taken/received in the time since the last clinic visit. The qualified healthcare professional 
reviewing these data will discuss the symptoms (if any) reported by the subject and will 
determine if any additional diagnoses and/or AEs are/were present. Adverse events 
reported by the subject and/or parent(s)/legal guardian(s) at this follow-up clinic visit 
must be recorded in the subject’s source document and on an Adverse Events CRF, as 
specified in Section 8.5, and not written on the script used for the interview. 
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 adverse events, 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 
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accordance with their institutional policy. Clinically significant abnormalities should be 
reported as an AE in the CRF. 
Blood sampling will be done as described in Section 8.4.2.1.  
The site should schedule the next study visit/ study activity safety call with the subject 
and/or parent(s)/legal guardian(s) at each visit. 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 hospitalisation or an emergency room visit. 
8.5.3. 
Safety Follow-up Calls 
Safety follow-up phone calls are made on Day 15 (T1), Day 75 (T2), Day 121 (T3), Day 
195 (T4), Day 241 (T5), Day 301 (T6), and Day 361 (T7). Safety follow-up calls are 
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 and/or parent(s)/legal guardian(s) will be interviewed at Day 15 
(SFU 1; T1), Day 75 (SFU 2; T2) and Day 195 (SFU 4; T4) according to the script, and 
information relating to any unsolicited AEs will be collected. 
At all safety follow-up phone calls (T1 to T7) information relating to SAEs, AESIs, 
medically attended AEs and AEs leading to withdrawal will be collected. At all Safety 
Follow-up Calls concomitant medications associated with the AE and concomitant 
vaccinations have to be collected. All safety information described by the subject must be 
written down in a designated location within the source document. If this script is used as 
a source document, ensure that it meets the definition of a source document as per ICH 
GCP and/or local requirements. 
The site should schedule the next study activity clinic (visit or safety call) with the 
subject and/or parent(s)/LAR(s). 
The subject and/or parent(s)/legal guardian(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 hospitalisation or 
an emergency room visit. 
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8.5.4. 
Time period and frequency for collecting AE and serious adverse event (SAE) information 
An overview of the protocol-required reporting periods for AEs, SAEs, AESIs and pregnancies is given in Table 14. Refer to the Section 
12.5.9.2 for details on the time period for recording safety information. 
Table 14 
Reporting periods for collecting safety information 
Event 
On 
V1* 
 
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
 
 
Study Conclusion 
 
D1*** 
D7 
D31 
D61 
D67 
D91 
 
D181 
D 187 
D 211 
 
D241 D301 
D 361 
Solicited local and 
systemic AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs leading to 
withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended 
AEs** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation  
or concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Event 
On 
V1* 
 
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
 
 
Study Conclusion 
 
D1*** 
D7 
D31 
D61 
D67 
D91 
 
D181 
D 187 
D 211 
 
D241 D301 
D 361 
AESIs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.; V: Visit; D: Day, M: Month; T,Telephone call; COVID-19, Coronavirus Disease 2019 
* i.e. consent obtained 
** Including COVID-19 infection related AEs.  
*** Except SAEs related to study participation or concurrent GSK medication/vaccine, all other safety data will be collected starting from Visit 1 after vaccine administration. 
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 Section 12.5. The investigator will 
submit any updated SAE/AESI data to the sponsor within 24 hours of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE reporting period defined in Table 14. 
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 vaccine(s)/product(s), the investigator will promptly notify the Study Contact for Reporting SAEs. 
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8.5.5. 
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 12.5.9. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subjects/subjects’ parent(s)/LAR(s) is the preferred 
method to inquire about AE occurrence.  
8.5.6. 
Reporting of serious adverse events, pregnancies, and other 
events 
(Amended 9 May 2021) 
Table 15 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK  
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* 
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 an 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 
8.5.6.1. 
Contact information for reporting of serious adverse events, AESIs and 
pregnancies  
Table 16 
Contact information for reporting of serious adverse events, 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 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 only: 
Fax: 1-610-787-7053 
Canadian sites only: 
Fax: 1-866-903-4718 
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8.5.6.2. 
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.  
8.5.7. 
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 SAE and non-serious AESIs (Refer Section 
12.5.6 for definition), will be followed until the event is resolved, stabilised, otherwise 
explained, or the subject is lost to follow-up. Further information on follow-up 
procedures is given in Section 12.5.12.4. 
8.5.8. 
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/ AESI 
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 7.5). 
8.5.9. 
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. 
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8.5.10. 
Medical device deficiencies 
(Amended 9 May 2021) 
The study interventions (MenABCWY and Bexsero) are combination products 
constituted of a device and biologic product (e.g., pre-filled syringes). Refer to Glossary 
of terms for the definition of a combination product and a medical device deficiency. 
8.5.10.1. 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 12.8 for definitions and details on recording and reporting of these events.  
The investigator will ensure that follow-up includes any additional investigations to 
elucidate the nature and/or related of the device deficiency to the incident. Follow-up 
applies to all participants, including those who discontinue study intervention or the 
study. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
8.5.10.2. Regulatory reporting of medical device deficiency when used as 
combination product  
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study to GSK. GSK has a legal responsibility to notify 
appropriate regulatory authorities and other entities about safety information linked to 
medical devices being used in clinical studies. Refer to Section 12.8.2 for details of 
reporting. 
The investigator, or responsible person according to local requirements (e.g. the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.6. 
Holding rules and safety monitoring 
There are no predetermined stopping rules other than circumstances for which subjects 
may not be eligible for additional study vaccinations or may be withdrawn from the study 
according to the best interests of the subject. 
8.7. 
Biomarkers and pharmacogenomics 
Biomarkers and pharmacogenomics are not evaluated in this study. 
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8.8. 
Study Termination Visit/ Study Conclusion 
The study termination call will occur on Day 361. The termination visit will be a phone 
call (also in case of early termination of the study).  
The date of termination is the date of the last contact (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 Section 8.8.1. 
During the phone call at the end of the study (Day 361), the following procedures will be 
performed: interview of subject and/or parent(s)/legal guardian(s) to collect SAEs, 
AESIs, medically attended AEs, pregnancies and/or concomitant medications/ 
vaccinations. 
The site will review with the subject and/or parent(s)/legal guardian(s) the plan of when 
information relating to the subject’s participation in the study may be available (e.g., 
study results, 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)/legal guardian(s) chooses to share this 
information. 
The site will complete the termination eCRF page and this will mark the completion of 
the subject’s participation in the study. 
8.8.1. 
Early Termination Visit 
When a subject is withdrawn from treatment or withdraws from the study, the 
investigator will perform the procedures listed below. The reason(s) for the early 
termination will be included in the subject’s source documentation. If the Early 
Termination Visit is a telephone call, collect as much information as possible. Early 
Termination Visits include subjects who were randomised but not treated. 
At the clinic visit or during the telephone call, the following procedures will be 
performed: 
• 
review of Subject eDiary (if applicable) 
• 
interview of subject and/or parent(s)/legal guardian(s) to collect all AEs if 
termination occurs within 30 days after vaccination. If the termination occurs more 
than 30 days after the vaccination, all AEs within 30 days after vaccination and 
medically attended AEs, AEs leading to withdrawal, SAEs, pregnancy, AESIs 
beyond the 30 days after vaccination have to be collected. 
• 
interview of subject and/or parent(s)/legal guardian(s) to collect concomitant 
medications administered to treat adverse events collected in the study, 
• 
blood sampling (if withdrawal occurs at or prior to Visit 4 (Day 91) or Visit 6 (Day 
211)) (if applicable) 
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The site will review with the subject and/or parent(s)/legal guardian(s) the plan of when 
information relating to the subject’s participation in the study may be available (e.g., 
study results, 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)/legal guardian(s) chooses to share this 
information. 
The site will complete the termination eCRF page and this will mark the completion of 
the subject’s participation in the study. 
8.9. 
Study procedures during special circumstances  
(Amended 9 May 2021) 
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 Subject 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 6). 
• 
Study visits may be performed at a different location* other than the study site (e.g. 
at subject’s home). For study visits involving blood draw, biological samples should 
not be collected if they cannot be processed in a timely manner or appropriately 
stored until the intended use.  
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 4), then the interval may be extended 
as described below in Table 17.  
• 
If despite best efforts it is not possible to administer the dose of study intervention as 
defined in the protocol (see Table 4), then the interval may be extended as described 
below in Table 17.  
* 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 
participants by investigator and staff at a site other than the designated study site.  
In case of home visits, the study procedures should be carried out by a qualified 
person/s as delegated by the Principal Investigator, provided that the compliance 
with protocol procedures are ensured. Refer to Schedule of Activities for the 
schedule of visits (see Table 3).  
Refer to local regulations on the conduct of clinical trials during the COVID-19 
pandemic for more details. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
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Table 17 
Intervals between study visits during special circumstances 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1 → Visit 2 
30 days 
23 to 58 days after vaccination at V1  
(from -7 to +28 days) 
Visit 1→Visit 3 
60 days 
53 to 88 days after vaccination at V1  
(from -7 to +28 days) 
Visit 3→Visit 4 
30 days 
23 to 58 days after vaccination at V3  
(from -7 to +28 days) 
Visit 3→Visit 5 
120 days 
110 to 148 days after vaccination at V3  
(from -10 to +28 days) 
Visit 5→Visit 6 
30 days 
23 to 58 days after vaccination at V5  
(from -7 to +28 days) 
8.10. 
Decentralised study procedures 
(Amended 9 May 2021) 
If local regulations allow and if quality of study procedures can be maintained, 
participant(s) can be offered remote visits (e.g. home visits) for the collection of 
biological samples and/or study intervention administration. These remote visits must 
be performed by qualified study staff/healthcare professionals HCPs. Refer to the 
Schedule of Activities (Table 3) for the timing of these visits. 
Following procedures can be performed remotely. Refer to the Glossary of terms for 
definitions of remote virtual visit: 
• 
Biological samples may be collected remotely by qualified study staff/HCPs. 
Biological samples should be collected only if they can be processed in a timely 
manner and appropriately stored until the intended use.  
• 
Administration of study intervention can be performed remotely/at participant’s 
home by qualified study staff/HCPs if appropriate storage conditions for the study 
intervention can be ensured. Furthermore, appropriate medical treatment must be 
readily available during 30 minutes after dosing in case of anaphylaxis, syncope. 
9. 
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.  
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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 
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 events (AEs) requiring expedited reporting (please refer to section 12.5.10.2 
for the details) 
• 
Unsolicited non-serious AE 
• 
Solicited AE 
• 
Protocol deviation  
• 
Withdrawal by subject, not due to an AE* 
• 
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/pregnancy 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/pregnancy 
until resolution of the event (see Section 12.5.12). 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician (Refer to Section 7.3.1). The primary reason for 
discontinuation (the event or condition which led to the unblinding) will be recorded in 
the eCRF. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the reason 
for discontinuing the study. This AE must be identified on the AE eCRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilisation. 
Subjects who develop a SAE judged to be possibly or probably related to the study 
vaccine, including hypersensitivity reactions, should not receive subsequent vaccination. 
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Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination eCRF page and the associated SAE that led to the death must be 
reported. 
Withdrawal of consent 
The subject and/or parent(s)/legal guardian(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)/legal guardian(s) intends 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. 
For sites in US: If a subject and/or parent(s)/legal guardian(s) withdraws consent but 
does not revoke the The Health Insurance Portability and Accountability Act (HIPAA) 
authorisation, the Sponsor will have full access to the subject’s medical records, 
including termination visit information. If a subject and/or parent(s)/legal guardian(s) 
revokes only the HIPAA authorisation, 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 
Refer to Section 9.2. 
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/stabilisation. 
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 jeopardises 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 authorised 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 
adequate contraception, will not receive further vaccination 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 (Refer to Section 12.5.9). 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. 
9.1. 
Discontinuation of study vaccine(s)/product(s) 
A ‘withdrawal’ from the study vaccine(s)/product(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)/product(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)/product(s) 
will be documented on the Vaccine Administration 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 
• 
Unsolicited non-serious adverse event (specify) 
• 
Solicited adverse event 
• 
Not willing to be vaccinated 
• 
Other (specify). 
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9.2. 
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. 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. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample size determination 
(Amended 9 May 2021) 
Three thousand six hundred fifty-one (3,651) subjects are to be enrolled in the study. 
Figure 1 presents the study design overview with the breakdown of sample size per study 
arm:  
• 
MenB_0_2_6: 912 subjects 
• 
MenB_0_6: 912 subjects 
• 
ABCWY-1: 548 subjects 
• 
ABCWY-2: 548 subjects 
• 
ABCWY-3: 548 subjects 
• 
ACWY: 183 subjects. 
It is assumed that 25% of the subjects will drop-out and not contribute to an evaluable 
result. The remaining subjects who do give an evaluable result provide 90% power to 
reject all hypotheses for the primary objectives of rMenB+OMV NZ and 92% power to 
reject all hypotheses for the primary objectives of MenABCWY vaccine. Additionally, 
the study is powered to reject key secondary objective for three N. meningitidis serogroup 
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B indicator strains (96217 (NadA), M14459 (fHbp), and M13520 (NHBA)) with 81% 
power. 
An explanation of the testing strategy and hypotheses can be found in Section 10.1.1 and 
its sub-sections. A breakdown of the power for the individual objectives can be found in 
Section 10.1.2 and its sub-sections. 
10.1.1. 
Hypothesis testing strategy 
Multiple objectives and endpoints require type I error control. Full alpha (0.05) is split 
equally (alpha=0.025) between rMenB+OMV NZ objectives and MenABCWY 
objectives. Furthermore, within rMenB+OMV NZ, as well as within MenABCWY, 
objectives are tested hierarchically. If the first null hypothesis is rejected, then the testing 
will continue with the second hypothesis at same alpha. Same for 3rd, 4th, and so forth. 
Whenever a null hypothesis is not rejected, then the testing will stop. 
As the comparator for MenABCWY non inferiority objective for the B component will 
be the selected schedule of rMenB+OMV NZ as determined in this study, the objectives 
of rMenB+OMV NZ will be analysed first. Additionally, if all null hypotheses related to 
rMenB+OMV NZ objectives will be rejected, the alpha (alpha=0.025) will be propagated 
to the MenABCWY part, and hypotheses related to MenABCWY objectives will be 
tested at full alpha (alpha=0.05). See Figure 2 for an explanation of the hierarchical 
testing (top to bottom, the order indicated by the arrows).  
Figure 2 
Hierarchical testing of hypothesis 
 
* Alpha split equally between rMenB+OMV NZ and MenABCWY vaccine objectives. 
 If all rMenB+OMV NZ objectives achieved, MenABCWY vaccine objectives will be tested at full alpha. 
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** If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 0,6-months 
is also not met, then the 0,2,6-months schedule will be the comparator.  
Refer to Glossary of terms for definitions of test-based and responder-based vaccine 
effectiveness. 
An explanation of the hypothesis testing is given in the following subsections: 
10.1.1.1. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
For demonstration of VE of rMenB+OMV NZ the following hypothesis will be tested:  
Null hypothesis:  
H0: VE ≤ 65% 
vs. Alternative hypothesis:  
H1: VE > 65% 
Where, VE represents the vaccine effectiveness, defined as 1- RR = (1- percentage of 
samples without bactericidal serum activity measured by enc-hSBA at a 1:4 dilution in 
the MenB group / percentage of samples without bactericidal serum activity at 1:4 
dilution in the ACWY group) x 100% and 65% is the pre-specified success criteria for 
VE. The VE against all 110 strains combined and associated 97.5% CI, will be computed 
by means of a generalised linear model. If the lower limit of the 97.5% CI for VE is > 
65% effectiveness will be claimed. 
10.1.1.2. Effectiveness (Responder-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
A responder is defined as a subject with at least 70% of the strains killed in sera, one 
month after vaccination schedule.  
Null hypothesis:  
H0: π B ≤ 65% 
vs. 
Alternative hypothesis:  
H1: π B   > 65% 
Where π B represents the percentages of responders observed at one month after 
vaccination schedule; and 65% is the pre-specified success criterion for the responder-
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based endpoint. The objective is to demonstrate that the lower limit of the 97.5% CI for 
the percentage of responders is higher than 65%. 
10.1.1.3. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,6-
months schedule) 
See Section 10.1.1.1 
10.1.1.4. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,6-months 
schedule) 
See Section 10.1.1.2 
10.1.1.5. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,2-
months schedule) 
See Section 10.1.1.1 
10.1.1.6. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,2-months 
schedule) 
See Section 10.1.1.2 
10.1.1.7. Lot-to-lot consistency: MenABCWY - ACWY component 
For demonstration of lot-to-lot consistency, the following equivalence hypotheses will be 
tested simultaneously for each of the 4 serogroups A, C, W, Y: 
Null hypothesis:  
H0:  
(μlot 1(i) - μlot 2(i)) ≤ 
 or (μlot 1(i) - μlot 2(i)) ≥ 
 or 
(μlot 1(i) - μlot 3(i)) ≤ 
 or (μlot 1(i) - μlot 3(i)) ≥ 
 or 
(μlot 2(i) - μlot 3(i)) ≤ 
 or (μlot 2(i) - μlot 3(i)) ≥ 
 
vs. 
H1:  
(μlot 1(i) - μlot 2(i)) > 
 and (μlot 1(i) - μlot 2(i)) < 
 and 
(μlot 1(i) - μlot 3(i) ) > 
 and (μlot 1(i) - μlot 3(i)) < 
 and 
(μlot 2(i) - μlot 3(i)) > 
 and (μlot 2(i) - μlot 3(i)) < 
 
Where μlot 1(i), μlot 2(i) and μlot 3(i) denote the means of log10-transformed titres for 
serogroups i=A, C, W and Y at 1 month after the second vaccination of the corresponding 
lot groups; and 0.5-2.0 are the non-inferiority margins for the ratio of GMTs between 
each pair of lots. Lot-to-lot consistency will be claimed if the two-sided 97.5% CIs for 
)5.0(
log10
)2(
log10
)5.0(
log10
)2(
log10
)5.0(
log10
)2(
log10
)5.0(
log10
)2(
log10
)5.0(
log10
)2(
log10
)5.0(
log10
)2(
log10
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the ratio of hSBA GMTs of antibodies against serogroups A, C, W and Y are within the 
[0.5;2.0] equivalence interval for each pair of lots.  
10.1.1.8. Immunological non-inferiority: MenABCWY vs. MenACWY  
For demonstration of non-inferiority of MenABCWY vs MenACWY in subjects without 
a previous MenACWY vaccination (unprimed), the following non-inferiority hypotheses 
will be tested simultaneously for each of the 4 serogroups A, C, W, and Y: 
Null hypothesis:  
H0: π ABCWY  – π ACWY  ≤ -10% 
vs. 
Alternative hypothesis:  
H1: π ABCWY  – π ACWY  > -10% 
Where: π ABCWY represents the percentages of subjects with a 4-fold rise 1 month after the 
last vaccination in the ABCWY group (pooled lots) and π ACWY represents the percentage 
of subjects with a 4-fold rise 1 month after the first vaccination in the ACWY group; and 
-10% is the non-inferiority margin for the difference in between ABCWY group (pooled 
lots) and ACWY group. Immunological non inferiority of MenABCWY to MenACWY 
will be claimed if the LL of the 2-sided 97.5% CI for the group difference in percentages 
of subjects achieving a 4-fold rise in hSBA titres is above -10% for each serogroup.  
10.1.1.9. Vaccine effectiveness (Test-based): MenABCWY  
See Section 10.1.1.1 
10.1.1.10. Effectiveness non-inferiority: MenABCWY vs. rMenB+OMV NZ 
For demonstration of non-inferiority of the VE of MenABCWY compared to the VE of 
rMenB+OMV NZ the following hypothesis will be tested: 
Null hypothesis:  
H0: π ABCWY  – π Control ≤ -5% 
vs. 
Alternative hypothesis:  
H1: π ABCWY  – π Control  > -5% 
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Where: π ABCWY and π Control  represent the percentages of samples with bactericidal serum 
activity at 1:4 dilution in the ABCWY group (pooled lots) 1 month after the last 
MenABCWY vaccination and in the MenB group one month after the last rMenB+OMV 
NZ vaccination of the final schedule as determined in this study; and -5% is the non-
inferiority margin for the difference in percentages of samples with bactericidal serum 
activity between ABCWY (pooled lots) and MenB group. Non inferiority of 
MenABCWY to rMenB+OMV NZ will be claimed if the LL of the 2-sided 97.5% CI for 
the group difference in percentages of samples with bactericidal serum activity at 1:4 
dilution is above -5%.  
10.1.1.11. Effectiveness (Responder-based): MenABCWY  
See Section 10.1.1.2 
10.1.2. 
Sample size justification 
Overall study sample size and its power is provided in Section 10.1. This sub-section 
provides a breakdown of the power calculation for each of the objectives. All calculations 
are based on number of evaluable subjects. 
10.1.2.1. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
The planned (target) number of strains to be tested for each subject will be 35 strains. A 
minimum amount of 5 mL of serum needs to be available to perform enc-hSBA testing. 
In case the volume of serum shipped to the laboratory for enc-hSBA testing is <5 mL, 
enc-hSBA testing will be still performed if the volume of serum allows to test a minimum 
number of 20 strains. Otherwise no enc-hSBA testing will be performed with the specific 
sample. The power was calculated for two situations: 30 and 35 strains to be tested per 
subject. 
In study V102_16E1, the observed raw percentages of samples without bactericidal 
serum activity at 1:4 dilution were 77.8% in the MenACWY vaccine group and 21.9% in 
the MenABCWY group one-month post 3rd vaccination. The estimated VE of 
MenABCWY compared to MenACWY was 71% (95% CI: 69% - 73%). For the sample 
size calculations, it is assumed that MenB (any schedule) will have similar results as 
MenABCWY 0,2,6-months. 
Table 18 shows the result of power calculation for a group size of 684 evaluable subjects 
in MenB group, (any schedule) and 137 subjects in MenACWY group. The percentage of 
tests without bactericidal serum activity for MenACWY is assumed to be 75%, while the 
estimation for MenB is 22%. Sample size calculations revealed >99.9% power to show 
that the lower limit of the two-sided 97.5% CI for the VE is >65% (Refer to Section 
10.1.1.1) 
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Table 18 
Power for VE 65% against all 110 strains combined, any schedule 
% of tests without bactericidal serum 
activity at 1:4 dilution 
Power 
MenACWY 
MenB 
Vaccine 
Effectiveness 
Success Criterion 
(LL of 97.5% CI) 
30 strains per 
subject 
35 strains per 
subject 
75% 
20% 
73% 
>65% 
99.9% 
99.9% 
77% 
20% 
74% 
>65% 
99.9% 
99.9% 
75% 
22% 
71% 
>65% 
99.9% 
99.9% 
77% 
22% 
71% 
>65% 
99.9% 
99.9% 
75% 
25% 
67% 
>65% 
84.4% 
89.3% 
77% 
25% 
68% 
>65% 
99.8% 
99.9% 
LL: lower level, CI: Confidence Interval, VE: Vaccine Effectiveness 
* Computed by 10,000 simulation runs each based on SAS GENMOD procedure.  
10.1.2.2. Effectiveness (Responder-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
Post-hoc calculations for study V102_16E1 were performed following a regulatory 
agency request. The calculated percentage of responders of subjects with >=70% of 
tested strains killed was 78.5% (95% CI [68.8%; 86.3%]) in the MenABCWY group one-
month post 3rd vaccination. To have overall power of 90% (refer to Section 10.1), the 
effectiveness (responder-based) endpoint needs to have 97% power. Six hundred eighty-
four (684) evaluable subjects will be necessary to demonstrate with at least 97% power 
that the lower limit of the 97.5% CI for proportion of responders in the MenB group (any 
schedule) is above 65% assuming the expected percentage in the study is 72.5% (see 
Table 19 below). 
Table 19 
Power for rMenB+OMV NZ Responder-based analysis 3 dose (0,2,6-
months schedule) 
N 
% Responders – MenB 
Success Criterion 
Power 
684 
69% 
65% 
48.4% 
684 
72.5% 
65% 
97.6% 
684 
75% 
65% 
>99.9% 
10.1.2.3. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,6-
months schedule) 
As the underlying assumptions for the rMenB+OMV NZ schedules are the same, see 
Section 10.1.2.1. 
10.1.2.4. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,6-months 
schedule) 
As the underlying assumptions for the rMenB+OMV NZ schedules are the same, see 
Section 10.1.2.2. 
10.1.2.5. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,2-
months schedule) 
As the underlying assumptions for the rMenB+OMV NZ schedules are the same, see 
Section 10.1.2.1. 
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10.1.2.6. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,2-months 
schedule) 
As the underlying assumptions for the rMenB+OMV NZ schedules are the same, see 
Section 10.1.2.2. 
10.1.2.7. Lot-to-lot consistency: MenABCWY - ACWY component 
One thousand two hundred thirty-three (1,233) evaluable subjects (411 evaluable subjects 
in each in ABCWY-1, ABCWY-2 and ABCWY-3 groups) are needed to demonstrate, for 
all pairs of lots, the two-sided 97.5% CIs for the ratio of hSBA GMTs of antibodies 
against serogroups A, C, W and Y are within the [0.5; 2.0] equivalence interval.   
Assuming standard deviations as the 80% upper confidence limit of the ones observed in 
a previous GSK study with MenABCWY vaccine (V102_15) to account for possible 
more variation in new data, an assumed underlying ratio between lots of 1.2 and 
independency, a single equivalence test based on 411 evaluable subjects per lot group has 
power 99.0%->99.9% (see Table 20). The resulting overall power is 96.1%, because the 
total number of comparisons is 12 (three pairwise comparisons for the 4 serogroups A, C, 
W, and Y). 
Table 20 
Power calculation to demonstrate lot-to-lot consistency  
Serogroup 
SD 
80% CI (UL) 
Assumed underlying 
ratio 
N 
Power 
A 
0.5651582 
0.616702951 
1.2 
411 
99.7% 
C 
0.5048067 
0.550847146 
1.2 
411 
>99.9% 
W 
0.370505 
0.404296579 
1.2 
411 
> 99.9% 
Y 
0.627423 
0.684646557 
1.2 
411 
99.0% 
Total (12 pairwise comparisons) 
 
 
 
 
96.1%% 
Note: SD – standard deviation; CI – confidence interval; UL – upper limit; N – number of evaluable subjects in each 
MenABCWY vaccine lot;  
10.1.2.8. Immunological non-inferiority: MenABCWY vs. MenACWY in subjects 
without a previous MenACWY vaccination (unprimed) 
Assuming at least 70% subjects without a previous MenACWY vaccination (unprimed), 
there will be at least  863 (70% out of 1233) evaluable subjects in the ABCWY group 
(pooled lots), at 1 month after the last vaccination, and 96 (70% out of 137) in the 
ACWY group at 1 month after the MenACWY vaccination (at Month 7 for ABCWY 
group (pooled lots) and at Month 1 for ACWY group). This sample size is sufficient to 
demonstrate that the lower limit of the two-sided 97.5% CIs for by percentage of subjects 
with 4-fold rise in hSBA titres against MenACWY indicator strains A, C, W and Y is > -
10%. 
Assuming similar underlying immune response after 2 doses of MenABCWY vaccine, as 
previously observed in study V102_16 (Column 2 and 3 of Table 21), the resulting 
overall power is 99.6%.  
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Table 21 
Power calculation to demonstrate non-inferiority for serogroups A, 
C, W and Y of MenABCWY compared to MenACWY in subjects 
without a previous MenACWY vaccination (unprimed), at 1 month 
after the second dose vs 1 month after a single dose 
Serogroup 
MenABCWY 
% 4-fold rise 
(2 doses) 
MenACWY 
% 4-fold rise (1 dose) 
Power (%) for 70% 
unprimed subjects 
A 
92.4% 
59.1% 
>99.9% 
C 
95.4% 
56.9% 
>99.9% 
W 
80.4% 
34.0% 
>99.9% 
Y 
90.9% 
62.8% 
>99.9% 
Total 
 
 
99.6% 
Unprimed = Subjects without a previous MenACWY vaccination 
10.1.2.9. Vaccine effectiveness (Test-based): MenABCWY  
As the underlying assumptions for MenABCWY 0-6M is the same as MenB, see Section 
10.1.2.1. 
10.1.2.10. Effectiveness non-inferiority: MenABCWY vs. rMenB+OMV NZ  
The target number of evaluable subjects of 684 (in ABCWY group (pooled lots)) and 684 
(in the Control group) at 1 month after the last vaccination is sufficient to demonstrate 
that the lower limit of the two-sided 97.5% CI for the difference in percentages of 
samples with bactericidal activity at 1:4 dilution in the ABCWY group (pooled lots) and 
in the Control group is above -5%. 
Assuming the percentage of samples with bactericidal serum activity at 1:4 dilution in 
ABCWY group (pooled lots) 75% and 75%-78% in MenB, the power to show non-
inferiority is ≥99.8%. (Table 22). 
Table 22 
Power calculation to demonstrate NI of MenABCWY to MenB  
Percentages of killed samples 
MenABCWY 0-6M 
Percentages of killed 
samples MenB 
Expected 
Difference 
N per group 
Power 
75% 
75% 
0% 
684 
> 99.9% 
75% 
76% 
-1% 
684 
> 99.9% 
75% 
77% 
-2% 
684 
> 99.9% 
75% 
78% 
-3% 
684 
99.8% 
75% 
79% 
-4% 
684 
64% 
10.1.2.11. Effectiveness (Responder-based): MenABCWY  
As the underlying assumptions for MenABCWY 0-6M is the same as MenB, see Section 
10.1.2.2. 
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10.1.2.12. Non inferiority of MenABCWY vs rMenB+OMV NZ measured by 
percentage of subjects with 4-fold rise in hSBA titres against MenB 
component indicator strains post 2nd dose 
(Amended 9 May 2021) 
Key secondary objective is to demonstrate non inferiority of MenABCWY vs 
rMenB+OMV NZ measured by the percentages of subjects with 4-fold rise in hSBA 
titres against the N. meningitidis serogroup B indicator strains post 2nd dose. Six hundred 
twenty (620) subjects are needed to demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the rMenB+OMV NZ as measured by the percentages 
of subjects achieving a 4-fold rise in hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the last MenABCWY vaccination (0,6-months schedule) 
and 1 month after the MenB vaccination (0,2,6-months or 0,6-months or 0,2-months) 
with 81% power calculated for three strains (96217 (NadA), M14459 (fHbp), and 
M13520 (NHBA)). NZ98/254 (PorA) is not powered for as the 4-fold rate for 
MenABCWY is predicted to be at least 10% less than the 4-fold rate for MenB. 
Non-inferiority will be demonstrated if the LL of the 2-sided 97.5% CI for the group 
difference in percentage of subjects achieving a 4-fold rise in hSBA titres against all N. 
meningitidis serogroup B indicator strains is above -10%. Table 23 presents the power to 
meet the objective.  
Table 23 
Power of Non inferiority of MenABCWY vs rMenB+OMV NZ 
Strain 
4-fold rise (MenABCWY) 
4-fold rise (rMenB+OMV NZ) 
Power 
96217 (NadA) 
80% 
80% 
98.5% 
M14459 (fHbp) 
60% 
60% 
91.2% 
M13520 (NHBA) 
45% 
45% 
90.3% 
NZ98/254 (PorA) 
53% 
76%  
0% 
10.2. 
Populations for analyses 
For purposes of analysis, the following analysis sets are defined: 
Analysis Set 
Description 
Enrolled Set 
Subject/ Subject for whom parent(s)/LAR’s agreed to participate in a clinical study after 
completion of the informed consent process, who meet screening/eligibility criteria and 
randomized and/or received study intervention or undergone an invasive procedure. 
Refer to Glossary of terms for definition of an enrolled subject. 
Exposed Set 
All subjects who received at least 1 dose of the study treatment. The allocation in a group is 
done in function of all administered treatments. 
Full Analysis Set 
All subjects who received at least 1 dose of the study treatment and have post-vaccination 
effectiveness or immunogenicity data  
Per Protocol Set 
All subjects who received at least 1 dose of the study treatment to which they are randomised 
and have post-vaccination data (Full Analysis Set) minus subjects with protocol deviations 
that lead to exclusion from the Per Protocol Set. 
Solicited Safety 
Set 
All subjects who received at least 1 dose of the study treatment (Exposed Set) who have 
solicited safety data 
Unsolicited 
Safety Set 
All subjects who received at least 1 dose of the study treatment (Exposed Set) that report 
unsolicited AEs/report not having unsolicited AEs 
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For analyses of the safety endpoints, subjects will be analysed “as treated” according to 
the actual vaccination a subject received. The list of protocol deviations that would result 
in exclusion from the PPS is available in Section 4.2.2.1 of the Statistical Analysis Plan. 
Subgroups: 
• 
Analyses of the primary objectives will be repeated by age group (10-17 years of age 
and 18-25 years of age), race, sex and US region, and subjects with and without a 
previous MenACWY vaccination (primed and unprimed) as relevant. 
• 
Additional subgroup analyses may be performed to assess the impact of any COVID-
19 pandemic. More details will be provided in the Statistical Analysis Plan if 
applicable. 
10.3. 
Statistical analyses 
10.3.1. 
Subjects disposition 
Number of subjects enrolled, vaccinated subjects (at least 1 vaccination, full vaccination 
course) 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 vaccine group. 
Distributions of subjects by sex, race, ethnic origin will be summarised overall and by 
vaccine group. 
10.3.3. 
Primary effectiveness and immunogenicity analyses 
Refer to Glossary of terms for definitions of test-based and responder-based vaccine 
effectiveness. 
10.3.3.1. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
Analysis set: Per-protocol set (PPS) will be the primary analysis population  
Statistical method: The VE is defined as 1- RR= (1- percentage of samples without 
bactericidal serum activity at 1:4 dilution in MenB group / percentage of samples without 
bactericidal serum activity at 1:4 dilution in the Control group) x100% and it will be 
analyzed using a generalised linear model with vaccine group, strain and centre as 
independent variables. Furthermore, a repeated statement will be used to estimate the 
variance of the RR including correlation within subject’s responses. A centre effect will 
be tentatively included in the analysis; if the statistical model does not converge due to 
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the factor “centre”, a model without centre effect will be fitted instead. The response 
variable of the model will be the Bernoulli distributed outcome without bactericidal 
activity at a 1:4 dilution (i.e. response is 1 if titre < 4, and 0 if titre ≥ 4), at 1 month after 
the last vaccination (Month 7) in the MenB group and at Month 1 for the ACWY group. 
Each subject will contribute with approximately 35 measures to this analysis, each of the 
measures corresponding to the response variable to one of the 35 strains randomly 
assigned to be tested with the samples available for that specific subject. For the 
statistical analysis it is assumed that the response to each strain is an independent 
measure with a unique true underlying rate and VEs are expected to vary among the 
strains. In order to obtain the VE measure which is a measure based on the relative risk 
(RR), a generalised linear model will be used with the Binary distribution and link 
function log in order to compute the log RR and the corresponding 97.5% CI. If this 
model would not converge, the Poisson distribution will be used instead. The obtained 
values will be exponentiated to obtain the RR and the corresponding 97.5% CI. The VE 
will be computed as 100% x (1 – RR). Effectiveness of rMenB+OMV NZ will be 
demonstrated if the lower limit of the two-sided 97.5% CI for VE against the selected 
strain panel between MenB and the ACWY group is above 65%. 
10.3.3.2. Effectiveness (Responder-based): rMenB+OMV NZ - 3 doses (0,2,6-
months schedule) 
Analysis set: FAS will be the primary analysis population. 
Statistical method: The percentage of responders (see definition in Section 10.1.1.2) and 
the corresponding exact two-sided 97.5% CI based on Clopper-Pearson method will be 
calculated [Clopper, 1934].  
The objective is to demonstrate that the lower limit of the 97.5% CI for the percentage of 
responders is higher than 65%. 
10.3.3.3. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,6-
months schedule) 
See Section 10.3.3.1 
10.3.3.4. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,6-months 
schedule) 
See Section 10.3.3.2 
10.3.3.5. Vaccine effectiveness (Test-based): rMenB+OMV NZ - 2 doses (0,2-
months schedule) 
See Section 10.3.3.1 
10.3.3.6. Effectiveness (Responder-based): rMenB+OMV NZ - 2 doses (0,2-months 
schedule) 
See Section 10.3.3.2 
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10.3.3.7. Lot-to-lot consistency: MenABCWY - ACWY component 
Analysis set: The analysis of lot-to-lot consistency will be based on the PPS. 
Statistical method: For each of the three ABCWY lots (Lots 1, 2 and 3 of the MenACWY 
component of the ABCWY vaccine), GMTs and 97.5% CIs will be calculated by 
exponentiating (base 10) the least squares means and the lower and upper limits of the 
97.5% CIs of the log transformed titres (base10) obtained from a two-way Analysis of 
Variance (ANOVA) with factors for vaccine lot and study centre. Additionally, lot-to-lot 
GMT ratios will be computed for each pair of ABCWY lots. Ninety-seven point five 
percent (97.5%) CIs for the ratios of GMTs will be constructed by exponentiating the 
difference of the least square means of the log transformed titres and the lower and upper 
limits of the 97.5% CIs on the difference obtained from the ANOVA model above. 
Lot-to-lot consistency criterion: The three ABCWY lots will be considered equivalent if 
for each of the 4 serogroups A, C, W and Y and each pair of vaccine lots, the two-sided 
97.5% CI on the ratio of GMTs at 1 month after the last vaccination will be contained 
within the interval [0.5, 2.0] 
10.3.3.8. Immunological non-inferiority: MenABCWY vs. MenACWY in subjects 
without a previous MenACWY vaccination (unprimed) 
Analysis set: PPS will be the primary analysis population. 
Statistical method: The percentage of subjects with 4-fold rise in hSBA titres against 
MenACWY indicator strains A, C, W and Y and the corresponding exact two-sided 
97.5% CIs based on Clopper-Pearson method will be calculated for the ABCWY (pooled 
lots) group and the ACWY group [Clopper, 1934]. The 97.5% CIs for the difference in 
percentages between ABCWY (pooled lots) and ACWY group will be constructed using 
the method of Miettinen and Nurminen [Miettinen, 1985].  
Non-Inferiority criterion: Non-inferiority of MenABCWY vaccine for the proportion of 
subjects with 4-fold rise will be demonstrated if the lower limit of the two-sided 97.5% 
CI for the difference in percentage of subjects with 4-fold rise between the 2 groups 
(ABCWY (pooled) lots –ACWY) is above -10%. 
10.3.3.9. Vaccine effectiveness (Test-based): MenABCWY 
See Section 10.3.3.1 
10.3.3.10. Effectiveness non-inferiority: MenABCWY vs. rMenB+OMV NZ 
Analysis set: PPS will be the primary analysis population. 
Statistical method: The percentage of samples with bactericidal activity measured by enc-
hSBA at 1:4 dilution and the corresponding exact two-sided 97.5% CIs based on 
Clopper-Pearson method will be calculated for the ABCWY (pooled lots) group and the 
Men B group. The 97.5% CIs for the difference in percentages between ABCWY (pooled 
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lots) and MenB group will be constructed using the method of Miettinen and Nurminen 
[Miettinen, 1985]. 
Non-Inferiority criterion: Non-inferiority of MenABCWY vaccine for the percentage of 
samples with bactericidal activity measured by enc-hSBA at 1:4 dilution will be 
demonstrated if the lower limit of the two-sided 97.5% CI for the difference between the 
2 groups (ABCWY (pooled) lots – MenB) is above -5%. 
10.3.3.11. Effectiveness (Responder-based): MenABCWY 
See Section 10.3.3.2 
10.3.4. 
Secondary effectiveness and immunogenicity analyses 
10.3.4.1. Immunological non-inferiority: MenABCWY vs. rMenB+OMV NZ 
(Amended 9 May 2021) 
Analysis set: PPS will be the primary analysis population. 
Statistical method: The percentages of subjects with 4-fold rise in hSBA titres against N. 
meningitidis serogroup B indicator strains (M14459, 96217, M13520 and NZ98/254 for 
fHbp, NadA, NHBA and PorA P1.4 antigens, respectively) at 1 month after the last 
vaccination for the ABCWY group (pooled lots) (Day 211, Month 7) and 1 month after 
the 3-dose vaccination series (Day 211, Month 7) in MenB_0_2_6 group or 2-dose 
vaccination series (Day 211, Month 7) in MenB_0_6 group or 2-dose vaccination series 
(Day 91, Month 3) in MenB_0_2_6 group and the corresponding exact 2-sided 95% CIs 
based on Clopper-Pearson method will be calculated [Clopper, 1934]. The 95% CIs for 
the difference in percentages between ABCWY group (pooled lots) and MenB_0_2_6 
group and MenB_0_6 group will be constructed using the method of Miettinen and 
Nurminen [Miettinen, 1985].  
Non-inferiority criterion: Non-inferiority of MenABCWY vaccine for the proportion of 
subjects with 4-fold rise will be demonstrated if the lower limit of the 2-sided 95% CI for 
the difference in percentage of subjects with 4-fold rise between the 2 groups (ABCWY 
group (pooled lots) –selected MenB group) is above -10%. 
10.3.4.2. Effectiveness by each of the endemic US N. meningitidis serogroup B 
strains 
Analysis set: FAS effectiveness will be the primary analysis population. A subset (VE 
subset) of approximately 684 evaluable subjects per group, ABCWY (pooled lots) and of 
the MenB_0_2_6 or MenB_0_6 group would be used for the purpose of this analysis.  
Statistical method: The VE per strain will be calculated as described in Section 10.3.3.1, 
using a generalised linear model with vaccine group, and centre as independent variables. 
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10.3.4.3. Distribution of percentages of serogroup B invasive disease strains 
killed 
Analysis set: FAS effectiveness will be the primary analysis population. A subset (VE 
subset) of approximately 684 evaluable subjects per group, ABCWY (pooled lots) and of 
the MenB_0_2_6 or MenB_0_6 group would be used for the purpose of this analysis. 
Statistical method: The distribution will be presented of subjects by percentages of 
serogroup B invasive disease strains killed using enc-hSBA at 1 month after the 3-dose 
(0,2,6-months in MenB_0_2_6 group) and 2-dose (0,6-months in MenB_0_6 group, 0,2-
months in MenB_0_2_6 group and 0,6-months in the ABCWY (pooled) group) 
vaccination series of rMenB+OMV NZ and MenABCWY vaccines. 
Summary statistics and 95% CI for the mean percentage will be presented, as well as a 
Figure of the cumulative distribution function. 
10.3.4.4. Immune response of MenABCWY, rMenB+OMV NZ and MenACWY 
(Amended 9 May 2021) 
Analysis set: The analysis will be based on the FAS. 
Statistical method: The hSBA titres at each time point for all groups (ABCWY group 
(pooled lots), MenB_0_2_6 and MenB_0_6 groups) will be logarithmically transformed 
(base10) to fulfil the normal distribution assumption. For each N. meningitidis serogroup 
A, C, W and Y and each B indicator strain (M14459, 96217, M13520 and NZ98/254 for 
fHbp, NadA, NHBA and PorA P1.4 antigens, respectively), the GMTs and GMRs (post-
vaccination/baseline) will be calculated with their associated 2-sided 95% CIs, by 
exponentiating the corresponding log-transformed means and their 95% CIs. The ratio of 
GMTs and GMRs between two groups and the corresponding CI will be constructed by 
exponentiating the mean difference and the confidence limits in log10 (titre), using 
ANOVA with study centre included as an independent variable.  
The total IgG as measured by ELISA GMCs against serogroups A, C, W and Y at 
baseline (Day 1, Month 0) and 
• 
at 1 month after the first (Day 31, Month 1) and the last vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots), and 
• 
at 1 month after the MenACWY vaccination in the ACWY group (Day 31, Month 
1), 
will be analyzed in a comparable way as described above for hSBA titres. 
For each N. meningitidis A, C, W and Y and each serogroup B indicator strain (M14459, 
M13520, 96217and NZ98/254) the percentages of subjects with hSBA titres ≥ LLOQ and 
of subjects with 4-fold rise and the corresponding exact 2-sided 95% CIs based on 
Clopper-Pearson method will be calculated for each study group at each timepoint not 
previously analyzed.  
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10.3.5. 
Safety analyses 
Distribution of subjects by vaccinations will be summarised by vaccine group for the 
Enrolled Set. In case of vaccination error, subjects will be analyzed “as treated” 
(according to the vaccine the subject actually received). 
Analysis sets: Solicited Safety Set (solicited local and systemic adverse events and other 
solicited adverse events), Unsolicited Safety Set (unsolicited adverse events), and Overall 
Safety Set. 
Endpoint 
Statistical Analysis Methods 
Primary 
Endpoints description: 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], nausea, fatigue, myalgia, arthralgia, headache) adverse events during the 7 days 
(including the day of vaccination) following each vaccination at Day 1, Day 61 and Day 181. 
All solicited adverse events will be summarised according to defined severity grading scales, see 
protocol section 12.5.9.3 
Frequencies and percentages of subjects experiencing each adverse event will be presented for 
each symptom severity. Summary tables showing the occurrence of any local or systemic 
adverse event overall and at each time point will also be presented. 
Post-vaccination solicited adverse events reported from Day 1 to Day 7 will be summarised for 
the intervals Day 1-3, Day 4-7, and Day 1-7 by maximal severity and by vaccine group, excluding 
the 30-minute measurement, which will be summarised separately. The severity of solicited local 
adverse events, including redness (erythema) at injection site, swelling of skin at injection site, 
and hardness of skin at injection site will be summarised according to categories based on linear 
measurement: None (1 to 24mm); Mild (25 to 50mm); Moderate (51 to 100mm); Severe 
(>100mm). 
Injection site tenderness and systemic reactions (except fever) occurring up to 7 days after each 
vaccination at Day 1, Day 61 and Day 181 will be summarised according to “mild”, “moderate” or 
“severe”. 
Each solicited local and systemic adverse event will also be further summarised as “none” 
versus “any” (for fever the latter will be ≥38.0 °C). 
Use of antipyretics and analgesics will be summarised by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. 
Body temperature will be summarised by 0.5 °C increments from 36.0 °C up to ≥40 °C and will 
be broken down according by route of measurement, if applicable. Frequencies and percentages 
of subjects with temperatures ≥ 38.0 °C and temperatures ≥ 40.0 °C will also be presented. 
 
Endpoints description: The frequencies and percentages of subjects with any unsolicited AEs 
(including all SAEs), AEs leading to withdrawal and medically attended AEs during the 7 and the 
30 days (including the day of vaccination) following each vaccination at Day 1, Day 61 and Day 
181. 
The frequencies and percentages of subjects with SAEs, AEs leading to withdrawal, AESIs and 
medically attended AEs throughout the study period. 
This analysis applies to all adverse events occurring during the study, judged either as possibly 
related, or not related to vaccination by the investigator, recorded in AE CRF, with a start date on 
or after the date of first vaccination. AE starting prior to the first vaccination will only be listed. 
The original verbatim terms used by investigators to identify adverse events in the CRFs will be 
mapped to preferred terms using the MedDRA dictionary. The adverse events will then be 
grouped by MedDRA preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as possibly 
related to study vaccine, will be summarised according to system organ class and preferred term 
within system organ class. These summaries will be presented by vaccine group and by interval 
of study observation. When an adverse event occurs more than once for a subject, the maximal 
severity and strongest relationship to the vaccine group will be counted. 
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Endpoint 
Statistical Analysis Methods 
Separate summaries will be produced for the following categories: 
• 
Serious adverse events. 
• 
Adverse events that are possibly related to vaccine. 
• 
Adverse events of special interest. 
• 
Adverse event leading to withdrawal. 
• 
Adverse events leading to a medically attended visit. 
Data listings of all adverse events will be provided by subject. In addition, adverse events in the 
categories above will be provided as listed data. 
Local and systemic AEs will be analyzed by point estimates with associated 95% CIs [Clopper, 
1934]. 
10.3.6. 
Other analyses 
Not applicable 
10.3.7. 
Interim analyses  
No interim analysis is planned for this study. 
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 
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 2011. MMWR 2011;60(30):1018-1019. 
Center for Disease Control (CDC). Enhanced meningococcal disease surveillance report, 
2018. CDC; 2018 [cited 20-DEC-2019]. Available from 
https://www.cdc.gov/meningococcal/downloads/NCIRD-EMS-Report-2018.pdf 
Clopper C J, Pearson ES. The use of confidential or fiducial limits illustrated in the case 
of the binomial. Biometrika 1934;26:401-403. 
Cohn A and MacNeil J. The Changing Epidemiology of Meningococcal Disease. Infect 
Dis Clin North Am. 2015;29(4):667-77.  
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) Invasive meningococcal 
disease – Annual epidemiological report (2016). 
https://ecdc.europa.eu/sites/portal/files/documents/AER_for_2016-invasive-
meningococcal-disease_1.pdf Accessed on 16 April 2019. 
Gossger N, Snape MD, Yu L-M et al. Immunogenicity and tolerability of recombinant 
serogroup B meningococcal vaccine administered with or without routine infant 
vaccinations according to different immunization schedules. JAMA: The Journal of the 
American Medical Association 2012;307(6):573–82. 
Halperin SA, Bettinger JA, Greenwood B, Harrison LH, Jelfs J, Ladhani SN, et al. The 
changing and dynamic epidemiology of meningococcal disease. Vaccine. 2012; 30 Suppl 
2:B26-B36.  
Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. 
Vaccine. 2009;27 Suppl 2: B51-B63. 
Heckenberg S, Brouwer M, van de Beek D. Bacterial Meningitis. Handbook of Clinical 
Neurology (121) Chapter 93. 2014. 
ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 (R1). 1997 
Federal Register, 62 (90):25691-25709 
IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. 2011. 
Washington, DC: The National Academies Press. 
Levine RJ. Ethics and Regulations of Clinical Research. 1998. New Haven: Yale 
University Press. 
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Miettinen O., Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4(2):213-26. 
Tingle AJ, Allen M, Petty RE Rubella-associated arthritis. I. Comparative study of joint 
manifestations associated with natural rubella infection and RA 27/3 rubella 
immunisation. Ann Rheum Dis. 1986;45(2):110-4. 
Welsch A et al. Breadth of coverage against a panel of 110 invasive disease isolates, 
immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine 
in US adolescents – Results from a randomized, controlled, observer-blind phase II study. 
Vaccine 2018;36(35):5309-5317. 
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 
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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations, glossary of terms and 
trademarks 
12.1.1. 
List of abbreviations 
(Amended 9 May 2021) 
2019-nCoV: 
2019 novel coronavirus disease 
ABCs: 
Active Bacterial Core Surveillance 
ACIP: 
Advisory Committee on Immunization Practices 
ADE: 
Adverse Device Effect 
AE: 
Adverse Event 
CBER: 
Center for Biologics Evaluation and Research, United 
States 
CDC: 
Centers for Disease Control and Prevention 
CHMP: 
Committee for Medicinal Products for Human Use 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
COVID-19 
Coronavirus disease 2019 
CRM: 
Cross-Reacting Material 
CRO: 
Contract Research Organisation 
CT: 
Computed tomography 
DMC: 
Data Monitoring Committee 
EC: 
Ethics Committee 
ECDC: 
European Center for Disease Prevention and Control 
eCRF: 
electronic Case Report Form 
EDC: 
Electronic Data Capture 
EMA: 
European Medicines Agency 
EMLA: 
Eutectic Mixture of Local Anesthetics 
Enc-hSBA: 
Endogenous complement human Serum Bactericidal 
Assay 
EoS: 
End of Study 
FAS: 
Full Analysis Set 
FDA: 
Food and Drug Administration, United States of America 
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fHbp: 
factor H binding protein 
GCP: 
Good Clinical Practice 
GSK: 
GlaxoSmithKline 
HIPAA: 
The Health Insurance Portability and Accountability Act 
hSBA: 
Human Serum Bactericidal Assay 
IAF: 
Informed Assent Form 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council on Harmonisation 
IEC: 
Independent Ethics Committee 
IM: 
Intramuscular 
IMD: 
Invasive meningococcal disease 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
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 groups A, C, W-135 and Y Conjugate 
Vaccine 
mL: 
Milliliter 
MLST: 
MultiLocus Sequence Typing 
NadA: 
Neisseria adhesin A  
NHBA: 
Neisserial Heparin Binding Antigen 
NZ: 
New Zealand 
OMV: 
Outer Membrane Vesicles 
PCD: 
Primary Completion Date 
PO: 
Per Os 
PorA: 
Porin A 
PP: 
Per protocol 
PPS: 
Per Protocol Set 
RR: 
Relative Risk 
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SADE: 
Serious Adverse Device Effect 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan 
SARI: 
Severe Acute Respiratory Illness 
SBA: 
Serum Bactericidal Activity 
SBIR: 
Source data Base for Internet Randomization  
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SoA: 
Schedule of Activities 
SOP: 
Standard Operating Procedure 
SPM: 
Study Procedures Manual 
SUSAR: 
Suspected Unexpected Serious Adverse Reactions 
T: 
Telephone call 
USADE 
Unanticipated Serious Adverse Device Effect 
VE: 
Vaccine Effectiveness 
VSAE: 
Vaccines Serious Adverse Event 
WHO: 
World Health Organization 
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12.1.2. 
Glossary of terms 
(Amended 9 May 2021) 
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 
characterise 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, organisation, 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 
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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. 
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) 
For studies with collection of human biological samples 
and/or imaging data, the EoS is defined as Last subject last 
visit (T7). or Last testing results released of samples 
collected at Visit 6*. 
* In this case EoS must be achieved no later than 8 months 
after LSLV.  
Enrolled 
‘Enrolled’ means a subject’s/parent’s/LAR’s agreement to 
participate in a clinical study following completion of the 
informed consent process. Potential subjects who are 
screened for the purpose of determining eligibility for the 
study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.  
Refer to Section 10.2 for the definition of “Enrolled set” 
applicable to the study. 
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. 
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Investigational 
vaccine/product: 
(Synonym of 
Investigational 
Medicinal Product) 
A pharmaceutical form of an active ingredient being tested in 
a clinical trial, including a product with a marketing 
authorisation 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.  
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 authorised 
representative are used 
in some settings.) 
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective subject, 
to the subject's participation in the clinical trial. 
Medically attended 
adverse events: 
Symptoms or illnesses requiring hospitalisation, or 
emergency room visit, or visit to/by a health care provider.  
Medical device 
deficiency: 
A device deficiency is an inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, 
safety, or performance. Device deficiencies include 
malfunctions, use errors and information supplied by the 
manufacturer. 
Pharmacogenomics 
The International Council on Harmonisation (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 
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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 International Council on Harmonisation (ICH) defines a 
protocol amendment as: ‘A written description of a change(s) 
to or formal clarification of a protocol.’ GSK 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.  
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 
jeopardises the subject’s health, safety, or rights. 
Qualified healthcare 
professional: 
Any licensed or certified healthcare professional who is 
permitted by institutional policy to perform protocol required 
procedures, and who is identified within the Delegation of 
Responsibilities Log.  
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
Remote visit: 
Refers to the visit conducted in the place other than the 
study site. 
Responder-based 
vaccine effectiveness: 
The enc-hSBA methodology involves testing the serum 
samples from each individual subject against a subset of 
around 35 strains randomly chosen from the overall panel of 
110 meningococcus B US strains. Responder-based vaccine 
effectiveness is assessed based on the percentage of subjects 
considered responders, i.e., subjects whose serum kills the 
majority (≥70% in this study) of the tested strains following 
vaccination. 
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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 
authorised 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)/product(s) or as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Test-based vaccine 
effectiveness: 
The enc-hSBA methodology involves testing the serum 
samples from each individual subject against a subset of 
around 35 strains randomly chosen from the overall panel of 
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110 meningococcus B US strains. Test-based vaccine 
effectiveness is assessed based on the overall percent of 
individual positive tests following vaccination and represents 
the reduction in risk compared to the placebo. 
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. 
Unblinded site staff: 
Study personnel aware of the subject treatment allocation, 
delegated for administering study vaccines to subjects but 
not involved in the safety or immunogenicity evaluation of 
the subjects. 
All study vaccines will be administered only by unblinded 
personnel who are qualified to perform that function under 
applicable laws and regulations for the specific study site. 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse event. 
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12.1.3. 
Trademarks 
Trademark Information 
Trademarks of the GSK group of 
companies 
 
Generic description 
Bexsero 
 
Meningococcal group B vaccine (rMenB 
proteins + OMV NZ 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 tests 
The tests detailed in Table 12 will be performed at GSK or at a laboratory designated by 
GSK where the assays are available and qualified for the intended use.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 6 of the protocol. 
A urine pregnancy test will be conducted as needed for women of childbearing potential 
(refer to Section 8.3.5). 
The investigator is not allowed to do extra testing on samples outside of what has been 
agreed upon by the ethic committees. 
12.2.1. 
Effectiveness Assessment: Endogenous complement serum 
bactericidal assay – rMenB + OMV NZ 
The measures of vaccine effectiveness against 110 invasive disease serogroup B strains 
will be based on the qualified endogenous complement serum bactericidal assay (enc-
hSBA). 
The qualified enc-hSBA assay provides a qualitative assessment (yes/no) of the presence 
of sufficient bactericidal antibodies in human sera to kill a meningococcal strain. In this 
study, test sera will be diluted 1:4 prior to testing. Serum samples will be collected using 
an appropriate process to preserve endogenous complement activity and to allow 
measurement of the bactericidal activity due to the antibodies present in the serum. This 
is in contrast to a traditional human serum bactericidal assay (hSBA) which heat 
inactivates the intrinsic complement proteins and uses an external source of human donor 
complement for each serum sample.  
The enc-hSBA will be performed for each subject against a target number of 35 strains. A 
minimum amount of 5 mL of serum needs to be available to perform enc-hSBA testing. 
In case the volume of serum shipped to the laboratory for enc-hSBA testing is <5 mL, 
enc-hSBA testing will be still performed if the volume of serum allows to test a minimum 
number of 20 strains. Refer to Section 10.1.2.1 for details. 
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A given serogroup B meningococcal strain will be considered ‘killed’ for each sample 
positive for the enc-hSBA testing. Post-dose 1 sera from the ACWY group receiving the 
MenACWY vaccine will also be tested against serogroup B meningococcal strains by 
enc-hSBA (as a control).  
12.2.2. 
MenB serum bactericidal assays using exogenous human 
complement (hSBA) – rMenB + OMV NZ  
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 M13520. Each of 
these strains measures bactericidal activity primarily directed against one of the major 
bacterial 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 M13520 measures hSBA against the 287 part of the 287-953 antigen, also known 
as NHBA. 
Serum bactericidal activity against rMenB+OMV NZ may be determined by performing 
serum bactericidal assays using human complement (hSBA) against an additional panel 
of Neisseria strains for exploratory objective if necessary. 
12.2.3. 
MenACWY serum bactericidal assays using human complement 
(hSBA): 
Serum bactericidal activity against MenACWY will be determined by using a validated 
agar-overlay hSBA. 
This hSBA is 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 titre 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 (detection of colony forming units, CFU). 
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12.2.4. 
MenACWY IgG ELISA 
The anti-MenACWY total IgG antibody (Ab) concentrations will be measured by using 
an Enzyme-Linked Immunosorbent Assay (ELISA), or equivalent, to evaluate the 
immunogenicity of the capsular polysaccharides of serogroups A, C, W and Y in 
MenACWY vaccine. 
The assay characteristics (e.g. validated assay cut-offs and units) for each of the 
serogroup will be determined at the time of the generation of validation data. 
Any change, including the change of the format of the assay, will be documented in a 
protocol amendment or in the clinical study report. 
12.3. 
Appendix 3: Clinical laboratories 
(Amended 9 May 2021) 
Table 24 
GSK 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 
* GSK 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 
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 Organisations 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), Investigator Brochure, 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.  
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− 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. 
− 
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. 
12.4.2. 
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 interest prior 
initiation of the centre and 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.  
12.4.3. 
Informed consent process 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 
"Assent" is a term used to express willingness to participate in research by persons who 
are by definition too young to give informed consent but who are old enough to 
understand the proposed research in general, its expected risks and possible benefits, and 
the activities expected of them as subjects. Assent by itself is not sufficient, however. If 
assent is given, informed consent must still be obtained from the subject's parent(s) or 
legal guardian(s). Local laws define who constitutes a "child," and such definitions 
dictate whether or not a person can legally consent to participate in a protocol [Levine, 
1988]. 
The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorised representative and answer all questions regarding the 
study. 
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Subjects/subjects’ parent(s)/LAR(s) must be informed that their participation is 
voluntary. 
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 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 centre. 
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 authorised 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 summarises 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. 
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 
Subject 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’s 
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 subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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GSK will also ensure the protection of personal data of investigator and the site staff 
which will be collected within the frame and for the purpose of the study.  
12.4.5. 
Committees structure 
12.4.5.1. Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 [ICH, 1997]. A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. 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. 
The investigator 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 all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
• 
Ensuring that appropriately trained healthcare professionals who can perform all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any AE related to the study. 
• 
If permission to do so is given by the subject and/or parent(s)/legal guardian(s), 
ensuring that the subject’s primary healthcare provider is informed of the subject’s 
participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/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 
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approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
i. 
to the IRB/IEC for review and approval/favourable opinion,  
ii. to the Sponsor for agreement and, if required, 
iii. to the regulatory authority(ies). 
12.4.6. 
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. 
12.4.7. 
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. 
12.4.8. 
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 statistical analysis plan 
will also be posted on ClinicalTrials.gov.  
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In addition, for studies that are in scope of the EU Clinical Trial Directive, summaries of 
the results of GSK interventional studies (phase I-IV) in paediatric/adult population will 
be posted within defined timelines on the publicly available 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.  
 
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, anonymised 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 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. 
12.4.9. 
Data quality assurance 
(Amended 9 May 2021) 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents (see Glossary of terms for the exact definition of 
essential and 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, CRF), the copy should fulfil the 
requirements for certified copies (see Glossary of terms for the exact definition of 
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 
electronically signing the eCRF. 
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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 see Glossary of 
terms for the exact definition of source documents) 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 (see Glossary of terms for the exact definition of 
source data). 
Study monitors will follow the Monitoring Plan to perform ongoing source data 
verification to confirm that data entered into the eCRF by authorised site personnel are 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not 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 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 summarised 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 
Clinical Study Report (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. 
12.4.10. 
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 
glossary of terms. 
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12.4.11. 
Study and site closure 
GSK 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, 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 
− Inadequate recruitment of subjects by the investigator 
− Discontinuation of further study treatment development 
Please refer to Section 8.8 for details. 
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. Examples of 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 vaccine(s)/product(s) 
administration even though they may have been present prior to the start of the study. 
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• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccine(s)/product(s) or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with study vaccine(s)/product(s) 
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). 
• 
Signs, symptoms that require medical attention (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. 
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. Examples of 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 
A SAE is any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation 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 
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that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred, or was necessary, 
the AE should be considered serious. 
Hospitalisation 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. 
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 hospitalisation but may jeopardise 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 hospitalisation. 
12.5.3. 
Solicited adverse events 
a. Solicited local (injection-site) AEs 
The following local (injection-site) AEs will be solicited: 
Table 25 
Solicited local adverse events 
All age groups 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
Induration at injection site 
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a. Solicited systemic AEs 
The following systemic AEs will be solicited: 
Table 26 
Solicited systemic adverse events 
Adult/Child (10 years) 
Fatigue 
Fever 
Nausea 
Headache 
Arthralgia 
Myalgia 
Note: subjects/subjects’ parent(s)/LAR(s) will be instructed to measure and record the 
oral body temperature in the evening, ideally at the same time each day. Should 
additional temperature measurements be performed at other times of day, 
subjects/subjects’ parent(s)/LAR(s) will be instructed to record the highest temperature in 
the eDiary.  
Note: If the body temperature is measured by any other route (other than oral), this also 
needs to be recorded in the subject’s eCRF. 
12.5.4. 
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 eDiary and subsequently recorded onto 
the eCRFs and subject medical records. 
The study staff must review the data entered into the Subject eDiary as described in 
Section 12.5.9. 
12.5.5. 
Unsolicited adverse events 
An unsolicited AE is an AE that was not solicited using an eDiary and that was 
spontaneously communicated by a subjects/parent(s)/LAR(s) who has signed the 
informed consent. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care provider). 
The subjects/ subject’s parent(s)/LAR(s) will be instructed to contact the site as soon as 
possible to report medically attended event(s), as well as any events that, though not 
medically attended, are of subject/ parental /LAR’s concern. Detailed information about 
reported unsolicited AEs will be collected by qualified site personnel and documented in 
the subject’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by 
subject/subject’s parent(s)/LAR(s) will be collected during interview with the 
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subjects/subject’s parent(s)/LAR(s) and by review of available medical records at the 
next visit. 
12.5.6. 
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 
characterise and understand it. 
12.5.6.1. 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 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 
characterise this AESI. 
12.5.6.2. 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 27. 
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 27 
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. 
12.5.7. 
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. 
12.5.8. 
Events or outcomes not qualifying as adverse events or serious 
adverse events 
12.5.8.1. Pregnancy 
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccine(s)/product(s) 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 12.5.10.1 and 12.5.10.4: 
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• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
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 recognised 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 vaccine(s)/product(s) will be 
reported to GSK as described in Section 12.5.10. While the investigator is not obligated 
to actively seek this information from former subjects, he/she may learn of a pregnancy 
through spontaneous reporting. 
12.5.9. 
Detecting and recording adverse events, serious adverse events 
and pregnancies 
An Electronic Diary (eDiary) hereafter referred to as Subject eDiary will be used in this 
study to capture solicited local and systemic AEs. The subject or subject’s parent/LAR 
should be trained on how and when to complete each field of the Subject eDiary. 
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 
or concerning.  
Subject eDiary training should be directed at the individual(s) who will perform the 
measurements of AEs and who will enter the information into the Subject eDiary. 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 eDiary, this 
person’s identity must be documented in the subject’s source document. Any individual 
that makes entries into the Subject eDiary must receive training on completion of the 
Subject eDiary at the time of the visit when Subject eDiary is dispensed. This training 
must be documented in the subject’s source document. 
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Note: Subject eDiary can be filled in by a minor subject under the supervision of the 
subject’s parent(s)/LAR(s) provided that the minor has the competency to assess and 
report the information to be provided in the diary card. The ultimate accountability for 
the completion of the Subject eDiary remains with the subject’s parent(s)/LAR(s). The 
investigator should discuss this accountability with the subject’s parent(s)/LAR(s). 
Each subject/subject’s parent(s)s/LAR(s) will be assigned a Subject eDiary at Visit 1 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 have to bring their completed eDiaries at 
Visit 2 and Visit 4, and return it at Visit 6. The returned Subject eDiaries should be 
verified during discussion with the subject/ subject’s parent(s)/LAR(s) at these visits. 
Note: If the Subject eDiary has been filled in by a minor subject, the investigator or 
delegate should verify the reported information during a discussion with the minor 
subject preferably in the presence of his/her parent(s)/LAR(s). 
Any unreturned Subject eDiary will be sought from the subject/subject’s 
parent(s)/LAR(s) through telephone call(s) or any other convenient procedure.  
Refer to the SPM for more information regarding the use of eDiary. 
Note: Any solicited AE that meets any of the following criteria must be entered into 
subjects’ source document (see Section 12.5.9) and also as an AE on the Adverse Event 
eCRF: 
• 
Solicited local or systemic AE that continues beyond day 7 after vaccination not 
captured in the eDiary. 
• 
Solicited local or systemic AE that leads to a visit to a healthcare provider (medically 
attended AE, see Section 12.5.9.3.3). 
• 
Solicited local or systemic AE leading to the subject withdrawing from the study or 
the subject being withdrawn from the study by the investigator (AE leading to 
withdrawal). 
• 
Solicited local or systemic AE that otherwise meets the definition of an SAE (see 
Section 12.5.2) or an AESI (See Section 12.5.6). 
Any new safety information reported during the safety follow-up phone call or site visits 
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 AE and therefore entered into the eCRF. 
The investigator or delegate will transcribe the required information into the eCRF in 
English.  
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12.5.9.1. 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 qualified healthcare professional at the site, and 
the safety data described must be written down in the subject’s medical chart. 
Refer to SPM for details on Subject eDiary alerts. 
12.5.9.2. Time period for detecting and recording adverse events, serious adverse 
events and pregnancies 
All solicited AEs during 7 days following administration of each dose of study 
vaccine(s)/product(s) (Day 1 to Day 7) (at Visit 1, Visit 3 and Visit 5) must be recorded 
in the eDiary, irrespective of intensity. Solicited local and systemic events that are 
ongoing after the 7-day reporting period may continue to be recorded in the eDiary until 
resolution or up to 30 days post-vaccination (ie, recording period for unsolicited AEs) 
whichever occurs first and do not need to be entered as an AE in the AE eCRF or the 
subject’s source document. 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). 
All other AEs during 30 days following administration of each dose of study 
vaccine(s)/product(s) (Day 1 to Day 30) (at Visit 1, Visit 3 and Visit 5) must be recorded 
in the appropriate section of the eCRF, irrespective of intensity or whether or not they are 
considered vaccination-related. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine(s)/product(s) and will end 6 months following administration of the study 
vaccines (Day 361 (T7) for each subject. See Section 12.5.10 for instructions on reporting 
of SAEs. In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
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. 
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccines and will end 6 months following administration of study vaccines (Day 
361 (T7). See section 12.5.10 for instructions on reporting of pregnancies. 
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The time period for collecting and recording of AESIs will begin at the first receipt of 
study vaccines and will end 6 months following administration of the study vaccines 
(Day 361 (T7). See section 12.5.10.5 for instructions on reporting of AESIs. 
12.5.9.3. Evaluation of adverse events and serious adverse events 
12.5.9.3.1. 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 vaccine(s)/product(s) or since the 
previous visit?’ (for subjects equal to and above 18 years of age) 
OR 
‘Has your child acted differently or felt different in any way since receiving the 
vaccine(s)/product(s) 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 instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK. 
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. 
12.5.9.3.2. Assessment of adverse events 
Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
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Table 28 
Intensity scales for solicited symptoms in adults and children of 10 
years of age or more  
Adults/Child (10 years)  
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. 
Redness at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Induration at injection site 
Record greatest surface diameter in mm 
Temperature* 
 
Record temperature in °C/°F (with 1 decimal) 
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 
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 
Myalgia  
0 
None 
1 
Mild: Myalgia present but does not interfere with activity 
2 
Moderate: Myalgia that interferes with normal activity 
3 
Severe: Myalgia that prevents normal activity 
Arthralgia 
0 
None 
1 
Mild: Arthralgia present but does not interfere with 
activity 
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 oral 
The maximum intensity of local Injection Site Induration, Swelling, Erythema (redness) 
will be scored at GSK as follows: 
0 
: 
1 – 24 mm 
1 
: 
25 - 50 mm 
2 
: 
51 - 100 mm 
3 
: 
>100 mm 
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The maximum intensity of fever will be scored at GSK as follows: 
0 
: 
< 38.0°C (100.4℉) 
1 
: 
≥ 38.0 (100.4°F) - 38.9°C (102.1°F) 
2 
: 
≥ 39.0 (102.2°F) - 39.9°C (103.9°F) 
3 
: 
≥ 40.0°C (104.0°F)  
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. 
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 a young child, such an AE would, for example, prevent 
attendance at school/kindergarten/a day-care centre and would 
cause the parent(s)/LAR(s) to seek medical advice. 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. 
Assessment of causality 
The investigator is obligated to assess the relationship between study 
vaccine(s)/product(s) and the occurrence of each AE/SAE using clinical judgement. In 
case of concomitant administration of multiple vaccines/products, if possible, the 
investigator should specify if the AE could be causally related to a specific 
vaccine/product administered (i.e. investigational, control/placebo or co-administered 
vaccine). When causal relationship to a specific vaccine(s)/product(s) cannot be 
determined, the investigator should indicate the AE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine(s)/product(s) will be considered and investigated. The investigator will also 
consult the IB and/or SmPC and/or Prescribing Information for marketed products to 
determine his/her assessment. 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. 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. The investigator may change his/her 
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opinion of causality in light of follow-up information and update the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
All solicited local and systemic AEs will be considered causally related to vaccination. 
Causality of all other AEs should be assessed by the investigator using the following 
question:  
Is there a reasonable possibility that the AE may have been caused by the study 
vaccine/product? 
YES 
: 
There is a reasonable possibility that the study vaccine(s)/product(s) 
contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine(s)/product(s). There are other, more 
likely causes and administration of the study vaccine(s)/product(s) is 
not suspected to have contributed to the AE. 
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)/product(s) (delete as applicable), if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
− Recovered/resolved. 
− Recovering/resolving. 
− Not recovered/not resolved. 
− Recovered with sequelae/resolved with sequelae. 
− Fatal (SAEs only). 
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12.5.9.3.3. Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject/subject’s 
parent(s)/LAR(s) will be asked if he/she/the subject received medical attention defined as 
hospitalisation, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF 
and source documents.  
12.5.9.4. 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] 
12.5.9.4.1. 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) 
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• 
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. 
12.5.10. 
Reporting of serious adverse events, pregnancies, and other 
events 
12.5.10.1. Prompt reporting of serious adverse events, pregnancies, and other 
events to GSK 
SAEs that occur in the time period defined in Section 12.5.9 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator becomes aware 
that the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 12.5.9 will be reported 
promptly to GSK within the timeframes described in Table 15, once the investigator 
becomes aware of the pregnancy.  
AESIs that occur in the time period defined in Section 12.5.9 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a AESIs. 
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12.5.10.2. SAEs requiring expedited reporting to GSK 
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. 
12.5.10.3. 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 or email it 
to the Study Contact for Reporting SAEs (refer to the SPONSOR INFORMATION) or to 
GSK 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.  
12.5.10.4. Completion and transmission of pregnancy reports to GSK  
(Amended 9 May 2021) 
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. 
12.5.10.5. Reporting of AESI’s to GSK 
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 to specify that the event is an AESI and whether it is serious or non-serious. The 
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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. 
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 12.5.10.3 for back-up system in case the electronic reporting system 
does not work. 
12.5.11. 
Updating of SAE, pregnancy, and AESI information after removal 
of write access to the subject’s eCRF 
When additional SAE or pregnancy 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 or emailed to the Study Contact for Reporting SAEs 
(refer to the SPONSOR INFORMATION) or to GSK Clinical Safety and 
Pharmacovigilance department within the designated reporting time frames specified in 
Table 15.  
12.5.12. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
12.5.12.1. Post-vaccination Procedures 
Post-vaccination procedures will be performed on Day 1, Day 61, Day 181 and Day 211. 
After vaccination, the subject will be observed for at least 30 minutes including 
observation for unsolicited AEs, solicited AEs, and body temperature measurement. 
Record all safety data collected during this time in the eCRF for Day 1, Day 61 and Day 
181. 
Refer to Section 8.2 for details. 
12.5.12.2. Post-vaccination Visit(s) 
Post-vaccination visits or calls will be performed on Day 15, 75, 121, 195, 241, 301, and 
361. 
Refer to Sections 8.5.2 and 8.5.3 for details. 
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12.5.12.3. Unscheduled Visits 
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated AEs or interventions. 
12.5.12.4. Follow-up of adverse events and serious adverse events 
12.5.12.4.1. 
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 
(within 24 hours for SAEs; refer to Table 15). 
All SAEs and AESIs 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. 
12.5.12.4.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
• 
With SAEs, AESIs (serious and non-serious) or subjects withdrawn from the study 
as a result of an AE, until the event has resolved, subsided, stabilised, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up.  
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK using a paper/electronic Expedited Adverse 
Events Report and/or pregnancy report as applicable. 
GSK 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 recognised follow-up period, GSK will be 
provided with any available post-mortem findings, including histopathology. 
12.5.12.4.3. 
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 using the 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. 
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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. 
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 provided in Table 29. 
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Table 29 
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 ovulation 
• 
oral 
• 
intravaginal  
• 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
injectable  
• 
oral  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomised partner  
(A vasectomised 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 sterilisation 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. 
12.6.3. 
Collection of pregnancy information 
12.6.3.1. Female Subjects who become pregnant 
(Amended 9 May 2021) 
• 
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.  
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• 
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 Section 12.5.10. 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.  
Please see section 12.5.9 , 12.5.10 and 12.5.12.4.3 for further information on detection, 
recording, reporting and follow-up of pregnancies. 
Any female subject who becomes pregnant while participating will discontinue study 
treatment. 
12.7. 
Appendix 7: Genetics  
Not applicable 
12.8. 
Appendix 8: Definition of medical device AE, adverse device 
effect (ADE), serious adverse device effect (SADE) and 
unanticipated SADE (USADE) 
(Amended 9 May 2021) 
12.8.1. 
Definition of medical device AE and adverse device effect (ADE) 
• 
Medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether considered related to a medical device or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medical device. This definition includes events related 
to the medical device or comparator and events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of a medical device. 
This definition includes any AE resulting from: 
− insufficient or inadequate instructions for use (i.e. user error), or 
− any malfunction of a medical device, or 
− intentional misuse of the medical device. 
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12.8.2. 
Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
a. Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted 
in: 
− A life-threatening illness or injury. The term ‘life-threatening' in the 
definition of ‘serious' refers to an event in which the participant was at risk 
of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
− A permanent impairment of a body structure or a body function. 
− Inpatient or prolonged 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 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product  
Serious Adverse Device Effect (SADE) definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• Any device deficiency that might have led to an SAE if appropriate action had 
not been taken or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome 
has not been identified in the current version of the IB. 
12.8.3. 
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 
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with device deficiency/incident report form’ sent by overnight mail or courier 
service. 
• 
Contacts for reporting can be found in Section 8.5.6.1. 
GSK will review all device deficiencies, determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs/IECs as required by national regulations. 
12.9. 
Appendix 9: Country-specific requirements 
None. 
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12.10. 
Appendix 9: Protocol Amendment/Administrative change 
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 
Protocol Amendment 4 Final 
9 May 2021 
Protocol Amendment 3 Final 
23 September 2020 
Protocol Amendment 2 Final 
18 March 2020 
Protocol Amendment 1 Final 
23 May 2019 
Protocol Final Version 1 
29 January 2015 
12.10.1. 
Protocol amendment 4 
Overall Rationale for the Amendment change: The protocol is being amended to 
document the increase in blood volumes drawn at certain visits (Visit 2 and Visit 6) to 
improve the serum yield which is critical to evaluate the study endpoints. The allowed 
windows for study visits during special circumstances have also been widened to 
maintain subject visit compliance during the COVID-19 pandemic. Additionally, 
considering that some of the study interventions are combination products constituted of 
a device and biologic product (pre-filled syringes), the amended protocol provides 
instructions for collection of safety information related to the use of medical devices. The 
reporting period for pregnancies has also been updated in line with the current guidelines. 
Table 2 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Overall design 
Section 5.2: Overall design 
Section 8.4.2.1: Blood sampling 
for effectiveness and 
immunogenicity response 
assessments 
 
 
The blood volume collected at Visit 2 
and Visit 6 has been increased from 
25mL to 30 mL. 
This change has been made to 
increase serum yield which is 
critical to evaluate study endpoints. 
Section 8.9: Study procedures 
during special circumstances 
The allowed windows for study visits 
during special circumstances (Table 17) 
has been changed from +21 days to 
+28 days. 
To allow for subject visit 
compliance during the global 
COVID-19 pandemic. 
Section 7.1: Treatments 
administered 
Section 8.5.10: Medical device 
deficiencies 
Section 12.8: Appendix 8: 
Definition of medical device AE, 
adverse device effect (ADE), 
serious adverse device effect 
Product category and Type included 
 
Implementation of wording on medical 
device deficiency for combination 
products for Post Marketing Safety 
Reporting  
In line with the FDA Combination 
Product Post Marketing Safety 
Reporting guidance. 
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Section # and Name 
Description of Change 
Brief Rationale 
(SADE) and unanticipated SADE 
(USADE) 
Synopsis Table 1: Objectives and 
endpoints 
Section 4, Table 6: Objectives 
and endpoints 
Section 8.4.3: Laboratory assays 
Section 8.4.4.1: Immunological 
read-outs 
Section 10.1: Sample size 
determination 
Section 10.1.2.12: Non inferiority 
of MenABCWY vs rMenB+OMV 
NZ measured by percentage of 
subjects with 4-fold rise in hSBA 
titres against MenB component 
indicator strains post 2nd dose 
Section 10.3.4.1: Immunological 
non-inferiority: MenABCWY vs. 
rMenB+OMV NZ 
Section 10.3.4.4: Immune 
response of MenABCWY, 
rMenB+OMV NZ and MenACWY 
Section 12.2.2: MenB serum 
bactericidal assays using 
exogenous human complement 
(hSBA) – rMenB + OMV NZ 
 
The NHBA strain has been changed 
from M07-0241084 to M13520. 
The new strain has been approved 
for use in this study by competent 
authority. 
Section 8.5.6: Reporting of 
serious adverse events, 
pregnancies and other events 
Section 12.5.10.4: Completion 
and transmission of pregnancy 
reports to GSK 
Section 12.6.3: Collection of 
pregnancy information 
The timeframe for submitting pregnancy 
report to GSK is now 24 hours (changed 
from 2 weeks) 
In line with the pregnancy reporting 
guidelines 
Synopsis: Overall design 
Section 2: Schedule of activities 
Section 5.2: Overall design 
Section 8.10: Decentralised study 
procedures 
Home/ remote visits (subject to 
allowance by local regulations and 
quality maintenance of study 
procedures) can be offered to subjects 
for the collection of biological samples 
and/or study intervention administration. 
In alignment to the decentralised 
study procedures. 
Section 8.4.3, Laboratory assays 
(Table 12) 
Section 12.3 Appendix 3 – 
Clinical laboratories 
The laboratory at Marburg is removed 
from the list of GSK laboratories. 
The laboratory at Marburg has 
become an external laboratory. 
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Detailed description of Protocol Amendment 4 changes: 
The changed text of the amendment is indicated in bold italics in the body of the 
protocol. The deleted text (strikethrough) and the changed text (bold italics) are provided 
here below. 
Cover page: Co-ordinating author(s) 
, Scientific Writer and 
, Scientific Writer for GSK 
Cover page: Contributing authors 
• 
 and 
 Cont Clinical Research and Development 
Leads 
• 
 and 
 - 
, Oversight Data Managers 
• 
 
, Clinical Laboratory Sciences Read-Out 
Team Lead 
• 
 and 
, Global Regulatory Affairs 
• 
 
, Across Country Expert, Local Delivery Lead 
• 
 and
 
, Global Patents 
In Protocol Amendment 4 Sponsor Signatory Approval: 
Note: Not applicable if an alternative signature process (e.g. electronic signature or 
email approval) is used to get the sponsor approval. 
In Synopsis (Synopsis Table 1) and Section 4 Objectives and Endpoints (Table 6): 
Safety 
To evaluate the safety and reactogenicity of the MenB, 
MenABCWY, and the MenACWY vaccines  
• 
The frequencies and percentages of 
subjects with solicited local (i.e., injection 
site pain, erythema, swelling, induration) 
and systemic (i.e., fever [body temperature 
≥ 38.0°C], nausea, fatigue, myalgia, 
arthralgia, headache) adverse events (AEs) 
during the 7 days (including the day of 
vaccination) following each vaccination at 
Day 1, Day 61 and Day 181. 
• 
The frequencies and percentages of 
subjects with any unsolicited AEs (including 
all SAEs, AEs leading to withdrawal, AESIs 
and medically attended AEs) during the 30 
days (including the day of vaccination) 
following each vaccination at Day 1, Day 61 
and Day 181. 
• 
The percentages of subjects with SAEs, 
AEs leading to withdrawal, AESIs and 
medically attended AEs throughout the 
study period [Month 0 to Month 18 12]. 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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N. meningitidis serogroup B indicator strains = M14459, 96217, M07-0241084 M13520 and NZ98/254 for fHbp, NadA, 
NHBA and PorA P1.4 antigens, respectively. The NHBA indicator strain may be subject to change during the study, 
before clinical testing starts. In this case, this change will be documented in the clinical report. 
In Synopsis Figure 1 and Section 5.2 Overall study design: 
Home visits may be performed only by sites authorised (as per local regulations and sponsor agreement), with 
approved site level standard operating procedures (SOP) provided that the compliance with protocol procedures are 
ensured.  
If local regulations allow and if quality of study procedures can be maintained, participant(s) can be offered 
remote visits (e.g. home visits) for the collection of biological samples and/or study intervention 
administration. These remote visits must be performed by qualified study staff/healthcare professionals 
(HCPs). Refer to Section 8.10 (decentralised study procedures) for details 
• 
Sampling schedule:  
− 
A total of 4 blood samples* will be collected from each subject at Day 1 (pre-
vaccination blood sample; approximately 20 mL), at Day 31 (post-vaccination 1 
blood sample; approximately 25 30 mL), at Day 91 (post-vaccination 2 blood 
sample; approximately 25 mL) and at Day 211 (post-vaccination 3 blood 
sample; approximately 25 30 mL). 
In Section 2 Schedule of activities, under Table 3: 
9 Home visits may be performed only by sites authorised (as per local regulations and sponsor agreement), with 
approved site level standard operating procedures (SOP) provided that the compliance with protocol procedures are 
ensured. Refer to Section 8.9 for information related to study procedures during special circumstances  
If local regulations allow and if quality of study procedures can be maintained, participant(s) can be offered 
remote visits (e.g. home visits) for the collection of biological samples and/or study intervention 
administration. These remote visits must be performed by qualified study staff/healthcare professionals 
(HCPs). Refer to Section 8.10 (decentralised study procedures) for details. 
10 Diagnosis of coronavirus 2019 (COVID-19) should be made in accordance with the World Health Organization case 
definitions. Cases should be reported as AEs or SAEs (refer to Section 12.5 for the definitions), and routine procedures 
for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance with the 
protocol-defined time periods (refer to Table 14). In addition, separate COVID-19 specific eCRF form(s) should be 
completed. Refer to Section 8.9 for information related to study procedures during special circumstances 
In Section 2 Schedule of activities, under Table 4 Intervals between study visits: 
Refer to Table 17 for intervals between study visits during special circumstances 
In Section 3.2 Background: 
The Meningococcal Group B Vaccine (Bexsero, rMenB+OMV NZ) contains three 
recombinant proteins [factor H binding protein (fHbp), Neisserial adhesin A (NadA), and 
Neisserial Heparin Binding Antigen (NHBA)], combined with Outer Membrane Vesicles 
(OMV) components from the New Zealand outbreak strain NZ98/254. rMenB+OMV NZ 
is immunogenic against the majority of circulating meningococcal serogroup B strains 
and has acceptable reactogenicity and safety profiles when administered to individuals 
across age groups. 
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In Section 5 Study design; Section 5.1 Scientific rationale for study design: 
Rationale for blood volume collected: 
In order to provide the necessary serum volume for the bactericidal assays (enc-hSBA 
and/ or hSBA(s)), and ELISA (or equivalent), approximately 30 mL whole blood will be 
collected at Visit 2 and Visit 6 and approximately 25 mL whole blood will be collected 
at Visit 2, Visit 4 and Visit 6. At pre-vaccination (Visit 1), 20 mL whole blood will be 
collected to provide the necessary serum volume for the hSBA and ELISA (or 
equivalent). 
In Section 6.3 Criteria for temporary delay for enrolment and vaccination and/or 
blood sampling: 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a 
pandemic) is organised by the public health authorities, outside the routine immunisation 
program, the time period described above can be reduced if necessary for that vaccine 
provided it is licensed and used according to its Prescribing Information and according to 
the local governmental recommendations and provided a written approval of that the 
Sponsor is obtained notified accordingly. 
In Section 7.1, Treatments administered, under Table 7: 
Study Treatment 
Name: 
Bexsero 
MenABCWY# 
Menveo*** 
Placebo 
Product category 
Combination 
Combination 
Biological 
Combination 
Type 
Study; 
Control 
Study 
Control 
Additional 
OMV = Outer Membrane Vesicles; SPM = Study procedure manual; CRM 197 = Corynebacterium diphtheriae cross 
reacting material-197; fHbp = factor H binding protein; GSK = GlaxoSmithKline; NaCl = sodium chloride; NHBA 
= Neisserial heparin binding antigen; NZ = New Zealand 
In Section 8.4.2.1, Blood sampling for effectiveness and immunogenicity response 
assessments: 
A minimum of approximately 20 mL of blood will be drawn from all subjects at visit 1 
before vaccination, .and aApproximately 30 mL sample of blood will be drawn from all 
subjects 30 days after the first and third vaccination [at Visit 2 (Day 31) and Visit 6 
(Day 211)] and approximately 25 mL sample of blood will be drawn from all subjects 
30 days after the first, second and third vaccination (at Visit 2 (Day 31), Visit 4 (Day 91) 
and Visit 6 (Day 211)). 
The blood samples should be collected before the study vaccination when applicable. The 
blood volume of 25 mL at Visit 2, Visit 4 and Visit 6 that is drawn as presented in Table 
11 is needed in order to provide the necessary serum volume for the bactericidal assays 
(enc-hSBA and hSBA(s)). Refer to Section 5.1 and Section 7.2.3.1 for further details on 
the rationale for the requirement of this blood volume. 
The total amount of blood collected over the study period per subject will be 
approximately 95 105mL. 
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Table 11 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Subject/Group 
Day 
Blood 
Approximately 20 
mL 
Visit 1 (Pre-Vacc) 
All 
Day 1 
Approximately 25 
30 
mL 
Visit 2 (Post-Vacc 1) 
All 
Day 31 
Approximately 25 
mL 
Visit 4 (Post-Vacc 2) 
All 
Day 91 
Approximately 25 
30 
mL 
Visit 6 (Post-Vacc 3) 
All 
Day 211 
Note: in case of local regulations limiting the amount of blood to be taken in the younger population (e.g 10-12 
years of age and/or at the lower bound of the percentile of the growth chart), a reduced amount of blood 
volume could be drawn at Visit 2 and Visit 6. In this population every effort must be done to collect at least 
25ml of blood volume, samples will be analysed according to priority ranking provided in Table 13 
In Section 8.4.3 Laboratory assays 
An Enzyme-Linked Immunosorbent Assay (ELISA), or equivalent, will be used to 
evaluate the serotype-specific IgG responses to A, C, W, and Y. 
Effectiveness testing by enc-hSBA and MenACWY immunogenicity testing by hSBA 
will be prioritised over any other assays using exogenous source of human complement, 
or ELISA (or equivalent), based on the volume of serum available for a visit from one 
subject. 
Table 12 
Laboratory assays 
System 
N meningitidis Strains* 
Method 
Kit/Manufacturer 
Unit 
Laboratory 
Serum 
N men B fHbp (M14459) Ab 
hSBA 
In house 
1/dilution 
 
N men B NadA (96217) Ab 
N men B PorA (NZ98/254) Ab 
N men B NHBA (M07-
0241084)* (M13520) Ab 
** GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium or Marburg, 
Germany. CLS may delegate testing to GSK Research laboratories in Sienna, Italy or to an external laboratory 
#For each of the MenACWY serogroups, ELISA (or equivalent assay) cut-offs will be determined following validation 
of the assay. This will be documented in the clinical report 
In Section 8.4.4.1 Immunological read-outs 
Table 13 
Immunological read-outs 
Blood sampling time 
point 
Group/ 
Subset 
name 
No. 
subjects Method1 
Component 
Components 
priority  
rank 
Type of 
contact and 
time point 
Sampling 
time point 
Visit 1  
(Day 1) 
Pre-Vacc 1  
For details on 
number of subjects 
and groups/ subsets 
please refer to 
Section 10.1.2 
hSBA 
N men A (3125) Ab  
1 
hSBA 
N men C (C11) Ab 
1 
hSBA 
N men W (240070) Ab  
1 
hSBA 
N men Y (860800) Ab 
1 
hSBA 
N men B fHbp (M14459) Ab 
2 
hSBA 
N men B NHBA2 (M07-0241084) 
(M13520) Ab 
2 
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Blood sampling time 
point 
Group/ 
Subset 
name 
No. 
subjects Method1 
Component 
Components 
priority  
rank 
Type of 
contact and 
time point 
Sampling 
time point 
hSBA 
N men B NadA (96217) Ab 
2 
hSBA 
N men B PorA (NZ98/254) Ab 
2 
Visit 2  
(Day 31) 
Post-Vacc 1  
enc-hSBA 
110 random US MenB strains 
1 
hSBA 
N men A (3125) Ab  
2 
hSBA 
N men C (C11) Ab 
2 
hSBA 
N men W (240070) Ab  
2 
hSBA 
N men Y (860800) Ab 
2 
ELISA 
N men A Ab IgG 
3 
ELISA 
N men C Ab IgG 
3 
ELISA 
N men W Ab IgG 
3 
ELISA 
N men Y Ab IgG 
3 
Visit 4  
(Day 91) 
Post-Vacc 2 
enc-hSBA 
110 random US MenB strains 
1 
hSBA 
N men B fHbp (M14459) Ab 
2 
hSBA 
N men B NHBA2 (M07-0241084) 
(M13520) Ab 
2 
hSBA 
N men B NadA (96217) Ab 
2 
hSBA 
N men B PorA (NZ98/254) Ab 
2 
Visit 6  
(Day 211) 
Post_vacc 3 
enc-hSBA 
110 random US MenB strains 
1 
 
 
hSBA 
N men A (3125) Ab IgG 
2 
hSBA 
N men C (C11) Ab IgG 
2 
hSBA 
N men W (240070) Ab IgG  
2 
hSBA 
N men Y (860800) Ab IgG 
2 
hSBA 
N men B fHbp (M14459) Ab 
3 
hSBA 
N men B NHBA2 (M07-0241084) 
(M13520) Ab 
3 
hSBA 
N men B NadA (96217) Ab 
3 
 
 
 
hSBA 
N men B PorA (NZ98/254) Ab 
3 
ELISA 
N men A Ab IgG 
4 
ELISA 
N men C Ab IgG 
4 
ELISA 
N men W Ab IgG 
4 
ELISA 
N men Y Ab IgG 
4 
2 The NHBA indicator strain may be subject to change during the study, before clinical testing starts. In this case, this 
change will be documented in the clinical report. 
In Section 8.5.6, Reporting of serious adverse events, pregnancies, and other events: 
Table 15 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK  
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  
2 weeks 24 
hours* 
electronic pregnancy report  
2 weeks 24 
hours * 
electronic pregnancy report 
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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 an 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 
Section 8.5.10 was added: 
8.5.10 Medical device deficiencies 
The study interventions (MenABCWY and Bexsero) are combination products 
constituted of a device and biologic product (e.g., pre-filled syringes). Refer to Glossary 
of terms for the definition of a combination product and a medical device deficiency. 
8.5.10.1 
Detection, follow-up and prompt reporting of medical device deficiency 
The investigator is responsible for the detection, documentation and prompt reporting 
of any medical device deficiency occurring during the study to GSK. This applies to 
any medical device provided for the conduct of the study.  
Device deficiencies will be reported to GSK within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. Refer to 
Section 10.6 for definitions and details on recording and reporting of these events.  
The investigator will ensure that follow-up includes any additional investigations to 
elucidate the nature and/or related of the device deficiency to the incident. Follow-up 
applies to all participants, including those who discontinue study intervention or the 
study. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
8.5.10.2 
Regulatory reporting of medical device deficiency when used as 
combination product  
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study to GSK. GSK has a legal responsibility to notify 
appropriate regulatory authorities and other entities about safety information linked to 
medical devices being used in clinical studies. Refer to Section 12.8.2 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. 
In Section 8.9 Study procedures during special circumstances: 
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Table 17 
Intervals between study visits during special circumstances 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1 → Visit 2 
30 days 
23 to 51 58 days after vaccination at V1  
(from -7 to +21 28 days) 
Visit 1→Visit 3 
60 days 
53 to 81 88 days after vaccination at V1  
(from -7 to +21 28 days) 
Visit 3→Visit 4 
30 days 
23 to 51 58 days after vaccination at V3  
(from -7 to +21 28 days) 
Visit 3→Visit 5 
120 days 
110 to 148 days after vaccination at V3  
(from -10 to +28 days) 
Visit 5→Visit 6 
30 days 
23 to 51 58 days after vaccination at V5  
(from -7 to +21 28 days) 
Section 8.10 has been added: 
8.10 
Decentralised study procedures 
If local regulations allow and if quality of study procedures can be maintained, 
participant(s) can be offered remote visits (e.g. home visits) for the collection of 
biological samples and/or study intervention administration. These remote visits must 
be performed by qualified study staff/healthcare professionals HCPs. Refer to the 
Schedule of Activities (Table 3) for the timing of these visits. 
Following procedures can be performed remotely. Refer to the Glossary of terms for 
definitions of remote virtual visit: 
• 
Biological samples may be collected remotely by qualified study staff/HCPs. 
Biological samples should be collected only if they can be processed in a timely 
manner and appropriately stored until the intended use.  
• 
Administration of study intervention can be performed remotely/at participant’s 
home by qualified study staff/HCPs if appropriate storage conditions for the study 
intervention can be ensured. Furthermore, appropriate medical treatment must be 
readily available during 30 minutes after dosing in case of anaphylaxis, syncope. 
In Section 10.1, Sample size determination: 
It is assumed that 25% of the subjects will drop-out and not contribute to an evaluable 
result. The remaining subjects who do give an evaluable result provide 90% power to 
reject all hypotheses for the primary objectives of rMenB+OMV NZ and 92% power to 
reject all hypotheses for the primary objectives of MenABCWY vaccine. Additionally, 
the study is powered to reject key secondary objective for three N. meningitidis serogroup 
B indicator strains (96217 (NadA), M14459 (fHbp), and M07-0241084 M13520 
(NHBA*)) with 81% power. 
* The NHBA indicator strain 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 Section 10.1.2.12, Non inferiority of MenABCWY vs rMenB+OMV NZ measured 
by percentage of subjects with 4-fold rise in hSBA titres against MenB component 
indicator strains post 2nd dose: 
Key secondary objective is to demonstrate non inferiority of MenABCWY vs 
rMenB+OMV NZ measured by the percentages of subjects with 4-fold rise in hSBA 
titres against the N. meningitidis serogroup B indicator strains post 2nd dose. Six hundred 
twenty (620) subjects are needed to demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the rMenB+OMV NZ as measured by the percentages 
of subjects achieving a 4-fold rise in hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the last MenABCWY vaccination (0,6-months schedule) 
and 1 month after the MenB vaccination (0,2,6-months or 0,6-months or 0,2-months) 
with 81% power calculated for three strains (96217 (NadA), M14459 (fHbp), and M07-
0241084 M13520 (NHBA*)). NZ98/254 (PorA) is not powered for as the 4-fold rate for 
MenABCWY is predicted to be at least 10% less than the 4-fold rate for MenB. 
*The NHBA indicator strain 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 23 
Power of Non inferiority of MenABCWY vs rMenB+OMV NZ 
Strain 
4-fold rise (MenABCWY) 
4-fold rise (rMenB+OMV NZ) 
Power 
96217 (NadA) 
80% 
80% 
98.5% 
M14459 (fHbp) 
60% 
60% 
91.2% 
M07-0241084 M13520 
(NHBA) 
45% 
45% 
90.3% 
NZ98/254 (PorA) 
53% 
76%  
0% 
In Section 10.3.4.1, Immunological non-inferiority: MenABCWY vs. rMenB+OMV 
NZ: 
Statistical method: The percentages of subjects with 4-fold rise in hSBA titres against N. 
meningitidis serogroup B indicator strains (M14459, 96217, M07-0241084* M13520 and 
NZ98/254 for fHbp, NadA, NHBA and PorA P1.4 antigens, respectively) at 1 month 
after the last vaccination for the ABCWY group (pooled lots) (Day 211, Month 7) and 1 
month after the 3-dose vaccination series (Day 211, Month 7) in MenB_0_2_6 group or 
2-dose vaccination series (Day 211, Month 7) in MenB_0_6 group or 2-dose vaccination 
series (Day 91, Month 3) in MenB_0_2_6 group and the corresponding exact 2-sided 
95% CIs based on Clopper-Pearson method will be calculated [Clopper, 1934]. The 95% 
CIs for the difference in percentages between ABCWY group (pooled lots) and 
MenB_0_2_6 group and MenB_0_6 group will be constructed using the method of 
Miettinen and Nurminen [Miettinen, 1985]. 
* The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report. 
In Section 10.3.4.4, Immune response of MenABCWY, rMenB+OMV NZ and 
MenACWY: 
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Statistical method: The hSBA titres at each time point for all groups (ABCWY group 
(pooled lots), MenB_0_2_6 and MenB_0_6 groups) will be logarithmically transformed 
(base10) to fulfil the normal distribution assumption. For each N. meningitidis serogroup 
A, C, W and Y and each B indicator strain (M14459, 96217, M07-0241084* M13520 and 
NZ98/254 for fHbp, NadA, NHBA and PorA P1.4 antigens, respectively), the GMTs and 
GMRs (post-vaccination/baseline) will be calculated with their associated 2-sided 95% 
CIs, by exponentiating the corresponding log-transformed means and their 95% CIs. The 
ratio of GMTs and GMRs between two groups and the corresponding CI will be 
constructed by exponentiating the mean difference and the confidence limits in log10 
(titre), using ANOVA with study centre included as an independent variable. 
For each N. meningitidis A, C, W and Y and each serogroup B indicator strain (M14459, 
M07-0241084* M13520, 96217and NZ98/254) the percentages of subjects with hSBA 
titres ≥ LLOQ and of subjects with 4-fold rise and the corresponding exact 2-sided 95% 
CIs based on Clopper-Pearson method will be calculated for each study group at each 
timepoint not previously analyzed.  
* The NHBA indicator strain may be subject to change during the study, before 
clinical testing starts. In this case, this change will be documented in the clinical 
report. 
In Section 12.1.1, Abbreviations: 
ADE: 
Adverse Device Effect 
NadA: 
Neisserial adhesin A  
NHBA: 
Neisserial Heparin Binding Antigen 
SADE: 
Serious Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
In 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. 
Medical device 
deficiency: 
A device deficiency is an inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, 
safety, or performance. Device deficiencies include 
malfunctions, use errors and information supplied by the 
manufacturer. 
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Remote visit: 
Refers to the visit conducted in the place other than the 
study site. 
In Section 12.2.2, MenB serum bactericidal assays using exogenous human 
complement (hSBA) – rMenB + OMV NZ: 
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 
M13520. Each of these strains measures bactericidal activity primarily directed against 
one of the major bacterial 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 M13520 measures hSBA against the 287 part of 
the 287-953 antigen, also known as NHBA. 
The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented in the clinical report. 
In Section 12.3, Clinical laboratories: 
Table 24 
GSK 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 
GSK Vaccines GmbH 
Clinical Laboratory Sciences, 
Marburg, Germany 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 
* GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium or Wavre, Belgium or 
Marburg, Germany. CLS may delegate testing to GSK Research laboratories in Sienna, Italy or to an external 
laboratory 
In Section 12.4.9, Data quality assurance: 
Quality tolerance limits (QTLs) will be pre-defined in the study management plan 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 summarised in 
the Clinical Study Report (CSR). 
In Section 12.5.10.4, Completion and transmission of pregnancy reports to GSK: 
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 2WEEKS 24 HOURS. 
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In Section 12.6.3.1, Female Subjects who become pregnant: 
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks 24 hours of learning of a subject's pregnancy. 
Section 12.8, Appendix 8 has been added: 
12.8 
Appendix 8: Definition of medical device AE, adverse device effect (ADE), 
serious adverse device effect (SADE) and unanticipated SADE (USADE) 
12.8.1 Definition of medical device AE and adverse device effect (ADE) 
• 
Medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether considered related to a medical device or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medical device. This definition includes events related 
to the medical device or comparator and events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of a medical device. 
This definition includes any AE resulting from: 
• 
insufficient or inadequate instructions for use (i.e. user error), or 
• 
any malfunction of a medical device, or 
• 
intentional misuse of the medical device. 
12.8.2 Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event that: 
e. 
Led to death  
f. 
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 
g. Led to fetal distress, fetal death or a congenital abnormality or birth defect 
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h. Is a suspected transmission of any infectious agent via a medicinal product  
Serious Adverse Device Effect (SADE) definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• Any device deficiency that might have led to an SAE if appropriate action had 
not been taken or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome 
has not been identified in the current version of the IB. 
12.8.3 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 8.5.6.1. 
GSK will review all device deficiencies, determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs/IECs as required by national regulations. 
12.10.2. 
Protocol amendment 3 
Overall Rationale for the Amendment: 
This protocol is amended primarily as a consequence of feedback from regulatory 
authorities of participating countries following their review of Protocol Amendment 2. 
Additional changes have been made to improve the clarity of the text. Table numbering 
and related in-text cross references have been updated from Table 18 onwards due to the 
inclusion of a new table in Section 8.9. 
Section # and Name 
Description of Change 
Brief Rationale 
Co-ordinating author(s) 
Name of science writer updated 
Change in study team members 
Contributing authors 
Names of US Medial Affairs Lead, and 
GP representatives updated. 
Change in study team members. 
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Section # and Name 
Description of Change 
Brief Rationale 
Cover page, page 2  
Short Title changed to Title 
To update to use the correct 
label. 
Synopsis Table 1 and Table 6 
Study objectives and endpoints 
Footnote added to clarify that primary NI 
objective (MenABCWY versus 
MenACWY vaccines) will be assessed 
only in subjects without a previous 
MenACWY vaccination (unprimed). 
Correction of a typographical error. 
CBER recommended to enrol a 
subset of subjects with a 
previous MenACWY vaccination 
(primed) to ensure adequate 
representation of US 
adolescents and young adults 
vaccinated in accordance with 
ACIP recommendations 
Synopsis Table 1, Table 6, Table 
12, Table 13, Section 10.1, Section 
10.1.2.12, Section 10.3.4.4, 
Section 12.2.2 
Footnote and text updated clarifying 
change to NHBA strain during the study 
will be documented in the clinical study 
report. 
Text adjusted to clarify reporting 
of changes to NHBA strain will 
be documented in the clinical 
study report 
Synopsis Figure 1, Synopsis 
(duration of the study; safety 
follow-up), Table 3 Schedule of 
Activities, Table 5 Intervals 
between study visits and phone 
calls, Section 5.2 Overall design, 
Figure 1, Section 5.4 Subject and 
study completion, Section 7.5.1 
Recording of concomitant 
medications/products, Section 
8.5.3 Safety Follow-up calls, Table 
14 Reporting period for collecting 
safety information, Section 8.8 
Study Termination Visit, Section 
12.1.2 Glossary of terms; Section 
12.5.9.2 Time period for detecting 
and recording AEs, SAEs and 
pregnancies; Section 12.5.12.2 
Post-vaccination Visit(s) 
All references to study conclusion (last 
subject last visit) changed to occur at 
Day 361, Telephone call T7. 
Extended safety follow-up will be 
for 6 months after last study 
vaccination at Visit 5. This is 
supported by the extensive 
evaluation of Bexsero and 
Menveo safety data in clinical 
trials and in post marketing 
reports which are closely 
monitored through the routine 
pharmacovigilance activities. 
Synopsis and Section 5.2 Overall 
design 
Description of study group MenB_0_2_6 
expanded. Explanatory notes referred to 
in the text in the bullet list were revised 
to clarify. 
Text added to clarify that both 
0,2- and 0,2,6-month schedules 
will be assessed in the same 
group. Presentation of notes 
associated with the text was 
adjusted to clarify. 
Synopsis Figure 1 and Figure 1 
Footnote regarding home visits 
amended to include reference to Section 
8.9 study procedures during special 
circumstances 
To signpost to the section 
providing information on study 
procedures during special 
circumstances 
Table 3 Schedule of Activities / 
Footnote 9 
Footnote 9 updated to include reference 
to Section 8.9 for information related to 
study procedures during special 
circumstances 
To signpost to the section 
providing information on study 
procedures during special 
circumstances 
Table 3 Schedule of Activities / 
Footnote 10 
Footnote 10 added regarding recording 
of COVID-19 infection related AEs and 
SAEs. 
To clarify diagnosis of COVID-19 
should be in accordance with the 
WHO case definition and routine 
procedures for recording, 
evaluation, follow-up and 
reporting of AEs and SAEs 
should be in accordance with 
protocol-defined time periods. In 
addition, separate COVID-19 
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Section # and Name 
Description of Change 
Brief Rationale 
specific eCRF form(s) should be 
completed 
Table 4 Interval between study 
visits 
Correction of typographical error 
To correct a typographical error 
Section 3.1 Study rationale 
Minor edit to text 
Minor edit to align abbreviation 
use 
Section 3.2 Background 
Minor edit to text 
Minor edit to align abbreviation 
use 
Section 5.1 Scientific rationale for 
study design  
Minor edits to text and wording added to 
rationale for 3-dose schedule 
Minor edits made to text to 
ensure consistency in the 
document. Wording added to 
strengthen the explanation for 
the selection of the 3-dose 
schedule.   
Section 6.1 Inclusion Criteria 
Correction of typographical error 
To correct a typographical error 
Section 6.1 Inclusion Criteria 
Inclusion criteria added for allowing 
enrolment of subjects both unvaccinated 
and vaccinated with MenACWY. 
The study will enrol subjects both 
previously vaccinated and 
unvaccinated with MenACWY, 
as requested by CBER. 
Section 6.2.2 Prior/Concomitant 
therapy 
Exclusion criterion related to vaccination 
with previous group B meningococcal 
vaccines updated. 
The study will allow participation 
of subjects primed and unprimed 
with MenACWY, as requested by 
CBER. 
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 
Section 6.3 Criteria for temporary 
delay for enrolment, vaccination 
and/or blood sampling 
Post-vaccination window added for 
receiving any other non-study vaccines. 
Footnote updated to include seasonal 
influenza vaccination 
To allow use of other non-study 
vaccines outside a specified 
window post-study vaccination. 
Section 7.1 Treatments 
administered 
Minor edits made to bulleted list of study 
vaccines/ products specific to this study 
Minor edits made for clarification 
and consistency 
Table 9 Treatments administered 
Formulations for Bexsero, MenABCWY, 
Menveo and footnote *** were updated  
Change to align the formulations 
for Bexsero, MenABCWY, 
Menveo with the certificate of 
analysis 
Table 9 Treatments administered 
Entry for placebo volume was updated 
and a footnote was added. 
Change in placebo volume from 
0.5 mL to 0.65 mL to be aligned 
with the certificate of analysis. A 
footnote was added to clarify that 
the volume of the pre-filled 
syringe administered will be 
within a range and the full 
volume should be injected. 
Section 7.2.2.2.1 Study group and 
treatment number allocation 
The minimisation procedure for the 
randomisation algorithm will account for 
previous MenACWY vaccination status 
(subjects with and without a previous 
MenACWY vaccination [primed and 
unprimed]).  
The study will enrol subjects with 
and without a previous 
MenACWY vaccination (primed 
and unprimed), as requested by 
CBER.  
Section 7.2.2.2.1 Study group and 
treatment number allocation 
Text on site staff accessing SBIR after 
signing consent updated. 
Any blinded site staff can access 
SBIR. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2.2.2.1 Study group and 
treatment number allocation 
Text on freezing enrolment in a given 
group updated and reference added to 
Study Procedures Manual (SPM). 
Further details will be provided in 
the SPM.  
Section 7.2.3.1 Randomisation to 
strains for enc-hSBA testing 
Text added to confirm the randomisation 
to strains for enc-HSBA testing 
To enable the estimation of the 
correlation between each pair of 
strains 
Section 7.3 Blinding and unblinding 
Removed list of tasks of unblinded site 
staff. 
The SPM has sufficient details. 
Section 7.3 Blinding and unblinding 
Sentence deleted on contacting the 
Sponsor in case of medical emergency. 
In case of medical emergency, 
the investigator is allowed to 
unblind the study treatment 
immediately. 
Section 7.3.1 Emergency 
unblinding – Table 10 Contact 
information for emergency 
unblinding 
Toll-free numbers removed and 
reference added to SPM for individual 
country numbers. 
Helpdesk numbers have been 
updated. 
Section 7.5.1 Recording of 
concomitant medications/products 
and vaccinations 
Sentence deleted regarding recording of 
all prior medications within 4 weeks of 
first study vaccination.  
Only specific prior medications 
listed in this section are to be 
recorded in the eCRF. 
Section 8.1 General study aspects 
Sentence added referring to adaptation 
of study procedures during special 
circumstances. 
Clarifying that procedures might 
be adapted during special 
circumstances. 
Section 8.2 Data Collected from 
Subjects, Section 12.5.9.2 Time 
period for detecting and recording 
AEs, SAEs and pregnancies 
Text added that solicited AEs ongoing 
after the 30-day post-vaccination period 
will be recorded in the eCRF. 
Solicited AEs ongoing after 30 
days post-vaccination period will 
be considered as unsolicited AEs 
and recorded accordingly. 
Clarification added that reporting 
of solicited AEs that have not 
resolved within 30 days post 
vaccination will be recorded in 
the eCRF. 
Section 8.3.5 Pregnancy test 
Correction of typographical error 
To correct a typographical error 
Section 8.4 Effectiveness and/or 
immunogenicity assessments 
Changed future research to further 
research 
To align with wording in the 
informed consent form (ICF) and 
electronic case report form 
(eCRF) 
Section 8.4.3 Laboratory assays 
Correction of typographical error 
To correct a typographical error 
Section 8.4.4.1 Immunological 
readouts / Table 13 Immunological 
read outs 
Updated footnote numbering to align 
with the numbering in the table 
To align footnote numbering with 
the numbering in the table 
Table 14 Reporting periods for 
collecting safety information 
Footnote added regarding COVID-19 
related AEs. Abbreviation COVID-19 
added to the list of abbreviations 
COVID-19 infection related AEs 
to be reported similar to all AEs. 
Section 8.5.6.2 Regulatory 
reporting requirements for SAEs 
Correction of typographical error 
To correct a typographical error 
Section 8.9 Study procedures 
during special circumstances 
Section “8.9. Study procedures during 
special circumstances” added. 
Certain study procedures can be 
adapted during special 
circumstances such as COVID-
19 pandemic. 
Section 10.1.1.8. Immunological 
non-inferiority: MenABCWY vs. 
MenACWY 
Text added    
To confirm demonstration of non-
inferiority of MenABCWY vs 
MenACWY will be in subjects 
without a previous MenACWY 
vaccination (unprimed) 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.2.8 Immunological 
non-inferiority: MenABCWY vs. 
MenACWY in subjects without a 
previous MenACWY vaccination 
(unprimed); Table 21 
Text added 
To update sample size 
justification for the analysis of 
non-inferiority of MenABCWY 
compared to MenACWY in 
subjects without a previous 
MenACWY vaccination 
(unprimed) considering the study 
will enrol subjects with and 
without a previous MenACWY 
vaccination (primed and 
unprimed), as requested by 
CBER 
Section 10.2 Population for 
analyses 
Reference added to Statistical Analysis 
Plan (SAP) for list of protocol deviation 
leading to exclusion from analyses. 
Included, as requested by 
CBER. 
Section 10.2 Population for 
analyses 
Sentence added to include a) sub-group 
analysis for secondary objectives based 
on previous MenACWY vaccination 
history (primed and unprimed); b) 
potential sub-group analyses assessing 
impact of COVID-19 pandemic.  
a) Included, as requested by 
CBER. 
b) In alignment with internal and 
external guidance on trials 
conducted during the COVID-19 
pandemic. 
Section 10.3.3.8 Immunological 
non-inferiority: MenABCWY vs. 
MenACWY 
Text added  
The study will enrol subjects with 
and without a previous 
MenACWY vaccination (primed 
and unprimed), as requested by 
CBER. 
Section 11 References 
Three references were deleted. Two 
references were added to World Health 
Organisation documents related to the 
COVID-19 case definition and laboratory 
testing 
To remove three references that 
linked to text deleted during 
Protocol Amendment 1 and 
Protocol Amendment 2. These 
references are no longer cited in 
the protocol. To provide 
references to source documents 
related to the COVID-19 case 
definition and laboratory testing 
Section 12.1.1 
Abbreviations COVID-19 CT, SARI and 
SARS-CoV-2 were added to the list of 
abbreviations 
New abbreviations were used in 
the main document 
Section 12.4.5.1 Responsibilities of 
the Investigator and IRB/EC 
Correction of typographical errors 
To correct typographical errors 
Section 12.5.9 Detecting and 
recording adverse events, serious 
adverse events and pregnancies 
Edits to existing text  
To clarify procedure for 
distribution, use and return of 
Subject eDiaries  
Section 12.5.9.2. 
Time period for 
detecting and recording adverse 
events, serious adverse events and 
pregnancies 
Text added related to the reporting of 
solicited AEs not resolved within 30 days 
of vaccination 
Solicited AEs ongoing after 30 
days post-vaccination period will 
be considered as unsolicited AEs 
and recorded accordingly. 
Clarification added that reporting 
of solicited AEs that have not 
resolved within 30 days post 
vaccination will be recorded in 
the eCRF. 
Section 12.5.9.3.2 Assessment of 
adverse events / Assessment of 
intensity 
Correction of typographical error 
To correct a typographical error 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.5.9.3.2 Assessment of 
adverse events / Assessment of 
causality 
Edit made to existing text 
Text edited to confirm all 
solicited local and systemic AEs 
Section 12.5.9.4 Recording of AEs 
related to COVID-19 and Section 
12.5.9.4.1 WHO Case Definition 
Section added “Recording of AEs related 
to COVID-19” 
To include the WHO COVID-19 
case definition relevant to the 
recording of AEs related to 
COVID-19 
Section 12.5.10.3 Back-up system 
in case the electronic reporting 
system does not work; Section 
12.5.11 Updating of SAE, 
pregnancy, and AESI information 
after removal of write access to the 
subject’s eCRF 
Inclusion of email as an option for 
reporting AEs  
To include email alongside fax 
as an alternative study contact 
following queries from site 
monitors as to whether this was 
a valid form of contact 
Section 12.6.2 Contraception 
guidance / Table 29 Highly 
effective contraceptive methods 
Addition of oral progestogen-only 
hormonal contraception 
To clarify the use of oral 
progestogen-only hormonal 
contraception is acceptable 
Detailed description of Protocol Amendment: 
The changed text of the amendment is indicated in bold italics in the body of the 
protocol. The deleted text (strikethrough) and the changed text (bold italics) are provided 
here below. 
Detailed description of Protocol Amendment 3 changes: 
Cover page: Co-ordinating author(s) 
, Scientific Writer and 
, Scientific Writer for GSK 
Cover page: Contributing authors 
• 
 and 
, US Medical Affairs Leads 
• 
 and 
, Global Patents 
Cover page: Page 2 
Short tTitle 
Synopsis: Objectives and Endpoints 
All objectives and endpoints have been edited/ rewritten in Amendment 2. For 
readability, the entire table is not written in black bold italics. Refer to Section 0 for 
details. 
Synopsis Table 1 
Study objectives and endpoints 
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Immunological non-inferiority: MenABCWY vaccine 
vs. MenACWY vaccine*** 
To demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the MenACWY 
vaccine as measured by the percentages of subjects 
achieving a 4-fold rise in hSBA titres against N. 
meningitidis serogroups A, C, W and Y at 1 month after 
the last MenABCWY vaccination (0,6-months) and 1 
month after the MenACWY vaccination. 
Criterion: 
LL of the two2-sided 97.5% CI^ for the group difference 
in percentages of subjects achieving a 4-fold rise* in 
hSBA titres is above -10%. 
The percentages of subjects with 4-fold rise* in hSBA 
titres against N. meningitidis serogroups A, C, W and Y 
at 1 month after the: 
• 
last vaccination for the ABCWY group (pooled lots) 
(Day 211, Month 7), and 
• 
1 month after the MenACWY vaccination for the 
ACWY group (Day 31, Month 1) 
relative to baseline (Day 1, Month 0). 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; Enc-hSBA = endogenous complement human serum 
bactericidal assay; GMC = geometric mean concentrations; GMT = geometric mean titre; GMR = geometric mean 
ratio; CI = confidence interval; hSBA = human serum bactericidal assay; LOD: limit of detection; LLOQ = lower limit of 
quantitation; LL = lower limit; AE = Adverse event; SAE = Serious adverse event; AESI = Adverse event of special 
interest 
N. meningitidis serogroup B indicator strains = M14459, 96217, M07-0241084 and NZ98/254 for fHbp, NadA, NHBA 
and PorA P1.4 antigens, respectively. The NHBA indicator strain may be subject to change during the study, before 
clinical testing starts. In this case, this change will be documented either in a protocol amendment or in the clinical 
report. 
Refer to Section 10 for details on evaluation of objectives and sample size justification. Refer to Glossary of terms for 
definitions of test-based and responder-based effectiveness 
^ If the co-primary effectiveness objectives for rMenB+OMV NZ are met, then all objectives for MenABCWY will be 
evaluated at 95% CI. Refer to Section 10.1 for details 
† If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 0,6-
months is also not met, then the 0,2,6-months schedule will be the comparator. 
*For the Men A, C, W, Y evaluation, the 4-fold rise is defined as: 
a post-vaccination hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD but <LLOQ, 
and 
a post-vaccination hSBA titre ≥4 times the pre-vaccination titre for subjects with a pre-vaccination hSBA titre 
≥LLOQ.  
**For the MenB evaluation, the 4-fold rise per each indicator strain is defined as: 
a post-vaccination‡ hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination‡ hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD and 
<LLOQ, and 
a post-vaccination‡ hSBA titre ≥4 times the pre-vaccination hSBA titre for subjects with a pre-vaccination hSBA 
titre ≥ LLOQ 
‡ = post-2nd vaccination for 0,6 and 0,2 schedule and post-3rd vaccination for 0,2,6 schedule). 
***The primary objective of immunological NI of the MenABCWY vaccine to MenACWY will be evaluated only in 
subjects without a previous MenACWY vaccination (unprimed). All other primary and secondary objectives 
will be evaluated in subjects with and without previous MenACWY vaccination (primed/unprimed).  
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Synopsis: Overall Design 
Synopsis Figure 1 
Study design overview  
 
 
 
N = number of subjects; d = dose; V = visit; D = day; T = telephone call; 
Refer to Table 3 for details on all visits 
# subjects will receive 2 doses of MenABCWY vaccine with Lot 1 or Lot 2 or Lot 3 of the MenACWY lyophilised vial 
component of the vaccine. Refer to the study groups description below the figure for details and Figure 1 for the 
detailed study design overview 
Notes:  
Home visits may be performed only by sites authorised (as per local regulations and sponsor agreement), with 
approved site level standard operating procedures (SOP) provided that the compliance with protocol procedures are 
ensured. 
Refer to Section 8.9 for information on study procedures during special circumstances.  
A total of 3651 healthy adolescents and young adults aged 10-25 years will be enrolled 
and randomised (5:5:3:3:3:1 ratio) to one of the six parallel study groups: 
• 
MenB_0_2_6 group*: subjects will receive 3 doses of rMenB+OMV NZ at Day 1, 
Day 61 and Day 181 (0,2 and 0,2,6-months schedule). These subjects will receive 1 
dose of the MenACWY at Day 211**. Data from this group will be used to assess 
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both the 0,2-months and 0,2,6-months schedules; the 0,2-months schedule will be 
assessed 1 month after the second rMenB+OMV NZ vaccination administered at 
Day 61 (Visit 3), and the 0,2,6-months schedule will be assessed 1 month after the 
third rMenB+OMV NZ vaccination at Day 181 (Visit 5), in the same group.  
• 
MenB_0_6 group: subjects will receive 2 doses of rMenB+OMV NZ at Day 1and 
Day 181 and 1 dose of MenACWY vaccine at Day 61 (0,6-months schedule). These 
subjects will receive 1 dose of the placebo at Day 211**. 
• 
ABCWY-1**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 1 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**.  
• 
ABCWY-2**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 2 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**. 
• 
ABCWY-3**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 3 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**. 
• 
ACWY group: subjects will receive 1 dose of MenACWY at Day 1, 1 dose of 
placebo at Day 61 and 2 doses of rMenB+OMV NZ at Day 181 and Day 211**. 
* MenB_0_2_6 group will also be evaluated for objectives pertaining to 0,2-months 
vaccination schedule. In order to let the subjects in MenB_0_2_6 group receive a 
dose of MenACWY vaccine and for subjects in ACWY group to receive the second 
dose of rMenB+OMV NZ in line with the vaccine as standard of care (also in line 
with the Advisory Committee on Immunization Practices (ACIP) recommendations 
in the US [ACIP, 2011]), the subjects in these groups will receive a vaccination of 
MenACWY and rMenB+OMV NZ vaccines, respectively, on Day 211 (Visit 6) after 
completion of the post-vaccination 3 blood sampling. To maintain the blinding of the 
study, subjects in the rest of the groups (MenB_0_6, ABCWY-1, ABCWY-2 and 
ABCWY-3) will receive a dose of Placebo. All these vaccines/ products 
administered at Day 211 are not associated with any study objectives/ endpoints 
(sSafety assessment conducted after 1 dose of rMenB+OMV NZ in the ACWY 
group at Day 181 is to maintain the blind of the study). 
** Note 1: (1) A single MenB lot will be used for the pre-filled syringe component 
of the MenABCWY vaccine; (2) Note 2: The groups ABCWY-1, ABCWY-2, 
ABCWY-3 will be pooled into a single group, ABCWY (pooled lots) (except for 
analysis of lot-to-lot consistency). 
Note 3:  
• 
Duration of the study: The study duration is approximately -18 12 months for each 
subject. 
• 
Safety follow-up: Regular safety follow-up will be done through telephone calls (T). 
There will also be an extended safety follow-up (ESFU) phone call 6 12 months 
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post-vaccination 3 (Day 181; Visit 5). This ESFU phone call (Day 361; T7 Day 541; 
T10) will also mark the study conclusion. Refer to Table 3 and Section 8.5.3 for 
details on the safety follow-up.  
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2 Schedule of Activities 
Table 3 
Schedule of Activities 
Age  
10 through 25 years of age at study start 
 
 
Type of contact 
Visit  
PC  
Visit 
Visit 
PC 
Visit 
PC 
Visit  
PC 
Visit  
PC 
PC 
PC 
PC 
PC 
PC 
Visit/Phone call no. 
V19  
T1  
V29 
V39  
T2 
V49 
T3  
V59 
T4  
V69 
T5  
T6  
T7  
T8 
T9 
T10 
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 
121 
Day  
181 
Day 
195 
Day 211 Day 241 Day 301 
Day 
361 
(ESFU) 
Day 421 Day 481 Day 541 
(ESFU) 
Informed consent2 
●1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed assent, if applicable2 
○1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record any concomitant 
medications/vaccinations 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Record any intercurrent 
medical conditions 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of any AEs leading 
to vaccine/study withdrawal, 
medically attended AEs, SAEs, 
pregnancies and AESIs10 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to 
study participation, or to a 
concurrent GSK 
medication/vaccine 
●7 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study Conclusion8 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
9 Home visits may be performed only by sites authorised (as per local regulations and sponsor agreement), with approved site level standard operating procedures (SOP) provided that 
the compliance with protocol procedures are ensured. Refer to Section 8.9 for information related to study procedures during special circumstances. 
10 Diagnosis of coronavirus 2019 (COVID-19) should be made in accordance with the World Health Organization case definitions. Cases should be reported as AEs or SAEs 
(refer to Section 12.5 for the definitions), and routine procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance 
with the protocol-defined time periods (refer to Table 14). In addition, separate COVID-19 specific eCRF form(s) should be completed. 
 
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Table 4 
Intervals between visits - footnote 
1 Subjects will not be eligible for inclusion in the Per-Protocol Set (PPS) for analysis of 
immunogenicity if the study visit is performed outside this interval.  
Table 5 
Intervals between study visits and phone calls 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1→T1 
15 days 
12 to 18 days after vaccination at V1  
(from -3 to +3 days) 
Visit 3→T2 
15 days 
12 to 18 days after vaccination at V3  
(from -3 to +3 days) 
Visit 3→T3 
60 days 
57 to 63 days after vaccination at V3 
 (from -3 to +3 days) 
Visit 5→T4 
15 days 
12 to 18 days after vaccination at V5  
(from -3 to +3 days) 
Visit 5→T5  
60 days 
53 to 74 days after vaccination at V5  
(from -7 to +14 days) 
Visit 5→T6 
120 days 
113 to 134 days after vaccination at V5  
(from -7 to +14 days) 
Visit 5→T7 (ESFU; study 
end) 
180 days 
173 to 194 days after vaccination at V5 
(from -7 to +14 days) 
Visit 5→T8 
240 days 
233 to 254 days after vaccination at V5  
(from -7 to +14 days) 
Visit 5→T9 
300 days 
293 to 314 days after vaccination at V5 
(from -7 to +14 days) 
Visit 5→T10 (ESFU; study 
end) 
360 days 
353 to 381 days after vaccination at V5  
(from -7 to +21 days) 
Section 3.1 Study rationale 
In 2013, the United States (US) Food and Drug Administration (FDA) agreed with the 
Company proposal to evaluate meningococcal B vaccine effectiveness against a large 
panel of the US epidemiologically relevant invasive disease strains of Neisseria 
meningitidis (N. meningitidis) serogroup B in adolescents using serum bactericidal assay 
with endogenous human complement (enc-hSBA). This panel includes 110 serogroup B 
strains selected from the original panel of 442 endemic strains identified as appropriately 
representative of invasive meningococcal serogroup B strains detected in the US by the 
US Centers for Disease Control (CDC) [Welsch, 2018]. Following licensure of Bexsero 
(rMenB+OMV NZ) in the US in 2015, under accelerated approval regulations, GSK was 
requested to demonstrate effectiveness of Bexsero via a post-approval confirmatory trial 
in US adolescents and young adults.  
Study 3.2 Background 
N.eisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide, 
capable of causing outbreaks and epidemics of invasive disease. N. meningitidis 
infections causing invasive meningococcal disease (IMD) are an important public health 
concern worldwide due to the substantial morbidity and mortality they cause, as well as 
the transmissibility of these infections. In healthy individuals, IMD can rapidly progress 
to serious clinical disease and may be associated with poor outcomes, including fatality in 
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~10% of cases. While the greatest IMD burden is in infants, there is a second peak of 
disease in adolescents and young adults.  
…. In the EU, the vaccine is indicated for use in individuals 2 years of age and older, and 
in the United States (US), in individuals 2 months to 55 years of age.  
Bexsero is indicated for active immunisation against invasive disease caused by Neisseria 
meningitidis (N. meningitidis) serogroup B.  
Section 4 Objective(s) and Endpoint(s) 
Table 6 
Study objectives and endpoints 
Immunological non-inferiority: MenABCWY vaccine 
vs. MenACWY vaccine*** 
To demonstrate the immunological non-inferiority of the 
MenABCWY vaccine compared to the MenACWY 
vaccine as measured by the percentages of subjects 
achieving a 4-fold rise in hSBA titres against N. 
meningitidis serogroups A, C, W and Y at 1 month after 
the last MenABCWY vaccination (0,6-months) and 1 
month after the MenACWY vaccination. 
Criterion: 
LL of the two2-sided 97.5% CI^ for the group difference 
in percentages of subjects achieving a 4-fold rise* in 
hSBA titres is above -10%. 
The percentages of subjects with 4-fold rise* in hSBA 
titres against N. meningitidis serogroups A, C, W and Y 
at 1 month after the: 
• 
last vaccination for the ABCWY group (pooled 
lots) (Day 211, Month 7), and 
• 
1 month after the MenACWY vaccination for the 
ACWY group (Day 31, Month 1) 
relative to baseline (Day 1, Month 0). 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; Enc-hSBA = endogenous complement human serum 
bactericidal assay; GMC = geometric mean concentrations; GMT = geometric mean titre; GMR = geometric mean 
ratio; CI = confidence interval; hSBA = human serum bactericidal assay; LOD: limit of detection; LLOQ = lower limit of 
quantitation; LL = lower limit; AE = Adverse event; SAE = Serious adverse event; AESI = Adverse event of special 
interest 
N. meningitidis serogroup B indicator strains = M14459, 96217, M07-0241084 and NZ98/254 for fHbp, NadA, NHBA 
and PorA P1.4 antigens, respectively. The NHBA indicator strain may be subject to change during the study, before 
clinical testing starts. In this case, this change will be documented either in a protocol amendment or in the clinical 
report.  
Refer to Section 10 for details on evaluation of objectives and sample size justification. Refer to Glossary of Terms for 
definitions of test-based and responder-based effectiveness 
^ If the co-primary effectiveness objectives for rMenB+OMV NZ are met, then all objectives for MenABCWY will be 
evaluated at 95% CI. Refer to Section 10.1 for details 
† If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 0,6-
months is also not met, then the 0,2,6-months schedule will be the comparator. 
*For the Men A, C, W, Y evaluation, the 4-fold rise is defined as: 
a post-vaccination hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD but <LLOQ, 
and 
a post-vaccination hSBA titre ≥4 times the pre-vaccination titre for subjects with a pre-vaccination hSBA titre 
≥LLOQ.  
**For the MenB evaluation, the 4-fold rise per each indicator strain is defined as: 
a post-vaccination‡ hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
a post-vaccination‡ hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD and 
<LLOQ, and 
a post-vaccination‡ hSBA titre ≥4 times the pre-vaccination hSBA titre for subjects with a pre-vaccination hSBA 
titre ≥ LLOQ 
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‡ = post-2nd vaccination for 0,6 and 0,2 schedule and post-3rd vaccination for 0,2,6 schedule). 
***The primary objective of immunological NI of the MenABCWY vaccine to MenACWY will be evaluated only in 
subjects without a previous MenACWY vaccination (unprimed). All other primary and secondary objectives 
will be evaluated in subjects with and without previous MenACWY vaccination (primed/unprimed).  
Section 5.1 
Scientific rationale for study design 
As the rMenB+OMV NZ licensure in the US was issued through accelerated approval, 
the FDA has requested to demonstrate the effectiveness of the vaccine against an 
extended panel of serogroup B meningococcal strains (MenB) as a post-marketing 
commitment in US adolescents and young adults, thus confirming that the vaccine can 
protect against diverse meningococcal B strains prevalent in the United StatesUS.  
The availability of a pentavalent meningococcal vaccine in a single administration would 
however reduce the number of injections and could increase coverage for meningococcal 
disease caused by N. meningitidis serogroups A, B, C, W, and Y worldwide. GSK’s 
investigational MenABCWY combination vaccine is intended to protect against 5 of the 
most prevalent serogroups of Neisseria N. meningitidis (A, B, C, W, Y) in humans. 
Rationale for the selected vaccination schedules 
rMenB+OMV NZ: This study aims at to demonstrate demonstrating the VE of the 
rMenB+OMV NZ vaccine administered as 2-dose vaccine, either with a shorter interval 
(0,2-months) or a prolonged interval (0,6-months) between doses. A 3-dose schedule has 
also been also added to better characterise the VE with an alternative dose regimen as a 
post approval requirement from the US FDA.  
Section 5.2 
Overall design 
Figure 1 
Study design overview 
 
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N = number of subjects; d = dose; V = visit; D = day; T = telephone call; 
Refer to Table 3 for details on all visits 
# subjects will receive 2 doses of MenABCWY vaccine with Lot 1 or Lot 2 or Lot 3 of the MenACWY lyophilised vial 
component of the vaccine. Refer to the study groups description below the figure for details and Figure 1 for the 
detailed study design overview 
Notes:  
Home visits may be performed only by sites authorised (as per local regulations and sponsor agreement), with 
approved site level standard operating procedures (SOP) provided that the compliance with protocol procedures are 
ensured  
Refer to Section 8.9 for information on study procedures during special circumstances. 
Section 5.2 
Overall design 
• 
MenB_0_2_6 group*: subjects will receive 3 doses of rMenB+OMV NZ at Day 1, 
Day 61 and Day 181 (0,2 and 0,2,6-months schedule). These subjects will receive 1 
dose of the MenACWY at Day 211**. Data from this group will be used to assess 
both the 0,2-months and 0,2,6-months schedules; the 0,2-months schedule will be 
assessed 1 month after the second rMenB+OMV NZ vaccination administered at 
Day 61 (Visit 3), and the 0,2,6-months schedule will be assessed 1 month after the 
third rMenB+OMV NZ vaccination at Day 181 (Visit 5), in the same group. 
• 
MenB_0_6 group: subjects will receive 2 doses of rMenB+OMV NZ at Day 1and 
Day 181 and 1 dose of MenACWY vaccine at Day 61 (0,6-months schedule). These 
subjects will receive 1 dose of the placebo at Day 211**. 
• 
ABCWY-1**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 1 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**.  
• 
ABCWY-2**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 2 of the MenACWY lyophilised 
vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**. 
• 
ABCWY-3**: subjects will receive 2 doses of MenABCWY vaccine 6 months apart 
(0,6-months schedule), at Day 1 and 181 with Lot 3 of the MenACWY lyophilised 
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vial component of the vaccine. They will receive 1 dose of placebo at Day 61 and at 
Day 211**. 
• 
ACWY group: subjects will receive 1 dose of MenACWY at Day 1, 1 dose of 
placebo at Day 61 and 2 doses of rMenB+OMV NZ at Day 181 and Day 211**. 
* MenB_0_2_6 group will also be evaluated for objectives pertaining to 0,2-months 
vaccination schedule. In order to let the subjects in MenB_0_2_6 group receive a 
dose of MenACWY vaccine and for subjects in ACWY group to receive the second 
dose of rMenB+OMV NZ in line with the vaccine as standard of care (also in line 
with the Advisory Committee on Immunization Practices (ACIP) recommendations 
in the US [ACIP, 2011]), the subjects in these groups will receive a vaccination of 
MenACWY and rMenB+OMV NZ vaccines, respectively, on Day 211 (Visit 6) after 
completion of the post-vaccination 3 blood sampling. To maintain the blinding of the 
study, subjects in the rest of the groups (MenB_0_6, ABCWY-1, ABCWY-2 and 
ABCWY-3) will receive a dose of Placebo. All these vaccines/ products 
administered at Day 211 are not associated with any study objectives/ endpoints 
(sSafety assessment conducted after 1 dose of rMenB+OMV NZ in the ACWY 
group at Day 181 is to maintain the blind of the study). 
** Note 1: (1) A single MenB lot will be used for the pre-filled syringe component 
of the MenABCWY vaccine; (2) Note 2: The groups ABCWY-1, ABCWY-2, 
ABCWY-3 will be pooled into a single group, ABCWY (pooled lots) (except for 
analysis of lot-to-lot consistency). 
Note 3:  
• 
Duration of the study: The study duration is approximately -18 12 months for each 
subject. 
• 
Primary completion Date (PCD): (T10; Day 541 Day 361; T7).  
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): the date of release of the last testing results, to be achieved not 
later than 8 months after Last Subject Last Visit (LSLV) (LSLV = T7)Day 541; T10. 
If the completion of testing occurs prior the completion of the LSLV the latter date 
defines the end of study visit.  
Refer to glossary of terms for the definition of EOS. 
• 
Safety monitoring: Regular safety follow-up will be done through telephone calls 
(T). There will also be an extended safety follow-up (ESFU) phone call 12 6 months 
post-vaccination 3 (Day 181; Visit 5). This ESFU phone call (Day 361; T7) will also 
mark the study conclusion. Refer to Table 3 and Section 8.5.3 for details on the 
safety follow-up.  
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Section 5.4. 
Subject and study completion 
A subject is considered to have completed the study, if the subject is available for the 
concluding contact (Day 361; T7 T10; Day 541) as described in the protocol.  
Section 6.1 Inclusion criteria for enrolment 
• 
Subjects 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 eDiaryies, return for follow-up visits and is 
available for telephone calls). 
• 
Subjects who are either unvaccinated with MenACWY vaccine or have received a 
single previous dose of MenACWY vaccine can participate in the study, if they 
have received it at least 4 years prior to informed consent and assent as applicable 
(with the exception of meningococcal C vaccination, if the last dose of MenC was 
received at ≤24 months of age). 
Section 6.2.2 Prior/Concomitant therapy 
• 
Previous vaccination against any group B meningococcal vaccine at any time prior 
to informed consent and assent as applicable. Previous vaccination with any 
meningococcal (MenB or MenACWY) vaccine at any time prior to informed 
consent/ assent (as applicable) with the exception of meningococcal C (conjugated or 
polysaccharide) vaccination, if the last dose of MenC was received at ≤24 months of 
age. 
Section 6.3 
Criteria for temporary delay for enrolment and vaccination and/or 
blood sampling 
• 
A positive test for current infection with COVID-19. The testing should have been 
done using a molecular (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.  
• 
Individuals who have received any other vaccines within 7 days (for inactivated 
vaccines) or 14 days (for live vaccines) prior to and following each vaccination up to 
Visit 5*.  
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained. 
In case of seasonal influenza vaccination, the time period described above can be 
reduced if necessary for that vaccine provided it is licensed and used according to 
its Prescribing Information and according to the local governmental 
recommendations.  
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Section 7.1 
Treatments administered  
The study vaccines/ products specific to this study are described below. 
• 
rMenB+OMV NZ (GSK’s Meningococcal Group B Vaccine, Bexsero); 
• 
MenABCWY (GSK’s combined investigational Meningococcal Groups A, B, C, W 
and Y Vaccine); 
• 
MenACWY (GSK’s Meningococcal Groups A, C, W, and Y conjugate Vaccine, 
Menveo); 
• 
Placebo.  
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Table 9 
Treatments administered 
Study Treatment Name: 
Bexsero 
MenABCWY# 
Menveo*** 
Placebo 
Vaccine(s)/Product(s) 
name 
rMenB+OMV NZ 
MenACWY lyo 
rMenB+OMV NZ 
MenA 
MenCWY 
NaCl 
Presentation 
Syringe 
Vial 
Syringe 
Vial 
Vial 
Syringe 
Dose form 
Suspension for injection 
Powder for 
suspension for 
injection 
Suspension for injection 
Powder for 
solution for 
injection 
Solution for injection 
Solution for 
injection 
Vaccines/ product 
formulation†: 
Recombinant N. meningitidis 
serogroup B NHBA fusion 
protein (50 µg) adsorbed on 
aluminium hydroxide; 
Recombinant N. meningitidis 
serogroup B NadA protein (50 
µg) adsorbed on aluminium 
hydroxide; Recombinant N. 
meningitidis serogroup B fHBP 
fusion protein (50 µg) adsorbed 
on aluminium hydroxide; Outer 
membrane vesicles OMV from 
N. meningitidis, serogroup B 
Strain NZ98/254 (25 µg PorA 
P1.4) adsorbed on aluminium 
hydroxide; Aluminium hydroxide 
(0.5 mg Al³⁺); Sucrose; 
Histidine; Sodium chloride; 
Water for injections q.s. 0.5 mL 
MenA(10 µg)-
CRM197; MenC(5 
µg)-CRM197; 
MenW135(5 µg)-
CRM197; MenY(5 
µg)-CRM197 
Recombinant N. 
meningitidis serogroup B 
NHBA fusion protein (50 
µg) adsorbed on 
aluminium hydroxide; 
Recombinant N. 
meningitidis serogroup B 
NadA protein (50 µg) 
adsorbed on aluminium 
hydroxide; Recombinant 
N. meningitidis 
serogroup B fHBP fusion 
protein (50 µg) adsorbed 
on aluminium hydroxide; 
Outer membrane 
vesicles OMV from N. 
meningitidis, serogroup B 
Strain NZ98/254 (25 µg 
PorA P1.4) adsorbed on 
aluminium hydroxide; 
Aluminium hydroxide (0.5 
mg Al³⁺); Sucrose; 
Histidine; Sodium 
chloride; Water for 
injections q.s. 0.5 mL 
MenA(10 µg)-
CRM197 (16.7–
33.3 µg) 
Meningococcal 
group A 
oligosaccharide 
(10 µg) 
conjugated to 
Corynebacterium 
diphtheriae 
(CRM197) protein 
(16.7-33.3 µg); 
Potassium 
dihydrogen 
phosphate; 
Sucrose 
MenC(5 µg)-CRM197 
(7.1–12.5 µg); 
MenW135(5 µg)-CRM197 
(3.3–8.3 µg); MenY(5 
µg)-CRM₁₉₇ (5.6–10 
µg); water for 
injections q.s. 0.5 mL 
Meningococcal group C 
oligosaccharide (5 µg) 
conjugated to 
Corynebacterium 
diphtheriae (CRM197) 
protein (7.1-12.5 µg); 
Meningococcal group W-
135 oligosaccharide (5 
µg) conjugated to 
Corynebacterium 
diphtheriae (CRM197) 
protein (3.3-8.3 µg); 
Meningococcal group Y 
oligosaccharide (5 µg) 
conjugated to 
Corynebacterium 
diphtheriae (CRM197) 
protein (5.6-10 µg); 
Sodium chloride; Sodium 
dihydrogen phosphate 
Sodium 
chloride 
(NaCl) 
(0.9%); 
Water for 
injections  
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Study Treatment Name: 
Bexsero 
MenABCWY# 
Menveo*** 
Placebo 
monohydrate; Disodium 
phosphate dihydrate; 
Water for injections q.s. 
0.5 mL 
Route of Administration 
Intramuscular use 
Intramuscular use 
Intramuscular use 
Intramuscula
r use 
Administration site: 
Location 
Deltoid 
Deltoid 
Deltoid 
Deltoid 
Laterality* 
Non-dominant 
Non-dominant 
Non-dominant 
Non-
dominant 
Number of doses to be 
administered: 
 
 
 
 
• 
MenB_0_2_6 group 
3 
- 
1 
- 
• 
MenB_0_6 group 
2 
- 
1 
1 
• 
ABCWY-1 group 
- 
2 
- 
2 
• 
ABCWY-2 group 
- 
2 
- 
2 
• 
ABCWY-3 group 
- 
2 
- 
2 
• 
ACWY group 
2 
- 
1 
1 
Volume to be 
administered** 
0.5 mL 
0.5mL 
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 
Refer to 
SPM for 
more details 
Manufacturer 
GSK Biologicals SA 
GSK Biologicals SA 
GSK Biologicals SA 
GSK 
Biologicals 
SA  
OMV = Outer Membrane Vesicles; SPM = study procedures manual 
**** The volume of the saline pre-filled syringe may be between 0.6ml and 0.8 mL. The full volume is to be injected.  
 
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Section 7.2.2.2.1 
Study group and treatment number allocation  
The target will be to enrol a total of 3651 eligible subjects who will be randomly assigned 
to 6 study groups in a 5:5:3:3:3:1 ratio (912 each in MenB_0_2_6 and MenB_0_6 groups, 
548 in each ABCWY group and 183 in ACWY group). 
Allocation of the subject to a study group/a treatment number at the investigator site will 
be performed using a randomisation system on internet (SBIR). The randomisation 
algorithm will use a minimisation procedure accounting for study, region (US and ex-US 
countries), previous MenACWY vaccination? (Yes and No)*, and age category (10-17 
years of age and 18-25 years of age). Minimisation factors will have equal weight in the 
minimisation algorithm. 
To ensure adequate representation in the US in line with the post-marketing commitment 
(Section 3.1), a minimum of 30% of adolescents and young adults will be enrolled in the 
US. 
After obtaining the signed and dated ICF/IAF from the subject/subject’s parent/LAR and 
having checked the eligibility of the subject, the blinded site staff in charge of the 
vaccine/product administration will access SBIR. Upon providing the subject 
identification number, the subject’s age category and previous MenACWY vaccination? 
(Yes/ No)*, the randomisation system will determine the study group and will provide the 
treatment number to be used for each dose. Region does not have to be given as an input 
by the site staff as SBIR deduces it from the site ID.  
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 SPM for specific 
instructions. 
If for any reason, after randomisation the subject fails to undergo treatment, this is an 
early Termination and the reason should be recorded in source document as specified in 
the SDA.  
Note that enrolment will be frozen as soon as the target numbers (Table 7) are reached 
in a group has been reached. Refer to the SPM for further details. (refer to Table 7), the 
enrolment will be frozen for this group. 
Note: * Subjects with and without a previous MenACWY vaccination (primed and 
unprimed). 
Section 7.2.3.1 Randomisation to strains for enc-hSBA testing 
The evaluation of the randomly selected panel of invasive serogroup B strains (110 
strains) for each vaccinated subject is not technically feasible with clinically acceptable 
blood volumes drawn from adolescents and young adults. Thus, in addition to 
randomisation of enrolled subjects to the rMenB+OMV NZ or MenABCWY and ACWY 
groups, For each applicable serum sample, 35 strains will be chosen completely at 
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random from the 110 strains. subjects will be randomly assigned to a starting strain 
resulting in a list of planned strains [from the 110-panel] per subject per acquired blood 
sample of sufficient volume for testing. 
• 
These strains were randomly ordered into a testing sequence. This testing sequence 
will be used to define a list of strains to be tested for each subject. Within each study 
group, each subject will be randomly assigned to a start strain in the pre-ordered 
sequence of 110 invasive disease serogroup B strains (e.g., strain 1 or 5 or 101). The 
randomisation algorithm will use a block size of 110 (i.e., a start strain will not be 
repeated for 110 subjects within each block), to ensure as much as possible, a similar 
number of subjects tested for each strain. 
• 
The target number of strains to be tested for each subject will be 35 strains. 
• 
The serum sample collected from each subject will be sent on an ongoing basis to 
GSK Clinical Laboratory Sciences or to laboratories delegated by GSK where the 
assays are available and qualified for the intended use. Aliquots for immunogenicity 
and enc-hSBA testing will be prepared depending on the serum volume available for 
a visit from one subject. A minimum amount of 5 mL of serum needs to be available 
to confirm eligibility to perform enc-hSBA testing. Additional instruction on the 
number of strains to be randomly assigned for enc-hSBA testing, according to the 
actual sample volume of serum provided to the laboratory, is provided in Section 
10.1.2. 
Section 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 vaccine(s)/product(s) recipient and those responsible 
for the evaluation of any study endpoint (e.g. safety, reactogenicity, and effectiveness) 
will all be unaware of which vaccine/product was administered. To do so, 
vaccine/product preparation and administration will be done by qualified healthcare 
professional who will not participate in any of the study clinical evaluation. A minimum 
number of study site personnel responsible for preparing and / or delivering the injections 
will be unblinded. See Glossary of terms for definition of qualified healthcare 
professional and unblinded study staff. The tasks of the unblinded site staff are limited to 
storage, registration of the storage temperature, drug accountability, preparation and 
administration of the study vaccines. No other tasks are to be performed. Site personnel 
responsible for delivering the injection must not be involved in study assessments. The 
study vaccine / placebo will be provided to the site as subjects’ kits, similar in 
appearance, identified with treatment information (either Meningococcal Group B 
Vaccine or Meningococcal Groups A, B, C, W and Y Vaccine or Meningococcal Groups 
A, C, Y and W Conjugate Vaccine or placebo). Refer to SPM for details. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator (See Section 7.3.1). 
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The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.  
The serological data, which could 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 or analysis. 
Section 7.3.1 Emergency unblinding / Table 10  
Table 10 
Contact information for emergency unblinding 
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
For US only Toll Free: + 1 844 446 3133 
Toll-free number: 877 870 0019; Turkey: 800 621 95 95  
Phone: +32 2 656 68 04 
Fax: +32 2 401 25 75 
Email: rix.ugrdehelpdesk@gsk.com 
Refer to SPM for other country-specific numbers. 
Section 7.5.1 Recording of concomitant medications/products and concomitant 
vaccinations 
All medications and vaccines taken or received by the subject within 4 weeks prior to the 
first study vaccination and all the blood products, corticosteroids (PO/IV/IM), 
antineoplastic and immunomodulating agents or radiotherapy taken or received by the 
subject within 90 days prior to the start of the study are considered prior medications and 
are to be recorded on the Prior and Concomitant Medications eCRF. Concomitant 
medications include all medications taken by/administered to the subject at and after 
enrolment to treat any AE collected in the eCRF and any vaccine administered to 
subjects. These medications/ vaccines must be documented on the Prior and Concomitant 
Medications and Vaccination eCRF.  
• Any concomitant vaccination administered in the period starting 14 days before the 
first dose of study vaccine(s)/product(s) and ending at the last study contact (Day -14 
to Day 361541).  
Section 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 
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personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
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 8.9 for further details.  
Section 8.2 Data collected from Subjects 
• 
Post-vaccination solicited local and systemic AEs collected at home by subject 
and/or subject’s parent(s)/LAR(s) and recorded in the Subject eDiary for 7 days 
following each vaccination visit (at Day 1, Day 61 and Day 181). Any ongoing event 
(beyond 7 days) may be followed up for 30 days or until resolution, whichever is 
earlier, in the eDiary. 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 
analyzed as unsolicited AEs (i.e. in the Unsolicited Safety Set). 
Section 8.3.5 Pregnancy test 
Urine samples will be collected for pregnancy testing in females of child-bearing 
potential, before vaccinations at Visits 1, 3, 5 and 6, and the results recorded in the source 
document and the eCRF.  
Section 8.4 Effectiveness and/or immunogenicity assessments 
Future findings may make it desirable to use the samples acquired in this study for future 
further research, not described in this protocol. Additional serological testing may be 
performed in the future to further characterise the antibody response to the antigens 
included in the study vaccines or hSBA against an additional panel of strains of Neisseria 
species. 
Therefore, all subjects in countries where this is allowed will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future further 
research. Future Further research will be subject to prior EC/IRB approval if required 
per local legislation. 
Section 8.4.3 Laboratory assays 
An Enzyme-Linked Immunosorbent Assay (ELISA) will be used to evaluate the 
serotype-specific IgG responses to A, C, W, and Y. The intent is to 
characterisecharacterize whether the immunogenicity measured by hSBA using the 
MenA, C, W and Y indicator strains may be confounded by the contribution of the 
responses against the MenB antigens of the combination vaccine. The ELISA procedure 
is used to detect the amount of serum immunoglobulin G (IgG) antibodies in response to 
specific N. meningitidis polysaccharide antigens.  
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Table 12 
Laboratory assays – table footnote 
* Strain(s) and/or assay cut-off(s) might be subject to change during the course of the 
study (e.g. in case of new qualification, (re-)validation or standardisation). In this case, 
this will be documented either in a protocol amendment or in the clinical report. 
Section 8.4.4.1 
Immunological read-outs / Table 13 
Immunological read-
outs – table footnotes 
12 For detail regarding the method refer to Table 12. 
23 The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report.  
Section 8.5.3 Safety Follow-up Calls 
Safety follow-up phone calls are made on Day 15 (T1), Day 75 (T2), Day 121 (T3), Day 
195 (T4), Day 241 (T5), Day 301 (T6), and Day 361 (T7), Day 421 (T8), Day 481 (T9) 
and Day 541 (T10). Safety follow-up calls are 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 and/or 
parent(s)/legal guardian(s) will be interviewed at Day 15 (SFU 1; T1), Day 75 (SFU 2; 
T2) and Day 195 (SFU 4; T4) according to the script, and information relating to any 
unsolicited AEs will be collected. 
At all safety follow-up phone calls (T1 to T710) information relating to SAEs, AESIs, 
medically attended AEs and AEs leading to withdrawal will be collected. At all Safety 
Follow-up Calls concomitant medications associated with the AE and concomitant 
vaccinations have to be collected. 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. If this script is used as a source document, ensure that 
it meets the definition of a source document as per ICH GCP and/or local 
requirements.   
The site should schedule the next study activity clinic (visit or safety call) with the 
subject and/or parent(s)/LAR(s). 
The subject and/or parent(s)/legal guardian(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 hospitalisation or 
an emergency room visit. 
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Section 8.5.4 Time period and frequency for collecting AE and serious adverse event (SAE) information – Table 14 Reporting 
period for collecting safety information, removal of last three columns of table 
Event 
On 
V1* 
 
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
 
 
Study 
Conclusion 
 
 
Study Conclusion 
T10 
 
D1*** 
D7 
D31 
D61 
D67 
D91 
 D181 
D 187 D 211  
D241 D301 
D 361 
D421 
D481 
D541 
Solicited local and 
systemic AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs leading to 
withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended 
AEs** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation  
or concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.; V: Visit; D: Day, M: Month; T,Telephone call; COVID-19, Coronavirus Disease 2019 
* i.e. consent obtained 
** Including COVID-19 infection related AEs.  
*** Except SAEs related to study participation or concurrent GSK medication/vaccine, all other safety data will be collected starting from Visit 1 after vaccine administration. 
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Section 8.5.6.2 
Regulatory reporting requirements for SAEs 
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.  
Section 8.8. 
Study Termination Visit/ Study Conclusion 
The study termination call will occur on Day 361541. The termination visit will be a 
phone call (also in case of early termination of the study).  
The date of termination is the date of the last contact (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 Section 8.8.1. 
During the phone call at the end of the study (Day 361541), the following procedures will 
be performed: interview of subject and/or parent(s)/legal guardian(s) to collect SAEs, 
AESIs, medically attended AEs, pregnancies and/or concomitant medications/ 
vaccinations. 
Section 8.9 
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 Subject 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 
6). 
• 
Study visits may be performed at a different location* other than the study site (e.g. 
at subject’s home). For study visits involving blood draw, biological samples 
should not be collected if they cannot be processed in a timely manner or 
appropriately stored until the intended use.  
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 4), then the interval may be extended 
as described below in Table 17.  
• 
If despite best efforts it is not possible to administer the dose of study intervention 
as defined in the protocol (see Table 4 then the interval may be extended as 
described below in Table 17.  
* 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. 
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This alternate location should be covered by proper insurance for the conduct of 
study on participants by investigator and staff at a site other than the designated 
study site.  
In case of home visits, the study procedures should be carried out by a qualified 
person/s as delegated by the Principal Investigator, provided that the compliance 
with protocol procedures are ensured. Refer to Schedule of Activities for the 
schedule of visits (see Table 3).  
Refer to local regulations on the conduct of clinical trials during the COVID-19 
(Coronavirus) pandemic for more details. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
Table 17 
Intervals between study visits during special circumstances 
Interval 
Length of interval  
Allowed interval (Visit window) 
Visit 1 → Visit 2 
30 days 
23 to 51 days after vaccination at V1  
(from -7 to +21 days) 
Visit 1→Visit 3 
60 days 
53 to 81 days after vaccination at V1  
(from -7 to +21 days) 
Visit 3→Visit 4 
30 days 
23 to 51 days after vaccination at V3  
(from -7 to +21 days) 
Visit 3→Visit 5 
120 days 
110 to 148 days after vaccination at V3  
(from -10 to +28 days) 
Visit 5→Visit 6 
30 days 
23 to 51 days after vaccination at V5  
(from -7 to +21 days) 
Section 10.1 Sample size determination 
* The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report.  
Section 10.1.1.8. 
Immunological non-inferiority: MenABCWY vs. MenACWY  
For demonstration of non-inferiority of MenABCWY vs MenACWY in subjects without 
a previous MenACWY vaccination (unprimed), the following non-inferiority hypotheses 
will be tested simultaneously for each of the 4 serogroups A, C, W, and Y:  
Section 10.1.2.8 
Immunological non-inferiority: MenABCWY vs. MenACWY 
in subjects without a previous MenACWY vaccination (unprimed) 
One thousand two hundred thirty three (1233) evaluable subjects in the ABCWY group 
(pooled lots) at 1 month after the last vaccination and 137 in the ACWY group at 1 
month after the MenACWY vaccination (at Month 7 for ABCWY group (pooled lots) 
and at Month 1 for ACWY group) Assuming at least 70% subjects without a previous 
MenACWY vaccination (unprimed), there will be at least  863 (70% out of 1233) 
evaluable subjects in the ABCWY group (pooled lots), at 1 month after the last 
vaccination, and 96 (70% out of 137) in the ACWY group at 1 month after the 
MenACWY vaccination (at Month 7 for ABCWY group (pooled lots) and at Month 1 
for ACWY group). This sample size is sufficient to demonstrate that the lower limit of 
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the two-sided 97.5% CIs for by percentage of subjects with 4-fold rise in hSBA titres 
against MenACWY indicator strains A, C, W and Y is > -10%. 
Assuming similar underlying immune response after 2 doses of MenABCWY vaccine, as 
previously observed in study V102_16 (Column 2 and 3 of Table 21), the resulting 
overall power is 99.6%.  
Table 21 
Power calculation to demonstrate non-inferiority for serogroups A, C, W 
and Y of MenABCWY compared to MenACWY in subjects without a 
previous MenACWY vaccination (unprimed), at 1 month after the second 
dose vs 1 month after a single dose 
Serogroup 
MenABCWY 
% 4-fold rise 
(2 doses) 
MenACWY 
% 4-fold rise (1 dose) 
Power (%) for 70% 
subjects unprimed with 
MenACWY 
A 
92.4% 
59.1% 
>99.9% 
C 
95.4% 
56.9% 
>99.9% 
W 
80.4% 
34.0% 
>99.9% 
Y 
90.9% 
62.8% 
>99.9% 
Total 
 
 
99.6% 
Unprimed subjects = Subjects without a previous MenACWY vaccination 
Section 10.1.2.12 
Non inferiority of MenABCWY vs rMenB+OMV NZ 
measured by percentage of subjects with 4-fold rise in hSBA titres against MenB 
component indicator strains post 2nd dose 
*The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report.  
Section 10.2 Populations for analyses 
For analyses of the safety endpoints, subjects will be analysed “as treated” according to 
the actual vaccination a subject received. The list of protocol deviations that would 
result in exclusion from the PPS is available in Section 4.2.2.1 of the Statistical 
Analysis Plan.  
Subgroups: 
• 
Analyses of the primary objectives will be repeated by age group (10-17 years of age 
and 18-25 years of age), race, sex and the US region, , and subjects with and 
without a previous MenACWY vaccination (primed and unprimed) as relevant.  
• 
Additional subgroup analyses may be performed to assess the impact of any 
COVID-19 pandemics. More details will be provided in the Statistical Analysis 
Plan if applicable.  
Section 10.3.3.8 
Immunological non-inferiority: MenABCWY vs. MenACWY  
10.3.3.8 
Immunological non-inferiority: MenABCWY vs. MenACWY in 
subjects without a previous MenACWY vaccination (unprimed) 
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Section 10.3.4.4 
Immune response of MenABCWY, rMenB+OMV NZ and Men 
ACWY 
* The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report.  
Section 11 
References 
Edmond K, Clark A, Korczak VS et al. Global and regional risk of disabling sequelae 
from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis 
2010;10:317-28. 
Harrison O, Claus H, Jiang Y. Epidemiology and nomenclature of N. meningitides 
capsule locus. Emerging Infectious Diseases 2009 19(4):566-573.  
Health Protection Agency. (2006) Laboratory reports of invasive meningococcal 
infections, England and Wales: weeks 46 to 52 2005; Enhanced surveillance of 
meningococcal disease: October to December 2005. CDR Weekly [serial online]; 16(8). 
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 
The following abbreviations were added to the existing list of abbreviations: 
COVID-19: 
Coronavirus disease 2019 
CT: 
Computed tomography 
2019-nCoV: 
2019 novel coronavirus disease 
SARI: 
Severe Acute Respiratory Illness 
Section 12.1.2 Glossary of terms 
End of Study (EoS)  
(Synonym of End of 
Trial) 
For studies with collection of human biological samples 
and/or imaging data, the EoS is defined as Last subject 
last visit (T7T10). or Last testing results released of 
samples collected at Visit 6*  
* In this case EoS must be achieved no later than 8 
months after LSLV.  
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Section 12.2.2 MenB serum bactericidal assays using exogenous human complement 
(hSBA) – rMenB + OMV NZ 
The NHBA indicator strain may be subject to change during the study, before clinical 
testing starts. In this case, this change will be documented either in a protocol amendment 
or in the clinical report.  
Section 12.4.5.1 
Responsibilities of the Investigator and IRB/EC 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favorable favourable opinion. As soon as possible, the implemented deviation 
or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted: 
i. 
to the IRB/IEC for review and approval/favorablefavourable opinion,  
Section 12.5.9 Detecting and recording adverse events, serious adverse events and 
pregnancies 
Subjects eDiaries will be distributed to Each subjects/subject’s parent(s)s/LAR(s) will be 
assigned a Subject eDiary at Visit 1 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.at each vaccination visit on Visit 1, Visit 3 and Visit 5.  
The subject/subject’s parent(s)/LAR(s) will have to must return bring their completed 
eDiaries on at Visit 2, and Visit 4, and return it at Visit 6. The returned Subject eDiaries 
should be verified during discussion with the subject/ subject’s parent(s)/LAR(s) at these 
visits. 
Note: If the diary card Subject eDiary has been filled in by a minor subject, the 
investigator or delegate should verify the reported information during a discussion with 
the minor subject preferably in the presence of his/her parent(s)/LAR(s). 
Section 12.5.9.2. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies 
All solicited AEs during 7 days following administration of each dose of study 
vaccine(s)/product(s) (Day 1 to Day 7) (at Visit 1, Visit 3 and Visit 5) must be recorded 
in the eDiary, irrespective of intensity or whether or not they are considered vaccination-
related. Solicited local and systemic events that are ongoing after the 7-day reporting 
period may continue to be recorded in the eDiary until resolution or up to 30 days post-
vaccination (ie, recording period for unsolicited AEs) whichever occurs first and do not 
need to be entered as an AE in the AE eCRF or the subject’s source document. 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). 
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All other AEs during 30 days following administration of each dose of study 
vaccine(s)/product(s) (Day 1 to Day 30) (at Visit 1, Visit 3 and Visit 5) must be recorded 
in the appropriate section of the eCRF, irrespective of intensity or whether or not they are 
considered vaccination-related. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine(s)/product(s) and will end 612 months following administration of the study 
vaccines (Day 361541 (T710) for each subject. See Section 12.5.10 for instructions on 
reporting of SAEs. In addition to the above-mentioned reporting requirements and in 
order to fulfil international reporting obligations, SAEs that are related to study 
participation (i.e. protocol-mandated procedures, invasive tests, a change from existing 
therapy) or are related to a concurrent GSK medication/vaccine will be collected and 
recorded from the time the subject consents to participate in the study until she/he is 
discharged from the study. 
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. 
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccines and will end 612 months following administration of study vaccines (Day 
361541 (T710). See section 12.5.10 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 612 months following administration of the study vaccines 
(Day 361541 (T710). See section 12.5.10.5 for instructions on reporting of AESIs. 
Section 12.5.9.3.2 
Assessment of adverse events / Assessment of intensity 
The maximum intensity of local Iinjection Site Induration, Swelling, Erythema (redness) 
will be scored at GSK as follows: 
Section 12.5.9.3.2 
Assessment of adverse events / Assessment of causality 
All solicited local and systemiclocal (injection site) AEs will be considered causally 
related to vaccination. Causality of all other AEs should be assessed by the investigator 
using the following question: 
Section 12.5.9.4 
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] 
12.5.9.4.1 
WHO Case Definition 
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• 
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 
C. A person with recent anosmia (loss of smell) or ageusia (loss of taste) in the 
absence of any other identified cause.  
OR 
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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 12.5.10.3 
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 or email 
it to the Study Contact for Reporting SAEs (refer to the SPONSOR INFORMATION) or 
to GSK Clinical Safety and Pharmacovigilance department within 24 hours.  
Section 12.5.11. 
Updating of SAE, pregnancy, and AESI information after 
removal of write access to the subject’s eCRF 
When additional SAE or pregnancy 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 or emailed to the Study Contact for Reporting SAEs 
(refer to the SPONSOR INFORMATION) or to GSK Clinical Safety and 
Pharmacovigilance department within the designated reporting time frames specified in 
Table 15.  
Section 12.5.12.2 
Post-vaccination Visit(s) 
Post-vaccination visits or calls will be performed on Day 15, 75, 121, 195, 241, 301, and 
361, 421, 481 and 541.  
Section12.6.2 Contraception guidance 
Table 29 
Highly Effective Contraceptive Methods 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
injectable  
• 
oral  
12.8.1 Protocol amendment 2 
Overall Rationale for the Amendment/Administrative change: This protocol has been 
amended as a consequence of feedback from Center for Biologics Evaluation and 
Research (CBER) [IND 14605 EOP2 Meeting - FDA's - V72_72 Endpoint Comments 
dated 11 October 2019]. The amendment has also implemented feedback from the Unites 
States (US) Institutional Review Board (IRB) on Protocol Amendment 1. In addition, the 
scope of this post-marketing commitment study has been extended to demonstrate the 
effectiveness, immunogenicity and safety of GSK’s investigational combined 
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meningococcal ABCWY vaccine (from a phase III MenABCWY study) along with the 
rMenB+OMV NZ vaccine. 
Section # and 
Name 
Description of Change 
Brief Rationale 
In this amendment, there has been a major update to the study in terms of objectives and study design. Therefore, 
almost all sections in the protocol have been impacted by the change and suitable changes have been made 
everywhere.  
Amendment 1 to Amendment 2 track changes document contains all changes made to the protocol (Amendment 1). 
Brief rationale has been added, as applicable sections in the protocol track changes document (in a different 
colour). 
Please find below the Section number and name of the sections most impacted and where changes have been 
made: 
Section # and Name 
Title page 
1. Synopsis 
2. Schedule of activities 
3.1 Study rationale 
3,2 Background 
3.3 Benefit/Risk section 
3.3.1 Risk assessment 
3.3.2 Benefit assessment 
3.3.3 Overall Benefit: Risk conclusion 
4. Objectives and Endpoints 
5.1 Scientific Rationale for study design 
5.1.1. Rationale for use of placebo 
5.2 Overall design 
5.3 Number of subjects 
6.1. Inclusion criteria for enrolment 
6.2. Exclusion criteria for enrolment 
6.3. Criteria for temporary delay for enrolment and vaccination 
6.4 Screen and baseline failures 
7.1. Treatments administered 
7.1.1. Precautions to be observed in administering study vaccine 
7.1.2 Vaccine Administration Error or Overdose of Vaccine 
7.2 Method of treatment assignment 
7.2.1. Subject identification 
7.2.2.2.1 Study group and treatment number allocation 
7.2.3. Allocation of subjects to assay subsets 
7.2.3.1 Randomisation to strains for enc-hSBA testing 
7.3. Blinding and unblinding 
7.3.1 Emergency unblinding 
7.5.1. Recording of concomitant medications/products and concomitant vaccinations 
7.5.2. Concomitant medications/products/vaccines that may lead to the elimination of a subject from per-protocol 
analyses 
7.6 Intercurrent medical conditions that may lead to elimination of a subject from per-protocol analyses 
7.8 Warnings and precautions 
7.9 Treatment after completion of the study 
8 Study Assessments And Procedures 
8.2. Data collected from Subjects 
8.3.1 Screening/ Eligibility criteria 
8.3.2. Collection of demographic data 
8.3.4. General and symptom-directed physical examination 
8.3.5. Pregnancy test 
8.4 Effectiveness and/or immunogenicity assessments 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.4.2.1. Blood sampling for effectiveness and immunogenicity response assessments 
8.4.2.2. Other biological samples 
8.4.3. Laboratory assays 
8.4.4.1. Immunological read-outs 
8.4.5. Immunological correlates of protection 
8.5.2. Follow-up Clinic Visit(s) 
8.5.3. Safety Follow-up Calls 
8.5.4. Time period and frequency for collecting AE and serious adverse event (SAE) information 
8.5.6.1 Contact information for reporting of serious adverse events, AESIs and pregnancies 
8.8. Study Termination Visit/ Study Conclusion 
8.8.1. Early Termination Visit 
9.1. Discontinuation from the study 
10. Statistical considerations 
10.1. Sample size determination (whole section) 
10.2. Populations for analyses 
10.3.3. Primary effectiveness and immunogenicity analyses 
10.3.4. Secondary effectiveness and immunogenicity analyses 
10.3.5. Safety analyses 
11. References 
12.1.1. List of abbreviations 
12.1.12. Glossary of terms 
12.2. Appendix 2: Clinical Laboratory tests 
12.3 Appendix 3: Clinical laboratories 
12.4.2. Financial disclosure 
12.4.5.1 Responsibilities of the Investigator and IRB/IEC 
12.4.9 Data quality assurance 
12.5.3. Solicited adverse events 
12.5.4. Other solicited adverse events 
12.5.5 Unsolicited adverse events 
12.5.9. Detecting and recording adverse events, serious adverse events and pregnancies 
12.5.9.1 Post-vaccination reminders 
12.5.9.2. Time period for detecting and recording adverse events, serious adverse events and pregnancies 
12.5.9.3. Evaluation of adverse events and serious adverse events 
12.5.9.3.2 Assessment of adverse events 
12.6.2. Contraception guidance 
12.6.3. Collection of pregnancy information 
Detailed description of Protocol Amendment changes: 
The changed text of the amendment is to be indicated in bold italics in the body of the 
protocol and the deleted text (strikethrough) and the changed text (bold italics) is to be 
provided here below. However, due to extensive changes to the protocol at Amendment 
2, most of which are applicable throughout the document (ex: group names), the amended 
text has been presented in black bold italics only at the first instance. In rest of the 
document it is written in `the section/ table applicable font. Only major changes have 
been presented below (deletions in strike-throughs and additions in bold italics). All 
changes from Amendment 1 including deletions have been presented in the Amendment 
2 track changes document. 
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Changes in contributing authors have been presented below: 
• 
 and 
 Cont, Clinical Research and Development 
Leads 
• 
, Clinical and Epidemiology Project Leader  
• 
 and 
, Study Statistician for GSK 
• 
 and 
, Lead Statisticians 
• 
 and 
 - 
, Oversight Data Managers 
• 
, 
 and 
, Clinical Trials Supply 
Manager 
• 
 and 
, Clinical Laboratory Sciences Read-
Out Team Lead 
• 
 and 
, Clinical Laboratory Sciences Study 
Managers 
• 
, SERM Safety Scientist 
• 
, SERM Safety Physician 
• 
, 
 and 
, Global Regulatory Affairs 
• 
, US Regulatory Affairs and 
, US Agent – Global 
Regulatory Affairs 
• 
, Local Delivery Lead 
• 
, Across Country Expert - Local Delivery Lead 
• 
, US Medical Affairs Lead 
• 
 and 
, Global Patents 
The following changes have been applied throughout the document: 
Phase: Phase 3b = Phase III 
Randomisation ratio: 1:1:1 = 5:5:3:3:3:1 
Study groups: 3 6 groups = rMenB_0_2_6 group, rMenB_0_6 group, ABCWY-1 group, 
ABCWY-2 group, ABCWY-3 group, Control ACWY group 
Epochs have been deleted throughout: 
Epoch 001: Starting at Visit 1 (Day 1) and ending at the post-vaccination 3 blood 
sampling visit (Visit 5; Day 211). 
Epoch 002: Starting after post-vaccination 3 blood sampling visit (Visit 5; Day 211) and 
ending at SFU 10 (T10; 360 days post-vaccination 3; Day 541). 
Indication: Indication of Bexsero is presented in Section 3.2 Background. 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Study visit: An additional study visit has been added (at Month 1, Day 31) – Visit 2. So 
Visit 1 (Day 1, Month 0), Visit 2 (Day 31, Month 1), Visit 3 (Day 61, Month 2), Visit 4 
(Day 91, Month 3), Visit 5 (Day 181, Month 6), Visit 6 (Day 211, Month 7). 
Formulations: Vaccine formulations have been updates as per the current Product 
Lifecycle Management (PLM) process. 
Objectives and endpoints: All objectives and endpoints have been edited/ rewritten. For 
readability, the entire table is not written in black bold italics. 
Objectives 
Endpoints 
Primary 
To assess the effectiveness of the rMenB+OMV NZ 
vaccine against a randomly selected panel of endemic 
US N. meningitidis serogroup B invasive disease 
strains as measured by bactericidal activity using enc-
hSBA at one month after the 2-dose (0-,2-M; 0-,6-M) 
and 3-dose (0-,2-,6-M) vaccination series when 
compared to the Control Group in adolescent and 
young adult subjects. 
Criterion to demonstrate effectiveness of rMenB+OMV 
NZ vaccine: lower limit of the two-sided 95% 
confidence interval (CI) for vaccine effectiveness 
against a randomly selected strain panel between the 
rMenB+OMV NZ and the Control group is above 40%. 
• 
The percentage of subjects without bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains, at one month after the 2-dose (0-,2-M; 0-, 
6-M) and 3-dose (0-,2-,6-M) vaccination series. 
The percentages of subjects will be averaged 
across all strains. 
The study is considered a success if the criterion to demonstrate effectiveness is met for at least one of the 
vaccination schedules. 
Secondary 
To assess the effectiveness of the rMenB+OMV NZ 
vaccine against each of the randomly selected 
endemic US N. meningitidis serogroup B invasive 
disease strains as measured by bactericidal activity 
using enc-hSBA at one month after the 2-dose (0-,2-
M; 0-,6-M) and 3-dose (0-,2-,6-M) vaccination series, 
when compared to the Control Group in adolescent 
and young adult subjects. 
• 
The percentage of subjects without bactericidal 
serum activity using enc-hSBA against each of 
the endemic US N. meningitidis serogroup B 
strains, at one month after the 2-dose (0-,2-M; 0-, 
6-M) and 3-dose (0-,2-,6-M) vaccination. 
To describe the distribution of subjects by percentages 
of serogroup B invasive disease strains killed using 
enc-hSBA at one month after the 2-dose (0-,2-M; 0-,6-
M) and 3-dose (0-,2-,6-M) vaccination series.   
• 
The percentage of serogroup B invasive disease 
strains killed using enc-hSBA in each subject, at 
one month after the 2-dose (0-,2-M; 0-,6-M) and 
3-dose (0-,2-,6-M) vaccination series. 
To assess the percentages of subjects whose sera kill 
≥70% of strains tested using enc-hSBA at one month 
after the 2-dose (0-,2-M; 0-,6-M) and 3-dose (0-,2-,6-
M) vaccination. 
• 
The percentages of subjects whose sera kill 
≥70% of the strains tested using enc-hSBA, at 
one month after the 2-dose dose (0-,2-M; 0-,6-M) 
and 3-dose (0-,2-,6-M) vaccination series.  
To assess the immune response to rMenB+OMV NZ 
vaccine against N. meningitidis serogroup B test 
strains M14459 (fHbp), 96217 (NadA), NZ98/254 
(PorA) and M07-0241084 (NHBA), at one month after 
the 2-dose (0-,2-M; 0-,6-M) and 3-dose (0-,2-,6-M) 
vaccination series, when compared to the Control 
Group. 
The immune response to rMenB+OMV NZ vaccine will 
be evaluated by measuring bactericidal activity against 
N. meningitidis serogroup B test strains as following: 
• 
The percentage of subjects with hSBA titers  
≥ lower limit of quantitation (LLOQ) for each and 
all serogroup B test strains at baseline and at one 
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Objectives 
Endpoints 
month after the 2-dose (0-,2-M; 0-,6-M) and 3-
dose (0-,2-M; 0-,6-M) vaccination series. 
• 
The percentage of subjects with fourfold increase 
in hSBA titers one month after the 2-dose (0-,2-M; 
0-,6-M) and 3-dose (0-,2-M; 0-,6-M) vaccination 
series relative to baseline defined as:  
− 
If the baseline titer is <limit of detection 
(LOD), then post-vaccination titer should be 
≥ 4x LOD or ≥LLOQ, whichever is greater 
− 
If the baseline titer is ≥LOD but <LLOQ, 
then post-vaccination titer should be ≥4x 
LLOQ 
− 
If the baseline titer is ≥LLOQ, then post-
vaccination titer should be ≥ 4x the baseline 
titer  
• 
Geometric mean titers (GMTs) at baseline and at 
one month after the 2-dose (0-,2-M; 0-,6-M) and 
3-dose (0-,2-,6-M) vaccination series and 
geometric mean ratios (GMRs) at one month after 
2-dose (0-,2-M; 0-,6-M) and 3-dose (0-,2-,6-M) 
vaccination series as compared to the baseline. 
To evaluate the safety and reactogenicity of the 
rMenB+OMV NZ and MenACWY vaccines in 
adolescent and young adult subjects. 
• 
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], nausea, fatigue, myalgia, 
arthralgia, headache) adverse events during the 7 
days (including the day of vaccination) following 
vaccination at Day 1, Day 61 and Day 181. 
• 
The frequencies and percentages of subjects with 
any unsolicited AEs (including all SAEs), AEs 
leading to withdrawal and medically attended AEs 
during the 7 and the 30 days (including the day of 
vaccination) following vaccination at Day 1, Day 
61 and Day 181. 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs throughout the study period. 
M = Month; AE = Adverse event; SAE = Serious adverse event; AESI = Adverse event of special interest 
Objectives 
Endpoints 
Primary 
Vaccine effectiveness (Test-based): rMenB+OMV 
NZ 
To demonstrate the effectiveness of the 
rMenB+OMV NZ vaccine against a randomly 
selected panel of endemic US N. meningitidis 
serogroup B invasive disease strains as measured 
by bactericidal activity using enc-hSBA at 1 month 
after the 3-dose (0,2,6-months) and 2-dose (0,6-
months; 0,2-months) vaccination series when 
 
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of the 
endemic US N. meningitidis serogroup B strains, 
at 1 month after the: 
• 
3-dose vaccination series in MenB_0_2_6 
group (Day 211, Month 7) 
• 
2-dose vaccination series in MenB_0_6 group 
(Day 211, Month 7), and 
• 
2-dose vaccination series in MenB_0_2_6 
group (Day 91, Month 3) 
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Objectives 
Endpoints 
compared to 1 month after the MenACWY 
vaccination. 
Criterion 
Lower limit (LL) of the two-sided 97.5% confidence 
interval (CI) for vaccine effectiveness is above 65% 
against a randomly selected strain panel between 
the: 
• 
MenB_0_2_6 and ACWY groups (for 0,2,6-
months schedule) 
• 
MenB_0_6 and ACWY groups (for 0,6-months 
schedule),  
• 
MenB_0_2_6 and ACWY groups (for 0,2-
months schedule)  
• 
1 month after the MenACWY vaccination in 
ACWY group (Day 31, Month 1). 
Effectiveness (Responder-based): rMenB+OMV NZ 
To demonstrate the effectiveness of the 
rMenB+OMV NZ vaccine by assessing the 
percentages of subjects whose sera kill ≥70% of 
strains tested using enc-hSBA at 1 month after the 
3-dose (0,2,6-months) and 2-dose (0,6-months; 0,2-
months) vaccination series of the rMenB+OMV NZ. 
Criterion: 
LL of the two-sided 97.5% CI for the percentages of 
subjects whose sera kill ≥70% of strains is above 
65%, tested for: 
• 
MenB_0_2_6 group (for 0,2,6-months 
schedule) 
• 
MenB_0_6 group (for 0,6-months schedule),  
• 
MenB_0_2_6 group (for 0,2-months schedule)  
 
The percentages of subjects whose sera kill ≥70% 
of the strains tested using enc-hSBA, at 1 month 
after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group)  
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group),  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group)  
The 3 vaccine schedules will be tested for both, test-based and responder-based, in a hierarchical way 
(starting from 0-2-6, to 0-6 and 0-2). Refer to Section 10.1 for details on continuing the evaluation. 
Lot-to-lot consistency: MenABCWY vaccine 
To demonstrate lot-to-lot consistency of the 
immune responses of 3 lots of the MenACWY 
component of the MenABCWY vaccine, as 
measured by hSBA GMTs directed against 
serogroups A, C, W and Y at 1 month after last 
vaccination (0,6-months). 
Criterion: 
The two-sided 97.5% CIs^ for the ratio of hSBA 
GMTs of antibodies against serogroups A, C, W 
and Y are within the [0.5;2.0] equivalence interval 
for each pair of lots. 
 
GMTs directed against serogroups A, C, W and Y 
for each lot (ABCWY-1 group, ABCWY-2 group, 
ABCWY-3 group) at 1 month after the last 
vaccination (Day 211, Month 7) 
Immunological non-inferiority: MenABCWY 
vaccine vs. MenACWY vaccine 
To demonstrate the immunological non-inferiority 
of the MenABCWY vaccine compared to the 
MenACWY vaccine as measured by the 
percentages of subjects achieving a 4-fold rise in 
hSBA titres against N. meningitidis serogroups A, 
C, W and Y at 1 month after the last MenABCWY 
 
The percentages of subjects with 4-fold rise* in 
hSBA titres against N. meningitidis serogroups A, 
C, W and Y at 1 month after the: 
• 
last vaccination for the ABCWY group (pooled 
lots) (Day 211, Month 7), and 
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Objectives 
Endpoints 
vaccination (0,6-months) and 1 month after the 
MenACWY vaccination. 
Criterion: 
LL of the 2-sided 97.5% CI^ for the group 
difference in percentages of subjects achieving a 
4-fold rise* in hSBA titres is above -10%. 
• 
1 month after the MenACWY vaccination for 
the ACWY group (Day 31, Month 1) 
relative to baseline (Day 1, Month 0). 
Vaccine effectiveness (Test-based): MenABCWY 
vaccine 
To demonstrate the effectiveness of the 
MenABCWY vaccine against a randomly selected 
panel of endemic US N. meningitidis serogroup B 
invasive disease strains as measured by enc-hSBA 
at 1 month after the last MenABCWY vaccination 
(0,6-months) when compared to 1 month after the 
MenACWY vaccination. 
Criterion: 
LL of the two-sided 97.5% CI^ for vaccine 
effectiveness is above 65% against a randomly 
selected strain panel between the ABCWY group 
(pooled lots) and the ACWY group. 
 
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of the 
endemic US N. meningitidis serogroup B strains, 
at 1 month after the: 
• 
last vaccination for the ABCWY group 
(pooled) (Day 211, Month 7), and  
• 
1 month after the MenACWY vaccination in 
the ACWY group (Day 31, Month 1).  
Effectiveness non-inferiority: MenABCWY vaccine 
vs. rMenB+OMV NZ vaccine 
To demonstrate the non-inferiority of the 
effectiveness of the MenABCWY vaccine (0,6-
months schedule) compared to the rMenB+OMV 
NZ vaccine (0,2,6-months or 0,6-months or 0,2-
months)† in terms of percentage of samples with 
bactericidal serum activity using enc-hSBA against 
a randomly selected panel of endemic US N. 
meningitidis serogroup B invasive disease strains. 
Criterion: 
 
LL of the two-sided 97.5% CI^ for the difference in 
percentages of samples with bactericidal serum 
activity using enc-hSBA against a randomly 
selected panel of endemic US N. meningitidis 
serogroup B invasive disease strains is above -5% 
at 1 month after: 
• 
 the last vaccination in ABCWY group (pooled 
lots) (for 0,6 months schedule), and 
• 
The last vaccination in MenB_0_2_6 group (for 
0,2,6-months schedule) or the last vaccination 
in MenB_0_6 group (for 0,6-months schedule) 
or the second vaccination in MenB_0_2_6 
group (for 0,2-months schedule  
 
The percentages of samples with bactericidal 
serum activity using enc-hSBA against each of the 
endemic US N. meningitidis serogroup B strains at 
1 month after the: 
• 
last MenABCWY vaccination (Day 211, Month 
7) for the ABCWY group (pooled lots), and 
• 
3-dose vaccination series of rMenB+OMV 
vaccine (Day 211, Month 7 in MenB_0_2_6 
group) or 2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group) or 2-dose 
vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
Effectiveness (Responder-based): MenABCWY 
vaccine 
To demonstrate the effectiveness of MenABCWY 
vaccine by assessing the percentages of subjects 
whose sera kill ≥70% of strains tested using enc-
 
The percentages of subjects whose sera kill ≥70% 
of the strains tested using enc-hSBA, at 1 month 
after the last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7). 
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Objectives 
Endpoints 
hSBA at 1 month after the last vaccination of 
MenABCWY (0,6-months). 
Criterion: 
LL of the two-sided 97.5% CI^ for the percentages 
of subjects whose sera kill ≥70% of strains tested 
for MenABCWY is above 65%. 
Safety 
To evaluate the safety and reactogenicity of the 
MenB, MenABCWY, and the MenACWY vaccines  
• 
The frequencies and percentages of subjects 
with solicited local (i.e., injection site pain, 
erythema, swelling, induration) and systemic 
(i.e., fever [body temperature ≥ 38.0°C], 
nausea, fatigue, myalgia, arthralgia, 
headache) adverse events (AEs) during the 7 
days (including the day of vaccination) 
following each vaccination at Day 1, Day 61 
and Day 181. 
• 
The frequencies and percentages of subjects 
with any unsolicited AEs (including all SAEs, 
AEs leading to withdrawal, AESIs and 
medically attended AEs) during the 30 days 
(including the day of vaccination) following 
each vaccination at Day 1, Day 61 and Day 
181. 
• 
The percentages of subjects with SAEs, AEs 
leading to withdrawal, AESIs and medically 
attended AEs throughout the study period 
[Month 0 to Month 18]. 
Secondary 
To demonstrate the immunological non-inferiority 
of the MenABCWY vaccine compared to the 
rMenB+OMV NZ vaccine as measured by the 
percentages of subjects achieving a 4-fold rise in 
hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the last 
MenABCWY vaccination (0,6-months schedule) 
and 1 month after the rMenB+OMV NZ vaccination 
(0,2,6-months or 0,6-months or 0,2-months)† 
Criterion: 
Non-inferiority will be demonstrated if the LL of the 
2-sided 95% CI for the group difference in 
percentage of subjects achieving a 4-fold rise** in 
hSBA titres against N. meningitidis serogroup B 
indicator strains is above 
 -10%. 
The percentages of subjects with 4-fold rise** in 
hSBA titres against N. meningitidis serogroup B 
indicator strains at 1 month after the: 
• 
last MenABCWY vaccination for the ABCWY 
group (pooled lots) (Day 211, Month 7), and 
• 
3-dose vaccination series of rMenB+OMV 
vaccine(Day 211, Month 7 in MenB_0_2_6 
group) or 2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group) or 2-dose 
vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) † 
 relative to baseline (Day 1, Month 0). 
 
To assess the effectiveness of the rMenB+OMV NZ 
and MenABCWY vaccines against each of the 
randomly selected endemic US N. meningitidis 
serogroup B invasive disease strains as measured 
by bactericidal activity using enc-hSBA at 1 month 
after the 3-dose (0,2,6-months in MenB_0_2_6 
group) and 2-dose (0,6-months in MenB_0_6 
The percentages of samples without bactericidal 
serum activity using enc-hSBA against each of the 
endemic US N. meningitidis serogroup B strains at 
1 month after the:  
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
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Objectives 
Endpoints 
group, 0,2-months in MenB_0_2_6 group and 0,6-
months in the ABCWY (pooled) group) vaccination 
series when compared to 1 month after the 
MenACWY vaccination. 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group) 
• 
last vaccination for the ABCWY group (pooled 
lots) (Day 211, Month 7), and 
• 
MenACWY vaccination (Day 31, Month 1 in 
ACWY group). 
To describe the distribution of subjects by 
percentages of serogroup B invasive disease 
strains killed using enc-hSBA at 1 month after the 
3-dose (0,2,6-months in MenB_0_2_6 group) and 2-
dose (0,6-months in MenB_0_6 group, 0,2-months 
in MenB_0_2_6 group and 0,6-months in the 
ABCWY (pooled) group) vaccination series of 
rMenB+OMV NZ and MenABCWY vaccines. 
The percentages of serogroup B invasive disease 
strains killed using enc-hSBA in each subject at 1 
month after the: 
• 
3-dose vaccination series (Day 211, Month 7 in 
MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, Month 7 in 
MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 3 in 
MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group (pooled 
lots) (Day 211, Month 7) 
To assess the immune response to the 
rMenB+OMV NZ (0,2,6-months, 0,6-months and 0,2-
months) and MenABCWY (0,6-months) vaccines 
against N. meningitidis serogroup B indicator 
strains at pre-vaccination (Day 1, Month 0) and at 1 
month after the last MenABCWY vaccination and at 
1 month after the second and third vaccination of 
rMenB+OMV NZ. 
The immune response to the rMenB+OMV NZ and 
ABCWY vaccines will be evaluated by measuring 
bactericidal activity against N. meningitidis 
serogroup B indicator strains as following: 
1. The percentages of subjects with hSBA titres  
≥ lower limit of quantitation (LLOQ) for each 
(individual response) and all (composite response) 
serogroup B indicator strains at baseline (Day 1, 
Month 0) and at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 
3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
2. The percentages of subjects with 4-fold rise** in 
hSBA titres at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 90, Month 
3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
relative to baseline (Day 1, Month 0). 
3. hSBA GMTs at baseline (Day 1, Month 0) and at 
1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
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Objectives 
Endpoints 
• 
2-dose vaccination series (Day 91, Month 
3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
4. hSBA GMRs at 1 month after the: 
• 
3-dose vaccination series (Day 211, 
Month 7 in MenB_0_2_6 group) 
• 
2-dose vaccination series (Day 211, 
Month 7 in MenB_0_6 group)  
• 
2-dose vaccination series (Day 91, Month 
3 in MenB_0_2_6 group), and 
• 
last vaccination for the ABCWY group 
(pooled lots) (Day 211, Month 7) 
relative to the baseline (Day 1, Month 0). 
To assess the immune response to MenABCWY 
(0,6-months schedule) and MenACWY (single 
dose) vaccines against N. meningitidis serogroups 
A, C, W and Y, at pre-vaccination (Day 1, Month 0) 
and at 1 month after the first and the last 
MenABCWY vaccination and 1 month after the 
MenACWY vaccination. 
1. The percentage of subjects with hSBA titres 
≥ LLOQ for serogroups A, C, W and Y at baseline 
(Day 1, Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) and 
the last MenABCWY vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots), 
and 
• 
at 1 month after the MenACWY vaccination in 
the ACWY group (Day 31, Month 1). 
2. The percentage of subjects with 4-fold rise* in 
hSBA titres at 1 month after the: 
• 
first vaccination (Day 31, Month 1) for the 
ABCWY group (pooled lots) compared to the 
MenACWY vaccination in the ACWY group 
(Day 31, Month 1)  
relative to baseline (Day 1, Month 0). 
3. hSBA GMTs against N. meningitidis serogroups 
A, C, W and Y at baseline (Day 1, Month 0) and: 
• 
at 1 month after the first (Day 31, Month 1) and 
the last MenABCWY vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots), 
and  
• 
at 1 month after the MenACWY vaccination in 
the ACWY group (Day 31, Month 1). 
4. hSBA GMRs against N. meningitidis serogroups 
A, C, W and Y at: 
• 
1 month after the first (Day 31, Month 1) and 
the last MenABCWY vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots) 
as compared to baseline (Day 1, Month 0), and  
• 
1 month after the single MenACWY 
vaccination in the ACWY group (Day 31, 
Month 1) as compared to baseline (Day 1, 
Month 0). 
5.The total IgG as measured by ELISA GMCs 
against serogroups A, C, W and Y at baseline (Day 
1, Month 0) and: 
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Objectives 
Endpoints 
• 
at 1 month after the first (Day 31, Month 1) and 
the last MenABCWY vaccination (Day 211, 
Month 7) for the ABCWY group (pooled lots), 
and  
• 
at 1 month after the MenACWY vaccination in 
the ACWY group (Day 31, Month 1). 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; Enc-hSBA = endogenous complement human 
serum bactericidal assay; GMC = geometric mean concentrations; GMT = geometric mean titre; GMR = 
geometric mean ratio; CI = confidence interval; hSBA = human serum bactericidal assay; LOD: limit of 
detection; LLOQ = lower limit of quantitation; LL = lower limit; AE = Adverse event; SAE = Serious adverse event; 
AESI = Adverse event of special interest 
N.meningitidis serogroup B indicator strains = M14459, 96217, M07-0241084 and NZ98/254 for fHbp, NadA, 
NHBA and PorA P1.4 antigens, respectively. The NHBA indicator strain may be subject to change during the 
study, before clinical testing starts. In this case, this change will be documented either in a protocol 
amendment or in the clinical report. 
Refer to Section 10 for details on evaluation of objectives and sample size justification. Refer to Glossary of 
terms for definitions of test-based and responder-based effectiveness 
^ If the co-primary effectiveness objectives for rMenB+OMV NZ are met, then all objectives for MenABCWY will 
be evaluated at 95% CI. Refer to Section 10.1 for details 
† If all objectives of rMenB+OMV NZ are met, the comparator will be the 0,2-months schedule. If the 0,2-months 
objective is not met, and the 0,6-months is met, then the 0,6-months schedule will be the comparator. If the 
0,6-months is also not met, then the 0,2,6-months schedule will be the comparator. 
*For the Men A, C, W, Y evaluation, the 4-fold rise is defined as: 
• 
a post-vaccination hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
• 
a post-vaccination hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD 
but <LLOQ, and 
• 
a post-vaccination hSBA titre ≥4 times the pre-vaccination titre for subjects with a pre-vaccination 
hSBA titre ≥LLOQ.  
**For the MenB evaluation, the 4-fold rise per each indicator strain is defined as: 
• 
a post-vaccination‡ hSBA titre ≥16 for subjects with a pre-vaccination hSBA titre <4 
• 
a post-vaccination‡ hSBA titre ≥4 times the LLOQ for subjects with a pre-vaccination hSBA titre ≥LOD 
and <LLOQ, and 
• 
a post-vaccination‡ hSBA titre ≥4 times the pre-vaccination hSBA titre for subjects with a pre-
vaccination hSBA titre ≥ LLOQ 
‡ = post-2nd vaccination for 0,6 and 0,2 schedule and post-3rd vaccination for 0,2,6 schedule) 
Entire statistical section (Section 10) has been rewritten in line with the current objectives 
and endpoints. 
The following section has been deleted as it is not applicable for this study (no 
information will be collected from any male subject’s female partners who become 
pregnant while the male subject is participating in this study): 
12.6.3.1 
Male subjects with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male subject’s 
female partner of a male study subject who becomes pregnant while participating in 
this study. This applies only to subjects who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
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appropriate form and submit it to GSK within 2 weeks of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
• 
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. 
12.8.1 Protocol amendment 1 
Overall Rationale for the Amendment/Administrative change: As per the 
recommendation from Center for Biologics Evaluation and Research (CBER) [IND 
11561 Amendments 257, 283 – CBER comments on Study Protocol V72_72 Version 1, 
dated February 08, 2019], the scope of the study has been extended to include the 3-dose 
(0-,2-,6-month) schedule and an additional 2-dose schedule (0-,6-month) along with the 
2-dose (0-,2-month) schedule planned originally. The study will assess the 
immunogenicity of the 2-dose and 3-doses vaccination with rMenB+OMV NZ vaccine 
along with effectiveness and safety. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page 
EudraCT number is added 
This study is in scope of EudraCT 
 
The company name is added to the Title 
In line with posting requirements 
In this amendment, there has been a major update to the study design in terms of study groups, 
vaccinations given, time points etc. The objectives and endpoints have been updated as well. Therefore, 
almost all sections in the protocol have been impacted by the change and suitable changes have been 
made everywhere. Please find below the Section number and name of the sections most impacted and 
where changes have been made: 
Section # and Name 
1. Synopsis 
2. Schedule of activities 
3.1 Study rationale 
3,2 Background 
3.3 Benefit/Risk section 
4. Objectives and Endpoints 
5.1. Scientific Rationale for study design 
5.1.1. Rationale for use of placebo 
5.2.Overall design 
5.3. Number of subjects 
5.4. Subject and study completion 
6.1. Inclusion criteria for enrolment 
6.2. Exclusion criteria for enrolment 
6.3. Criteria for temporary delay for enrolment and vaccination 
7.1. Treatments administered 
7.1.1. Precautions to be observed in administering study vaccine 
7.2.1. Subject identification 
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Section # and 
Name 
Description of Change 
Brief Rationale 
7.2.2. Randomisation of treatment 
7.2.3. Allocation of subjects to assay subsets 
7.3. Blinding and unblinding 
7.5.1. Recording of concomitant medications/products and concomitant vaccinations 
7.5.2. Concomitant medications/products/vaccines that may lead to the elimination of a subject from per-protocol 
analyses 
8.2. Data collected from Subjects 
8.3.2. Collection of demographic data 
8.3.4. General and symptom-directed physical examination 
8.3.6. Pre-vaccination body temperature 
8.4. Effectiveness and/or immunogenicity assessments 
8.4.2. Biological samples 
8.4.3. Laboratory assays 
8.5.2. Follow-up Clinic Visit(s) 
8.5.3. Safety Follow-up Calls 
8.5.7. Follow-up of AEs and SAEs 
8.8. Study Termination Visit/ Study Conclusion 
8.8.1. Early Termination Visit 
10.1. Sample size determination 
10.2. Populations for analyses 
10.3.2. Demography and baseline characteristics analyses  
10.3.3. Effectiveness analyses 
10.3.4. Immunogenicity analyses 
10.3.5. Safety analyses 
11. References 
12.1.1. List of abbreviations 
12.1.12. Glossary of terms 
12.2. Appendix 2: Clinical Laboratory tests 
12.5.3. Solicited adverse events 
12.5.6. Adverse events of special interest 
12.5.9. Detecting and recording adverse events, serious adverse events and pregnancies 
12.5.12. Follow-up of adverse events, serious adverse events, and pregnancies 
Detailed description of Protocol Amendment changes: As per process, the changed 
text of the amendment change should be indicated in bold italics in the body of the 
protocol. The deleted text (strikethrough) and the changed text (bold italics) is to be 
provided in this appendix. However due to the extensive nature of this amendment, the 
changes in the body of the protocol are indicated in the bold italics only at one instance. 
In this section, explanation has been provided for the changes done throughout the 
document. The track changes document can be referred to see all the changes made to the 
protocol (at Amendment 1). 
Other changes: As the sponsorship of the study has changed from Novartis Vaccines to 
GlaxoSmithKline Biologicals’ (GSK), the protocol has been transcribed to the GSK’s 
protocol template (DS-BIO-CLIN-1000 vs 16.1). All applicable & mandatory sections 
and text have been included during the template transfer without highlighting the 
changes. Table 2 and Section 12.9 only present the rationale and the changes made to the 
protocol amendment. 
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