Conditions: Influenza, Human
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 833
Healthy volunteers: yes

Brief summary:
Study to evaluate the safety and immunogenicity of H7N9 antigen in combination with full or half doses of AS03 adjuvant system in healthy adults.

Detailed description:

Arms:
arm 1: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 1 vaccine and AS03B adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 2: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 1 vaccine and AS03A adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 3: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 2 vaccine and AS03B adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 4: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 2 vaccine and AS03A adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 5: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 3 vaccine and AS03B adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 6: Healthy male and female participants who received two doses of FLU-Q-PAN H7N9 Formulation 3 vaccine and AS03A adjuvant. Participants received the first dose at Day 1 and the second dose at Day 22. arm 7: Healthy male and female participants who received two doses of placebo, the first dose at Day 1 and the second dose at Day 22.

Interventions: intervention 1: FLU-Q-PAN H7N9 Formulation 1 intervention 2: FLU-Q-PAN H7N9 Formulation 2 intervention 3: FLU-Q-PAN H7N9 Formulation 3 intervention 4: AS03B intervention 5: AS03A intervention 6: Placebo
Intervention descriptions: intervention 1: Participants received two doses of the FLU-Q-PAN H7N9 Formulation 1 vaccine by intramuscular injection in the non-dominant arm. intervention 2: Participants received two doses of the FLU-Q-PAN H7N9 Formulation 2 vaccine by intramuscular injection in the non-dominant arm. intervention 3: Participants received two doses of the FLU-Q-PAN H7N9 Formulation 3 vaccine by intramuscular injection in the non-dominant arm. intervention 4: Participants received two doses of the AS03B adjuvant by intramuscular injection in the non-dominant arm. intervention 5: Participants received two doses of the AS03A adjuvant by intramuscular injection in the non-dominant arm. intervention 6: Participants received two doses of Placebo by intramuscular injection in the non-dominant arm.

Protocol document:
Prot_000.pdf: 
Protocol
Study ID: 209671
Official Title of Study: A Phase I/II, Observer-Blind, Randomized, Placebo-Controlled, 
Multi-Center Trial to Evaluate the Safety and Immunogenicity of Different Formulations 
of Monovalent Influenza A/Hong Kong/125/2017-like (H7N9) Virus Vaccine with AS03 
Adjuvant System, Given as a Two-Dose Series to Adults 18 to 64 Years of Age and 65 
Years of Age and Older
NCT ID: NCT04789577
Date of Document: 22 February 2022


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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89 
1330 Rixensart, Belgium 
Primary Study 
vaccine/product and number 
GlaxoSmithKline Biologicals’ Influenza A/Hong 
Kong/125/2017-like (H7N9) virus vaccine: 
GSK3206641A (Q-PAN H7N9 vaccine adjuvanted 
with AS03) 
Other Study vaccine/product 
Placebo 
eTrack study number and 
abbreviated title 
209671 (FLU Q-PAN H7N9=AS03-002) 
Date of protocol 
Final: 13 February 2020 
Date of protocol amendment 
Amendment 1 Final: 27 August 2020 
Amendment 2 Final: 22 February 2022 
Title 
A phase I/II observer-blind, randomized, 
placebo-controlled, multi-center trial to evaluate the 
safety and immunogenicity of different formulations 
of monovalent Influenza A/Hong Kong/125/2017-
like (H7N9) virus vaccine with AS03 adjuvant 
system, given as a two-dose series to adults 18 to 
64 years of age and 65 years of age and older 
Short title 
An observer-blind study to evaluate the safety and 
immunogenicity of GlaxoSmithKline Biologicals’ 
influenza vaccine GSK3206641A administered in 
adults 18 to 64 years of age and 65 years of age and 
older 
IND number 
015763 
Based on GSK Biologicals’ Protocol WS v17.0 
© 2020 GSK group of companies or its licensor. 


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Protocol Amendment 2 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
209671 (FLU Q-PAN H7N9=AS03-002) 
Date of protocol amendment 
Amendment 2 Final: 22 February 2022 
Title  
A phase I/II observer-blind, randomized, 
placebo-controlled, multi-center trial to evaluate the 
safety and immunogenicity of different formulations 
of monovalent Influenza A/Hong Kong/125/2017-
like (H7N9) virus vaccine with AS03 adjuvant 
system, given as a two-dose series to adults 18 to 
64 years of age and 65 years of age and older 
Sponsor signatory 
Andrew Hastie, Clinical and Epidemiology Project 
Lead, Vaccines for Influenza (Amended 22 
February 2022) 
 
 
Signature 
 
 
 
Date 
 
 
 


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3 
Protocol Amendment 2 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 Biologicals SA (GSK). 
• 
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 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 participant and/or the participant’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 representatives of GSK Biologicals in the monitoring process 
of the study and in resolution of queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the trial. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information for the 
solely for the purpose of complying with regulatory requirements. 


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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 
209671 (FLU Q-PAN H7N9=AS03-002) 
Date of protocol amendment 
Amendment 2 Final: 22 February 2022 
Title 
A phase I/II observer-blind, randomized, 
placebo-controlled, multi-center trial to evaluate the 
safety and immunogenicity of different formulations 
of monovalent Influenza A/Hong Kong/125/2017-
like (H7N9) virus vaccine with AS03 adjuvant 
system, given as a two-dose series to adults 18 to 
64 years of age and 65 years of age and older 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 


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6 
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 
Central Back-up Study Contact for Reporting SAEs: refer to the protocol 
Section 8.3.3.1. 
Study Contact for Reporting SAEs: refer to the local study contact information 
document. 
5. Details for Emergency Unblinding 
Refer to the protocol Section 6.3.5.1. 
 
This project has been funded in whole or in part with Federal funds from the 
Department of Health and Human Services; Office of the Assistant Secretary for 
Preparedness and Response; Biomedical Advanced Research and Development 
Authority, under Contract No. HHSO100201600004I. 
BARDA Number CLIN 0013 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document history 
Document 
Date 
Amendment 2 
22 February 2022 
Amendment 1 
27 August 2020 
Original Protocol 
13 February 2020 
Amendment 2 22 February 2022 
Overall Rationale for the Amendment: 
Additional analysis sets (modified per protocol sets) have been defined to incorporate 
individuals with extended intervals between vaccination Visit 1 (Day 1) and Visit 2 
(Day 22), and between Visit 2 (Day 22) and Visit 3 (Day 43).  
These analysis sets are included because of the observation of a higher than anticipated 
number of out of window visits impacting the per protocol sets (PPS). 
Additionally, aligned with current document standards, the timeframe for reporting of 
pregnancies by the investigator to the sponsor was updated from 2 weeks to 24 hours, and 
the list of potential immune-mediated disease (pIMDs) was updated. 
Updates regarding study endpoints and planned analyses were made for clarity. 
List of main changes in the protocol and their rationale 
Section # and 
Name 
Description of Change 
Brief Rationale 
8.3.3 Regulatory 
reporting 
requirements for 
SAEs, 
pregnancies, and 
other events 
In Table 12, the timeframe for reporting 
pregnancies for Initial Reports and Follow-up 
of Relevant Information on a Previous Report 
was modified to: 
24 hours  
Updated to match current document 
standards. 
9.3 Population for 
Analyses 
The following text was added to Table 16: 
Modified PPS (mPPS) 1: The mPPS 1 is a 
subset of FAS 1. The mPPS 1 includes all 
FAS 1 participants with no major protocol 
deviations that led to exclusion at or prior 
to Visit 3 (Day 43). The time window 
between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set 
is between 18-32 study days. The interval 
between Visit 2 and Visit 3 will be 14-32 
calendar days. 
 
Major protocol deviations leading to 
exclusion will be defined in the Statistical 
Analysis Plan (SAP) and the Study 
Deviation Rules Document and will be 
Additional analysis sets have been defined to 
incorporate individuals with extended 
intervals between vaccination Visit 1 (Day 1) 
and Visit 2 (Day 22), and between Visit 2 
(Day 22) and Visit 3 (Day 43).  
These analysis sets are included because of 
the observation of a higher than anticipated 
number of out of window visits impacting the 
per protocol sets. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
finalized prior to the interim analysis 
defined in Section 9.5.  
 
mPPS 2: The mPPS 2 is a subset of FAS 2. 
The mPPS 2 includes all FAS 2 
participants with no major protocol 
deviations that lead to exclusion at or 
prior to Visit 2 (Day 22). The time window 
between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set 
is between 18-32 study days. 
  
Major protocol deviations leading to 
exclusion will be defined in the SAP and 
the Study Deviation Rules document and 
will be finalized prior to the interim 
analysis defined in Section 9.5. 
 
MN mPPS 1: All participants in the MN Set 
who are also part of the mPPS 1. 
 
MN mPPS 2: All participants in the MN Set 
who are also part of the mPPS 2. 
9.4.1 General 
Considerations 
The following text was modified as follows: 
− 
The primary and secondary HI 
immunogenicity analyses will be based 
on the applicable Per Protocol Set 
(PPS) as described in Section 9.3 
(Table 16). Supplementary analyses 
for primary and secondary HI 
immunogenicity analyses will be 
based on the applicable mPPS. If the 
difference between PPS 1 and FAS 1 is 
greater than 10%, a second analysis 
based on the FAS will be performed to 
complement the PPS analysis. 
− 
The MN immunogenicity analyses will 
be based on the applicable 
Microneutralization Per Protocol Set 
(MNPPS) as described in Section 9.3 
(Table 16). Supplementary analyses 
for MN immunogenicity analyses will 
be based on the applicable MN 
mPPS. 
Additional analysis sets have been defined to 
incorporate individuals with extended 
intervals between vaccination Visit 1 (Day 1) 
and Visit 2 (Day 22), and between Visit 2 
(Day 22) and Visit 3 (Day 43).  
These analysis sets are included because of 
the observation of a higher than anticipated 
number of out of window visits impacting the 
per protocol sets. 
Few editorial changes were made for clarity. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
9.4.2 Participants 
disposition 
The following text was modified as follows: 
Major deviations will be summarized for the 
Exposed Set (ES) for each study group, age 
group, and overall. The reason for elimination 
from the PPS 1 and PPS 2 and mPPS 1 and 
mPPS 2 will also be summarized. The same 
will be done for MNPPS 1, MNPPS 2, MN 
mPPS 1 and MN mPPS 2. 
Additional analysis sets have been defined to 
incorporate individuals with extended 
intervals between vaccination Visit 1 (Day 1) 
and Visit 2 (Day 22), and between Visit 2 
(Day 22) and Visit 3 (Day 43).  
These analysis sets are included because of 
the observation of a higher than anticipated 
number of out of window visits impacting the 
per protocol sets. 
9.4.3.1 
Immunogenicity 
The following text was added: 
Supplementary immunogenicity analyses 
will be based on the mPPS 1 set. 
Additional analysis sets have been defined to 
incorporate individuals with extended 
intervals between vaccination Visit 1 (Day 1) 
and Visit 2 (Day 22), and between Visit 2 
(Day 22) and Visit 3 (Day 43). 
These analysis sets are included because of 
the observation of a higher than anticipated 
number of out of window visits impacting the 
per protocol sets. 
9.4.3.2 Safety 
The following text was modified (see 
Appendix 8 for deleted text):  
Unsolicited AE endpoints 
− 
Occurrence and relationship to 
vaccination of unsolicited AEs within 
21 days after each vaccination. 
− 
Occurrence and relationship to 
vaccination of AEs with MAEs within 
21 days after each vaccination. 
Updates were made for clarity regarding 
safety endpoints.  
9.4.4.1 
Immunogenicity 
The following text was modified: 
For a subset of participants (MNPPS 1 and 
MNPPS 2 sets and MN mPPS 1 and 
MN mPPS 2), the following aggregate 
variables will be calculated for each vaccine 
group for vaccine-homologous H7N9 MN 
antibody titer: 
Additional analysis sets have been defined to 
incorporate individuals with extended 
intervals between vaccination Visit 1 (Day 1) 
and Visit 2 (Day 22), and between Visit 2 
(Day 22) and Visit 3 (Day 43). 
These analysis sets are included because of 
the observation of a higher than anticipated 
number of out of window visits impacting the 
per protocol sets. 
9.4.5.1 
Demography and 
baseline 
characteristics 
analyses 
The following text was modified (see 
Appendix 8 for deleted text): 
The analysis of demographics will be 
performed separately for the ES and for the 
participants contributing to the PPS (and 
mPPS). 
Editorial changes were made to clarify the 
language in this section. 
9.5.1.1 Analysis at 
Day 43 
The following text was modified regarding 
analyses planned at Day 43 (see Appendix 8 
for deleted text):  
− 
Analyses of unsolicited AEs and 
MAEs up to 21 days after each 
vaccination on as clean as possible 
data. 
Updates were made for clarity regarding 
safety endpoints and related planned 
statistical analyses. 
 


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Section # and 
Name 
Description of Change 
Brief Rationale 
− 
Analyses of SAEs, pIMDs, pregnancies 
and withdrawals due to AEs collected 
up to the Day 43 post-vaccination visit 
will be carried out. 
9.5.1.2 Final 
analysis (Month 
13) 
The following text was modified regarding 
analyses planned at end of study (Month 13 
(see Appendix 8 for deleted text): 
− 
Unsolicited AEs and MAEs reported up 
to 21 days after each vaccination. 
− 
Concomitant medications reported up 
to 21 days after each vaccination. 
Updates were made for clarity regarding 
safety endpoints and related planned 
statistical analyses. 
9.5.2 Statistical 
consideration for 
interim analysis 
Since the primary immunogenicity 
endpoints for the study will be complete by 
the Day 43 visit (collection past Day 43 
includes only assessments for unsolicited 
AEs leading to study withdrawal, SAEs, 
and pIMDs), no statistical consideration for 
multiplicity will be given to account for 
changes in the results reported at the interim 
analysis compared to the final analysis. 
(see Appendix 8 for deleted text) 
Updates were made for clarity regarding 
study endpoints and related planned 
statistical analyses. 
10.3.5.1 Potential 
immune-mediated 
diseases 
Table 19 was modified to current GSK 
protocol requirements 
The pIMD list was updated to reflect changes 
following MedDRA (Medical Dictionary for 
Regulatory Activities) updates and also to 
consider emerging pIMDs of interest in the 
context of COVID-19 vaccine safety 
monitoring. 
10.3.8.1 Time 
period for 
collecting and 
recording AEs 
The following text was modified (see 
Appendix 8 for deleted text): 
All AEs that occur within 21 days following 
administration of each dose of study 
vaccine/product must be recorded into the 
appropriate section of the eCRF, irrespective 
of intensity or whether or not they are 
considered vaccination-related. 
Updates were made for clarity regarding 
safety endpoints. 
 


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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
Document history ..................................................................................................... 7 
List of main changes in the protocol and their rationale ............................................ 7 
1. 
PROTOCOL SUMMARY ........................................................................................ 17 
1.1. 
Synopsis ..................................................................................................... 17 
1.2. 
Schema ...................................................................................................... 17 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 20 
2.1. 
Study rationale ............................................................................................ 20 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/Risk assessment ............................................................................. 21 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 22 
4. 
STUDY DESIGN .................................................................................................... 23 
4.1. 
Overall design ............................................................................................. 23 
4.2. 
Scientific rationale for study design ............................................................. 26 
4.3. 
Justification for dose ................................................................................... 26 
4.4. 
End of Study definition ................................................................................ 27 
5. 
STUDY POPULATION ........................................................................................... 27 
5.1. 
Inclusion criteria for enrollment ................................................................... 27 
5.2. 
Exclusion criteria for enrollment .................................................................. 28 
5.2.1. 
Medical conditions ....................................................................... 28 
5.2.2. 
Prior/Concomitant therapy ........................................................... 29 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 29 
5.2.4. 
Other exclusions .......................................................................... 29 
5.3. 
Lifestyle considerations ............................................................................... 29 
5.4. 
Screen failures ............................................................................................ 29 
6. 
STUDY INTERVENTION ........................................................................................ 30 
6.1. 
Study intervention(s) administered .............................................................. 30 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 33 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 33 
6.3.1. 
Participant identification ............................................................... 33 
6.3.2. 
Randomization to study intervention ............................................ 33 
6.3.3. 
Intervention allocation to the participant ....................................... 33 
6.3.4. 
Allocation of participants to assay subsets ................................... 34 
6.3.5. 
Blinding and unblinding ................................................................ 34 
6.3.5.1. 
Emergency unblinding ................................................ 35 
6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs ......... 35 
6.4. 
Study intervention compliance .................................................................... 36 
6.5. 
Concomitant therapy ................................................................................... 36 
6.6. 
Dose modification ....................................................................................... 36 
6.7. 
Intervention after the end of the study ......................................................... 36 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 37 
7.1. 
Discontinuation of study intervention ........................................................... 37 
7.1.1. 
Criteria for temporary delay for enrollment and/or 
vaccination ................................................................................... 37 
7.1.2. 
Contraindications to subsequent vaccine(s) administration .......... 37 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 38 
7.3. 
Lost to follow-up.......................................................................................... 39 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 39 
8.1. 
Efficacy and/or immunogenicity assessments ............................................. 40 
8.1.1. 
Biological samples ....................................................................... 40 
8.1.2. 
Laboratory assays ....................................................................... 40 
8.1.3. 
Immunological read-outs .............................................................. 42 
8.1.4. 
Immunological correlates of protection ......................................... 42 
8.2. 
Safety Assessments ................................................................................... 43 
8.2.1. 
Pre-vaccination procedures ......................................................... 43 
8.2.1.1. 
Informed consent ........................................................ 43 
8.2.1.2. 
Check inclusion and exclusion criteria ........................ 43 
8.2.1.3. 
Collection of demographic data .................................. 43 
8.2.1.4. 
Medical history ........................................................... 43 
8.2.1.5. 
Physical examination .................................................. 43 
8.2.1.6. 
History of adjuvanted vaccine and influenza 
vaccine ....................................................................... 44 
8.2.1.7. 
Pregnancy test ........................................................... 44 
8.2.1.8. 
Assess pre-vaccination body temperature .................. 44 
8.2.2. 
Study holding rules and safety monitoring.................................... 44 
8.2.2.1. 
Internal Safety Review Committee .............................. 44 
8.2.2.2. 
Outcome of safety evaluation ..................................... 44 
8.2.2.3. 
Study holding rules ..................................................... 45 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
events of interest ........................................................................................ 46 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 46 
8.3.2. 
Method of detecting AEs and SAEs, pregnancies and 
other events ................................................................................. 47 
8.3.2.1. 
Clinically significant abnormal laboratory 
findings ....................................................................... 47 
8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies, 
and other events .......................................................................... 47 
8.3.3.1. 
Contact information for reporting of SAEs, 
pIMDs, pregnancies and study holding rules .............. 48 
8.3.4. 
Treatment of adverse events ....................................................... 48 
8.3.5. 
Participant card ............................................................................ 49 
8.4. 
Treatment of overdose ................................................................................ 49 
8.5. 
Pharmacokinetics ....................................................................................... 49 
8.6. 
Pharmacodynamics .................................................................................... 49 
8.7. 
Genetics ..................................................................................................... 49 
8.8. 
Biomarkers ................................................................................................. 49 
8.9. 
Health outcomes ......................................................................................... 49 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 49 


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9.1. 
Statistical hypotheses ................................................................................. 49 
9.2. 
Sample size determination .......................................................................... 50 
9.2.1. 
Immunogenicity............................................................................ 50 
9.2.2. 
Safety .......................................................................................... 51 
9.3. 
Populations for analyses ............................................................................. 53 
9.3.1. 
Criteria for elimination from analysis ............................................ 54 
9.3.1.1. 
Intercurrent medical conditions and 
concomitant medications/products/vaccines 
that may lead to elimination of a participant 
from per-protocol analyses ......................................... 54 
9.4. 
Statistical analyses ..................................................................................... 54 
9.4.1. 
General considerations ................................................................ 54 
9.4.2. 
Participants disposition ................................................................ 55 
9.4.3. 
Primary endpoint(s) ..................................................................... 56 
9.4.3.1. 
Immunogenicity .......................................................... 56 
9.4.3.2. 
Safety ......................................................................... 56 
9.4.4. 
Secondary endpoint(s) ................................................................. 58 
9.4.4.1. 
Immunogenicity .......................................................... 58 
9.4.5. 
Other analyses ............................................................................ 58 
9.4.5.1. 
Demography and baseline characteristics 
analyses ..................................................................... 58 
9.4.5.2. 
COVID-19 assessments ............................................. 59 
9.5. 
Interim analyses .......................................................................................... 59 
9.5.1. 
Sequence of analyses.................................................................. 59 
9.5.1.1. 
Analysis at Day 43 ...................................................... 59 
9.5.1.2. 
Final analysis (Month 13) ........................................... 60 
9.5.2. 
Statistical consideration for interim analysis ................................. 60 
9.6. 
Data Monitoring Committee (DMC) ............................................................. 61 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 61 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 61 
10.1.1. 
Regulatory and ethical considerations ......................................... 61 
10.1.2. 
Financial disclosure ..................................................................... 62 
10.1.3. 
Informed consent process ............................................................ 62 
10.1.4. 
Data protection ............................................................................ 62 
10.1.5. 
Committees structure ................................................................... 63 
10.1.6. 
Dissemination of clinical study data ............................................. 63 
10.1.7. 
Data quality assurance ................................................................ 64 
10.1.8. 
Source documents ....................................................................... 64 
10.1.9. 
Study and site start and closure ................................................... 65 
10.1.10. Publication policy ......................................................................... 65 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 66 
10.2.1. 
Protocol-required safety laboratory assessments ......................... 66 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of AE .................. 66 
10.3.1. 
Definition of an Adverse Event (AE) ............................................. 66 
10.3.1.1. Events Meeting the AE Definition ............................... 67 
10.3.1.2. Events NOT Meeting the AE Definition ....................... 67 
10.3.2. 
Definition of a Serious Adverse Event (SAE) ............................... 68 
10.3.3. 
Solicited events............................................................................ 69 


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10.3.4. 
Unsolicited adverse events .......................................................... 69 
10.3.5. 
Adverse events of special interest (AESIs) .................................. 70 
10.3.5.1. Potential immune-mediated diseases ......................... 70 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 76 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs ..................... 76 
10.3.7.1. Pregnancy .................................................................. 76 
10.3.8. 
Recording and follow-up of AEs, SAEs, pIMDs and 
pregnancies ................................................................................. 76 
10.3.8.1. Time period for collecting and recording AEs.............. 78 
10.3.8.2. Follow-up of AEs, SAEs, pIMDs or any other 
events of interest ........................................................ 78 
10.3.8.2.1. Follow-up during the study ...................... 78 
10.3.8.2.2. Follow-up after the participant is 
discharged from the study ...................... 78 
10.3.8.2.3. Follow-up of pregnancies ........................ 78 
10.3.8.3. Updating of SAE, pIMD and pregnancy 
information after removal of write access to the 
participant’s eCRF ...................................................... 79 
10.3.9. 
Assessment of intensity and toxicity ............................................. 79 
10.3.9.1. Assessment of intensity .............................................. 79 
10.3.9.2. Assessment of causality ............................................. 81 
10.3.9.3. Medically attended visits ............................................. 82 
10.3.9.4. Assessment of outcomes............................................ 82 
10.3.10. Reporting of SAEs, pIMDs, pregnancies and other events ........... 83 
10.3.10.1. Events requiring expedited reporting to GSK .............. 83 
10.3.10.2. Back-up system in case facsimile or electronic 
reporting system does not work .................................. 83 
10.4. 
Appendix 4: COVID-19 definition and assessment card .............................. 83 
10.4.1. 
COVID-19 assessment card ........................................................ 85 
10.5. 
Appendix 5: Contraceptive guidance and collection of pregnancy 
information .................................................................................................. 88 
10.5.1. 
Definitions .................................................................................... 88 
10.5.1.1. Women of childbearing potential................................. 88 
10.5.1.1.1. Women not considered as women 
of childbearing potential .......................... 88 
10.5.2. 
Contraception guidance ............................................................... 89 
10.5.3. 
Collection of pregnancy information ............................................. 89 
10.5.3.1. Female participants who become pregnant ................ 89 
10.6. 
Appendix 6: Country-specific requirements ................................................. 90 
10.7. 
Appendix 7: Abbreviations and glossary of terms ........................................ 90 
10.7.1. 
List of abbreviations ..................................................................... 90 
10.7.2. 
Glossary of terms ......................................................................... 92 
10.8. 
Appendix 8: Protocol Amendment change history ....................................... 95 
11. REFERENCES ..................................................................................................... 112 
 


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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 18 
Table 2 
Intervals between study visits ................................................................. 20 
Table 3 
Study objectives and endpoints .............................................................. 22 
Table 4 
Study groups, intervention and blinding foreseen in the study ................ 25 
Table 5 
Study groups foreseen in the study ........................................................ 26 
Table 6 
Study interventions administered ........................................................... 31 
Table 7 
Biological samples ................................................................................. 40 
Table 8 
Laboratory assays .................................................................................. 41 
Table 9 
Immunological read-outs ........................................................................ 42 
Table 10 
Study holding rules ................................................................................. 45 
Table 11 
Timeframes for collecting and reporting of safety information ................. 46 
Table 12 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to PPD Pharmacovigilance .................................... 48 
Table 13 
Contact information for reporting of SAEs, pIMDs, pregnancies 
and study holding rules .......................................................................... 48 
Table 14 
Criteria to evaluate primary objective with respect to SCR and 
SPR for anti-HA, 21 days after the second vaccination .......................... 51 
Table 15 
Exact 95% CI on the percentage of participants with AEs 
following vaccination for 60 participants per group ................................. 52 
Table 16 
Populations for analyses ........................................................................ 53 
Table 17 
Solicited administration site events......................................................... 69 
Table 18 
Solicited systemic events ....................................................................... 69 
Table 19 
List of potential immune-mediated diseases (pIMDs) (Amended 
22 February 2022) .................................................................................. 70 
Table 20 
Intensity scales for solicited events in adults 18 years of age or 
more ....................................................................................................... 79 
Table 21 
Highly effective contraceptive methods .................................................. 89 
 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 23 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Rationale: 
Since the notification of emergence of a novel reassortant influenza A/H7N9 virus on 
31 March 2013, 1568 laboratory-confirmed cases of human infection with avian 
influenza A/H7N9 virus in China have been reported to the World Health Organization 
(WHO), including 616 deaths [WHO, 2019; FAO, 2019]. Most human infections, 
associated with poultry exposure, resulted in severe respiratory illness. Although some 
limited human-to-human infection has been reported, no sustained human-to-human 
H7N9 influenza virus transmission has been observed [Xiang, 2016; Zhou, 2017].  
Vaccination is the primary measure to control the spread of influenza virus infection in 
humans. Efforts are therefore underway to develop vaccines that could mitigate the 
impact of an A/H7N9 influenza pandemic. GlaxoSmithKline Biologicals SA (GSK) has 
produced an investigational AS03-adjuvanted influenza A/Hong Kong/125/2017-like 
(H7N9) virus vaccine and will conduct a clinical trial in the United States (US) to assess 
the safety and immunogenicity of different formulations of H7N9 split virus vaccine 
produced in GSK’s Québec facility, administered with AS03 adjuvant. 
In addition, this study is also intended to capture COVID-19 cases among study 
participants based on the WHO criteria (suspected, probable, and confirmed cases). 
Objectives and Endpoints:  
Objectives and endpoints can be found in Table 3. 
1.2. 
Schema 
The study design overview can be found in Figure 1.  
1.3. 
Schedule of Activities (SoA) 
The schedule of activities can be found in Table 1. 
 


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Table 1 
Schedule of Activities 
 
Primary 
Follow-up 
Type of contact 
Visit 1  
TC1  
Visit 2  
TC2  
Visit 3  
TC3  
TC4  
TC5  
TC6  
Time points 
Day 1  
Day 8  
Day 22  
Day 29  
Day 43  
Month 4 
Month 7  Month 10  Month 13  
Sampling time points 
Pre-Vacc I  
 
Pre-Vacc II  
 
Post-Vacc II 
Informed consent  
●  
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
 
 
 
 
 
Collect demographic data 
●  
 
 
 
 
 
 
 
 
Vaccine/Product 
Study group and intervention number allocation 
O 
 
 
 
 
 
 
 
 
Intervention number allocation for subsequent dose 
 
 
O 
 
 
 
 
 
 
Recording of administered intervention number 
● 
 
● 
 
 
 
 
 
 
Vaccine administration 
●  
 
●  
 
  
 
 
 
 
Clinical specimens for laboratory assays 
Blood sampling for antibody determination (25 mL) 
●  
 
● 
 
●  
 
 
 
 
Safety assessments 
Medical history1 
● 
 
 
 
 
 
 
 
 
Physical examination2 
● 
 
 
 
 
 
 
 
 
History of administration of adjuvanted vaccine and influenza 
vaccine1 
● 
 
 
 
 
 
 
 
 
Urine pregnancy test3 
●  
 
●  
 
 
 
 
 
 
Check warnings and precautions to vaccination 
● 
 
● 
 
 
 
 
 
 
Pre-vaccination body temperature4 
●  
 
●  
 
 
 
 
 
 
Record any concomitant medication/vaccination 
●  
 
●  
 
●  
 
 
 
 
Distribution of diary cards and COVID-19 assessment card5 
O 
 
O 
 
 
 
 
 
 
Telephone contact  
 
● 
 
● 
 
● 
● 
● 
● 
Recording of solicited administration site and systemic 
events (Days 1-7 after each vaccination)6 
●  
 
●  
 
 
 
 
 
 
Recording of unsolicited adverse events and MAEs 
(Days 1-21 after each vaccination)6  
●  
● 
● 
● 
● 
 
 
 
 
Occurrence of urticaria/rash within 30 minutes 
post-vaccination observation 
●  
 
●  
 
 
 
 
 
 
Return of diary cards and COVID-19 assessment card5  
 
 
O 
 
O 
 
 
 
 
Diary card transcription by investigator or delegate6 
 
 
● 
 
● 
 
 
 
 
Reporting of pIMDs 
●  
● 
●  
● 
●  
●  
● 
● 
● 


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Primary 
Follow-up 
Type of contact 
Visit 1  
TC1  
Visit 2  
TC2  
Visit 3  
TC3  
TC4  
TC5  
TC6  
Time points 
Day 1  
Day 8  
Day 22  
Day 29  
Day 43  
Month 4 
Month 7  Month 10  Month 13  
Sampling time points 
Pre-Vacc I  
 
Pre-Vacc II  
 
Post-Vacc II 
Reporting of SAEs, pregnancies  
●  
● 
●  
● 
●  
●  
●  
●  
●  
Study conclusion  
 
 
 
 
 
 
 
 
●  
Note: The double-line borders indicate analyses which will be performed on all data obtained up to those time points. 
Note: Participants who discontinue or withdraw from the study should be followed with telephone contacts at Months 4, 7, 10, and 13 (as applicable) for safety follow-up. 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
O is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1 Medical history data should include the presence or absence or risk factors for complications associated with influenza. Influenza vaccination history covers influenza vaccines 
administered in the previous 3 influenza seasons (if any). 
2 At a minimum, temperature and vital signs (e.g. heart rate and respiratory rate, blood pressure) must be collected prior to vaccination. Clinically significant abnormalities are to be 
captured in the eCRF as adverse events. 
3 Urine pregnancy test to be performed for women of childbearing potential; a negative result must be obtained prior to each vaccination. 
4 Fever is defined as temperature  38.0°C/100.4°F. The preferred location for measuring temperature in this study will be oral. Participants with a minor illness (such as mild diarrhea, 
mild upper respiratory infection) without fever may be enrolled and/or vaccinated at the discretion of the investigator. 
5 Diary cards used to capture both solicited administration site and systemic events (Days 1-7 after each vaccination) and unsolicited adverse events (Days 1-21 after each vaccination) 
and COVID-19 assessment cards are provided at the time of each vaccination and collected at the next visit following each vaccination (solicited administration and systemic events 
portion of card) and at the subsequent visit (unsolicited adverse events portion of card) or by mail using the pre-stamped envelope received at the site. 
6 Participant records occurrence, intensity, and duration of solicited administration site events and of each solicited systemic event and unsolicited adverse event. Investigator or 
delegate later assesses and records relationship of each unsolicited adverse event. 
eCRF: electronic case report form; MAEs: medically attended adverse events; Pre-Vacc: pre-vaccination; pIMDs: potential immune-mediated diseases; Post-Vacc: post-vaccination; 
SAEs: serious adverse events; TC: telephone contact 
 


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Table 2 
Intervals between study visits 
Interval 
(by visit number) 
Interval  
(by visit name) 
Optimal interval 
length1 (Days) 
Allowed interval 
(Study Day) 
Visit 1 - TC1 
Visit Day 1 - Telephone Contact Day 8 
7 
6-10 
Visit 1 - Visit 2 
Visit Day 1 - Visit Day 22 
21 
18-252 
Visit 2 - TC2 
Visit Day 22 - Telephone Contact Day 29 
7 
26-30 
Visit 2 - Visit 3 
Visit Day 22 - Visit Day 43 
21 
38-462 
Visit 1 - TC3 
Visit Day 1 - Month 4 Telephone Contact 
90 
80-100 
Visit 1 - TC4 
Visit Day 1 - Month 7 Telephone Contact 
182 
172-192 
Visit 1 - TC5 
Visit Day 1 - Month 10 Telephone Contact 
270 
260-280 
Visit 1 - TC6 
Visit Day 1 - Month 13 Telephone Contact 
385 
375-395 
1 The investigator should arrange study visits within this interval. 
2 Participants may not be eligible for inclusion in the Per Protocol Set (PPS) for immunogenicity analysis for the 
specified interval if blood collections are outside this interval. Refer to Table 16 for populations for analyses. 
TC: telephone contact 
2. 
INTRODUCTION 
2.1. 
Study rationale 
Novel influenza A viruses, including subtypes H5N1, H3N2v, H9N2, A(H1N1)pdm09, 
and H7N9, continue to emerge and infect humans; therefore, it is imperative that 
preparation be maintained for the next influenza pandemic. 
The US National Pre-Pandemic Influenza Vaccine Stockpile contains various influenza 
virus vaccines, including influenza A(H5) and A(H7) virus vaccines, as well as 
adjuvants, including AS03, for administration with the vaccine antigens to improve the 
immunogenicity and achieve antigen dose-sparing. 
Since the notification of emergence of a novel reassortant influenza A/H7N9 virus on 
31 March 2013, 1568 laboratory-confirmed cases of human infection with avian 
influenza A/H7N9 virus in China have been reported to the WHO, including 616 deaths 
[WHO, 2019; FAO, 2019]. Most human infections, associated with poultry exposure, 
resulted in severe respiratory illness. Although some limited human-to-human infection 
has been reported, no sustained human-to-human H7N9 influenza virus transmission has 
been observed [Xiang, 2016; Zhou, 2017]. 
Vaccination is the primary measure to control the spread of influenza virus infection in 
humans. Efforts are therefore underway to develop vaccines that could mitigate the 
impact of an A/H7N9 influenza pandemic. GSK has produced an investigational 
AS03-adjuvanted influenza A/Hong Kong/125/2017-like (H7N9) virus vaccine and will 
conduct a clinical trial in the US to assess the safety and immunogenicity of different 
formulations of H7N9 split virus vaccine produced in GSK’s Quebec facility, 
administered with AS03 adjuvant. 


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2.2. 
Background 
Influenza pandemics occur when a novel influenza virus emerges against which the vast 
majority of the world’s population has no immunity. This phenomenon only occurs with 
influenza A viruses and is attributed to the emergence of a new antigenic variant. This 
phenomenon, known as antigenic shift, typically represents introduction of a novel 
hemagglutinin (HA) antigen displayed on the surface of the virus, with or without a 
concomitant change in neuraminidase, the other major surface antigen. The reservoir of 
viruses bearing surface antigens to which humans are immunologically naïve is in wild 
water birds, and these viruses are believed to contribute their surface antigens to new 
strains capable of infecting humans by the process of gene reassortment, potentially 
occurring in swine or other domestic mammals. Alternatively, some strains of avian 
viruses may be able to invade human hosts directly, although these often replicate poorly 
and are transmitted inefficiently. If such a virus acquires the ability to spread efficiently 
from person to person, the potential result is a global outbreak of disease affecting a high 
percentage of individuals in a short period of time, a pandemic, and this is likely to cause 
significant morbidity and mortality throughout the world. 
GSK’s clinical development program for immunization against influenza caused by 
potential pandemic subtypes deploys its proprietary Adjuvant System 03 (AS03). This 
adjuvant system contains α-tocopherol (11.86 mg for “AS03A”; 5.93 mg for “AS03B”) 
and squalene in an oil-in-water emulsion. Data with antigen-sparing formulations 
containing AS03 have been or are being generated in the context of multiple potential 
pandemic influenza threats. 
Despite the development of antiviral drugs, vaccination remains the most effective way 
of controlling influenza during inter-pandemic periods. As part of US Department of 
Health and Human Services pandemic preparedness activities, the safety, 
immunogenicity, and dose-sparing ability of full and half doses of AS03 adjuvant in 
combination with influenza A/Hong Kong/125/2017-like (H7N9) virus vaccine will be 
evaluated. 
Please refer to the current Investigator’s Brochure (IB) for information regarding 
pre-clinical and clinical studies and the potential risks and benefits of GSK’s 
AS03-adjuvanted pandemic influenza vaccines. 
2.3. 
Benefit/Risk assessment 
Considering the measures taken to minimize risk to participants enrolled in this study, the 
potential or identified risks are justified by the potential benefits (prevention) that may be 
afforded to participants. 
Detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of GSK’s AS03-adjuvanted pandemic influenza vaccines 
can be found in the IB. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 3 
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
Co-primary 
Immunogenicity: 
• 
To evaluate whether the monovalent influenza 
A/Hong Kong/125/2017-like (H7N9) virus vaccine 
containing 1.9 µg, 3.75 µg, or 7.5 µg of 
hemagglutinin (HA) adjuvanted with AS03A or 
AS03B elicits a hemagglutination inhibition (HI) 
antibody response to the vaccine-homologous 
virus that meets or exceeds the US Food and Drug 
Administration, Center for Biologics Evaluation and 
Research immunogenicity criteria at the Day 43 
visit. 
• 
Humoral immune response in terms of 
vaccine-homologous HI antibody titers: 
− 
Seroprotection rates (SPR) at Day 43 
− 
Seroconversion rates (SCR) at Day 43 
Safety: 
• 
To describe the safety and reactogenicity of the 
different vaccine formulations through the Day 43 
visit. 
• 
Occurrence of adverse events (AEs) 
− 
Solicited administration site events during a 
7-day follow-up period (i.e. day of 
vaccination and 6 subsequent days) after 
each vaccination 
− 
Solicited systemic events during a 7-day 
follow-up (i.e. day of vaccination and 
6 subsequent days) after each vaccination 
− 
Unsolicited AEs and medically attended 
adverse events (MAEs) for 21 days after 
each vaccination 
− 
Serious adverse events (SAEs), potential 
immune-mediated disease (pIMDs) up to 
Day 43 visit 
Safety: 
• 
To describe the safety of the different vaccine 
formulations through Month 13 
 
• 
Occurrence of pIMDs and SAEs until Month 13 
Secondary 
• 
To describe the vaccine homologous H7N9 HI 
antibody profile in all study groups at Days 1, 22, 
and 43 
• 
Vaccine-homologous (H7N9) HI antibody titers 
for each study group: 
− 
Geometric Mean Titers (GMTs) at Days 1, 
22, and 43 
− 
Seropositivity rates at Days 1, 22 and 43 
− 
SCR at Days 22 
− 
SPR at Days 1 and 22 
− 
Mean Geometric Increase (MGI) at Days 
22 and 43 
• 
To describe the vaccine homologous (H7N9) 
Microneutralization (MN) antibody profiles in a 
subset of participants at Days 1, 22, and 43 
• 
Vaccine-homologous (H7N9) MN antibody titers 
for subset of participants: 
− 
GMTs at Days 1, 22, and 43 
− 
Seropositivity rates at Days 1, 22, and 43 
− 
Vaccine response rate (VRR) at Days 22 
and 43 
See List of abbreviations and Glossary of terms for the definitions of AE, GMT, HI, MAE, MGI, MN, pIMD, SAE, SCR, 
SPR, and VRR. 


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4. 
STUDY DESIGN 
4.1. 
Overall design 
Figure 1 
Study design overview 
 
Note: Study groups and intervention (2 doses) to be administered: 190_B: 1.9 µg Hemagglutinin (HA) and AS03B; 
190_A: 1.9 µg HA and AS03A; 375_B: 3.75 µg HA and AS03B; 375_A: 3.75 µg HA and AS03A; 750_B: 7.5 µg HA and 
AS03B; 750_A: 7.5 µg HA and AS03A; and Placebo: formulation buffer S9b (phosphate buffered saline). 
Note: At least 2 internal Safety Review Committee (iSRC) reviews are planned. During each review, reactogenicity and 
safety data for approximately 140 participants (approximately 10 participants per vaccine group and placebo group) will 
be monitored. The first iSRC review will occur when data collected for 7 days post-Dose 1 (i.e. Day 1 to Day 7, 
inclusive) are available; the second review will occur based on the available data collected 7 days post-Dose 2 (i.e. 
Day 22 to Day 28, inclusive) for the same group of participants. Additional iSRC reviews may be carried out as needed 
(Section 8.2.2.2). 
AE: adverse event; M: Month; MAE: medically attended adverse events; N: number of participants; pIMD: potential 
immune-mediated disease; SAE: serious adverse event; TC: telephone contact 


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This is a Phase I/II, observer-blind, randomized, placebo-controlled, age stratified, 
multi-center study with 7 parallel groups, that will be conducted in the US. 
The study will enroll approximately 840 participants randomly assigned to 1 of 7 groups 
of equal size to receive 2 doses of study vaccine or placebo administered intramuscularly 
21 days apart. Each participant will participate for approximately 12 months after receipt 
of the final dose administered. 
The enrollment will be performed to evenly distribute participants across the 2 age 
groups (18-64 years, ≥ 65 years) (i.e. of the 120 participants in each study group, 
60 participants will be aged 18 to 64 years and 60 participants will be aged ≥ 65 years).   
Within the 18-64 years age group, the enrollment is further stratified into 18-49 years and 
50-64 years to allow an even distribution of participants in terms of intervention 
allocation. 
In addition, this study is also intended to capture COVID-19 cases among study 
participants based on the WHO criteria [WHO, 2020]: suspected, probable, or confirmed. 
COVID-19 infection cases will be reported as AEs per normal reporting mechanisms. All 
AEs should be considered as to whether they meet SAE criteria, and if so, submitted 
through the SAE reporting mechanism. The COVID-19 eCRF page will be used to 
capture additional COVID-19 case details that would not normally be contained 
elsewhere in the eCRF. 
• 
Type of study: self-contained. 
• 
Experimental design: Phase I/II, observer-blind, randomized, placebo-controlled, age 
stratified, multi-center study with 7 parallel groups. 
• 
Duration of study: Each participant will participate for approximately 13 months 
(403 days) after receipt of the initial vaccine dose. 
• 
Control: placebo. 
• 
Blinding: observer-blind. 
• 
Data collection: electronic case report form (eCRF). Solicited administration site or 
systemic events and any unsolicited AEs will be collected using a Participant Diary 
(Paper Diary [pDiary]). 
• 
Safety monitoring: Refer to Section 8.2.2 for the description of review of safety data 
by an internal Safety Review Committee (iSRC) and details regarding holding rules 
and safety monitoring. 


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Table 4 
Study groups, intervention and blinding foreseen in the study 
Intervention 
name 
Vaccine/Product name 
Study groups 
Blinding 
190_B 190_A 375_B 375_A 750_B 750_A Placebo Observer-
Blind 
1.9 μg HA + 
AS03B 
FLU-Q-PAN H7N9 (1.9) 
● 
 
 
 
 
 
 
● 
AS03B 
● 
 
 
 
 
 
 
● 
1.9 μg HA + 
AS03A 
FLU-Q-PAN H7N9 (1.9) 
 
● 
 
 
 
 
 
● 
AS03A 
 
● 
 
 
 
 
 
● 
3.75 μg HA + 
AS03B 
FLU-Q-PAN H7N9 (3.75) 
 
 
● 
 
 
 
 
● 
AS03B 
 
 
● 
 
 
 
 
● 
3.75 μg HA + 
AS03A 
FLU-Q-PAN H7N9 (3.75) 
 
 
 
● 
 
 
 
● 
AS03A 
 
 
 
● 
 
 
 
● 
7.5 μg HA + 
AS03B 
FLU-Q-PAN H7N9 (7.5) 
 
 
 
 
● 
 
 
● 
AS03B 
 
 
 
 
● 
 
 
● 
7.5 μg HA + 
AS03A 
FLU-Q-PAN H7N9 (7.5) 
 
 
 
 
 
● 
 
● 
AS03A 
 
 
 
 
 
● 
 
● 
Placebo 
Formulation buffer S9b 
 
 
 
 
 
 
● 
● 
AS03A and AS03B refer to AS03A and AS03B. 
Formulation buffer S9b is a phosphate buffered saline. 


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Table 5 
Study groups foreseen in the study 
Study Intervention 
Study Groups 
Number of 
participants per 
study group 
Age group 
Number of 
participants per age 
group* 
1.9 μg HA + AS03B 
190_B 
120 
18 - 64 years 
60 
 65 years 
60 
1.9 μg HA + AS03A 
190_A 
120 
18 - 64 years 
60 
 65 years 
60 
3.75 μg HA + AS03B 
375_B 
120 
18 - 64 years 
60 
 65 years 
60 
3.75 μg HA + AS03A 
375_A 
120 
18 - 64 years 
60 
 65 years 
60 
7.5 μg HA + AS03B 
750_B 
120 
18 - 64 years 
60 
 65 years 
60 
7.5 μg HA + AS03A 
750_A 
120 
18 - 64 years 
60 
 65 years 
60 
Placebo 
Placebo 
120 
18 - 64 years 
60 
 65 years 
60 
Total number of participants 
840 
 
 
* Within each of the 7 study groups, approximately 60 participants per age group will be enrolled with 57 evaluable 
participants accounting for possible 5% dropout. 
4.2. 
Scientific rationale for study design 
The study will evaluate the safety and immunogenicity of H7N9 antigen (A/Hong 
Kong/125/2017) in combination with full or half doses of AS03 adjuvant system. 
Non-adjuvanted H7 influenza antigens have been poorly immunogenic in vaccine studies 
to date. For this reason, GSK anticipates that an adjuvanted vaccine, administered as a 
two-dose series, will be required to elicit a potentially protective immune response. 
The inclusion of a placebo control group in this observer-blind study will permit unbiased 
assessment of vaccine safety and reactogenicity. 
4.3. 
Justification for dose 
The rationale for evaluating 1.9 g, 3.75 g and 7.5 g doses of H7N9 antigen is based 
on the Biomedical Advanced Research and Development Authority (BARDA) 
requirement to assess the dose-sparing ability of influenza A/Hong Kong/125/2017-like 
(H7N9) virus vaccine in combination with full or half doses of AS03. All 3 antigen doses 
have been part of GSK’s clinical development program with an AS03-adjuvanted split 
virus H5N1 and H7N9 influenza vaccines. 


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AS03A (11.86 mg tocopherol in 0.25 mL) and AS03B (5.93 mg tocopherol in 0.125 mL) 
will be evaluated in this study, since both AS03 formulations have been shown to 
improve the immunogenicity of inactivated split-virion H5N1 and H7N9 influenza 
vaccines in studies conducted by GSK. 
4.4. 
End of Study definition 
A participant is considered to have completed the study if he/she is available for the last 
scheduled contact at Month 13 as described in the protocol. 
End of Study:  Last subject last visit (telephone contact at Month 13). 
5. 
STUDY POPULATION 
5.1. 
Inclusion criteria for enrollment 
Adherence to these criteria as specified in the protocol is essential. Inclusion criteria 
deviations are not allowed because they can jeopardize the scientific integrity or 
regulatory acceptability of the study or participant safety.  
All participants must satisfy ALL of the following criteria at study entry: 
1. Healthy participants as established by medical history and clinical examination 
before entering into the study. 
2. A male or female ≥ 18 years of age at the time of first vaccination. 
3. Participants, who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards and COVID-19 
assessment card, return for follow-up visits, or return the diary cards and COVID-19 
assessment card in a timely manner using the pre-stamped envelope received at the 
site). 
4. Written or witnessed/thumb printed informed consent obtained from the participant 
prior to performance of any study specific procedure. 
5. Female participants of non-childbearing potential may be enrolled in the study. 
Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion hysterectomy, bilateral ovariectomy or post-menopause. 
Female participants of childbearing potential may be enrolled in the study, if the 
participant: 
• 
has practiced adequate contraception for 1 month prior to vaccination, and 
• 
has a negative pregnancy test on the day of vaccination, and 
• 
has agreed to continue adequate contraception during the entire treatment period and 
for 2 months after completion of the vaccination series. 
Refer to Section 10.5.1 for definitions of women of childbearing potential and adequate 
contraception. 


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5.2. 
Exclusion criteria for enrollment 
Adherence to criteria specified in the protocol is essential. Exclusion criteria deviations 
are not allowed because they can potentially jeopardize the scientific integrity or 
regulatory acceptability of the study or safety of the participant. 
The following criteria should be checked at the time of study entry. The potential 
participant MUST NOT be included in the study if ANY exclusion criterion applies: 
5.2.1. 
Medical conditions 
1. Current diagnosis or history of autoimmune disorder(s). Refer to Table 19 for 
conditions that constitute autoimmune disorder(s). 
2. History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
3. Hypersensitivity to latex. 
4. Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality that appears uncontrolled, as determined by history or 
physical examination. 
5. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
6. Recurrent history or uncontrolled neurological disorders or seizures. 
7. History of Guillain-Barré syndrome. 
8. Diagnosed with narcolepsy; or history of narcolepsy in a participant’s parent, sibling 
or child. 
9. Diagnosed with cancer, or treatment for cancer within 3 years. 
− 
Persons with a history of cancer who are disease-free without treatment for 
3 years or more are eligible. 
− 
Persons with a history of histologically-confirmed basal cell carcinoma of the 
skin successfully treated with local excision only are accepted and are eligible, 
but other histologic types of skin cancer are exclusionary. 
− 
Women who are disease-free 3 years or more after treatment for breast cancer 
and receiving long-term prophylaxis (for example, with tamoxifen) are eligible. 
10. Documented human immunodeficiency virus-positive participant. 
11. Any clinically significant* hematological laboratory abnormality. 
*The investigator should use his/her clinical judgement to decide which 
abnormalities are clinically significant. 
12. Bedridden participants. 
13. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the study. 


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5.2.2. 
Prior/Concomitant therapy 
1. Use of any investigational or non-registered product (drug, vaccine or medical 
device) other than the study vaccine/product during the period beginning 30 days 
before the first dose of study vaccine/product (Day -29 to Day 1), or planned use 
during the study period. 
2. Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
3. Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 3 months before the first dose of study vaccine/product or 
planned administration during the study period. 
4. Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
3 months prior to the first vaccine/product dose. For corticosteroids, this will mean 
prednisone equivalent ≥ 20 mg/day. Inhaled and topical steroids are allowed. 
5.2.3. 
Prior/Concurrent clinical study experience 
1. Concurrently participating in another clinical study, at any time during the study 
period, in which the participant has been or will be exposed to an investigational or a 
non-investigational vaccine/product (drug or medical device). 
5.2.4. 
Other exclusions 
1. Pregnant or lactating female. 
2. Female planning to become pregnant or planning to discontinue contraceptive 
precautions within 2 months after completion of the vaccination series. 
3. History of or current chronic alcohol consumption and/or drug abuse. 
4. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the study. 
5. Any study personnel or immediate dependents, family, or household member. 
5.3. 
Lifestyle considerations 
Not applicable 
5.4. 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomly assigned to study intervention. 


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6. 
STUDY INTERVENTION 
A ‘study intervention’ is defined as a set of investigational or marketed product(s) or 
placebo intended to be administered to a participant during the study. 
Refer to the Study Procedures Manual (SPM) for additional details. 
6.1. 
Study intervention(s) administered 
Dose preparation is to be performed by an unblinded member of the site staff. For study 
vaccines adjuvanted with AS03, thorough mixing of the antigen and adjuvant 
components is required. Placebo does not require mixing. Detailed instructions for 
vaccine and placebo preparation will be provided separately in the SPM.  
All vials of vaccine/product provided in this study are intended for single use only. 
All used vials will be retained for monitoring and reconciliation purposes. 
All doses are administered intramuscularly into the deltoid region of the non-dominant 
arm. All study vaccines will be administered by an unblinded member of the site staff 
who may also participate in dose preparation, but who is barred from participation in any 
other study functions and may not contribute any observations.  
The needle for any intramuscular injection should be long enough to reach the muscle 
mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to 
involve underlying nerves and blood vessels or bone. Vaccinators should be familiar with 
the anatomy of the area into which they are injecting vaccine. 
A summary of the study interventions can be found in Table 6. The schedule of study 
intervention administration can be found in Section 4. 
 


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Table 6 
Study interventions administered 
Study Intervention 
Name: 
1.9 μg HA + AS03B ** 
1.9 μg HA + AS03A * 
3.75 μg HA + AS03B ** 
3.75 μg HA + AS03A * 
Vaccine/Product name: FLU-Q-PAN H7N9 
(1.9) 
AS03B  
FLU-Q-PAN H7N9 
(1.9) 
AS03A  
FLU-Q-PAN H7N9 
(3.75) 
AS03B  
FLU-Q-PAN H7N9 
(3.75) 
AS03A  
Presentation: 
Suspension for 
suspension for 
injection in vial 
Emulsion for 
suspension for 
injection in vial 
Suspension for 
suspension for 
injection in vial 
Emulsion for 
suspension for 
injection in vial 
Suspension for 
suspension for 
injection in vial 
Emulsion for 
suspension for 
injection in vial 
Suspension for 
suspension for 
injection in vial 
Emulsion for 
suspension for 
injection in vial 
Vaccine/product 
formulation: 
A/Hong 
Kong/125/2017 - 
like (H7N9) (1.9 µg 
HA); Water for 
injections q.s. 
0.125 mL 
AS03B: DL-α-
tocopherol and 
squalene in an o/w 
emulsion (5.93 mg 
DL-α-tocopherol); 
Water for injections 
q.s. 0.125 mL 
A/Hong 
Kong/125/2017 - 
like (H7N9) (1.9 µg 
HA); Water for 
injections q.s. 
0.125 mL 
AS03A: DL-α-
tocopherol and 
squalene in an o/w 
emulsion (11.86 
mg DL-α-
tocopherol); Water 
for injections q.s. 
0.25 mL 
A/Hong 
Kong/125/2017 - 
like (H7N9) (3.75 
µg HA); Water for 
injections q.s. 
0.125 mL 
AS03B: DL-α-
tocopherol and 
squalene in an o/w 
emulsion (5.93 mg 
DL-α-tocopherol); 
Water for injections 
q.s. 0.125 mL 
A/Hong 
Kong/125/2017 - 
like (H7N9) (3.75 
µg HA); Water for 
injections q.s. 0.25 
mL 
AS03A: DL-α-
tocopherol and 
squalene in an o/w 
emulsion (11.86 
mg DL-α-
tocopherol); Water 
for injections q.s. 
0.25 mL 
Volume to be 
administered: 
0.25 milliliter(s)  
0.375 milliliter(s) 
0.25 milliliter(s) 
0.5 milliliter(s) 
Number of doses to be 
administered: 
2 
2 
2 
2 
Route of 
Administration: 
Intramuscular use 
Administration site: 
Location 
Deltoid  
Directionality  
Not applicable 
Laterality**** 
Non-dominant  
Packaging and 
Labelling: 
Refer to the Standard Procedures Manual for more details 
Manufacturer: 
GSK Biologicals SA  
Type of contact/ Time 
points: 
Visit 1 (Day 1), Visit 2 (Day 22) 


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Study Intervention Name: 
7.5 μg HA + AS03B ** 
7.5 μg HA + AS03A * 
Placebo  
Vaccine/Product name: 
FLU-Q-PAN H7N9 (7.5) 
AS03B  
FLU-Q-PAN H7N9 (7.5) 
AS03A  
Formulation buffer S9b *** 
Presentation: 
Suspension for suspension for 
injection in vial 
Emulsion for suspension for 
injection in vial 
Suspension for suspension 
for injection in vial 
Emulsion for 
suspension for injection 
in vial 
Solution for injection in vial 
Vaccine/product formulation: 
A/Hong Kong/125/2017-like 
(H7N9) (7.5 µg HA); Water for 
injections q.s. 0.25 mL 
AS03B: DL-α-tocopherol and 
squalene in an o/w emulsion 
(5.93 mg DL-α-tocopherol); 
Water for injections q.s. 
0.125 mL 
A/Hong Kong/125/2017-like 
(H7N9) (7.5 µg HA); Water 
for injections q.s. 0.25 mL 
AS03A:  DL-α-
tocopherol and 
squalene in an o/w 
emulsion (11.86 mg 
DL-α-tocopherol); 
Water for injections q.s. 
0.25 mL 
Sodium Chloride (3.85 mg); 
Potassium Chloride (100 µg); 
Magnesium Chloride (50 µg); 
Disodium Hydrogen Phosphate (1.3 
mg); Potassium Dihydrogen 
Phosphate (186 µg); Water for 
injections q.s. 0.5 mL 
Volume to be administered: 
0.375 milliliter(s) 
0.5 milliliter(s) 
0.5 milliliter(s) 
Number of doses to be 
administered: 
2 
2 
2 
Route of Administration: 
Intramuscular use 
Administration site: 
Location 
Deltoid  
Directionality  
Not applicable 
Laterality**** 
Non-dominant  
Packaging and Labelling: 
Refer to the Standard Procedures Manual for more details 
Manufacturer: 
GSK Biologicals SA  
Type of contact/ Time points: 
Visit 1 (Day 1), Visit 2 (Day 22) 
* The AS03A doses will be prepared using adjuvant vialed at a concentration of 47.44 mg/mL tocopherol. The final AS03A doses will contain 11.86 mg tocopherol. 
** The AS03B doses will be prepared as half a dilution of AS03A (with AS03A vialed at concentration of 47.44 mg/mL). 
*** Placebo: formulation buffer S9b is a phosphate buffered saline. 
**** 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. 
o/w: oil/water 
q.s.: “Quantity sufficient” stands for the Latin term “quantum satis” which means “as much as necessary” i.e. adding enough of a constituent to achieve a specific final volume or total 
weight. QS is a placeholder for an amount or volume which has to be “adjusted” by the given circumstances in a particular preparation [EMA] 
 


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The participants must be observed closely for at least 30 minutes after the administration 
of the vaccine/product. Appropriate medical treatment must be readily available during 
the observation period in case of anaphylaxis and/or syncope. 
6.2. 
Preparation/Handling/Storage/Accountability 
The study vaccine/product must be stored in a safe, locked place at the temperature 
specified on the vaccine/product label. The storage temperature should be continuously 
monitored with calibrated (if not validated) temperature monitoring device(s) and 
recorded. Only authorized study personnel should be allowed access to the study 
vaccine/product. Storage conditions will be assessed by a sponsor study contact during 
pre-study activities. Refer to the section on Study Supplies in the SPM for more details 
on storage and handling of the study vaccine/product.  
6.3. 
Measures to minimize bias: randomization and blinding  
6.3.1. 
Participant identification 
Participant identification numbers will be assigned sequentially to the participants who 
have consented to participate in the study, according to the range of participant 
identification numbers allocated to each study center. 
6.3.2. 
Randomization to study intervention 
The randomization list used to number the supplies will be based on a blocking scheme 
using a 1:1:1:1:1:1:1 ratio (approximately 120 participants in each study group). 
The intervention numbers will be allocated by component. 
To allow GSK to take advantage of greater rates of recruitment than anticipated at 
individual centers in this multi-center study and to reduce the overall study recruitment 
period, an over-randomization of supplies of at least 5% will be prepared.  
6.3.3. 
Intervention allocation to the participant 
The enrollment will be performed to evenly distribute participants across the 2 age 
groups (18-64 years, ≥ 65 years) (i.e. of the 120 participants in each study group, 
60 participants will be aged 18 to 64 years and 60 participants will be aged 
≥ 65 years). Within the 18-64 years age group, the enrollment is further stratified into 
18-49 years and 50-64 years to allow an even distribution of participants in terms of 
intervention allocation. 
Central randomization will be performed using PPD Interactive Response Technology 
(IRT). 
Allocation of the participant to a study group at the investigator site will be performed 
using the PPD IRT. 


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The IRT will determine the study group and will provide the intervention number to be 
used for the first vaccination. The intervention number(s) to be used for subsequent dose 
administration(s) will be provided by the same IRT. 
The number of each administered intervention kit must be recorded in the eCRF on the 
Vaccine Administration form/screen. 
Refer to the SPM for additional information relative to the intervention number 
allocation. 
6.3.4. 
Allocation of participants to assay subsets  
Vaccine-homologous microneutralization (MN) will be evaluated in a subset of 
approximately 420 participants (60 per group). A selection consistent of approximately 
50% of participants per H7N9 vaccine group, and approximately 50% of participants 
from the placebo group will be generated. 
PPD will select the first 30 participants per treatment group in the ≥ 65 age group and 
then the first 15 participants in 18 to 49 years and 50 to 64 years age groups. If there are 
not 15 participants for the 18 to 49 or 50 to 64 years age groups, PPD will select 
whichever has the smaller number fully and then have a total of 30 for the total among 
these 2 age groups per treatment group. 
All samples will be collected first, then selected for the subset. PPD will supply the list of 
selected participants to Q2 Solutions. 
6.3.5. 
Blinding and unblinding 
Data will be collected in an observer-blind manner. To do so, vaccine/product will be 
prepared and administered by qualified study personnel who will not participate in data 
collection, evaluation, review or the entry of any study endpoint (i.e. reactogenicity, 
safety, efficacy). 
The laboratory in charge of the sample testing will be blinded to the intervention 
assignment. Codes will be used to link the participant and study (without any link to the 
intervention attributed to the participant) to each sample. 
Investigators will remain blinded to each participant’s assigned study intervention 
throughout the course of the study. In order to maintain this blind, an otherwise 
uninvolved third party will be responsible for the reconstitution and dispensation of all 
study intervention and will endeavor to ensure that there are no differences in time taken 
to dispense following randomization.  
This third party will instruct the participant to avoid discussing the dosing site or visual 
appearance of the study intervention with the investigator. Unblinded monitors, and in the 
event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that the randomization/dispensing has 
been done accurately. 


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The IRT will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Please refer to the Section 6.3.5.1 for details 
regarding emergency unblinding. 
A statistical team will be unblinded for the interim analysis outlined in Section 9.5. 
6.3.5.1. 
Emergency unblinding 
Unblinding a participant’s individual intervention number should occur ONLY in case of 
a medical emergency when knowledge of the intervention is essential for the clinical 
management or welfare of the participant. 
The emergency unblinding process enables the investigator to have unrestricted, 
immediate and direct access to the participant’s individual study intervention via IRT. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact PPD prior to unblinding 
a participant’s intervention assignment unless this could delay emergency treatment of 
the participant. If a participant’s intervention assignment is unblinded, PPD must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and eCRF, as applicable. Refer to 
Section 8.3.3.1 for emergency contact information. 
6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded provided that there are no safety concerns for the participant per the 
investigator’s judgement. 
GSK policy (which incorporates International Council on Harmonisation [ICH] E2A 
guidance, the EU Clinical Trial Directive and US Federal Regulations) is to unblind the 
report of any unexpected Serious Adverse Event (SAE) and which is 
attributable/suspected to be attributable to the study vaccine/product, prior to regulatory 
reporting. Vaccines Clinical Safety and Pharmacovigilance (VCSP) is responsible for 
unblinding the intervention assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to the Section 10.3.10.1).  
In addition, GSK VCSP staff may unblind the intervention assignment for any participant 
with a Suspected Unexpected Serious Adverse Reaction (SUSAR) or an SAE that is fatal 
or life threatening. If the SAE requires an expedited regulatory report be sent to 1 or more 
regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 


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6.4. 
Study intervention compliance 
All doses will be administered at the site under medical supervision. Each dose will be 
administered by an unblinded member of the site staff who could also participate in dose 
preparation but who is barred from participation in any other study functions and cannot 
contribute to any observations. The date and time of each dose administered in the clinic 
will be recorded in the source documents and in the eCRF. The dose of study intervention 
and study participant identification will be confirmed at the time of dosing by a member 
of the study site staff other than the person administering the study intervention. The 
number of each administered intervention kit must be recorded in the eCRF on the 
Vaccine Administration form/screen. 
6.5. 
Concomitant therapy 
At each study visit, the investigator or delegate should question the participant about any 
medications/products taken and vaccinations received by the participant. 
The following concomitant medications/products/vaccines must be recorded in the eCRF: 
• 
All concomitant vaccines/medications/products associated with an AE, except 
vitamins and dietary supplements, administered following the first dose of study 
vaccine (Day 1 to Day 43). 
• 
Any concomitant medications/products/vaccines leading to the withdrawal or non-
eligibility of the participant from the study. 
• 
Any concomitant medications/products/vaccines relevant to an SAE/potential 
immune-mediated disease (pIMD) to be reported as per protocol or administered at 
any time during the study period for the treatment of an SAE/pIMD. Concomitant 
medications relevant to SAEs and pIMD must be recorded on the Expedited Adverse 
Events report. 
An antipyretic is considered prophylactic when it is given in the absence of fever and any 
other symptom, to prevent fever from occurring. 
The PPD Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.6. 
Dose modification 
Not applicable 
6.7. 
Intervention after the end of the study 
No intervention is planned after participants complete the study. No additional care will 
be provided to participants after they complete or discontinue the study. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
‘Discontinuation’ of study vaccine/product means any participant who has not received 
all planned doses of vaccine/product. A participant who discontinued study 
vaccine/product should be encouraged to, if deemed appropriate by the investigator, 
continue other study procedures (e.g. safety or immunogenicity) if planned in the study 
protocol.  
The primary reason for premature discontinuation of the study vaccine/product will be 
documented on the eCRF based on the following: 
• 
Adverse event requiring expedited reporting to GSK 
• 
Unsolicited non-SAE  
• 
Solicited AE 
• 
Protocol deviation 
• 
Not willing to be vaccinated 
• 
Other (specify). 
7.1.1. 
Criteria for temporary delay for enrollment and/or vaccination 
Vaccination may be postponed within the permitted time interval until transient 
circumstances cited below are resolved:  
• 
Acute disease and/or fever at the time of vaccination. Refer to the SoA (Section 1.3) 
for fever definition and preferred location for measuring temperature in this study. 
• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled and/or vaccinated at the discretion of the 
investigator. 
• 
Use of antipyretics and/or analgesics and/or antibiotics within 12 hours prior to 
vaccination. 
7.1.2. 
Contraindications to subsequent vaccine(s) administration 
Participants must be evaluated to confirm they are eligible for subsequent vaccination 
before administering each additional study vaccine dose.  
Participants who meet any of the criteria listed below or criteria listed in Sections 5.2.1 
and 5.2.2 should not receive additional vaccinations. However, these participants should 
be encouraged to continue other study procedures at the discretion of the investigator 
(Section 10.3.8.2). The relevant criteria for discontinuing vaccination must be recorded in 
the eCRF.  


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• 
Participants who experience any SAE judged to be possibly or probably related to 
study vaccine or non-study vaccines, including hypersensitivity reactions. 
• 
Participants who develop any new condition which, in the opinion of the 
investigator, may pose additional risk to the participant if he/she continues to 
participate in the study. 
• 
Anaphylaxis following the administration of vaccine/product. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Occurrence of a new pIMD that, in the opinion of the investigator, expose the 
participant to unacceptable risk from subsequent vaccination. In such cases, the 
investigator should use his/her clinical judgment prior to administering the next dose 
of the vaccine/product. Refer to Section 10.3.5.1 for the definition of pIMDs. 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant 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 participant from the date of withdrawal/last contact. 
From an analysis perspective, a ‘withdrawal’ from the study refers to any participant who 
was not available for the concluding contact foreseen in the protocol.  
Investigators will attempt to contact those participants who do not return for scheduled 
visits or follow-up. 
All data and samples collected until the date of withdrawal/last contact of the participant 
will be used for the analysis. 
The primary reason for study withdrawal will be documented in the eCRF based on the 
list below: 
• 
Adverse events requiring expedited reporting to GSK 
• 
Unsolicited non-SAE 
• 
Solicited AE 
• 
Protocol deviation  
• 
Withdrawal by participant, not due to an AE* 
• 
Migrated/Moved from the study area 
• 
Lost to follow-up 
• 
Sponsor study termination 
• 
Other (specify) 


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*If a participant is withdrawn from the study because he/she has withdrawn consent and 
provided the reason for its withdrawal, the investigator must document this reason in the 
eCRF. 
Participants who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigators will 
follow participants who are withdrawn from the study as result of an SAE/AE until the 
event is resolved. (see Section 10.3.8.2). 
7.3. 
Lost to follow-up 
A participant will be considered ‘lost to follow-up’ if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site. 
Please refer to the SPM for a description of the actions to be taken before considering the 
participant as lost to follow-up.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
Adherence to the protocol is required for study conduct. 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
an immediate safety concerns.  
The investigator is not allowed to do testing on samples outside of what has been agreed 
upon by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB). 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team is aware of them. The purpose of this communication is to 
determine if the participant(s) should discontinue the study intervention. 
All screening evaluations must be completed and the results reviewed before confirming 
that potential participants meet all eligibility criteria.  
The investigator will maintain a screening log of all participants screened. All relevant 
information, such as confirmation of eligibility and reasons for screening failure will be 
mentioned in this screening log.  
Procedures conducted as part of routine clinical management (e.g. hematologic profiles) 
and obtained before the participant signed the Informed Consent Form (ICF) may be used 
for screening and/or for establishing a clinical baseline, provided the procedure met 
protocol-specified criteria and was performed within the time frame defined in the SoA 
(Section 1.3). 
The SPM provides the investigator and site personnel with administrative and detailed 
technical information that does not impact participant safety. 


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8.1. 
Efficacy and/or immunogenicity assessments 
Collected biological 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.  
Future findings may make it desirable to use the samples acquired in this study for future 
research not described in this protocol. All participants will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to prior IEC/IRB approval if required per local legislation. 
Information on further investigations and their rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the individual 
participant.  
If additional testing is performed, the marker priority ranking given in Section 8.1.3 may 
be changed. 
Collected samples will be stored for a maximum of 20 years. This storage period begins 
when the last participant performed the last study visit, unless local rules, regulations or 
guidelines require different timeframes or procedures, which would then be in line with 
participant consent. These extra requirements need to be communicated formally to, and 
discussed and agreed with, GSK. 
8.1.1. 
Biological samples 
Approximately 80 mL of blood will be collected during the entire study period.  
Table 7 
Biological samples 
Sample type 
Quantity 
Unit 
Time point 
Subset name* 
Blood 
At least 25 mL 
mL 
Days 1, 22, and 43 
All participants 
* Refer to Section 6.3.4 for subset description. 
8.1.2. 
Laboratory assays 
All laboratory testing will be performed in a laboratory designated by GSK Biologicals.  
Microneutralization and hemagglutination inhibition (HI) assays development, 
qualification and clinical testing will be outsourced. 


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Table 8 
Laboratory assays  
Assay type 
System 
Component 
Challenge 
Method 
Laboratory* 
Humoral 
Immunity 
(Antibody 
determination) 
Serum 
Vaccine-homologous 
Influenza A/Hong 
Kong/125/2017-like 
Virus 
 
HI 
Q2 Solutions 
Serum 
Vaccine-homologous 
Influenza A/Hong 
Kong/125/2017-like 
Virus 
MN 
Q2 Solutions 
* Refer to the list of clinical laboratories for details. 
HI: hemagglutination inhibition; MN: microneutralization 
Please refer to the Section 10.2 for a brief description of the assays performed in the 
study. 
The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol. 
The clinical laboratories have established a Quality System supported by procedures. The 
activities of the clinical laboratories are audited regularly for quality assessment by an 
internal (sponsor-dependent) but laboratory-independent Quality Department. Clinical 
laboratories contracted by GSK also conform to Good Laboratory Practice guidelines and 
operate in compliance with regulatory standards. 


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8.1.3. 
Immunological read-outs  
Table 9 
Immunological read-outs 
Blood sampling time point 
Subset name 
No. 
participants 
Component 
Components 
priority rank 
Type of contact and 
timepoint 
Sampling 
time point 
Visit 1 (Day 1) 
Pre-Vacc I 
HI 
840 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
1 
Visit 1 (Day 1) 
Pre-Vacc I 
MN 
420 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
2 
Visit 2 (Day 22) 
Pre-Vacc II 
HI 
840 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
1 
Visit 2 (Day 22) 
Pre-Vacc II 
MN 
420 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
2 
Visit 3 (Day 43) 
Post-Vacc II 
HI 
840 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
1 
Visit 3 (Day 43) 
Post-Vacc II 
MN 
420 
Vaccine-
homologous 
Influenza 
A/Hong 
Kong/125/2017-
like Virus 
2 
HI: hemagglutination inhibition; MN: microneutralization; Post-Vacc: post-vaccination; Pre-Vacc: pre-vaccination 
8.1.4. 
Immunological correlates of protection 
Although there is no accepted correlate of protection against influenza virus, either 
seasonal or pandemic, the protective role of antibodies against HA and, to a lesser extent, 
neuraminidase, is well established and has been demonstrated both in experimentally 
infected animals and humans [Rimmelzwaan, 2008] 


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For this reason, the induction of HA-specific antibodies is used as a marker of potential 
vaccine efficacy and the serum HI assay is used to demonstrate this humoral response. 
Hemagglutination inhibition antibody titers of 1:40 or greater have been associated with 
protection from influenza illness in at least 50% of participants in challenge studies 
[Hannoun, 2004] and correlate with vaccine effectiveness [Beyer, 1989]. 
8.2. 
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 intervention or the study, or that caused the participant to discontinue the study. 
8.2.1. 
Pre-vaccination procedures 
8.2.1.1. 
Informed consent 
The signed informed consent of the participant must be obtained before study 
participation. Refer to Section 10.1.3 for the requirement on how informed consent will 
be obtained. 
8.2.1.2. 
Check inclusion and exclusion criteria 
All inclusion and exclusion criteria will be checked as described in Sections 5.1 and 5.2 
before dosing on Day 1. 
8.2.1.3. 
Collection of demographic data 
Demographic data such as age, year of birth, gender, height, weight, race, and ethnicity 
will be recorded in the participant’s eCRF. 
8.2.1.4. 
Medical history 
Obtain the participant’s medical history by interviewing the participant and/or review of 
the participant’s medical records. Record any pre-existing participant conditions, signs 
and/or symptoms present prior to the first vaccination in the eCRF. 
8.2.1.5. 
Physical examination 
At a minimum, temperature and vital signs (e.g. heart rate and respiratory rate, blood 
pressure) must be collected. Participants will undergo a physical examination and vital 
signs are to be taken prior to the first vaccination and will consist of 1 heart rate and 
1 blood pressure measurement. Blood pressure and pulse measurements will be assessed 
by a completely automated device. Manual techniques will be used only if an automated 
device is not available. Collected information will be recorded in the eCRF. 


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If the investigator determines that the participant’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled. 
8.2.1.6. 
History of adjuvanted vaccine and influenza vaccine 
For each of the 2017/2018, 2018/2019, and 2019/2020 influenza seasons, record whether 
the participant received an adjuvanted vaccine or influenza vaccine and if so, the 
administration method in the eCRF. 
8.2.1.7. 
Pregnancy test 
Female participants of childbearing potential must perform a urine pregnancy test prior to 
any study vaccine administration. Pregnancy testing must be performed even if the 
participant is menstruating at the time of the study visit. The study vaccine/product may 
only be administered if the pregnancy test is negative.  
Refer to the Section 10.5.3.1 for the information on study continuation for participant 
who becomes pregnant during the study. 
8.2.1.8. 
Assess pre-vaccination body temperature 
The body temperature of the participant must be measured prior to any study 
vaccine/product administration. The preferred location for recording temperature in this 
study is oral. If the participant has a temperature ≥ 38.0°C/100.4°F by any route on the 
day of dosing, the dosing visit will be rescheduled within the allowed interval (Table 2). 
8.2.2. 
Study holding rules and safety monitoring 
8.2.2.1. 
Internal Safety Review Committee 
At least 2 iSRC reviews are planned. 
The iSRC members are GSK employees and will not be otherwise involved in the 
conduct of the study and will be independent from GSK’s Pandemic Influenza Safety 
Review Team. The iSRC members will have access to all available data. The iSRC 
composition, responsibilities and operational details will be outlined in an iSRC charter. 
8.2.2.2. 
Outcome of safety evaluation 
During each iSRC review, reactogenicity and safety data for approximately 
140 participants (approximately 10 participants per vaccine group and placebo group 
stratified by age) will be monitored. The first iSRC review will occur when data collected 
for 7 days post dose (i.e. Day 1 to Day 7, inclusive) are available; the second review will 
occur based on the available data collected 7 days post dose 2 (i.e. Day 22 to Day 28, 
inclusive) for the same group of participants. Additional iSRC reviews may be carried out 
as needed. 


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If a safety signal is observed, GSK may decide to suspend further vaccinations in all 
groups or in selected groups. Guidance about how to proceed will be provided should 
such a decision be made. 
8.2.2.3. 
Study holding rules 
The safety holding rules are defined in Table 10. Holding rules 1a-b will be assessed by 
each investigator on a continuous basis. Meeting any of these holding rules will trigger a 
hold of vaccination irrespective of number of participants enrolled and/or timing of the 
event. 
The final responsibility to recommend whether the study should be continued in all or in 
selected groups, modified or stopped permanently, rests with the Sponsor, after having 
considered all the safety information available. If the study is stopped or modified, a 
letter indicating the reasons will be sent to the IRB(s)/IEC(s) via the investigator(s), and 
to Center for Biologics Evaluation and Research (CBER), via GSK. 
Of note, no formal holding rules will be applied for other safety data such as 
non-life-threatening SAEs, missed visits due to vaccine-related AEs, Grade 1 and 
Grade 2 solicited administration site and systemic events and unsolicited AEs in the 
7-day follow-up period and unsolicited AEs collected from Day 8 to Day 22 and Day 29 
to Day 43 after vaccination. However, if available, these data will also be reviewed by the 
iSRC in order to allow an overall assessment of the benefit/risk ratio of vaccination. 
Table 10 
Study holding rules 
Holding 
Rule 
Event 
Number of 
Participants 
1a 
Death or any life-threatening SAE that can be reasonably attributed to the vaccination 
≥ 1 
1b 
Any non-life-threatening SAE that can be reasonably attributed to the vaccination occurring 
within 21 days from vaccination 
≥ 1 
If any investigator becomes aware of a holding rule being met, he/she will suspend 
vaccination and inform the PPD Medical Monitor immediately (e.g. meeting of holding 
rules 1a-b). Refer to the Table 13 for contact information.  
When a holding rule is identified the following communication flow will occur: 
1. The investigator will notify the PPD Medical Monitor by calling the PPD 
Pharmacovigilance SAE Hotline at 1-800-201-8725. 
2. The PPD Medical Monitor or delegate will notify the study sites and IRT manager. 
The IRT manager will block IRT from allowing randomization (or screening, if 
applicable). Study sites will not randomize or screen participants until notification 
that the hold is released.  
3. The study site will confirm receipt of notification (in writing). Clinical team manager 
at PPD will collect study site acknowledgement. 
4. PPD Medical Monitor will notify GSK Clinical Research and Development Lead. 


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5. GSK Clinical Research and Development Lead will notify Vaccine Safety 
Monitoring Board (VSMB) and iSRC. 
6. iSRC will review unblinded data and make recommendation to VSMB. 
7. VSMB will make final decision whether to continue or stop the study. 
8. GSK will notify CBER. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
other events of interest 
8.3.1. 
Time period and frequency for collecting AE, SAE and other 
safety information 
Table 11 
Timeframes for collecting and reporting of safety information 
Event 
Pre- 
V1* 
V1 
 
 
V2 
 
 
V3 
TC3 TC4 TC5 TC6 
 
D1 
D7 
 
D22 
D28 
 
D43 
M4 
M7 
M10 M13 
Solicited administration site 
and systemic events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs and MAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* i.e. consent obtained.  
AEs: adverse events; D: Day; M: Month; MAEs: medically attended adverse events; pIMDs: potential immune-
mediated diseases; Pre-V: pre-vaccination; SAE: serious adverse events; TC: telephone contact; V: vaccination 
The investigator or designee will record and immediately report all SAEs to the sponsor 
or designee via the Expedited AE Reporting Form. This reporting should, under no 
circumstances, occur later than 24 hours after the investigator becomes aware of an SAE, 
as indicated in Section 10.3.10. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available. 


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A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 11. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event to be reasonably related to the study vaccine/product, the 
investigator will promptly notify the Study Contact for Reporting SAEs mentioned in the 
Table 13. 
8.3.2. 
Method of detecting AEs and SAEs, pregnancies and other 
events 
Methods of detecting and recording AE/SAE/pIMDs/pregnancies are detailed in the 
Section 10.3.8. The assessment of AE/SAE intensity, causality and outcome are provided 
in the Section 10.3.9.  
Open-ended and non-leading verbal questioning of the participants is the preferred 
method of acquiring information related to an AE/SAE/pIMDs/pregnancy. 
8.3.2.1. 
Clinically significant abnormal laboratory findings 
Clinical laboratory measurements are not scheduled to be taken during the study; 
however, clinical laboratory tests may be performed and the results obtained as part of 
critical care or follow-up due to the occurrence of medically attended adverse events 
(MAEs), SAEs, or pIMDs during the study. 
The investigator must review the laboratory report, document that he/she did so, and 
record any clinically relevant changes occurring during the study in the eCRF. Clinically 
significant abnormal laboratory findings are those which are associated with an 
underlying disease judged by the investigator to be more severe than expected for the 
participant's condition. 
8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies, and 
other events 
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/pIMDs/pregnancy, he/she must report it to PPD Pharmacovigilance 
using the required documentation, and within the timeframes, mentioned in the Table 12. 
This is essential for meeting legal obligations and ethical responsibilities for participant 
safety and the safety of a study intervention under clinical investigation. 
For SAEs/pIMDs, the investigator will always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.9.2. 
Local regulatory requirements and sponsor policy for the preparation of an investigator 
safety report for SUSAR must be followed. These reports will be forwarded to 
investigators as necessary. 


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The sponsor has a legal responsibility to notify regulatory agencies about the safety of a 
study intervention under clinical investigation. The sponsor will comply with 
country-specific regulatory requirements related to safety reporting to the regulatory 
authority, IRB/IEC, and investigators. 
Please refer to Section 10.3.10 for further details regarding the reporting of 
SAEs/pIMDs/pregnancies. 
Table 12 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to PPD Pharmacovigilance 
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* 
(Amended 
22 February 
2022) 
Paper pregnancy 
notification report 
24 hours* 
(Amended 
22 February 
2022) 
Paper pregnancy follow-up 
report 
pIMDs 
24 hours** ‡  
Electronic Expedited 
Adverse Events Report 
24 hours* 
Electronic Expedited Adverse 
Events Report 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
** Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMDs. 
‡ The investigator will be required to confirm review of the SAE/pIMDs causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMDs. 
8.3.3.1. 
Contact information for reporting of SAEs, pIMDs, pregnancies and 
study holding rules 
Table 13 
Contact information for reporting of SAEs, pIMDs, pregnancies and 
study holding rules 
Study contact for questions regarding SAEs, pIMDs, 
pregnancies 
Study contact for reporting of study holding rules 
Refer to the local study contact information document 
As soon as the investigator is aware that a holding rule 
is met, he/she must immediately inform the PPD 
Medical Monitor (refer to Section 8.2.2.3).  
Back-up study contact for reporting SAEs, pIMDs, 
pregnancies 
Available 24/24 hours and 7/7 days: 
Back-up study contact for escalation of holding 
rules 
PPD Pharmacovigilance 
Phone: 1-800-201-8725 
Fax: 1-888-488-9697 
PPD Clinical Safety & Pharmacovigilance 
 
SAE Hotline for North America 
Phone: 1-800-201-8725 
Fax: 1-888-488-9697 
E-mail: WIL Safety (SM) wilsafety@ppdi.com 
 
8.3.4. 
Treatment of adverse events 
Any medication administered for the treatment of an SAE/pIMD should be recorded in 
the Expedited Adverse Events Report of the participant’s eCRF screen (refer to the 
Section 10.3.10.1). 


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8.3.5. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
keep the participant card in his/her/their possession at all times throughout the study. In 
an emergency, this card serves to inform the responsible attending physician that the 
participant is in a clinical study and that relevant information may be obtained by 
contacting the investigator. 
8.4. 
Treatment of overdose 
For this study, any dose of study intervention greater than 1.9 µg, 3.75 µg, or 7.5 µg 
given outside of the Study Day 18 to Study Day 25 interval will be considered an 
overdose. 
GSK does not recommend specific treatment for an overdose. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Not applicable 
8.8. 
Biomarkers 
Not applicable 
8.9. 
Health outcomes 
Not applicable 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses 
The hypothesis test is planned to demonstrate whether vaccination with monovalent 
influenza A/Hong Kong/125/2017-like (H7N9) virus vaccine containing 1.9 µg, 3.75 µg 
or 7.5 µg of HA adjuvanted with AS03A or AS03B elicits an HI antibody response to the 
vaccine-homologous virus that meets or exceeds the CBER immunogenicity criteria 
21 days after the second dose of H7N9 vaccine [CBER, 2007].   


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Each null hypothesis (H0) is that the lower limit (LL) of the confidence interval (CI) for 
seroconversion (SCR)/seroprotection (SPR) rate will not meet or exceed the threshold set 
in the CBER guidelines. Each alternative hypothesis (Ha) is that the LL of the CI for the 
SCR/SPR meets or exceeds the threshold set in the CBER guidelines. The overall type I 
error rate is fixed at 5% for each age group, and a Bonferroni adjustment was applied to 
allow simultaneous multiple comparisons of each antigen/adjuvant group. 
9.2. 
Sample size determination 
Approximately 840 participants will be randomized to achieve 798 evaluable 
participants. 
Withdrawals will not be replaced. 
9.2.1. 
Immunogenicity 
The primary immunogenicity objective of the study is to evaluate whether vaccination 
with monovalent influenza A/Hong Kong/125/2017-like (H7N9) virus vaccine containing 
1.9 µg, 3.75 µg or 7.5 µg of HA adjuvanted with AS03A or AS03B elicits an HI antibody 
response to the vaccine-homologous virus that meets or exceeds the US Food and Drug 
Administration, CBER immunogenicity criteria at the Day 43 visit. [CBER, 2007].* 
* The age appropriate CBER criteria will be used and assessed separately:  
• 
CBER immunogenicity criteria for SCR for 18 to 64 years of age will be shown if 
the LL of the 99.17% CI for SCR meets or exceeds 40%. 
• 
CBER immunogenicity criteria for SPR for 18 to 64 years of age will be shown if the 
LL of the 99.17% CI for the incidence rate of HI Reciprocal Titers ≥ 40 meets or 
exceeds 70%. 
• 
CBER immunogenicity criteria for SCR for ≥ 65 years of age will be shown if the 
LL of the 99.17% CI for SCR meets or exceeds 30%. 
• 
CBER immunogenicity criteria for SPR for ≥ 65 years of age will be shown if the LL 
of the 99.17% CI for the incidence rate of HI Reciprocal Titers ≥ 40 meets or 
exceeds 60%. 
A total of 840 participants are planned to be enrolled, with 60 participants per 
antigen/adjuvant/age group. A drop-out/protocol violation rate of not more than 5% 
yields an approximate sample size of 57 evaluable participants per group, giving 82% 
overall power to fulfil the CBER (SCR, SPR) immunogenicity criteria in any one of the 
12 adjuvanted vaccine treatment groups, assuming that the reference rate for SPR and 
SCR is 91% and 80% for participants 18 to 64 years of age and 86% and 75% for 
participants ≥ 65 years of age, respectively. 


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The 2-sided exact Clopper-Pearson 99.17% CI for SCR or SPR is to allow parallel 
assessment of the 6 antigen/adjuvant combinations within each age group, addressing 
multiple comparisons using a Bonferroni adjustment by dividing the 5% Type I error 
equally 6 ways. Success can be declared for any antigen/adjuvant group within an age 
range if CBER criteria is met even if any other group does not meet the CBER criteria. 
Table 14 presents the power for 1 group to meet the CBER immunogenicity criteria, 
assuming the enrollment is 60 participants per group and non-evaluable rate is about 5%. 
Table 14 
Criteria to evaluate primary objective with respect to SCR and SPR 
for anti-HA, 21 days after the second vaccination 
To meet CBER 
Criteria 
Endpoint 
Statistical Success Criteria 
N evaluable 
Reference 
value 
Power* 
18-64 years of age 
Anti-HA: SCR 
LL of 99.17% CI of SCR > 40% 
57 
80% 
99.99%* 
Anti-HA: SPR 
LL of 99.17% CI of SPR > 70% 
57 
91% 
86.26%* 
≥65 years of age 
Anti-HA: SCR 
LL of 99.17% CI of SCR > 30% 
57 
75% 
>99.99%* 
Anti-HA: SPR 
LL of 99.17% CI of SPR > 60% 
57 
86% 
95.12%* 
 
 
 
Overall power 
82% 
* Power estimated using PASS 2012, 1-Sided Exact test on the proportions, alpha = 0.415%. 
CBER: Center for Biologics Evaluation and Research; CI: confidence interval; HA: hemagglutinin; LL: lower limit; SCR: 
seroconversion rate; SPR: seroprotection rate. 
9.2.2. 
Safety 
In this study, descriptive safety assessment of the different vaccine formulations is a 
primary objective. Table 15 presents the 95% CIs for a given percentage of participants 
reporting a symptom after vaccination, assuming a sample size of 60 participants per 
vaccine group. 


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Table 15 
Exact 95% CI on the percentage of participants with AEs following 
vaccination for 60 participants per group 
Number of 
participants with a 
symptom 
% of participants with a 
symptom (N=60) 
95% confidence interval 
Lower Limit 
Upper Limit 
0 
0 
0 
6 
1 
1.7 
0 
8.9 
2 
3.3 
0.4 
11.5 
3 
5 
1 
13.9 
4 
6.7 
1.8 
16.2 
5 
8.3 
2.8 
18.4 
6 
10 
3.8 
20.5 
7 
11.7 
4.8 
22.6 
8 
13.3 
5.9 
24.6 
9 
15 
7.1 
26.6 
10 
16.7 
8.3 
28.5 
11 
18.3 
9.5 
30.4 
12 
20 
10.8 
32.3 
13 
21.7 
12.1 
34.2 
14 
23.3 
13.4 
36 
15 
25 
14.7 
37.9 
16 
26.7 
16.1 
39.7 
17 
28.3 
17.5 
41.4 
18 
30 
18.8 
43.2 
19 
31.7 
20.3 
45 
20 
33.3 
21.7 
46.7 
21 
35 
23.1 
48.4 
22 
36.7 
24.6 
50.1 
23 
38.3 
26.1 
51.8 
24 
40 
27.6 
53.5 
25 
41.7 
29.1 
55.1 
26 
43.3 
30.6 
56.8 
27 
45 
32.1 
58.4 
28 
46.7 
33.7 
60 
29 
48.3 
35.2 
61.6 
30 
50 
36.8 
63.2 


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9.3. 
Populations for analyses 
Table 16 
Populations for analyses 
Analysis set 
Description 
Enrolled  
Participant’s agreed to participate in a clinical study after completion of the 
informed consent process. Refer to the Glossary of terms for the definition of 
‘enrolled’.  
Randomized 
All participants who were randomized to receive a study vaccine. 
Exposed Set (ES) 
(Amended 22 February 
2022) 
All participants who received any study vaccination. The allocation in a group is 
done in function of the administered intervention. The analysis of primary and 
secondary safety endpoints will be based on this set. 
Full Analysis Set (FAS) 1 
All participants in the Exposed Set who have post-vaccination immunogenicity 
data at Visit 3 (Day 43). Participants will be analyzed as “randomized” (i.e. 
according to the vaccine[s] the participant was randomized to receive). 
FAS 2 
All participants in the Exposed Set who have post-vaccination immunogenicity 
data at Visit 2 (Day 22). Participants will be analyzed as “randomized” (i.e. 
according to the vaccine[s] the participant was randomized to receive). 
Per Protocol Set (PPS) 1 
The PPS 1 is a subset of FAS 1. The PPS 1 includes all FAS 1 participants with no 
major protocol deviations that lead to exclusion at or prior to Visit 3 (Day 43). 
Major protocol deviations leading to exclusion will be defined in the Statistical 
Analysis Plan (SAP) and the Study Deviation Rules document and will be finalized 
prior to the interim analysis defined in Section 9.5. Primary immunogenicity data 
will be evaluated based on this set. 
Modified PPS (mPPS) 1 
The mPPS 1 is a subset of FAS 1. The mPPS 1 includes all FAS 1 
participants with no major protocol deviations that led to exclusion at or 
prior to Visit 3 (Day 43). The time window between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set is between 18-32 study days. The 
interval between Visit 2 and Visit 3 will be 14-32 calendar days. 
 
Major protocol deviations leading to exclusion will be defined in the 
Statistical Analysis Plan (SAP) and the Study Deviation Rules Document and 
will be finalized prior to the interim analysis defined in Section 9.5. 
(Amended 22 February 2022) 
PPS 2 
The PPS 2 is a subset of FAS 2. The PPS 2 includes all FAS 2 participants with no 
major protocol deviations that lead to exclusion at or prior to Visit 2 (Day 22). 
Major protocol deviations leading to exclusion will be defined in the SAP and the 
Study Deviation Rules document and will be finalized prior to the interim analysis 
defined in Section 9.5. Secondary immunogenicity data will be evaluated based on 
this set. 
mPPS 2 
The mPPS 2 is a subset of FAS 2. The mPPS 2 includes all FAS 2 
participants with no major protocol deviations that lead to exclusion at or 
prior to Visit 2 (Day 22). The time window between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set is between 18-32 study days. 
 
Major protocol deviations leading to exclusion will be defined in the SAP and 
the Study Deviation Rules document and will be finalized prior to the interim 
analysis defined in Section 9.5. (Amended 22 February 2022) 
Microneutralization (MN) 
All participants in the Randomized Set who were also selected to the subset of MN 
evaluation.  
Microneutralization Per 
Protocol Set (MNPPS) 1 
All participants in the MN Set who are also part of the PPS 1. 
MN mPPS 1 
All participants in the MN Set who are also part of the mPPS 1. (Amended 22 
February 2022) 
MNPPS 2 
All participants in the MN Set who are also part of the PPS 2. 
MN mPPS 2 
All participants in the MN Set who are also part of the mPPS 2. (Amended 22 
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9.3.1. 
Criteria for elimination from analysis  
9.3.1.1. 
Intercurrent medical conditions and concomitant 
medications/products/vaccines that may lead to elimination of a 
participant from per-protocol analyses  
If the participant meets one of the criteria mentioned in the Section 7.1.2, he/she may be 
eliminated from per protocol analysis sets. 
If the participant has a protocol deviation deemed as major, he/she may be eliminated 
from the per protocol analysis sets. Major protocol deviations leading to exclusion will be 
defined in the Statistical Analysis Plan (SAP) and the Study Deviation Rules document 
and will be finalized prior to the interim analysis defined in Section 9.5. 
Key major deviations include, but are not limited to, the following: 
• 
Participants enrolled who did not meet entry criteria including age at enrollment  
• 
Participants incorrectly vaccinated  
• 
Participants who did not receive study vaccinations as planned in protocol 
• 
Participants who did not have blood draws as planned in protocol 
• 
Participants with a blood draw outside of allowed time window 
• 
Participants with a vaccination done outside of allowed time window 
These key major deviations will be assessed based on the data collected in the eCRFs.  
9.4. 
Statistical analyses 
9.4.1. 
General considerations 
Derived and transformed data: 
• 
Immunogenicity (Note: The cut-off value for antibody titer is defined by the 
laboratory before the analysis and will be specified in the clinical study report). 
− 
A seronegative participant is a participant whose antibody titer is below the 
assay cut-off value. 
− 
A seropositive participant is a participant whose antibody titer is greater than or 
equal to the assay cut-off value. 
− 
Seroprotection is defined as an HI antibody titer ≥ 40 1/DIL. 
− 
SPR is defined as the percentage of participants with an HI antibody titer 
≥ 40 1/DIL. 
− 
Seroconversion is defined as a post-vaccination antibody titer ≥ 40 1/DIL in the 
serum of participants seronegative before vaccination (i.e. titer < assay cut-off at 
Day 1). For seropositive participants (i.e. titer ≥ assay cut-off at Day 1), 


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seroconversion will require a 4-fold rise in post-vaccination HI antibody titer 
(but at least a titer of 40 1/DIL). 
− 
SCR is defined as the percentage of participants who seroconvert post-
vaccination. 
− 
Vaccine response is defined as at least a 4-fold increase in antibody titer as 
compared to the antibody titer at Day 1 (pre-vaccination). Antibody titers below 
the cut-off of the assay are given an arbitrary value of half the cut-off for the 
purpose of vaccine response calculation. 
− 
Vaccine Response Rate (VRR) is defined as the percentage of participants with 
vaccine response. 
− 
The geometric mean titers (GMTs) calculations are performed by taking the 
anti-log of the mean of the log concentration/titer transformations. Values for 
the antibody concentrations/titers below the assay cut-off will be assigned half 
the assay cut-off value for the purpose of GMT computation.  
− 
Handling of missing data: for a given participant and a given immunogenicity 
measurement, missing or non-evaluable measurements will not be replaced. 
− 
The primary and secondary HI immunogenicity analyses will be based on the 
applicable Per Protocol Set (PPS) as described in Section 9.3 (Table 16). 
Supplementary analyses for primary and secondary HI immunogenicity 
analyses will be based on the applicable mPPS. If the difference between PPS 1 
and FAS 1 is greater than 10%, a second analysis based on the FAS will be 
performed to complement the PPS analysis. (Amended 22 February 2022) 
− 
The MN immunogenicity analyses will be based on the applicable 
Microneutralization Per Protocol Set (MNPPS) as described in Section 9.3 
(Table 16). Supplementary analyses for MN immunogenicity analyses will be 
based on the applicable MN mPPS. (Amended 22 February 2022) 
• 
Reactogenicity and Safety 
− 
Handling of missing data: For safety analyses, participants who missed reporting 
symptoms (solicited or unsolicited) or concomitant medications will not be 
imputed. Therefore, the analysis of the solicited symptoms based on the 
Exposed Set (ES) will include only participants/doses with documented safety 
data (i.e. symptom screen/sheet completed). Further details on the handling of 
missing data will be described in the SAP. 
• 
Summaries will be presented by each study group, age group, and overall. The 
≥ 65 years age group will also be presented by 65-74 years, ≥ 75 years, and overall. 
No randomization stratification or enrollment constraints will be imposed for these 
additional age categorizations.   
9.4.2. 
Participants disposition 
Participant disposition will be summarized for the ES, for each study group, age group, 
and overall. The summary will include the number of participants in each analysis set 
defined in Section 9.3, the number and percentage of participants who received any and 


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each study vaccination, the number and percentage of participants who completed the 
study and the primary reason for withdrawal from the study, the number and percentage 
of participants who completed the study vaccinations and the primary reason for 
withdrawal of study vaccination. 
The number and percentage of participants who were screen failures and major reason for 
screen failure will be summarized for the Enrolled Set as overall.   
Major deviations will be summarized for the ES for each study group, age group, and 
overall. The reason for elimination from the PPS 1 and PPS 2 and mPPS 1 and mPPS 2 
will also be summarized. The same will be done for MNPPS 1, MNPPS 2, MN mPPS 1 
and MN mPPS 2. (Amended 22 February 2022) 
Listings will be provided for disposition data and deviation data based on the Enrolled 
Set. 
9.4.3. 
Primary endpoint(s) 
9.4.3.1. 
Immunogenicity 
Primary immunogenicity analyses will be based on the PPS 1 set. 
Supplementary immunogenicity analyses will be based on the mPPS 1 set. (Amended 
22 February 2022) 
The following aggregate variables will be calculated for each vaccine group for vaccine 
homologous H7N9 HI antibody titer along with Clopper-Pearson exact two-sided 99.17% 
CIs: 
• 
SCR at Day 43 
• 
SPR at Day 43 
9.4.3.2. 
Safety 
The analysis of reactogenicity and unsolicited events will be based on the ES. 
Solicited administration site and systemic endpoints 
• 
Occurrence of each solicited administration site events during a 7-day follow-up 
period (Day 1 to Day 7) after each vaccination. 
• 
Occurrence of each solicited systemic events during a 7-day follow-up period (Day 1 
to Day 7) after each vaccination. 
All solicited events will be summarized according to defined severity grading scales. 
Frequencies and percentages of participants experiencing each event will be presented for 
each symptom severity. Summary tables showing the occurrence of any solicited 
administration site events or solicited systemic events overall and at each time point will 


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also be presented and will be tabulated with Clopper-Pearson exact 95% CIs. Solicited 
administration site events will be assessed according to which vaccine was administered. 
If a solicited event occurs more than once for a participant, it will be counted in the 
summary only once for each level of summarization, according to the maximal severity. 
Summary tables showing the occurrence of any solicited administration site events or 
solicited systemic events overall will be presented. 
Unsolicited AE endpoints (Amended 22 February 2022) 
• 
Occurrence and relationship to vaccination of unsolicited AEs within 21 days after 
each vaccination. 
• 
Occurrence and relationship to vaccination of AEs with MAEs within 21 days after 
each vaccination. 
SAE endpoints 
• 
Occurrence and relationship to vaccination of SAEs and pIMDs up to Day 43 visit. 
• 
Occurrence and relationship to vaccination of SAEs and pIMDs until Month 13. 
This analysis applies to all AEs, whether judged either as probably related, possibly 
related, or not related to vaccination by the investigator, recorded in the Adverse Events 
eCRF, with a start date on or after the date of first vaccination and not later than 21 days 
of the most recent vaccination. Adverse events starting prior to the first vaccination will 
only be listed. The original verbatim terms used by investigators to identify AEs in the 
eCRFs will be mapped to preferred terms using the Medical Dictionary for Regulatory 
Activities. The AEs will then be grouped by Medical Dictionary for Regulatory Activities 
preferred terms into frequency tables according to system organ class. 
All reported AEs, as well as AEs judged by the investigator as at least possibly related to 
study vaccine(s), will be summarized according to system organ class and preferred term 
within system organ class. These summaries will be presented by study group and by 
interval of study observation. When an AE occurs more than once for a participant, the 
maximal severity and strongest relationship to the study group will be counted. 
Separate summaries will be produced for the following categories: 
• 
SAEs 
• 
AEs that are possibly or probably related to vaccine(s) 
• 
AEs leading to withdrawal 
• 
MAEs 
• 
pIMDs 
Data listings of all AEs will be provided by participant. In addition, AEs in the categories 
above will be provided as listed data.  


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9.4.4. 
Secondary endpoint(s) 
9.4.4.1. 
Immunogenicity 
The following aggregate variables will be calculated for each vaccine group for vaccine 
homologous H7N9 HI antibody titer: 
• 
GMTs at Days 1, 22, and 43 
• 
Seropositivity rates at Days 1, 22, and 43 
• 
SCR at Day 22 
• 
SPR at Days 1 and 22 
• 
Mean Geometric Increase (MGI) at Days 22 and 43 
For a subset of participants (MNPPS 1 and MNPPS 2 sets and MN mPPS 1 and 
MN mPPS 2), the following aggregate variables will be calculated for each vaccine 
group for vaccine-homologous H7N9 MN antibody titer: (Amended 22 February 2022) 
• 
GMTs at Days 1, 22, and 43 
• 
Seropositivity rates at Days 1, 22, and 43 
• 
VRR at Days 22 and 43 
The GMTs/MGIs with 95% CIs will be tabulated by visit for each treatment group, age 
group and overall. For seropositivity/VRR, percentage of participants will be calculated 
with Clopper-Pearson exact two-sided 95% CIs. For SCR/SPR, percentage of participants 
will be calculated with Clopper-Pearson exact two-sided 99.17% CIs. 
9.4.5. 
Other analyses 
9.4.5.1. 
Demography and baseline characteristics analyses 
Demographic characteristics (age, gender, race, center, height, weight, and ethnicity) will 
be tabulated per study group for each analysis set, age group and overall as described in 
the SAP. 
The mean of continuous variables (plus range and standard deviation) of the enrolled 
participants, as a whole and per study group, age group and overall, will be calculated. 
The distribution of discrete variables will be tabulated as a whole and per study group, 
age group and overall as described in the SAP. 
The analysis of demographics will be performed separately for the ES and for the 
participants contributing to the PPS (and mPPS). (Amended 22 February 2022) 


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Demographic characteristics (including but not limited to age, gender, race, height, 
weight, and ethnicity) will be summarized by group using descriptive statistics: 
• 
For categorical variables such as center, the number and frequency in each category 
will be provided. 
• 
Number (number of participants in the analysis), mean, median, minimum and 
maximum, and standard deviation will be provided for continuous data such as age. 
Listings will be provided for demographic characteristic data based on the Enrolled Set. 
9.4.5.2. 
COVID-19 assessments 
Frequencies and percentages of participants with suspected, probable, or confirmed 
COVID-19 cases will be summarized for the ES for each study group, age group, and 
overall. Additional COVID-19 case details will be presented in data listings. 
Participants with COVID-19 cases or who take COVID-19 vaccine may be excluded 
from the per protocol analysis depending on timing of the infection or the vaccination. 
For example, if a participant has COVID-19 infection between Day 22 and Day 43, the 
participant may be excluded from analysis of Day 43 data but still be included in the 
analysis for Day 22 data.  
The COVID-19 related protocol deviations (eg, blood draw outside of allowed time 
window due to COVID-19 related restrictions of movement) will be reviewed together 
with other protocol deviations. Participants with major protocol deviations may be 
excluded from per protocol analysis sets, as described in Section 9.3.1. 
If study procedures are modified due to special circumstances, there may be requirement 
to conduct analyses that separately describe the data collected during the period of 
modified study procedures. 
9.5. 
Interim analyses  
An interim analysis will be performed on data collected through the Day 43 visit. This 
interim analysis will provide treatment-level unblinded summaries for GSK, BARDA, 
and regulatory agency review, and no individual unblinding data will be provided. The 
details of the interim analysis are provided in Section 9.5.1 and will be fully detailed in 
the SAP. 
9.5.1. 
Sequence of analyses 
9.5.1.1. 
Analysis at Day 43 
An analysis will be performed on data collected through the Day 43 visit. Elements will 
include: 
• 
Analyses of cleaned immunogenicity data collected through the Day 43 visit will be 
conducted. 


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• 
Analyses of cleaned solicited administration site events and solicited systemic events 
data collected during a 7-day follow-up period (Day 1 to Day 7) after each 
vaccination will be conducted. 
• 
Analyses of unsolicited AEs and MAEs up to 21 days after each vaccination on as 
clean as possible data. (Amended 22 February 2022) 
• 
Analyses of SAEs, pIMDs, pregnancies and withdrawals due to AEs collected up to 
the Day 43 post-vaccination visit will be carried out. (Amended 22 February 2022). 
• 
Results will be presented in a Day 43 statistical report. Access to individual 
treatment codes will be restricted to the designated statisticians in charge of the 
analysis. No individual listings or data with the participants’ identifying information 
will be disseminated. Listings of final data will be provided with the Month 13 
report. 
All analyses will be performed on data that has been cleaned and locked. The possibility 
of post-analysis changes to data evaluated at Day 43 exists, since data collection and data 
entry may continue through Month 13. All final data will be presented in the listings 
provided at Month 13. 
9.5.1.2. 
Final analysis (Month 13) 
A final data analysis will be performed at the end of study (Month 13) of all primary and 
secondary endpoints based on the clean data, including evaluations of: 
• 
Immunogenicity at all measured time points (Days 1, 22 and 43). 
• 
Solicited administration site events and solicited systemic events data reported 
7 days after each vaccination (Day 1 to Day 7 and Day 22 to Day 28). 
• 
Unsolicited AEs and MAEs reported up 21 days after each vaccination. (Amended 
22 February 2022) 
• 
Concomitant medications reported up to 21 days after each vaccination. (Amended 
22 February 2022) 
• 
SAEs, pIMDs, and withdrawals due to AEs collected throughout the entire study. 
• 
Pregnancies throughout the entire study. 
An integrated clinical study report containing all data will be written and made available 
to the investigators. 
9.5.2. 
Statistical consideration for interim analysis 
Since the primary immunogenicity endpoints for the study will be complete by the Day 
43 visit (collection past Day 43 includes only assessments for unsolicited AEs leading to 
study withdrawal, SAEs, and pIMDs), no statistical consideration for multiplicity will be 
given to account for changes in the results reported at the interim analysis compared to 
the final analysis. (Amended 22 February 2022) For the primary immunogenicity 
analysis, which will be reported at Day 43 the overall type I error rate is fixed at 5% and 


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a Bonferroni adjustment will be applied to allow simultaneous multiple comparisons of 
each antigen/adjuvant group. For the primary safety analyses no adjustment for multiple 
comparisons will be made in each antigen/adjuvant group. 
9.6. 
Data Monitoring Committee (DMC) 
Not applicable 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF or Informed Assent Form, IB, and other 
relevant documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator for review and approval. These documents will be signed and dated by 
the investigator before the study is initiated.  
• 
Any protocol amendments 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 participants.  
• 
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/IEC. 
− 
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. 


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10.1.2. 
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 financial interest information prior initiation 
of the center and at the end of the study. Investigators are responsible for providing a 
Financial Disclosure update if their financial interests change at any point during their 
participation in a study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary.  
Freely given and written informed consent must be obtained from each participant, as 
appropriate, prior to participation in the study.  
The content of the ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written or witnessed/thumb printed 
informed consent was obtained before the participant was enrolled in the study and the 
date the consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.  
Participants 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 participants.  
10.1.4. 
Data protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participants must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law.  
The participants must be informed of their rights regarding the use of their personal data 
in accordance with the data privacy Section of the ICF. 


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The participants must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
GSK will also ensure protection of the personal data of the investigator and site staff 
which will be collected within the framework and for the purpose of the study in 
accordance with the Data Privacy Notice that will be sent to the site staff.  
10.1.5. 
Committees structure 
Conduct of the study includes, but is not limited to, the following: 
• 
IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments 
• 
Participant informed consent 
• 
Investigator reporting requirements as stated in the protocol. 
Details for the structure of the iSRC can be found in Sections 8.2.2.1 and 8.2.2.2. 
The details of the analyses to be provided to the iSRC will be fully described in the SAP. 
10.1.6. 
Dissemination of clinical study data 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study register in compliance with the 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines.  
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical trial registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and 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 participants, as appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by trial 
participants are used to maximum effect in the creation of knowledge and understanding. 


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10.1.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the trial and for 
archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
Essential trial documents may be added or removed where justified (in advance of trial 
initiation) based on their 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.  
All participant 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.  
The investigator must maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial participants (see Glossary 
of terms for the exact definition of source documents) that support information entered in 
the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data.  
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not 
obscure the original entry, and should be explained if necessary (e.g. via an audit trail). 
The safety and rights of participants 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.  
Trial records and source documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 15 years from the issue of the final 
Clinical Study Report/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.  
10.1.8. 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Investigator should maintain a record of the location(s) 
of their source documents.  


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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. 
10.1.9. 
Study and site start and closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
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 
occur 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 participants by the investigator 
• 
Discontinuation of further study intervention development 
At the end of the study, each investigator will: 
• 
Review data collected to ensure accuracy and completeness 
• 
Complete the Study Conclusion screen in the eCRF. 
10.1.10. 
Publication policy 
GSK aims to submit for publication the results of the study in searchable, peer reviewed 
scientific literature within 18 months from Last Subject Last Visit (LSLV) for 
interventional studies and follows the guidance from the International Committee of 
Medical Journal Editors. 


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10.2. 
Appendix 2: Clinical laboratory tests 
Hemagglutination-inhibition Assay 
Hemagglutination inhibition antibody titers are determined using the method derived 
from the WHO Manual on Animal Influenza Diagnosis and Surveillance, 
WHO/CDS/CSR/NCS/2002.5. 
Measurements are conducted on thawed frozen serum samples with a standardized and 
comprehensively validated micromethod. The standard operating procedure describes a 
HI test for detecting H7N9 influenza A specific antibody responses, such as those 
following influenza virus vaccinations. Briefly, serum samples are treated with receptor 
destroying enzyme overnight, diluted to 1:10, and serial diluted 2-fold in triplicate from 
1:10 to 1:10240. After addition of an equal volume of standardized virus (4 HAU / 
25 μL), neutralization is performed for 1 hour at room temperature, followed by addition 
of the red blood cells. After 30 minutes, plates are tilted and the titer is the reciprocal of 
the last dilution that fully inhibits hemagglutination as compared to a red blood cell 
control well. Each sera sample will be tested in triplicate within the same assay. The three 
titer results will be reported, as will the GMT for the triplicate. 
Microneutralization Assay 
Measurements are conducted on thawed frozen serum samples. Samples are heat 
inactivated for 30 minutes at 56°C. A standardized amount of virus is mixed with serial 
dilutions of serum and incubated to allow binding of the antibodies to the virus. A cell 
suspension containing a defined amount of Madin-Darby Canine Kidney cells is then 
added to the mixture of virus and antiserum and incubated at 37°C for 18 to 20 hours. 
After overnight incubation, plates are fixed and the amount of virus per well is detected 
by enzyme-linked immunosorbent assay using anti-nucleoprotein monoclonal antibodies. 
The virus neutralizing antibody titer is determined using a formula that calculates the 
midpoint optical density of uninfected cells and virus infected (without neutralization) 
cells. 
10.2.1. 
Protocol-required safety laboratory assessments 
There are no protocol-required safety laboratory assessments for this study.  
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of 
AE 
10.3.1. 
Definition of an Adverse Event (AE)  
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 


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• 
NOTE: 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 study intervention. 
10.3.1.1. 
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/product administration 
even though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccine/product or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs or symptoms temporally associated with study vaccine/product 
administration. 
• 
Signs, symptoms that require medical attention (e.g. hospital stays, physician visits 
and emergency room visits) 
• 
Pre- or post- intervention events that occur as a result of protocol-mandated 
procedures (i.e. invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
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. 
• 
AEs to be recorded as solicited AEs are described in the Section 10.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
10.3.1.2. 
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.  


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• 
Pre-existing conditions or signs and/or symptoms present in a participant prior to 
the first vaccination. These events will be recorded in the medical history section 
of the eCRF.  
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline. 
• 
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 participant’s condition, or that are present or 
detected at the start of the study and do not worsen. 
10.3.2. 
Definition of a Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that: 
a. 
Results in death 
b. Is life-threatening 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the 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, had it been more 
severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the participant has been admitted at 
the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or in an out-patient setting. 
Complications that occur during hospitalization are also considered as AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalization’ 
occurred, or was necessary, the AE should be considered serious. 
d. Results in disability/incapacity  
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza like illness, and accidental trauma 
(e.g. sprained ankle) which may interfere or prevent everyday life functions but do 
not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Other situations 
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 


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immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These should also 
be considered serious. Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization. 
10.3.3. 
Solicited events 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 17 
Solicited administration site events 
All age groups 
Pain  
Redness  
Swelling  
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 18 
Solicited systemic events 
All age groups 
Fatigue 
Fever 
Headache 
Muscle ache all over body 
Joint pain 
Shivering (Chills) 
Sweating 
Gastrointestinal symptoms: 
Nausea 
Vomiting 
Diarrhea 
Abdominal pain 
Note: participants will be instructed to measure and record the oral body temperature in 
the evening. Should additional temperature measurements be performed at other times of 
day, participants will be instructed to record the highest temperature in the diary card. 
10.3.4. 
Unsolicited adverse events 
An unsolicited AE is an AE that was not solicited using a Participant Diary and that was 
spontaneously communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 


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Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or emergency room visit, or visit to/by a health care provider). 
The participants will be instructed to contact the site as soon as possible to report 
MAE(s), as well as any events that, though not medically attended, are of participant 
concern. Detailed information about reported unsolicited AEs will be collected by 
qualified site personnel and documented in the participant’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participants and by review of available 
medical records at the next visit. 
10.3.5. 
Adverse events of special interest (AESIs) 
Potential immune-mediated diseases are the only AESIs that will be collected during the 
study. 
10.3.5.1. 
Potential immune-mediated diseases 
Potential immune-mediated diseases 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 etiology. Adverse events that need to be recorded and 
reported as pIMDs include those listed in the Table 19. 
However, the investigator will exercise his/her medical and scientific judgement to 
determine whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.  
Table 19 
List of potential immune-mediated diseases (pIMDs) (Amended 22 
February 2022) 
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
• 
Includes warm antibody hemolytic anemia and cold antibody 
hemolytic anemia 
Autoimmune lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
• 
Frequently used related terms include: “autoimmune 
thrombocytopenic purpura”, “idiopathic thrombocytopenic 
purpura (ITP)”, “idiopathic immune thrombocytopenia”, “primary 
immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 


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Medical Concept 
Additional Notes 
Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
 
Thrombotic thrombocytopenic 
purpura 
• 
Also known as “Moschcowitz-syndrome” or “microangiopathic 
hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 
Idiopathic 
Myocarditis/Pericarditis 
Including but not limited to: 
• 
Autoimmune / Immune-mediated myocarditis 
• 
Autoimmune / Immune-mediated pericarditis 
• 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
• 
Idiopathic interstitial pneumonia (frequently used related terms 
include “Interstitial lung disease”, “Pulmonary fibrosis”, 
“Immune-mediated pneumonitis”) 
• 
Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis  
• 
Silent thyroiditis  
• 
Thyrotoxicosis 
Autoimmune diseases of the 
testis and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome and Graves' ophthalmopathy, 
also known as thyroid eye disease (TED) or endocrine 
ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular 
outer retinopathy) 
• 
Autoimmune / Immune-mediated retinopathy  


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Medical Concept 
Additional Notes 
• 
Autoimmune / Immune-mediated uveitis, including idiopathic 
uveitis and sympathetic ophthalmia  
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to:  
• 
Crohn’s disease  
• 
Microscopic colitis  
• 
Terminal ileitis 
• 
Ulcerative colitis  
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• 
Dermatomyositis 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• 
Rheumatoid arthritis associated conditions 
• 
Juvenile idiopathic arthritis 
• 
Palindromic rheumatism 
• 
Still's disease 
• 
Felty’s syndrome 
Sjögren’s syndrome 
 


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Medical Concept 
Additional Notes 
Spondyloarthritis 
Including but not limited to:  
• 
Ankylosing spondylitis 
• 
Juvenile spondyloarthritis 
• 
Keratoderma blenorrhagica 
• 
Psoriatic spondylitis  
• 
Reactive Arthritis (Reiter's Syndrome) 
• 
Undifferentiated spondyloarthritis 
Systemic Lupus Erythematosus  
• 
Includes Lupus associated conditions (e.g. Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (Systemic 
Sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with 
diffuse scleroderma and systemic sclerosis with limited 
scleroderma (also known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
other inflammatory-
demyelinating variants  
Includes the following: 
• 
Acute necrotising myelitis 
• 
Bickerstaff's brainstem encephalitis  
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis,  
or acute necrotizing hemorrhagic encephalomyelitis)  
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  
Guillain-Barré syndrome (GBS) 
• 
Includes variants such as Miller Fisher syndrome and the acute 
motor and sensory axonal neuropathy (AMSAN) 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis) 
Including but not limited to: 
• 
Cranial nerve neuritis (e.g. Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (e.g. Bell’s palsy) 
• 
Melkersson-Rosenthal syndrome 
• 
Multiple cranial nerve palsies/paresis  
Multiple Sclerosis (MS) 
Includes the following: 
• 
Clinically isolated syndrome (CIS)  
• 
Malignant MS (the Marburg type of MS)  
• 
Primary-progressive MS (PPMS) 
• 
Radiologically isolated syndrome (RIS) 
• 
Relapsing-remitting MS (RRMS) 
• 
Secondary-progressive MS (SPMS) 
• 
Uhthoff's phenomenon  
Myasthenia gravis 
• 
Includes ocular myasthenia and Lambert-Eaton myasthenic 
syndrome 


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Medical Concept 
Additional Notes 
Narcolepsy 
• 
Includes narcolepsy with or without presence of unambiguous 
cataplexy 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner 
Syndrome or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy 
(CIDP), including atypical CIDP variants (e.g. multifocal acquired 
demyelinating sensory and motor neuropathy also known as 
Lewis-Sumner syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute 
complete transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / Immune-mediated 
blistering dermatoses  
Including but not limited to:  
• 
Bullous Dermatitis 
• 
Bullous Pemphigoid  
• 
Dermatitis herpetiformis  
• 
Epidermolysis bullosa acquisita (EBA)  
• 
Linear IgA-mediated bullous dermatosis (LABD), also known as 
Linear IgA disease 
• 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Reactive granulomatous 
dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 


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Medical Concept 
Additional Notes 
Lichen planus 
• 
Includes liquen planopilaris 
Localised Scleroderma 
(Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson Syndrome 
(SJS) 
Including but not limited to:  
• 
Toxic Epidermal Necrolysis (TEN)  
• 
SJS-TEN overlap 
Sweet’s syndrome 
• 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
• 
Arteritic anterior ischemic optic neuropathy (AAION or arteritic 
AION) 
• 
Giant cell arteritis (also called temporal arteritis)  
• 
Takayasu's arteritis  
Medium sized and/or small 
vessels vasculitis  
Including but not limited to: 
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis 
(type unspecified)  
• 
Behcet's syndrome  
• 
Buerger’s disease (thromboangiitis obliterans) 
• 
Churg–Strauss syndrome (allergic granulomatous angiitis)  
• 
Erythema induratum (also known as nodular vasculitis) 
• 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
• 
Microscopic polyangiitis 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic 
vasculitis, hypersensitivity vasculitis and acute hemorrhagic 
edema of infancy (AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include : “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include : “pulmonary renal 
syndrome” and “anti-Glomerular Basement Membrane disease 
(anti-GBM disease)” 
Immune-mediated enhancement 
of disease 
• 
Includes vaccine associated enhanced disease (VAED and 
VAERD). Frequently used related terms include “vaccine-
mediated enhanced disease (VMED)”, “enhanced respiratory 
disease (ERD)”, “vaccine-induced enhancement of infection”, 


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Medical Concept 
Additional Notes 
“disease enhancement”, “immune enhancement”, and “antibody-
dependent enhancement (ADE) 
Immunoglobulin G4 related 
disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• 
Kawasaki’s disease 
• 
Multisystem inflammatory syndrome in adults (MIS-A) 
• 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• 
Includes Loefgren syndrome 
Susac's syndrome 
 
10.3.6. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs 
In the absence of a diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments (e.g. physical examination 
findings) the investigator considers clinically significant will be recorded as an AE or 
SAE if they meet the definition of an AE or SAE (refer to the Sections 10.3.1 and 10.3.2).  
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. 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs  
10.3.7.1. 
Pregnancy 
Female participants who become pregnant after the first vaccination must not receive 
subsequent doses of the study vaccine/product, but may continue other study procedures 
at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any abnormal pregnancy 
outcome or complication or elective termination of a pregnancy for medical reasons will 
be recorded and reported as an SAE. Please refer to the Section 10.3.2 for definition of 
SAE.  
10.3.8. 
Recording and follow-up of AEs, SAEs, pIMDs and pregnancies 
The participants will be instructed to contact the investigator immediately should the 
participants manifest any signs or symptoms they perceive as serious.  


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When an AE/SAE/pIMD/pregnancy 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/pIMD/pregnancy in the eCRF. The investigator is not allowed to 
send photocopies of the participant’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 participant 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. 
A Paper Diary (pDiary), hereafter referred to as Participant Diary will be used in this 
study to capture solicited administration site or systemic events. The participant should 
be trained on how and when to complete each field of the Participant Diary. 
At each vaccination visit, diary cards will be provided to the participant. The participant 
will be instructed to measure and record the oral body temperature and any solicited 
administration site/systemic events (i.e. on the day of vaccination and during the next 
6 days) or any unsolicited AEs (i.e. on the day of vaccination and during the next 20 days 
occurring after vaccination). For solicited events continuing after 7 days, the participant 
will be instructed to record events until 21 days post-vaccination or until resolution. 
Solicited events that continue after 7 days will be recorded as an unsolicited AE. The 
participant will be instructed to return the completed diary card to the investigator at the 
next study visit or by mail using the pre-stamped envelope received at the site. Details on 
the timing and collection of the solicited administration site and systemic events on the 
diary card will be described in the SPM. 
At each vaccination visit, a COVID-19 assessment card will be provided to the 
participant. The participant will be instructed to return the completed assessment card to 
the investigator at the next study visit or by mail using the pre-stamped envelope received 
at the site. 
In addition, solicited events with a start day after day 7 post-vaccination (e.g. Day 8 after 
dose 1 and Day 28 after dose 2) will be recorded as unsolicited AEs. 
Any individual(s) who performs the measurements of administration site or systemic 
events and who will enter the information into the Participant Diary should be trained on 
the use of the Diary. This training must be documented in the participant’s source record. 
If any other individual, the participant is making entries in the Participant Diary, their 
identity should be documented in the Participant Diary/participant’s source record. 
• 
Collect and verify completed diary cards during discussion with the participant on 
Visit 2 and Visit 3. 
• 
Any unreturned diary cards will be sought from the participant through telephone 
call(s) or any other convenient procedure.  


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The investigator or delegate will transcribe the required information into the eCRF in 
English.  
10.3.8.1. 
Time period for collecting and recording AEs 
All AEs that occur within 21 days following administration of each dose of study 
vaccine/product must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related. (Amended 22 
February 2022) 
10.3.8.2. 
Follow-up of AEs, SAEs, pIMDs or any other events of interest 
After the initial AE/SAE/pIMD or any other event of interest for the study, the 
investigator is required to proactively follow each participant at subsequent 
visits/contacts. The investigator will follow participants with SAEs, pIMDs (serious or 
non-serious), or participants withdrawn from the study as a result of an AE, until the 
event has resolved, subsided, stabilized, disappeared, or until the event is otherwise 
explained, or the participant is lost to follow-up. 
Other non-serious AEs must be followed until the event is resolved, stabilized, otherwise 
explained or until the participant is lost to follow-up. 
10.3.8.2.1. Follow-up during the study 
AEs/pIMDs documented at a previous visit/contact and defined as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 
If participant dies during participation in the study or during a recognized follow-up 
period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.3.8.2.2. Follow-up after the participant is discharged from the study 
The investigator will provide any new or updated relevant information on previously 
reported SAE/pIMD to GSK using a paper/electronic Expedited Adverse Events Report 
and/or pregnancy report as applicable. The investigator is obliged to perform or arrange 
for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the AE or SAE as fully as possible.   
10.3.8.2.3. Follow-up of pregnancies 
Pregnant participants 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 paper pregnancy follow-up 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. 


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Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is an 
SAE, it should always be reported as an SAE. 
Furthermore, in case if the investigator becomes aware of any SAE occurring as a result 
of a post-study pregnancy AND considered by the investigator to be reasonably related to 
the study vaccine/product, he/she has to report this information to GSK as described in 
the Section 10.3.10. 
10.3.8.3. 
Updating of SAE, pIMD and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, pIMD or pregnancy information is received after removal of write 
access to the participant’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Section 8.3.3.1) or to GSK Clinical Safety and Pharmacovigilance department within the 
defined reporting time frames specified in the Table 12. 
10.3.9. 
Assessment of intensity and toxicity 
10.3.9.1. 
Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 20 
Intensity scales for solicited events in adults 18 years of age or 
more 
Adults (18 years) 
Event 
Intensity grade 
Parameter 
Pain at administration 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. 
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. 
Muscle ache all over body 
0 
Normal 
 
1 
Mild: Muscle aches that are easily tolerated. 
 
2 
Moderate: Muscle aches that interfere with normal 
activity. 
 
3 
Severe: Muscle aches that prevent normal activity. 
Joint pain 
0 
Normal 
 
1 
Mild: Joint pain that is easily tolerated. 
 
2 
Moderate: Joint pain that interferes with normal activity. 


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Adults (18 years) 
Event 
Intensity grade 
Parameter 
 
3 
Severe: Joint pain that prevents normal activity. 
Shivering (chills) 
0 
Normal 
 
1 
Mild: Shivering (chills) that is easily tolerated. 
 
2 
Moderate: Shivering (chills) that interferes with normal 
activity. 
 
3 
Severe: Shivering (chills) that prevents normal activity. 
Sweating 
0 
Normal 
 
1 
Mild: Sweating that is easily tolerated. 
 
2 
Moderate: Sweating that interferes with normal activity. 
 
3 
Severe: Sweating that prevents normal activity. 
Gastrointestinal symptoms: nausea, 
vomiting, diarrhea and/or abdominal 
pain 
0 
Normal 
 
1 
Mild: Gastrointestinal symptoms that are easily tolerated. 
 
2 
Moderate: Gastrointestinal symptoms that interfere with 
normal activity. 
 
3 
Severe: Gastrointestinal symptoms that prevent normal 
activity. 
Redness at administration site 
Record greatest surface diameter in mm 
Swelling at administration site 
Record greatest surface diameter in mm 
Temperature* 
 
Record temperature in °C/°F 
* Refer to the SoA (Section 1.3) for the definition of fever and the preferred location for temperature measurement. 
The maximum intensity of local injection site redness/swelling will be scored at GSK as 
follows: 
0: 
≤ 20 mm 
1: 
> 20 to 50 mm 
2: 
> 50 to 100 mm 
3: 
> 100 mm 
The maximum intensity of fever will be scored at GSK as follows: 
0: 
< 38.0°C (< 100.4°F) 
1: 
≥ 38.0 – 38.4°C (≥100.4 – 101.2°F) 
2: 
≥ 38.5 – 38.9°C (≥ 101.3 – 102.1°F) 
3: 
≥ 39.0 – 40.0°C (≥ 102.2 – 104.0°F) 
4: 
> 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. 


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The intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the participant, causing 
minimal discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
In adults, 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 an 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 the Section 10.3.2. 
10.3.9.2. 
Assessment of causality 
All solicited administration-site and systemic events will be considered causally related 
to vaccination. The complete list of these events is provided in the Table 17 and Table 18.  
The investigator must assess the relationship between study vaccine/product and the 
occurrence of each unsolicited AE/SAE using clinical judgement. Where several different 
vaccines/products were administered, the investigator should specify, when possible, if 
the unsolicited AE/SAE could be causally related to a specific vaccine/product (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine/product cannot be determined, the investigator should indicate the 
unsolicited AE/SAE 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/product will be considered and investigated. The investigator will also 
consult the IB to determine his/her assessment. 
Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the 
study vaccine/product? 
YES 
: 
There is a reasonable possibility that the study vaccine/product 
contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine/product. There are other, more 
likely causes and administration of the study vaccine/product is not 
suspected to have contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator to determine ALL possible 
contributing factors for each SAE. 


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Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine/product, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify).  
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important to 
record an assessment of causality for every event before submitting the Expedited 
Adverse Events Report to GSK.  
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality after receiving 
additional information and update the SAE information accordingly. 
10.3.9.3. 
Medically attended visits 
For each solicited and unsolicited symptom the participant experiences, the participant 
will be asked if he/she received medical attention defined as hospitalization, or an 
otherwise unscheduled visit to or from medical personnel for any reason, including 
emergency room visits. This information will be recorded in the eCRF.  
10.3.9.4. 
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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10.3.10. 
Reporting of SAEs, pIMDs, pregnancies and other events 
10.3.10.1. Events requiring expedited reporting to GSK 
Once an investigator becomes aware that an SAE has occurred in a study participant, the 
investigator (or designee) must complete 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 an 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. 
Refer to the Table 12 for the details on timeframes for reporting of 
SAEs/pIMDs/pregnancies.  
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. 
Refer to the Section 10.3.10.2 for the back-up system in case the electronic reporting 
system does not work. 
10.3.10.2. Back-up system in case facsimile or electronic reporting system does 
not work 
In rare circumstances if the electronic reporting system does not work, the investigator 
(or designee) must fax completed, dated and signed paper Expedited Adverse Events 
Report to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or to 
GSK Clinical Safety and Pharmacovigilance department within 24 hours.  
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours upon electronic reporting system is resumed. The information reported 
through the electronic SAE reporting system will be considered valid for regulatory 
reporting purposes. 
10.4. 
Appendix 4: COVID-19 definition and assessment card 
COVID-19 cases will be captured based on the WHO criteria using the following 
categories: suspected, probable and confirmed cases. These COVID-19 infection cases 
will be submitted as AEs per normal reporting mechanisms. Investigators will have to use 
the case definitions provided below [WHO, 2020]. All AEs will have to be considered as 
to whether they meet SAE criteria, and if so, submitted through the SAE reporting 
mechanism. The COVID-19 eCRF page will have to be used to capture additional 
COVID-19 case details that would not normally be contained elsewhere in the eCRF.  
Case Definition for COVID-19 Coronavirus Infection  


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WHO Case Definition (March 27, 2020 Version):  
Suspected case  
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease during 
the 14 days prior to symptom onset;  
OR  
B. A patient with any acute respiratory illness AND having been in contact (see 
definition of “contact” below) with a confirmed or probable COVID-19 case (see 
definition of contact) in the last 14 days prior to symptom onset; 
OR  
C. A patient with severe acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath; AND requiring hospitalization) AND 
in the absence of an alternative diagnosis that fully explains the clinical presentation.  
Probable case  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive (Inconclusive 
being the result of the test reported by the laboratory).  
OR  
B. A suspect case for whom testing could not be performed for any reason.  
Confirmed case  
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical 
signs and symptoms.  
A contact is a person who experienced any one of the following exposures during the 
2 days before and the 14 days after the onset of symptoms of a probable or confirmed 
case:  
1. Face-to-face contact with a probable or confirmed case within 1 meter and for more 
than 15 minutes;  
2. Direct physical contact with a probable or confirmed case;  
3. Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; OR  
4. Other situations as indicated by local risk assessments. 
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation. 


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10.4.1. 
COVID-19 assessment card 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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10.5. 
Appendix 5: Contraceptive guidance and collection of 
pregnancy information 
10.5.1. 
Definitions 
10.5.1.1. 
Women of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
10.5.1.1.1. Women not considered as women of childbearing potential 
• 
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.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of study intervention, additional 
evaluation should be considered. 
• 
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 participant’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 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 follicle stimulating hormone 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 enrollment. 


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10.5.2. 
Contraception guidance 
• 
Female participants 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 21.  
Table 21 
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 (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.)  
Male partner sterilization prior to the female participant’s entry into the study, and this male is the sole partner for that 
participant, 
(The information on the male sterility can come from the site personnel’s review of the participant’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 intervention. 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 participant.)  
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 participants in clinical studies.  
10.5.3. 
Collection of pregnancy information 
10.5.3.1. 
Female participants who become pregnant 
Refer to the Sections 8.3.1, 8.3.2, 10.3.8.1 and 10.3.8.3 for further information on 
detection, recording, reporting and follow-up of pregnancies. 
Any female participant who becomes pregnant during the study will discontinue study 
intervention. 


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10.6. 
Appendix 6: Country-specific requirements 
Not applicable 
10.7. 
Appendix 7: Abbreviations and glossary of terms 
10.7.1. 
List of abbreviations  
AE: 
Adverse event 
AESI: 
Adverse event of special interest 
BARDA: 
Biomedical Advanced Research and Development 
Authority 
CBER: 
Center for Biologics Evaluation and Research 
CI: 
Confidence interval 
COVID-19: 
Coronavirus disease 2019 
DIL: 
dilution 
eCRF: 
electronic case report form 
ES: 
Exposed Set 
GCP: 
Good Clinical Practice 
GMT: 
Geometric mean titers 
GSK: 
GlaxoSmithKline 
HA: 
Hemagglutinin 
HAU: 
Hemagglutinin units 
HI: 
Hemagglutination inhibition 
IB: 
Investigator Brochure 
ICF: 
Informed consent form 
ICH: 
International Council on Harmonisation 
IEC: 
Independent Ethics Committee 
IRB: 
Institutional Review Board 


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IRT: 
Interactive Response Technology 
iSRC: 
Internal Safety Review Committee 
LL: 
Lower limit 
MAE: 
Medically attended adverse event 
MN: 
Microneutralization 
MN mPPS: 
Microneutralization modified per protocol set 
(Amended 22 February 2022) 
MNPPS: 
Microneutralization per protocol set 
mPPS: 
Modified per protocol set (Amended 22 February 
2022) 
pIMD: 
Potential Immune-Mediated Disease 
PPS: 
Per protocol set 
SAE: 
Serious adverse event 
SAP: 
Statistical analysis plan 
SCR: 
Seroconversion rate 
SoA: 
Schedule of Activities 
SPM: 
Study Procedures Manual 
SPR: 
Seroprotection rate 
SUSAR: 
Serious Unexpected Serious Adverse Reaction 
TOC: 
Table of Contents 
US: 
United States 
VCSP: 
Vaccines Clinical Safety and Pharmacovigilance 
VSMB: 
Vaccine Safety Monitoring Board 
WHO: 
World Health Organization 


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10.7.2. 
Glossary of terms 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the 
use of a medicinal product, whether or not considered 
related to the medicinal product.  
An adverse event (AE) can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal 
product. For marketed medicinal products, this also 
includes failure to produce expected benefits (i.e. lack of 
efficacy), abuse or misuse. 
Blinding: 
A procedure in which 1 or more parties to the trial are 
kept unaware of the intervention 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 participant, the site 
and sponsor personnel involved in the clinical evaluation 
of the participants are blinded while other study 
personnel may be aware of the treatment assignment. 
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. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrolled: 
‘Enrolled’ means a participant’s agreement to participate 
in a clinical study following completion of the informed 
consent process. Potential participants 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 the Section 9.3 for the definition of ‘enrolled’ 
applicable to the study. 


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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 9.3 for 
details on criteria for evaluability). 
Immunological correlate of 
protection: 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intervention: 
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 participant. 
Intervention number: 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational 
vaccine/product: 
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use.  
Synonym: Investigational Medicinal Product 
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. 
Participant: 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or 
participates in the clinical study, either as a recipient of 
the vaccine/product or as a control. 
Synonym: subject 


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Participant number: 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Primary completion: date: 
The date that the final participant 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. 
Randomization: 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Site Monitor: 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Solicited event: 
Events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the participant 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 legible documents, data, and records (e.g. 
hospital records, clinical and office charts, laboratory 
notes, memoranda, participants' 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, participant files, and records 
kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical trial). 
Study vaccine/product: 
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/product/placebo as a 
reference or administered concomitantly, in a clinical 
trial that evaluates the use of an investigational 
vaccine/product. 


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Sub-cohort: 
A group of participants for whom specific study 
procedures are planned as compared to other participants 
or a group of participants who share a common 
characteristic (e.g. ages, vaccination schedule…) at the 
time of enrollment. 
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. 
10.8. 
Appendix 8: Protocol Amendment 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 
Amendment 2 
22 February 2022 
Amendment 1 
27 August 2020 
Original Protocol 
13 February 2020 
Amendments summary of changes table 
Document 
Date 
of 
issue 
Section # and 
Name 
Description of Change 
Brief Rationale 
Amendment 
1 
27 
August 
2020 
1.1 Synopsis 
The following text was added: 
In addition, this study is also intended to 
capture COVID-19 cases among study 
participants based on the WHO criteria 
(suspected, probable, and confirmed cases).  
Due to the COVID-
19 pandemic, GSK 
anticipates that 
209671 (FLU Q-PAN 
H7N9=AS03-002) 
may receive cases of 
suspected or 
confirmed COVID-19 
infections. A 
standardized 
approach to case 
definition, case 
reporting, and case 
detail data collection 
is put in place. 
Amendment 
1 
27 
August 
2020 
1.3 Schedule 
of Activities 
(SoA) 
The text was modified as follows: 
Distribution of diary cards and COVID-19 
assessment card5 
Return of diary cards and COVID-19 
assessment card5 
5. Diary cards used to capture both solicited 
administration site and systemic events (Days 1-
7 after each vaccination) and unsolicited 
To reflect study 
procedures during 
special 
circumstances 
(COVID-19). 


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Document 
Date 
of 
issue 
Section # and 
Name 
Description of Change 
Brief Rationale 
adverse events (Days 1-21 after each 
vaccination) and COVID-19 assessment cards 
are provided at the time of each vaccination and 
collected at the next visit following each 
vaccination (solicited administration and 
systemic events portion of card) and at the 
subsequent visit (unsolicited adverse events 
portion of card) or by mail using the pre-
stamped envelope received at the site.  
Amendment 
1 
27 
August 
2020 
3. Objectives 
and Endpoints 
This objective/endpoint was moved from 
secondary to primary: 
Occurrence of pIMDs and SAEs until Month 
13 
Changed due to 
feedback from 
Regulatory 
Authorities. 
Amendment 
1 
27 
August 
2020 
4.1 Overall 
design 
The following text was added: 
In addition, this study is also intended to 
capture COVID-19 cases among study 
participants based on the WHO criteria 
[WHO, 2020]: suspected, probable, or 
confirmed. COVID-19 infection cases will be 
reported as AEs per normal reporting 
mechanisms. All AEs should be considered 
as to whether they meet SAE criteria, and if 
so, submitted through the SAE reporting 
mechanism. The COVID-19 eCRF page will 
be used to capture additional COVID-19 case 
details that would not normally be contained 
elsewhere in the eCRF. 
Due to the COVID-
19 pandemic, GSK 
anticipates that study 
209671 (FLU Q-PAN 
H7N9=AS03-002) 
will receive cases of 
suspected or 
confirmed COVID-19 
infections. A 
standardized 
approach to case 
definition, case 
reporting, and case 
detail data collection 
is put in place. 
Amendment 
1 
27 
August 
2020 
5.1 Inclusion 
criteria for 
enrollment 
The text was modified as follows:  
3. Participants, who, in the opinion of the 
investigator, can and will comply with the 
requirements of the protocol (e.g. completion of 
the diary cards and COVID-19 assessment 
card, return for follow-up visits, or return the 
diary cards and COVID-19 assessment card 
in a timely manner using the pre-stamped 
envelope received at the site).  
To reflect study 
procedures during 
special 
circumstances 
(COVID-19). 
Amendment 
1 
27 
August 
2020 
9.4.3.2 Safety 
This endpoint was moved from secondary to 
primary: 
Occurrence and relationship to vaccination 
of SAEs and pIMDs until Month 13. 
Changed due to 
feedback from 
Regulatory 
Authorities. 
Amendment 
1 
27 
August 
2020 
9.4.5.2 
COVID-19 
assessments 
The following text was added: 
Frequencies and percentages of participants 
with suspected, probable, or confirmed 
COVID-19 cases will be summarized for the 
ES for each study group, age group, and 
overall. Additional COVID-19 case details will 
be presented in data listings. 
Participants with COVID-19 cases or who 
take COVID-19 vaccine may be excluded 
from the per protocol analysis depending on 
timing of the infection or the vaccination. For 
To reflect additional 
analyses due to 
special 
circumstances 
(COVID-19). 


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Document 
Date 
of 
issue 
Section # and 
Name 
Description of Change 
Brief Rationale 
example, if a participant has COVID-19 
infection between Day 22 and Day 43, the 
participant may be excluded from analysis of 
Day 43 data but still be included in the 
analysis for Day 22 data.  
The COVID-19 related protocol deviations 
(eg, blood draw outside of allowed time 
window due to COVID-19 related restrictions 
of movement) will be reviewed together with 
other protocol deviations. Participants with 
major protocol deviations may be excluded 
from per protocol analysis sets, as described 
in Section 9.3.1. 
If study procedures are modified due to 
special circumstances, there may be 
requirement to conduct analyses that 
separately describe the data collected during 
the period of modified study procedures. 
Amendment 
1 
27 
August 
2020 
10.3.8 
Recording and 
Follow-up of 
AEs, SAEs, 
pIMDS, and 
pregnancies 
The text was modified as follows: 
The participant will be instructed to return the 
completed diary card to the investigator at the 
next study visit or by mail using the pre-
stamped envelope received at the site. 
Details on the timing and collection of the 
solicited administration site and systemic events 
on the diary card will be described in the SPM.  
At each vaccination visit, a COVID-19 
assessment card will be provided to the 
participant. The participant will be instructed 
to return the completed assessment card to 
the investigator at the next study visit or by 
mail using the pre-stamped envelope 
received at the site. 
To reflect study 
procedures during 
special 
circumstances 
(COVID-19). 
Amendment 
1 
27 
August 
2020 
10.4 Appendix 
4: COVID-19 
definition and 
assessment 
card 
The case definition for COVID-19 as defined by 
WHO was added. 
The protocol was 
amended due to the 
COVID-19 pandemic 
and the need for a 
standardized 
approach to case 
definition, case 
reporting, and case 
detail data collection. 
Amendment 
1 
27 
August 
2020 
10.4.1 
COVID-19 
assessment 
card 
A COVID-19 assessment card was added. 
The protocol was 
amended due to the 
COVID-19 pandemic 
and the need for a 
standardized 
approach to case 
definition, case 
reporting, and case 
detail data collection. 


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Document 
Date 
of 
issue 
Section # and 
Name 
Description of Change 
Brief Rationale 
Amendment 
1 
27 
August 
2020 
10.6.1 List of 
Abbreviations 
Two abbreviations were added: 
COVID-19, TOC 
The protocol was 
amended due to the 
COVID-19 pandemic 
and the need for a 
standardized 
approach to case 
definition, case 
reporting, and case 
detail data collection. 
Amendment 
1 
27 
August 
2020 
11. 
References 
The following references were added: 
Food and Drug Administration (FDA). 
Guidance for Industry, Investigators, and 
Institutional Review Boards. FDA Guidance 
on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health 
Emergency. July 2020. 
https://www.fda.gov/media/136238/download. 
Accessed: 31 JULY 2020  
World Health Organization (WHO). 
Coronavirus disease 2019 (COVID-19) 
Situation Report – 67. 2020. Available at: 
https://www.who.int/docs/default-
source/coronaviruse/situation-
reports/20200327-sitrep-67-covid-
19.pdf?sfvrsn=b65f68eb_4. Accessed: 31 
JULY 2020.  
Reference for the 
FDA COVID-19 
clinical trial guidance 
and WHO case 
definition of 
COVID-19. 
Detailed description of Protocol Amendment 2: 
Amended text has been included in bold italics in the body of the protocol. The 
amended text (in bold italics) and the deleted text (in strikethrough) are provided 
below: 
Sponsor Signatory Approval 
Andrew Hastie Jerome Wilson, Clinical and Epidemiology Project Lead, Vaccines for 
Influenza 


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Section 8.3.3 Regulatory reporting requirements for SAEs, pregnancies, and other 
events 
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* 
2 weeks 
Paper pregnancy 
notification report 
24 hours* 
2 weeks 
Paper pregnancy follow-up 
report 
pIMDs 
24 hours** ‡  
Electronic Expedited 
Adverse Events Report 
24 hours* 
Electronic Expedited Adverse 
Events Report 
Section 9.3 Populations for Analyses 
Analysis set 
Description 
Enrolled  
Participant’s agreed to participate in a clinical study after completion of the 
informed consent process. Refer to the Glossary of terms for the definition of 
‘enrolled’.  
Randomized 
All participants who were randomized to receive a study vaccine. 
Exposed Set (ES) 
All participants who received any study vaccination. The allocation in a group is 
done in function of the administered intervention. The analysis of primary and 
secondary safety endpoints will be based on this set. 
Full Analysis Set (FAS) 1 
All participants in the Exposed Set who have post-vaccination immunogenicity 
data at Visit 3 (Day 43). Participants will be analyzed as “randomized” (i.e. 
according to the vaccine[s] the participant was randomized to receive). 
FAS 2 
All participants in the Exposed Set who have post-vaccination immunogenicity 
data at Visit 2 (Day 22). Participants will be analyzed as “randomized” (i.e. 
according to the vaccine[s] the participant was randomized to receive). 
Per Protocol Set (PPS) 1 
The PPS 1 is a subset of FAS 1. The PPS 1 includes all FAS 1 participants with no 
major protocol deviations that lead to exclusion at or prior to Visit 3 (Day 43). 
Major protocol deviations leading to exclusion will be defined in the Statistical 
Analysis Plan (SAP) and the Study Deviation Rules document and will be finalized 
prior to the interim analysis defined in Section 9.5. Primary immunogenicity data 
will be evaluated based on this set. 
Modified PPS (mPPS) 1 
The mPPS 1 is a subset of FAS 1. The mPPS 1 includes all FAS 1 
participants with no major protocol deviations that led to exclusion at or 
prior to Visit 3 (Day 43). The time window between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set is between 18-32 study days. The 
interval between Visit 2 and Visit 3 will be 14-32 calendar days. 
 
Major protocol deviations leading to exclusion will be defined in the 
Statistical Analysis Plan (SAP) and the Study Deviation Rules Document and 
will be finalized prior to the interim analysis defined in Section 9.5. 
PPS 2 
The PPS 2 is a subset of FAS 2. The PPS 2 includes all FAS 2 participants with no 
major protocol deviations that lead to exclusion at or prior to Visit 2 (Day 22). 
Major protocol deviations leading to exclusion will be defined in the SAP and the 
Study Deviation Rules document and will be finalized prior to the interim analysis 
defined in Section 9.5. Secondary immunogenicity data will be evaluated based on 
this set. 
mPPS 2 
The mPPS 2 is a subset of FAS 2. The mPPS 2 includes all FAS 2 
participants with no major protocol deviations that lead to exclusion at or 
prior to Visit 2 (Day 22). The time window between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set is between 18-32 study days. 
  


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Analysis set 
Description 
Major protocol deviations leading to exclusion will be defined in the SAP and 
the Study Deviation Rules document and will be finalized prior to the interim 
analysis defined in Section 9.5. 
Microneutralization (MN) 
All participants in the Randomized Set who were also selected to the subset of MN 
evaluation.  
Microneutralization Per 
Protocol Set (MNPPS) 1 
All participants in the MN Set who are also part of the PPS 1. 
MN mPPS 1 
All participants in the MN Set who are also part of the mPPS 1. 
MNPPS 2 
All participants in the MN Set who are also part of the PPS 2. 
MN mPPS 2 
All participants in the MN Set who are also part of the mPPS 2. 
Section 9.4.1 General considerations 
Derived and transformed data: 
• 
Immunogenicity (Note: The cut-off value for antibody titer is defined by the 
laboratory before the analysis and will be specified in the clinical study report). 
− 
A seronegative participant is a participant whose antibody titer is below the 
assay cut-off value. 
− 
A seropositive participant is a participant whose antibody titer is greater than or 
equal to the assay cut-off value. 
− 
Seroprotection is defined as an HI antibody titer ≥ 40 1/DIL. 
− 
SPR is defined as the percentage of participants with an HI antibody titer 
≥ 40 1/DIL. 
− 
Seroconversion is defined as a post-vaccination antibody titer ≥ 40 1/DIL in the 
serum of participants seronegative before vaccination (i.e. titer < assay cut-off at 
Day 1). For seropositive participants (i.e. titer ≥ assay cut-off at Day 1), 
seroconversion will require a 4-fold rise in post-vaccination HI antibody titer 
(but at least a titer of 40 1/DIL). 
− 
SCR is defined as the percentage of participants who seroconvert post-
vaccination. 
− 
Vaccine response is defined as at least a 4-fold increase in antibody titer as 
compared to the antibody titer at Day 1 (pre-vaccination). Antibody titers below 
the cut-off of the assay are given an arbitrary value of half the cut-off for the 
purpose of vaccine response calculation. 
− 
Vaccine Response Rate (VRR) is defined as the percentage of participants with 
vaccine response. 
− 
The geometric mean titers (GMTs) calculations are performed by taking the 
anti-log of the mean of the log concentration/titer transformations. Values for 
the antibody concentrations/titers below the assay cut-off will be assigned half 
the assay cut-off value for the purpose of GMT computation.  
− 
Handling of missing data: for a given participant and a given immunogenicity 
measurement, missing or non-evaluable measurements will not be replaced. 


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− 
The primary and secondary HI immunogenicity analyses will be based on the 
applicable Per Protocol Set (PPS) as described in Section 9.3 (Table 16). 
Supplementary analyses for primary and secondary HI immunogenicity 
analyses will be based on the applicable mPPS. If the difference between PPS 1 
and FAS 1 is greater than 10%, a second analysis based on the FAS will be 
performed to complement the PPS analysis. 
− 
The MN immunogenicity analyses will be based on the applicable 
Microneutralization Per Protocol Set (MNPPS) as described in Section 9.3 
(Table 16). Supplementary analyses for MN immunogenicity analyses will be 
based on the applicable MN mPPS. 
Section 9.4.2 Participants disposition 
Major deviations will be summarized for the ES for each study group, age group, and 
overall. The reason for elimination from the PPS 1 and PPS 2 and mPPS 1 and mPPS 2 
will also be summarized. The same will be done for MNPPS 1, MNPPS 2, MN mPPS 1 
and MN mPPS 2. 
Section 9.4.3.1 Immunogenicity 
Primary immunogenicity analyses will be based on the PPS 1 set. 
Supplementary immunogenicity analyses will be based on the mPPS 1 set. 
The following aggregate variables will be calculated for each vaccine group for vaccine 
homologous H7N9 HI antibody titer along with Clopper-Pearson exact two-sided 99.17% 
CIs: 
• 
SCR at Day 43 
• 
SPR at Day 43 
Section 9.4.3.2 Safety 
Unsolicited AE endpoints 
• 
Occurrence and relationship to vaccination of unsolicited AEs within 21 days (Day 1 
to Day 21, Day 22 to Day 43) after each vaccination. 
• 
Occurrence and relationship to vaccination of AEs with MAEs within 21 days 
(Day 1 to Day 21, Day 22 to Day 43) after each vaccination. 
Section 9.4.4.1 Immunogenicity 
The following aggregate variables will be calculated for each vaccine group for vaccine 
homologous H7N9 HI antibody titer: 
• 
GMTs at Days 1, 22, and 43 
• 
Seropositivity rates at Days 1, 22, and 43 


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• 
SCR at Day 22 
• 
SPR at Days 1 and 22 
• 
Mean Geometric Increase (MGI) at Days 22 and 43 
For a subset of participants (MNPPS 1 and MNPPS 2 sets and MN mPPS 1 and 
MN mPPS 2), the following aggregate variables will be calculated for each vaccine 
group for vaccine-homologous H7N9 MN antibody titer: 
• 
GMTs at Days 1, 22, and 43 
• 
Seropositivity rates at Days 1, 22, and 43 
• 
VRR at Days 22 and 43 
Section 9.4.5.1 Demography and baseline characteristics analyses 
Demographic characteristics (age, gender, race, center, height, weight, and ethnicity) will 
be tabulated per study group for each analysis set, age group and overall as described in 
the SAP. 
The mean of continuous variables (plus range and standard deviation) of the enrolled 
participants, as a whole and per study group, age group and overall, will be calculated. 
The distribution of discrete variables will be tabulated as a whole and per study group, 
age group and overall as described in the SAP. 
The analysis of demographics will be performed separately for the ES for each vaccine 
dose and for the participants contributing to the PPS (and mPPS) of each vaccine dose. 
Demographic characteristics (including but not limited to age, gender, race, height, 
weight, and ethnicity) will be summarized by group using descriptive statistics: 
• 
For categorical variables such as center, the number and frequency in each category 
will be provided. 
• 
Number (number of participants in the analysis), mean, median, minimum and 
maximum, and standard deviation will be provided for continuous data such as age. 
Listings will be provided for demographic characteristic data based on the Enrolled Set. 
Section 9.5.1.1 Analysis at Day 43 
An analysis will be performed on data collected through the Day 43 visit. Elements will 
include: 
• 
Analyses of cleaned immunogenicity data collected through the Day 43 visit will be 
conducted. 
• 
Analyses of cleaned solicited administration site events and solicited systemic events 
data collected during a 7-day follow-up period (Day 1 to Day 7) after each 
vaccination will be conducted. 


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• 
Analyses of unsolicited AEs and MAEs up to 21 days after each vaccination on as 
clean as possible data. Analyses of unsolicited AEs reported up to the Day 43 visit 
and cleaned in so far as is possible will be carried out. 
• 
Analyses of MAEs,SAEs, pIMDs, pregnancies and withdrawals due to AEs collected 
up to the Day 43 post-vaccination visit will be carried out. 
• 
Results will be presented in a Day 43 statistical report. Access to individual 
treatment codes will be restricted to the designated statisticians in charge of the 
analysis. No individual listings or data with the participants’ identifying information 
will be disseminated. Listings of final data will be provided with the Month 13 
report. 
All analyses will be performed on data that has been cleaned and locked. The possibility 
of post-analysis changes to data evaluated at Day 43 exists, since data collection and data 
entry may continue through Month 13. All final data will be presented in the listings 
provided at Month 13. 
Section 9.5.1.2 Final analysis (Month 13) 
A final data analysis will be performed at the end of study (Month 13) of all primary and 
secondary endpoints based on the clean data, including evaluations of: 
• 
Immunogenicity at all measured time points (Days 1, 22 and 43). 
• 
Solicited administration site events and solicited systemic events data reported 
7 days after each vaccination (Day 1 to Day 7 and Day 22 to Day 28). 
• 
Unsolicited AEs and MAEs reported up to the Day 43 visit (21 days after each 
vaccination). 
• 
Concomitant medications reported up to the Day 43 visit 21 days after each 
vaccination. 
• 
SAEs, pIMDs, and withdrawals due to AEs collected throughout the entire study. 
• 
Pregnancies throughout the entire study. 
An integrated clinical study report containing all data will be written and made available 
to the investigators. 
Section 9.5.2 Statistical consideration for interim analysis 
Since the primary immunogenicity endpoints for the study will be complete by the Day 
43 visit (collection past Day 43 includes only assessments for unsolicited AEs leading to 
study withdrawal, SMAEs, and pIMDs), no statistical consideration for multiplicity will 
be given to account for changes in the results reported at the interim analysis compared to 
the final analysis. For the primary immunogenicity analysis, which will be reported at 
Day 43 the overall type I error rate is fixed at 5% and a Bonferroni adjustment will be 
applied to allow simultaneous multiple comparisons of each antigen/adjuvant group. For 
the primary safety analyses no adjustment for multiple comparisons will be made in each 
antigen/adjuvant group. 


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Section 10.3.5.1 Potential immune-mediated diseases 
Table 19 List of potential immune-mediated diseases (pIMDs) 
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
• 
Includes warm antibody hemolytic anemia and cold antibody 
hemolytic anemia 
Autoimmune lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
• 
Frequently used related terms include: “autoimmune 
thrombocytopenic purpura”, “idiopathic thrombocytopenic 
purpura (ITP)”, “idiopathic immune thrombocytopenia”, “primary 
immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
 
Thrombotic thrombocytopenic 
purpura 
• 
Also known as “Moschcowitz-syndrome” or “microangiopathic 
hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 
Idiopathic 
Myocarditis/Pericarditis 
Including but not limited to: 
• 
Autoimmune / Immune-mediated myocarditis 
• 
Autoimmune / Immune-mediated pericarditis 
• 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
• 
Idiopathic interstitial pneumonia (frequently used related terms 
include “Interstitial lung disease”, “Pulmonary fibrosis”, 
“Immune-mediated pneumonitis”) 
• 
Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis  
• 
Silent thyroiditis  


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Medical Concept 
Additional Notes 
• 
Thyrotoxicosis 
Autoimmune diseases of the 
testis and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome and Graves' ophthalmopathy, 
also known as thyroid eye disease (TED) or endocrine 
ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular 
outer retinopathy) 
• 
Autoimmune / Immune-mediated retinopathy  
• 
Autoimmune / Immune-mediated uveitis, including idiopathic 
uveitis and sympathetic ophthalmia  
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to:  
• 
Crohn’s disease  
• 
Microscopic colitis  
• 
Terminal ileitis 
• 
Ulcerative colitis  
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 


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Medical Concept 
Additional Notes 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• 
Dermatomyositis 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• 
Rheumatoid arthritis associated conditions 
• 
Juvenile idiopathic arthritis 
• 
Palindromic rheumatism 
• 
Still's disease 
• 
Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to:  
• 
Ankylosing spondylitis 
• 
Juvenile spondyloarthritis 
• 
Keratoderma blenorrhagica 
• 
Psoriatic spondylitis  
• 
Reactive Arthritis (Reiter's Syndrome) 
• 
Undifferentiated spondyloarthritis 
Systemic Lupus Erythematosus  
• 
Includes Lupus associated conditions (e.g. Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (Systemic 
Sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with 
diffuse scleroderma and systemic sclerosis with limited 
scleroderma (also known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
other inflammatory-
demyelinating variants  
Includes the following: 
• 
Acute necrotising myelitis 
• 
Bickerstaff's brainstem encephalitis  
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis,  
or acute necrotizing hemorrhagic encephalomyelitis)  
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  


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Medical Concept 
Additional Notes 
Guillain-Barré syndrome (GBS) 
• 
Includes variants such as Miller Fisher syndrome and the acute 
motor and sensory axonal neuropathy (AMSAN) 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis) 
Including but not limited to: 
• 
Cranial nerve neuritis (e.g. Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (e.g. Bell’s palsy) 
• 
Melkersson-Rosenthal syndrome 
• 
Multiple cranial nerve palsies/paresis  
Multiple Sclerosis (MS) 
Includes the following: 
• 
Clinically isolated syndrome (CIS)  
• 
Malignant MS (the Marburg type of MS)  
• 
Primary-progressive MS (PPMS) 
• 
Radiologically isolated syndrome (RIS) 
• 
Relapsing-remitting MS (RRMS) 
• 
Secondary-progressive MS (SPMS) 
• 
Uhthoff's phenomenon  
Myasthenia gravis 
• 
Includes ocular myasthenia and Lambert-Eaton myasthenic 
syndrome 
Narcolepsy 
• 
Includes narcolepsy with or without presence of unambiguous 
cataplexy 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner 
Syndrome or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy 
(CIDP), including atypical CIDP variants (e.g. multifocal acquired 
demyelinating sensory and motor neuropathy also known as 
Lewis-Sumner syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute 
complete transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 


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Medical Concept 
Additional Notes 
• 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / Immune-mediated 
blistering dermatoses  
Including but not limited to:  
• 
Bullous Dermatitis 
• 
Bullous Pemphigoid  
• 
Dermatitis herpetiformis  
• 
Epidermolysis bullosa acquisita (EBA)  
• 
Linear IgA-mediated bullous dermatosis (LABD), also known as 
Linear IgA disease 
• 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Reactive granulomatous 
dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 
Lichen planus 
• 
Includes liquen planopilaris 
Localised Scleroderma 
(Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson Syndrome 
(SJS) 
Including but not limited to:  
• 
Toxic Epidermal Necrolysis (TEN)  
• 
SJS-TEN overlap 
Sweet’s syndrome 
• 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
• 
Arteritic anterior ischemic optic neuropathy (AAION or arteritic 
AION) 
• 
Giant cell arteritis (also called temporal arteritis)  
• 
Takayasu's arteritis  
Medium sized and/or small 
vessels vasculitis  
Including but not limited to: 
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis 
(type unspecified)  
• 
Behcet's syndrome  
• 
Buerger’s disease (thromboangiitis obliterans) 
• 
Churg–Strauss syndrome (allergic granulomatous angiitis)  
• 
Erythema induratum (also known as nodular vasculitis) 


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Medical Concept 
Additional Notes 
• 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
• 
Microscopic polyangiitis 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic 
vasculitis, hypersensitivity vasculitis and acute hemorrhagic 
edema of infancy (AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include : “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include : “pulmonary renal 
syndrome” and “anti-Glomerular Basement Membrane disease 
(anti-GBM disease)” 
Immune-mediated enhancement 
of disease 
• 
Includes vaccine associated enhanced disease (VAED and 
VAERD). Frequently used related terms include “vaccine-
mediated enhanced disease (VMED)”, “enhanced respiratory 
disease (ERD)”, “vaccine-induced enhancement of infection”, 
“disease enhancement”, “immune enhancement”, and “antibody-
dependent enhancement (ADE) 
Immunoglobulin G4 related 
disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• 
Kawasaki’s disease 
• 
Multisystem inflammatory syndrome in adults (MIS-A) 
• 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• 
Includes Loefgren syndrome 
Susac's syndrome 
 
The table below was deleted: 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and paresis 
(e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), including: 
• 
Diffuse Scleroderma, 
• 
CREST syndrome. 
• 
Idiopathic inflammatory 
myopathies, including: 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis). 


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• 
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. 
• 
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. 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localized Scleroderma 
(Morphea). 
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),  
• 
Necrotizing vasculitis 
(cutaneous or systemic),  
• 
Anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune 
glomerulonephritis 
including: 
• 
IgA nephropathy,  
• 
Glomerulonephritis rapidly 
progressive,  
• 
Membranous 
glomerulonephritis,  
• 
Membranoproliferative 
glomerulonephritis,  
• 
Mesangioproliferative 
glomerulonephritis.  
• 
Tubulointerstitial nephritis 
and uveitis syndrome. 
• 
Ocular autoimmune 
diseases including: 
• 
Autoimmune uveitis.  
• 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson 
syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 


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• 
Henoch-Schonlein purpura (IgA 
vasculitis),  
• 
Behcet's syndrome, 
• 
Leukocytoclastic vasculitis. 
• 
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. 
Section 10.3.8.1 Time period for collecting and recording AEs 
All AEs that occur within 21 days following administration of each dose of study 
vaccine/product (Day 1 to Day 21 and Day 22 to Day 43) must be recorded into the 
appropriate section of the eCRF, irrespective of intensity or whether or not they are 
considered vaccination-related. 
Section 10.7.1 List of abbreviations 
mPPS: 
Modified per protocol set 
MN mPPS: 
Microneutralization modified per protocol set 
 
Section 11 References 
Food and Drug Administration (FDA). Guidance for Industry, Investigators, and 
Institutional Review Boards. FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency. July 2020. 
https://www.fda.gov/media/136238/download. Accessed: 31 July 2020.  
 


CONFIDENTIAL 
209671 (FLU Q-PAN H7N9=AS03-002) 
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112 
11. 
REFERENCES 
Beyer WE, Palache AM, Baljet M, Masurel N. Antibody induction by influenza vaccines 
in the elderly: a review of the literature. Vaccine. 1989; 7:385-94. 
Center for Biologics Evaluation and Research (CBER). Guidance for Industry. Clinical 
data needed to support the licensure of pandemic influenza vaccines. May 2007. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-
data-needed-support-licensure-pandemic-influenza-vaccines. 
EMA, https://spor.ema.europa.eu/rmswi/#/lists/100000000008/terms; (accessed 
28 November 2019). List name Quantity Operator; Term name quantity sufficient. 
Food and Agriculture Organization of the United Nations (FAO). Agriculture and 
Consumer Protection Department. Animal Production and Health. H7N9 situation update. 
Avian Influenza A (H7N9) 4 September 2019. 
http://www.fao.org/ag/againfo/programmes/en/empres/h7n9/situation_update.html. 
Accessed 2 October 2019. 
(Amended 22 February 2022) 
Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 
vaccination. Vir Res. 2004; 103:133-8. 
Rimmelzwaan GF, McElhaney JE. Correlates of protection: novel generations of 
influenza vaccines. Vaccine. 2008; 26 (Suppl 4): D41-4. 
World Health Organization (WHO). Avian Influenza Weekly Update Number 694. 
20 September 2019. https://www.who.int/docs/default-source/wpro---
documents/emergency/surveillance/avian-influenza/ai-
20190920.pdf?sfvrsn=30d65594_36. Accessed: 2 October 2019 
World Health Organization (WHO). Coronavirus disease 2019 (COVID-19) Situation 
Report – 67. 2020. Available at: https://www.who.int/docs/default-
source/coronaviruse/situation-reports/20200327-sitrep-67-covid-
19.pdf?sfvrsn=b65f68eb_4. Accessed: 31 July 2020. 
Xiang N, Li X, Ren R, Wang D, Zhou S, Greene CM, et al. Assessing change in avian 
influenza A(H7N9) virus infections during the fourth epidemic - China, 
September 2015-August 2016. MMWR Morb Mortal Wkly Rep.2016;65(49):1390-94.  
Zhou L, Ren R, Yang L, Bao C, Wu J, Wang D, et al. Sudden increase in human 
infection with avian influenza A(H7N9) virus in China, September-December 2016. 
Western Pac Surveill Response J. 2017;8(1):6-14. 

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  209671
Official Title of Study: A Phase I/II, Observer-Blind, Randomized, Placebo-Controlled, 
Multi-Center Trial to Evaluate the Safety and Immunogenicity of Different Formulations 
of Monovalent Influenza A/Hong Kong/125/2017-like (H7N9) Virus Vaccine with AS03 
Adjuvant System, Given as a Two-Dose Series to Adults 18 to 64 Years of Age and 65 
Years of Age and Older
NCT ID: NCT04789577
Date of Document: 17 March 2022


 
  
1 
 
 
 
 
 
 
 
 
 
 
GlaxoSmithKline Biologicals 
 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
A Phase I/II, Observer-Blind, Randomized, Placebo-Controlled, 
Multi-Center Trial to Evaluate the Safety and Immunogenicity of 
Different Formulations of Monovalent Influenza A/Hong 
Kong/125/2017-like (H7N9) Virus Vaccine with AS03 Adjuvant 
System, Given as a Two-Dose Series to Adults 18 to 64 Years of 
Age and 65 Years of Age and Older  
 
17MAR2022 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
, PPD 
PPD


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
2 
 
 
 
Version  
Detail of Change  
1.0 
Original final version. 
1.1 
New draft version updated according to protocol amendment 2 
1.2 
New draft version updated according to GSK comments for v1.1 
1.3 
New draft version updated according to GSK comments for v1.2 
1.4 
New draft version updated according to GSK comments for v1.3 
1.5 
New draft version to address the modifications included in the 
final Protocol amendment 2  
1.6 
New draft version updated according to GSK comments for v1.5 
1.7 
New draft version updated according to GSK comments for v1.6 
1.8 
New draft version updated according to GSK comments for v1.7 
2.0 
New final version  


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
3 
 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................5 
LIST OF ABBREVIATIONS ...............................................................................6 
1 
INTRODUCTION......................................................................................7 
2 
OBJECTIVES ............................................................................................8 
2.1 
CO-PRIMARY OBJECTIVES .......................................................................... 8 
2.2 
SECONDARY OBJECTIVES ........................................................................... 8 
3 
INVESTIGATIONAL PLAN ...................................................................9 
3.1 
OVERALL STUDY DESIGN AND PLAN .......................................................... 9 
3.2 
STUDY ENDPOINTS ................................................................................... 14 
3.2.1 
Primary Endpoints .............................................................................14 
3.2.2 
Secondary Endpoints .........................................................................15 
4 
GENERAL STATISTICAL CONSIDERATIONS ..............................15 
4.1 
GENERAL DEFINITIONS ........................................................................... 15 
4.2 
DATA TRANSFORMATIONS AND DISPLAY ................................................. 17 
4.3 
SAMPLE SIZE ............................................................................................ 19 
4.4 
RANDOMIZATION, STRATIFICATION, AND BLINDING ................................ 21 
4.5 
DATA HANDLING ...................................................................................... 22 
4.6 
ANALYSIS SETS ........................................................................................ 26 
4.6.1 
Enrolled Set ........................................................................................26 
4.6.2 
Randomized Set .................................................................................26 
4.6.3 
Exposed Set ........................................................................................26 
4.6.4 
Full Analysis Sets (FASx) .................................................................26 
4.6.5 
Per Protocol Set (PPSx) .....................................................................26 
4.6.6 
Modified Per Protocol Set (mPPSx) ..................................................27 
4.6.7 
Microneutralization Set ......................................................................27 
4.6.8 
Microneutralization Per Protocol Set (MNPPSx) ..............................27 
4.6.9 
Microneutralization modified Per Protocol Set (MNmPPSx) ...........28 
5 
PARTICIPANT DISPOSITION.............................................................28 
5.1 
DISPOSITION ............................................................................................. 28 
5.2 
MAJOR PROTOCOL DEVIATIONS ............................................................... 28 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...........33 
6.1 
DEMOGRAPHICS ........................................................................................ 33 
6.2 
BASELINE CHARACTERISTICS ................................................................... 33 
6.3 
MEDICAL HISTORY ................................................................................... 33 
6.4 
INCLUSION AND EXCLUSION CRITERIA ..................................................... 34 
7 
TREATMENTS AND MEDICATIONS ................................................34 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
4 
 
7.1 
VACCINATION HISTORY, CONCOMITANT VACCINATIONS, AND 
CONCOMITANT MEDICATIONS ............................................................................ 34 
7.1.1 
Vaccination History and Concomitant Vaccinations .........................34 
7.1.2 
Concomitant Medications ..................................................................34 
7.2 
EXTENT OF EXPOSURE .............................................................................. 35 
7.2.1 
Compliance ........................................................................................35 
7.2.2 
Visit Attendance.................................................................................35 
8 
IMMUNOGENICITY ANALYSIS ........................................................36 
8.1 
Seroconversion Rate (SCR) and Seroprotection Rate (SPR) .............37 
8.2 
Geometric Mean Titer ........................................................................37 
8.3 
Mean Geometric Increases (MGIs) ....................................................38 
8.4 
Seropositivity .....................................................................................39 
8.4.1 
Vaccine Response Rate (VRR) ..........................................................39 
9 
SAFETY ANALYSIS...............................................................................39 
9.1 
ADVERSE EVENTS ..................................................................................... 39 
9.1.1 
Solicited Events .................................................................................41 
9.1.2 
Unsolicited Adverse Events ...............................................................44 
9.2 
COVID-19 ASSESSMENTS ........................................................................ 45 
9.3 
CLINICAL LABORATORY EVALUATIONS ................................................... 46 
9.4 
PHYSICAL EXAMINATION AND VITAL SIGNS ............................................ 47 
9.5 
PREGNANCY ............................................................................................. 47 
10 
SEQUENCE OF ANALYSES .................................................................47 
10.1 
ISRC REVIEW ........................................................................................ 47 
10.2 
ANALYSIS AT DAY 43............................................................................ 48 
10.3 
FINAL ANALYSIS AT MONTH 13 ............................................................ 49 
10.4 
STATISTICAL CONSIDERATIONS FOR THE ANALYSIS AT DAY 43 ........... 49 
11 
CHANGES TO THE PROTOCOL PLANNED ANALYSIS ..............49 
12 
REFERENCES .........................................................................................50 
13 
APPENDICES ..........................................................................................51 
13.1 
SCHEDULE OF STUDY EVENTS ............................................................... 51 
 
 
 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
5 
 
List of Tables 
 
Table 1 Study Groups, Intervention and Blinding Foreseen in the Study .............. 9 
Table 2 Study Groups Foreseen in the Study........................................................ 10 
Table 3 Intervals Between Study Visits ................................................................ 13 
Table 4 Study Holding Rules ................................................................................ 14 
Table 5 Intervention Labels .................................................................................. 17 
Table 6 Strata Labels ............................................................................................ 17 
Table 7 Criteria to Evaluate Primary Objective with Respect to SCR and SPR for 
Anti-HA, 21 Days After the Second Vaccination ................................................. 21 
Table 8 Analysis Visit Names ............................................................................... 22 
Table 9 Significant Protocol Deviation that leads in an exclusion ....................... 30 
Table 10 Solicited Event Intensity Grades ............................................................ 42 
Table 11 List of Study Procedures ........................................................................ 51 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
6 
 
List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AS03 
Adjuvant System 03 
BMI 
Body mass index 
CBER 
Center for Biologics Evaluation and Research 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CSR 
Clinical Study Report 
DIL 
dilution 
eCRF 
Electronic case report form  
FASx 
Full Analysis Set (x = 1, 2) 
FDA 
Food and Drug Administration 
GMT 
Geometric mean titer 
GSD 
Geometric standard deviation 
GSK 
GlaxoSmithKline 
GSKDrug 
GSK Drug Dictionary 
H7N9 
Monovalent Influenza A/Hong Kong/125/2017-like H7N9 
HA 
Hemagglutinin 
HI 
Hemagglutination inhibition 
IRT 
Interactive response technology 
iSRC 
Internal Safety Review Committee 
LL 
Lower Limit 
MAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGI 
Mean Geometric Increase 
MN 
Microneutralization 
MNPPSx 
Microneutralization Per Protocol Set x (x=1, 2) 
MNmPPSx 
Microneutralization modified Per Protocol Set x (x=1, 2) 
mPPSx 
Modified per protocol set x (x = 1, 2) 
NC 
Not calculated 
pDiary 
Paper diary 
pIMD 
Potential Immune-Mediated Disease 
PPSx 
Per Protocol Set x (x = 1, 2)  
SAE 
Serious adverse event 
SCR 
Seroconversion rate 
SD 
Standard deviation 
SPR 
Seroprotection rate 
TLFs 
Table, Listings, Figures 
ToC 
Table of Contents 
US 
United States 
VRR 
Vaccine response rate 
WHO 
World Health Organization 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
7 
 
1 
Introduction 
Novel influenza A viruses, including subtypes H5N1, H3N2v, H9N2, 
A(H1N1)pdm09, and influenza A/Hong Kong/125/2017-like (H7N9), continue to 
emerge and infect humans; therefore, it is imperative that preparation be 
maintained for the next influenza pandemic.  For this statistical analysis plan 
influenza A/Hong Kong/125/2017-like H7N9 will be referred to as H7N9. 
 
The United States (US) National Pre-Pandemic Influenza Vaccine Stockpile 
contains various influenza virus vaccines, including influenza A(H5) and A(H7) 
virus vaccines, as well as adjuvants, including Adjuvant System 03 (AS03), for 
administration with the vaccine antigens to improve the immunogenicity and 
achieve antigen dose-sparing. 
 
Since the notification of emergence of a novel reassortant influenza A/H7N9 virus 
on 31 March 2013, 1568 laboratory-confirmed cases of human infection with 
avian influenza A/H7N9 virus in China have been reported to the World Health 
Organization (WHO), including 616 deaths. Most human infections, associated 
with poultry exposure, resulted in severe respiratory illness. Although some 
limited human-to-human infection has been reported, no sustained human-to-
human H7N9 influenza virus transmission has been observed. 
 
Vaccination is the primary measure to control the spread of influenza virus 
infection in humans. Efforts are therefore underway to develop vaccines that 
could mitigate the impact of an A/H7N9 influenza pandemic. GlaxoSmithKline 
Biologicals SA (GSK) has produced an investigational AS03-adjuvanted H7N9 
virus vaccine and will conduct a clinical trial in the US to assess the safety and 
immunogenicity of different formulations of H7N9 split virus vaccine produced in 
GSK’s Quebec facility, administered with AS03 adjuvant. 
 
Influenza pandemics occur when a novel influenza virus emerges against which 
the vast majority of the world’s population has no immunity. This phenomenon 
only occurs with Influenza A viruses and is attributed to the emergence of a new 
antigenic variant. This phenomenon, known as antigenic shift, typically represents 
introduction of a novel hemagglutinin (HA) antigen displayed on the surface of 
the virus, with or without a concomitant change in neuraminidase, the other major 
surface antigen. The reservoir of viruses bearing surface antigens to which 
humans are immunologically naïve is in wild water birds, and these viruses are 
believed to contribute their surface antigens to new strains capable of infecting 
humans by the process of gene reassortment, potentially occurring in swine or 
other domestic mammals. Alternatively, some strains of avian viruses may be able 
to invade human hosts directly; although these often replicate poorly and are 
transmitted inefficiently. If such a virus acquires the ability to spread efficiently 
from person to person, the potential result is a global outbreak of disease affecting 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
8 
 
a high percentage of individuals in a short period of time, a pandemic; and this is 
likely to cause significant morbidity and mortality throughout the world. 
 
GSK’s clinical development program for immunization against influenza caused 
by potential pandemic subtypes deploys its proprietary AS03. This adjuvant 
system contains α-tocopherol (11.86 mg for “AS03A”; 5.93 mg for “AS03B”) and 
squalene in an oil-in-water emulsion. Data with antigen-sparing formulations 
containing AS03 have been or are being generated in the context of multiple 
potential pandemic influenza threats. 
 
Despite the development of antiviral drugs, vaccination remains the most 
effective way of controlling influenza during inter-pandemic periods. As part of 
US Department of Health and Human Services pandemic preparedness activities, 
the safety, immunogenicity, and dose-sparing ability of full and half doses of 
AS03 adjuvant in combination with H7N9 virus vaccine will be evaluated. 
 
2 
Objectives 
2.1 
Co-primary Objectives 
 
Immunogenicity Objective 
• To evaluate whether the monovalent  A/Hong Kong/125/2017-like 
(H7N9) virus vaccine containing 1.9 µg, 3.75 µg, or 7.5 µg of HA 
adjuvanted with AS03A or AS03B elicits a hemagglutination inhibition 
(HI) antibody response to the vaccine-homologous virus that meets or 
exceeds the US Food and Drug Administration (FDA), Center for 
Biologics Evaluation and Research (CBER) immunogenicity criteria at the 
Day 43 visit. 
Safety Objectives 
• To describe the safety and reactogenicity of the different vaccine 
formulations through the Day 43 visit. 
• To describe the safety of the different vaccine formulations through Month 
13. 
2.2 
Secondary Objectives 
• To describe the vaccine homologous H7N9 HI antibody profile in all 
study groups at Days 1, 22, and 43 
• To describe the vaccine homologous H7N9 Microneutralization (MN) 
antibody profiles in a subset of participants at Days 1, 22, and 43 


GlaxoSmithKline Biologicals SA 
 
Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
9 
 
3 
Investigational Plan 
3.1 
Overall Study Design and Plan 
 
This is a Phase I/II, observer-blind, randomized, placebo-controlled, age stratified, 
multi-center study with 7 parallel groups, that will be conducted in the US. 
 
The study will enroll approximately 840 participants randomly assigned to 1 of 7 
groups of equal size to receive 2 doses of study vaccine or placebo administered 
intramuscularly 21 days apart. Each participant will participate for approximately 
12 months after receipt of the final dose administered. 
 
The enrollment will be performed to evenly distribute participants across the 2 
age groups (18-64 years, ≥ 65 years) (i.e. of the 120 participants in each study 
group, 60 participants will be aged 18 to 64 years and 60 participants will be aged 
≥ 65 years). Within the 18-64 years age group, the enrollment is further stratified 
into 18-49 years and 50-64 years to allow an even distribution of participants in 
terms of intervention allocation. 
 
In addition, this study is also intended to capture coronavirus disease 2019 
(COVID-19) cases among study participants based on the WHO criteria 
[27-Mar-2020 version]: suspected, probable, or confirmed. COVID-19 infection 
cases will be reported as AEs per normal reporting mechanisms. All AEs should 
be considered as to whether they meet serious adverse event (SAE) criteria, and if 
so, submitted through the SAE reporting mechanism. The COVID-19 eCRF page 
will be used to capture additional COVID-19 case details that would not normally 
be contained elsewhere in the eCRF. 
 
Details of the study groups, interventions, and blinding foreseen in the study can 
be found in Table 1 and Table 2. 
 
Table 1 Study Groups, Intervention and Blinding Foreseen in the Study 
Intervention 
name 
Vaccine/Product 
name 
Study groups 
Blinding 
190_B 190_A 375_B 375_A 750_B 750_A Placebo Observer-
Blind 
1.9 μg HA + 
AS03B 
FLU-Q-PAN H7N9 
(1.9)  
● 
 
 
 
 
 
 
● 
AS03B  
● 
 
 
 
 
 
 
● 
1.9 μg HA + 
AS03A 
FLU-Q-PAN H7N9 
(1.9) 
 
● 
 
 
 
 
 
● 
AS03A  
 
● 
 
 
 
 
 
● 


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Statistical Analysis Plan, Final Version 2.0 
209671 (FLU Q-PAN H7N9=AS03-002) 
 
Date Issued 17MAR2022 
 
10 
 
3.75 μg HA + 
AS03B 
FLU-Q-PAN H7N9 
(3.75) 
 
 
● 
 
 
 
 
● 
AS03B  
 
 
● 
 
 
 
 
● 
3.75 μg HA + 
AS03A 
FLU-Q-PAN H7N9 
(3.75) 
 
 
 
● 
 
 
 
● 
AS03A  
 
 
 
● 
 
 
 
● 
7.5 μg HA + 
AS03B 
FLU-Q-PAN H7N9 
(7.5) 
 
 
 
 
● 
 
 
● 
AS03B  
 
 
 
 
● 
 
 
● 
7.5 μg HA + 
AS03A 
FLU-Q-PAN H7N9 
(7.5) 
 
 
 
 
 
● 
 
● 
AS03A  
 
 
 
 
 
● 
 
● 
Placebo 
 Formulation buffer 
S9b  
 
 
 
 
 
 
● 
● 
AS03A and AS03B refer to AS03A and AS03B. 
Formulation buffer S9b is a phosphate buffered saline. 
 
Table 2 Study Groups Foreseen in the Study 
Study Intervention 
Study Groups 
Number of 
participants per 
study group 
Age group 
Number of 
participants per 
age group* 
1.9 μg HA + AS03B 
190_B 
120 
18 - 64 years 
60 
 65 years 
60 
1.9 μg HA + AS03A 
190_A 
120 
18 - 64 years 
60 
 65 years 
60 
3.75 μg HA + AS03B 
375_B 
120 
18 - 64 years 
60 
 65 years 
60 
3.75 μg HA + AS03A 
375_A 
120 
18 - 64 years 
60 
 65 years 
60 
7.5 μg HA + AS03B 
750_B 
120 
18 - 64 years 
60 
 65 years 
60 
7.5 μg HA + AS03A 
750_A 
120 
18 - 64 years 
60 
 65 years 
60 
Placebo 
Placebo 
120 
18 - 64 years 
60 
 65 years 
60 
Total number of participants 
840 
 
 
AS03A and AS03B refer to AS03A and AS03B. 
* Within each of the 7 study groups, approximately 60 participants per age group will be enrolled with 57 
evaluable participants accounting for possible 5% dropout. 


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The study design diagram is provided in Figure 1. 
 
Figure 1 Study Design Overview 
 
 
 
Note: Study groups and intervention (2 doses) to be administered: 190_B: 1.9 µg Hemagglutinin (HA) and 
AS03B; 190_A: 1.9 µg HA and AS03A; 375_B: 3.75 µg HA and AS03B; 375_A: 3.75 µg HA and AS03A; 
750_B: 7.5 µg HA and AS03B; 750_A: 7.5 µg HA and AS03A; and Placebo: formulation buffer S9b 
(phosphate buffered saline). 
Note: At least 2 internal Safety Review Committee (iSRC) reviews are planned. During each review, 
reactogenicity and safety data for approximately 140 participants (approximately 10 participants per vaccine 
group and placebo group) will be monitored. The first iSRC review will occur when data collected for 7 days 
post-Dose 1 (i.e. Day 1 to Day 7, inclusive) are available; the second review will occur based on the available 
data collected 7 days post-Dose 2 (i.e. Day 22 to Day 28, inclusive) for the same group of participants. 
Additional iSRC reviews may be carried out as needed (Protocol Section 8.2.2.2). 
AE: adverse event; M: Month; MAE: medically attended adverse event; N: number of participants; pIMD: 
potential immune-mediated disease; SAE: serious adverse event; TC: telephone contact 
 
Whenever possible, the investigator should arrange study visits within the optimal 
intervals described in Table 3. Visits that occur outside of the allowed intervals 
will be categorized as significant protocol deviations leading to the exclusion of a 


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participant from one of the Per Protocol sets (PPSx) or modified Per Protocol sets 
(mPPSx). 
 
A detailed list of study procedures can be found in Section 13. 
 
The informed consent of the participant must be signed before study participation. 
All inclusion and exclusion criteria will be checked as described in Protocol 
Sections 5.1 and 5.2 before dosing on Day 1. 
On Visit 1 (Day 1) informed consent will be obtained and pre-vaccination 
procedures will be carried out.  Upon satisfactory completion of pre-vaccination 1 
procedures, participants will be randomized to a study group and intervention 
number and will have blood samples drawn before receiving the first dose of 
study vaccine.    
Participants will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily 
available in case of anaphylaxis and/or syncope.   
Participants will have a second dose of study vaccine/product administered at 
Visit 2 following satisfactory completion of pre-vaccination 2 procedures.  
Participants will have blood drawn at Visit 1 pre-vaccination, Visit 2 
pre-vaccination and Visit 3 to test for immune response.  
An unsolicited AE is an AE that was not solicited using a Participant Diary and 
that was spontaneously communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
Unsolicited AEs will be recorded for 21 days following administration of study 
vaccine/product.  AEs will be recorded starting from informed consent date.   
Serious adverse events (SAEs), medically attended AEs (MAEs), AEs/SAEs 
leading to withdrawal, SAEs related to study participation or concurrent GSK 
medication/vaccines and potential immune mediated diseases (pIMDs) will be 
recorded from the date of informed consent through Month 13.  The pIMDs are 
listed in Protocol Table 19. 
Solicited events include administration site and systemic events and are solicited 
using a Participant Diary.  Solicited administration site events include pain, 
redness, and swelling. Solicited systemic events include fatigue, fever, 
gastrointestinal (nausea, vomiting, diarrhea, abdominal pain), headache, muscle 
ache, joint pain, shivering (chills), and sweating. 
Participants will receive a safety follow-up call after each visit where study 
vaccine/product is administered.  Solicited events will be recorded in participant 
diaries by the participant for 7 days after the vaccine/product is administered 
(including the day on which the vaccine/product is administered). For solicited 
events continuing after 7 days, the participant will be instructed to record events 


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until 21 days post-vaccination or until resolution. The participant will be 
instructed to return the completed diary card and COVID-19 assessment card to 
the investigator at the next study visit. Details on the timing and collection of the 
solicited administration site and systemic events on the diary card are described in 
the Study Procedures Manual. 
Female participants who become pregnant after the first vaccination must not 
receive subsequent doses of the study vaccine/product, but may continue other 
study procedures at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any abnormal pregnancy 
outcome or complication or elective termination of a pregnancy for medical 
reasons will be recorded and reported as an SAE. 
Table 3 Intervals Between Study Visits 
Interval 
(by visit number) 
Interval  
(by visit name) 
Optimal interval 
length1 (Days) 
Allowed interval 
(Study Day) 
Visit 1 - TC1 
Visit Day 1 - Telephone Contact Day 8 
7 
6-10 
Visit 1 - Visit 2 
Visit Day 1 - Visit Day 22 
21 
18-252 
Visit 2 - TC2 
Visit Day 22 - Telephone Contact Day 
29 
7 
26-30 
Visit 2 - Visit 3 
Visit Day 22 - Visit Day 43 
21 
38-462 
Visit 1 - TC3 
Visit Day 1 - Month 4 Telephone 
Contact 
90 
80-100 
Visit 1 - TC4 
Visit Day 1 - Month 7 Telephone 
Contact 
182 
172-192 
Visit 1 - TC5 
Visit Day 1 - Month 10 Telephone 
Contact 
270 
260-280 
Visit 1 - TC6 
Visit Day 1 - Month 13 Telephone 
Contact 
385 
375-395 
1 The investigator should arrange study visits within this interval. 
2 Participants may not be eligible for inclusion in the Per Protocol analysis set (PPS) for immunogenicity 
analysis for the specified interval if blood collections are outside this interval. Refer to Section 4.6 for 
populations for analyses. 
TC: telephone contact 
 
At least 2 iSRC reviews are planned. During each iSRC review, reactogenicity 
and safety data for approximately 140 participants (approximately 10 participants 
per vaccine group and placebo group stratified by age) will be monitored. The 
first iSRC review will occur when data collected for 7 days post dose (i.e. Day 1 
to Day 7, inclusive) are available; the second review will occur based on the 
available data collected 7 days post dose 2 (i.e. Day 22 to Day 28, inclusive) for 
the same group of participants. Additional iSRC reviews may be carried out as 
needed.  
If a safety signal is observed, GSK may decide to suspend further vaccinations in 
all groups or in selected groups. Guidance about how to proceed will be provided 
should such a decision be made. 


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The safety holding rules are defined in Table 4. Holding rules 1a-b will be 
assessed by each investigator on a continuous basis. Meeting any of these holding 
rules will trigger a hold of vaccination irrespective of number of participants 
enrolled and/or timing of the event. 
 
Table 4 Study Holding Rules 
Holding 
Rule 
Event 
Number of 
Participants 
1a 
Death or any life-threatening SAE that can be reasonably attributed to the 
vaccination 
≥ 1 
1b 
Any non-life-threatening SAE that can be reasonably attributed to the vaccination 
occurring within 21 days from vaccination 
≥ 1 
 
When a holding rule is identified the iSRC will review unblinded data. 
3.2 
Study Endpoints 
3.2.1 Primary Endpoints 
Immunogenicity Endpoints 
• Humoral immune response in terms of vaccine-homologous HI antibody 
titers: 
− Seroprotection rate (SPR) at Day 43 
− Seroconversion rate (SCR) at Day 43 
Safety Endpoints 
• Occurrence of AEs 
− Solicited administration site events during a 7-day follow-up 
period (i.e. day of vaccination and 6 subsequent days) after each 
vaccination 
− Solicited systemic events during a 7-day follow-up (i.e. day of 
vaccination and 6 subsequent days) after each vaccination 
− Unsolicited AEs and MAEs for 21 days after each vaccination 
− SAEs, pIMDs up to Day 43 visit 
− pIMDs and SAEs until Month 13 
 
 


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3.2.2 Secondary Endpoints 
Immunogenicity Endpoints 
• Vaccine-homologous (H7N9) HI antibody titers for each study group: 
− Geometric Mean Titers (GMTs) at Days 1, 22, and 43 
− Seropositivity rates at Days 1, 22 and 43 
− SCR at Day 22 
− SPR at Days 1 and 22 
− Mean Geometric Increase (MGI) at Days 22 and 43 
• Vaccine-homologous (H7N9) MN antibody titers for subset of 
participants: 
− GMTs at Days 1, 22, and 43 
− Seropositivity rates at Days 1, 22, and 43 
− Vaccine response rate (VRR) at Days 22 and 43 
4 
General Statistical Considerations 
4.1 
General Definitions 
• Age will be calculated as the integer part of the difference between birth 
date and the treatment start date divided by 365.25. Birth date with 
missing day will be imputed as day 15 and birth data with missing day 
and month will be imputed as 30-June. For non-vaccinated subjects, age 
will be calculated considering Informed Consent date. 
The following Age groups will be created for the analysis: 
− “18 – 49 years” if calculated year is between the interval 18-49, 
including both values. 
− “50 – 64 years” if calculated year is between the interval 50-64, 
including both values. 
− “≥ 65 years” if calculated year is greater or equal to 65. 
− “65 – 74 years” if calculated year is between the interval 65-74, 
including both values. 
− “≥ 75 years” if calculated year is greater or equal to 75. 
− “18 – 64 years” if calculated year is between the interval 18-64, 
including both values (only for web disclosure table). 


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− “65 – 84 years” if calculated year is between the interval 65-84, 
including both values (only for web disclosure table). 
− “≥ 85 years” if calculated year is greater or equal to 85 (only for web 
disclosure table). 
 
• The antibody titer cut-off value for HI will be set as 10 1/dilution [DIL]. 
• The LLOQ (cut-off) of Q² MN assay with the A/Hong Kong/125/2017-
like (H7N9) will be set as 28.3 NT50. In case a different RBC will be used 
the new cut-off value will be confirmed with the lab. A footnote will be 
added in all MN-related tables confirming the cut-off value used in the 
analyses. 
• A seronegative participant is a participant whose antibody titer is below 
the cut-off value. 
• A seropositive participant is a participant whose antibody titer is greater 
than or equal to the cut-off value. 
• Seroconversion for HI is defined as a post-vaccination antibody titer ≥ 40 
1/DIL in the serum of participants seronegative before vaccination (i.e. 
titer < assay cut-off at Day 1). For seropositive participants (i.e. titer ≥ 
assay cut-off at Day 1), seroconversion will require a 4-fold rise in post-
vaccination HI antibody titer (but at least a titer of 40 1/DIL). 
• SCR is defined as the percentage of participants who seroconvert post-
vaccination. 
• Seroprotection rate  for HI is defined as the percentage of participants 
with an HI antibody titer ≥ 40 1/DIL. 
• MGI is defined as the geometric mean of the within-subject ratios of the 
post-vaccination HI antibody titer to the Day 1 HI antibody titer. 
• Vaccine response for MN is defined as at least a 4-fold increase in 
antibody titer as compared to the antibody titer at Day 1 (pre-
vaccination). Antibody titers below the cut-off of the assay are given an 
arbitrary value of half the cut-off for the purpose of vaccine response 
calculation. 
• Vaccine Response Rate (VRR) for MN is defined as the percentage of 
participants with vaccine response. 
 
 


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4.2 
Data Transformations and Display  
 
Interventions will be labelled on all outputs as described in Table 5.  
 
Table 5 Intervention Labels 
Intervention Number 
Intervention Label 
1 
1.9 ug HA + AS03B 
2 
1.9 ug HA + AS03A 
3 
3.75 ug HA + AS03B 
4 
3.75 ug HA + AS03A 
5 
7.5 ug HA + AS03B 
6 
7.5 ug HA + AS03A 
7 
Placebo 
AS03A and AS03B refer to AS03A and AS03B. 
 
Strata will be labelled on all outputs as described in Table 6.  
 
Table 6 Strata Labels 
Strata Number 
Strata Label 
1 
18 - 49 years 
2 
50 – 64 years 
3 
≥ 65 years 
 
Summaries will be presented by each study group, age group, and overall. The 
≥ 65 years age group will also be presented by 65-74 years, ≥ 75 years, and 
overall.  
Data will be displayed in all listings sorted by study group and age group.  
Participants will be identified in the listings by the participant identification 
number. 
 
Categorical data will be described using the participant count and percentage in 
each category.  For a given participant and a given immunogenicity measurement, 
missing or non-evaluable measurements will not be replaced. A row denoted 
‘Missing’ will be displayed to account for missing values in categorical 
summaries.  The ‘Missing’ row will only be displayed if at least one study group 
has a non-zero count for this category.  Note percentages will not be displayed in 
the ‘Missing’ row, to draw attention to the percentages for the non-missing 
categories.  Unless specified otherwise, percentages for analysis of unsolicited 


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AEs will be based on the number of participants vaccinated in each study group 
and age group within the analysis population, and percentages for the analysis of 
immunogenicity data and solicited events will be based on the number of 
participants with non-missing data in each study group and age group within the 
analysis population.  Percentages will not be displayed if the corresponding count 
is zero, in order to draw attention to the percentages for non-zero counts. 
Percentages will be displayed using one decimal place. 
 
Continuous data will be described using descriptive statistics (i.e. n, mean, 
standard deviation, minimum and maximum).  For the summary statistics of all 
numerical variables unless otherwise specified, minimum and maximum will be 
displayed to the same level of precision as reported. Mean will be displayed to 
one level of precision greater than the data collected. Standard deviation/standard 
error will be displayed to two levels of precision greater than the data collected.  
 
If statistical analysis cannot be performed for a particular age group or study 
group, then these should be displayed as “NC.” (not calculated).  Confidence 
intervals that cannot be calculated should be displayed as “(NC.)”.   
 
For the primary immunogenicity analysis, which will be reported at Day 43 the 
overall type I error rate is fixed at 5% (two-sided tests) and a Bonferroni 
adjustment will be applied to allow simultaneous multiple comparisons of each 
antigen/adjuvant group. No further adjustment will be used since the tests will be 
applied sequentially. For the secondary immunogenicity and primary safety 
analyses no adjustment for multiple comparisons will be made in each 
antigen/adjuvant group as the analyses are descriptive.  Confidence intervals (CIs) 
will be presented and p-values will not be presented. For the secondary 
immunogenicity and safety analyses, CIs are presented for descriptive purposes 
only. 
 
Baseline will be defined as the value recorded at Visit 1. The study day will be 
calculated as assessment date - first dose date of study vaccine + 1 if the study 
date is on or after first dose date of study vaccine, or assessment date – first dose 
date of study vaccine if the study date is prior to the first dose date of study 
vaccine. 
 
Throughout the study, logarithmic transformations and anti-logarithms will use 
base 10. 
 
 
 


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Statistical analysis will be performed using SAS® Version 9.4 or higher.  
Standardized and validated SAS macros from PPD will be used to set up table, 
listing, figure formats (headers/footers and tabulation format) and tabulate the 
summaries. All tables and listings will be independently validated using double 
programming; datasets behind the figures will be independently validated using 
double programming and figure outputs will be independently validated manually.   
4.3 
Sample Size 
The primary immunogenicity objective of the study is to evaluate whether 
vaccination with monovalent H7N9 virus vaccine containing 1.9 µg, 3.75 µg or 
7.5 µg of HA adjuvanted with AS03A or AS03B elicits an HI antibody response to 
the vaccine-homologous virus that meets or exceeds the US FDA, CBER 
immunogenicity criteria at the Day 43 visit. 
 
The age-appropriate CBER criteria will be used and assessed separately:  
 
• CBER immunogenicity criteria for SCR for 18 to 64 years of age will be 
shown if the lower limit (LL) of the 99.17% CI for SCR meets or exceeds 
40%. 
• CBER immunogenicity criteria for SPR for 18 to 64 years of age will be 
shown if the LL of the 99.17% CI for the incidence rate of HI Reciprocal 
Titers ≥ 40 meets or exceeds 70%. 
• CBER immunogenicity criteria for SCR for ≥ 65 years of age will be 
shown if the LL of the 99.17% CI for seroconversion rate meets or 
exceeds 30%. 
• CBER immunogenicity criteria for SPR for ≥ 65 years of age will be 
shown if the LL of the 99.17% CI for the incidence rate of HI Reciprocal 
Titers ≥ 40 meets or exceeds 60%. 
The statistical testing sequence is illustrated below.  The 6 antigen/adjuvant 
combinations will be assessed simultaneously for a particular endpoint (SCR or 
SPR) and age category using Bonferroni Type 1 error adjustment.  The order of 
statistical testing is SCR for 18-64 years of age, SPR for 18-64 years of age, SCR 
for ≥65 years of age, SPR for ≥65 years of age.  Testing will progress in the 
sequence only if current test is a success, so that no further adjustment of alpha is 
needed.  Success is reached if at least one antigen/adjuvant combination does 
fulfill the CBER requirements for SCR and for SPR for at least one age category 
after all permitted statistical tests are completed.   


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A total of 840 participants are planned to be enrolled, with 60 participants per 
antigen/adjuvant/age group. A drop-out/protocol violation rate of not more than 
5% yields an approximate sample size of 57 evaluable participants per group, 
giving 82% overall power to fulfil the CBER (SCR, SPR) immunogenicity criteria 
in any one of the 12 adjuvanted vaccine intervention groups, assuming that the 
reference rate for SPR and SCR is 91% and 80% for participants 18 to 64 years of 
age and 86% and 75% for participants ≥ 65 years of age, respectively. 
 
The 2-sided exact Clopper-Pearson 99.17% CI for SCR or SPR is to allow parallel 
assessment of the 6 antigen/adjuvant combinations addressing multiple 
comparisons using a Bonferroni adjustment by dividing the 5% Type I error (two-
sided tests) equally 6 ways.  Success can be declared for any antigen/adjuvant 
group if CBER criteria is met even if any other group does not meet the CBER 
criteria. 
 
Table 7 presents the power for 1 group to meet the CBER immunogenicity 
criteria, assuming the enrollment is 60 participants per group and non-evaluable 
rate is about 5%. 
 


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Table 7 Criteria to Evaluate Primary Objective with Respect to SCR and 
SPR for Anti-HA, 21 Days After the Second Vaccination 
To meet CBER 
Criteria 
Endpoint 
Stage in testing 
sequence 
Statistical Success 
Criteria 
N 
evaluable 
Referen
ce value Power* 
18-64 years of age 
Anti-HA: 
SCR 
1 
LL of 99.17% two-
sided CI of SCR > 40% 
57 
80% 
99.99%* 
Anti-HA: 
SPR 
2 
LL of 99.17% two-
sided CI of SPR > 70% 
57 
91% 
86.26%* 
≥65 years of age  
Anti-HA: 
SCR 
3 
LL of 99.17% two-
sided CI of SCR > 30% 
57 
75% 
>99.99%* 
Anti-HA: 
SPR 
4 
LL of 99.17% two-
sided CI of SPR > 60% 
57 
86% 
95.12%* 
 
 
 
 
Overall power 
82% 
* Power estimated using PASS 2012, 1-Sided Exact test on the proportions, alpha = 0.415%. Overall power 
is the product of power for the 4 hypotheses within a formulation across the 2 age groups. 
CBER: Center for Biologics Evaluation and Research; CI: confidence interval; HA: hemagglutinin; LL: lower 
limit; SCR: seroconversion rate; SPR: seroprotection rate. 
 
4.4 
Randomization, Stratification, and Blinding 
The enrollment will be performed to evenly distribute participants across the 2 
age groups (18-64 years, ≥ 65 years) (i.e. of the 120 participants in each study 
group, 60 participants will be aged 18 to 64 years and 60 participants will be aged 
≥ 65 years). Within the 18-64 years age group, the enrollment is further stratified 
into 18-49 years and 50-64 years to allow an even distribution of participants in 
terms of intervention allocation. 
 
Allocation of the participant to a study group at the investigator site will be 
performed using central randomization on the PPD Interactive Response 
Technology (IRT). 
 
The study will enroll approximately 840 participants randomly assigned to 1 of 7 
groups of equal size to receive 2 doses of study vaccine or placebo administered 
intramuscularly 21 days apart. Each participant will participate for approximately 
12 months after receipt of the final dose administered. 
 
This is an observer-blinded study.  Data will be collected in an observer-blind 
manner. To do so, vaccine/product will be prepared and administered by qualified 
study personnel who will not participate in data collection, evaluation, review or 
the entry of any study endpoint (i.e. reactogenicity, safety, immunogenicity).  
 
The laboratory in charge of the sample testing will be blinded to the intervention 
assignment. Codes will be used to link the participant and study (without any link 
to the intervention attributed to the participant) to each sample.   
 


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Investigators will remain blinded to each participant’s assigned study intervention 
throughout the course of the study. In order to maintain this blind, an otherwise 
uninvolved third party will be responsible for the reconstitution and dispensation 
of all study intervention and will endeavor to ensure that there are no differences 
in time taken to dispense following randomization.  
This third party will instruct the participant to avoid discussing the dosing site or 
visual appearance of the study intervention with the investigator. Unblinded 
monitors, and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
the randomization/dispensing has been done accurately. 
The IRT will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. 
 
A statistical team will be unblinded for the interim analysis outlined in Section 
10.2 and will prepare the iSRC analyses outlined in Section 10.1. 
4.5 
Data Handling 
Analysis Visit Names for Immunogenicity Analysis 
Study visits will be derived as in Table 8.  Analysis Visit names (AVISIT) will be 
used within the Immunogenicity and Safety Analyses.  
 
Table 8 Analysis Visit Names 
Visit Name 
AVISIT 
Visit 1 Day 1 
V1 DAY 1 
Telephone Contact 1 Day 8 
SC1 DAY 8 
Visit 2 Day 22 
V2 DAY 22 
Telephone Contact 2 Day 29 
SC2 DAY 29 
Visit 3 Day 43 
V3 DAY 43 
Telephone Contact 3 Month 4 
SC3 MONTH 4 
Telephone Contact 4 Month 7 
SC4 MONTH 7 
Telephone Contact 5 Month 10 
SC5 MONTH 10 
Telephone Contact 6 Month 13 
SC6 MONTH 13 
Note: Vx = Visit x, SCx=Safety Call x. 
 
Titer Results 
For a given participant and a given immunogenicity measurement, missing or 
non-evaluable measurements will not be replaced.  Summaries and analyses will 
be performed using all available non-missing titer results for the included 
population. 
   


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Titer results recorded as below the cut-off will be imputed with a numeric value 
of half the cut-off for summaries and analyses and will be listed as reported in the 
raw data.  For example, if an assay records a cut-off of 10 for HI and a sample is 
reported to have “< 10” as the titer level, a value of 5 will be used for the 
statistical summaries and analyses.  Titer results recorded as “1:x” (where x is the 
dilution factor) will be assigned a numeric value of x.  Titer results recorded as 
“>1:x” will be assigned a numeric value of x to be used for the statistical 
summaries and analyses. 
 
The cut-off values for antibody titer are defined by the laboratory before the 
analysis, and will be specified in the CSR. 
 
Missing Data 
For safety analyses, participants who missed reporting symptoms (solicited or 
unsolicited), concomitant medications, or concomitant vaccinations will not be 
imputed but will be presented as missing for the summaries. 
 
In order to minimize the effect of missing data, the study period will be divided 
into time intervals for the safety analyses. For unsolicited AEs, the study period 
will be divided into the following intervals: all unsolicited AEs and MAEs 
reported from Day 1 to Day 21 after each vaccination, AEs leading to premature 
withdrawal from the study during the entire study period, SAEs reported during 
the entire study period and pIMD reported during the study period for the 
Exposed Set. Unsolicited AEs will be assigned to the study periods based upon 
the start date and times recorded in the eCRF. Concomitant medications will be 
assessed up to 21 days after each vaccination for the Exposed Set in a summary 
table. All concomitant medications collected in the database will presented in a 
data listing. 
A participant will be classified as having missing data within the specified 
intervals as described below: 
Category 
Regarded as Missing When: 
Non serious AEs 
No AEs are recorded and there is no response to “Have any non-serious 
adverse events occurred which are required to be reported as per 
protocol?” (Non Serious Adverse Event YN electronic Case Report Form 
[eCRF] page). 
Medically attended AEs 
If AEs are recorded and there is no response to “Medically attended visit” 
(Non Serious Adverse Events eCRF page or Serious/Expedited Event 
eCRF page). 
AEs leading to withdrawal 
from the study vaccine 
If AEs are recorded and there is no response to “Action Taken with study 
vaccine(s) as a Result of the AE” (Non Serious Adverse Events eCRF 
page or Serious/Expedited Event eCRF page). 


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Serious AEs 
If no SAEs are recorded and there is no response to “Did the subject 
experience any Serious Adverse Event and/or pIMD and/or other AESI 
and/or Non-Serious related AE (ADR) that are required to be reported per 
protocol?” (Serious/Expedited Event YN eCRF page), or if the answer was 
“Yes” and there is no response to “Serious?” (Serious/Expedited Event 
eCRF page). 
pIMD 
No pIMD events recorded and there is no response to “Did the subject 
experience any Serious Adverse Event and/or pIMD and/or other AESI 
and/or Non-Serious related AE (ADR) that are required to be reported per 
protocol?” (Serious/Expedited Event YN eCRF page), or if the answer was 
“Yes” and there is no response to “Adverse Event of Special Interest 
(AESI)?” (Serious/Expedited Event eCRF page). 
Concomitant medications 
If no concomitant medications are recorded on the Concomitant 
Medications eCRF page, and there is no response to “Have any 
medications that are required to be reported per protocol been taken?” on 
the Concomitant Medications and Vaccinations YN eCRF page. 
Concomitant vaccinations 
If no concomitant vaccinations are recorded on the Concomitant 
Medications and Vaccinations eCRF page, and there is no response to 
“Have any vaccines required to be reported as per protocol other than 
study vaccine(s) been administered?” on the Concomitant Medications and 
Vaccinations YN eCRF page. 
 
Missing Values for Solicited Adverse Events When Leading Questions Have 
Been Answered 
 
The eCRF pages Solicited Administration Site Events and Solicited Systemic 
Events contain the following leading questions: 
• Did the subject experience any of the solicited systemic signs/symptoms 
between Day 1 and Day 7? 
• Did the subject experience any solicited administration site events 
between Day 1 and Day 7? 
If the answer is ‘No’ then the investigator is asked not to complete the intensities 
or measurements for the individual symptoms and individual timepoints.  Values 
in the solicited adverse events dataset will be set as ‘None’ (for intensity) or ‘0’ 
(for measurement). 
 
The analysis of solicited systemic symptoms will include all subjects for whom 
the question about the presence of a solicited systemic symptoms has been 
answered by ‘Yes’ or ‘No’.  If the answer is ‘No’, the subject will be considered 
as not having that symptom after that dose.  If the answer is “Yes”, the maximum 
intensity recording over the considered follow-up period will be used for the 
analysis of the percentage of subjects with symptoms. 
 


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Subjects who documented the presence of a specific symptom (e.g. fever, fatigue, 
etc.) but partially recorded daily measurement (e.g. intensity missing for Day 3) 
over the considered solicited period will be included in the summaries and 
classified according to their maximum observed daily recording over the solicited 
period.  
 
When no daily measurement is recorded when the presence of a symptom is Yes, 
- For the symptoms Headache, Fatigue, Muscle aches, Gastrointestinal 
Symptoms (nausea, vomiting, diarrhea and/or abdominal pain), Joint Pain, 
Shivering (chills), and Sweating; those subjects will not be counted in the 
summary of subjects with a symptoms by grade but will be part of the 
summary corresponding to the ‘All’ category 
 
- For Fever, those subjects will not be counted in the summary of subjects 
with symptoms above a specified threshold, however they will be part of 
the summary corresponding to the ‘All’ category. 
 
The analysis of solicited local symptoms will include all subjects for whom the 
question about the presence of a solicited local symptoms has been answered by 
‘Yes’ or ‘No’.  
 
For each solicited administration site symptom, if the answer to the presence of a 
local symptom is ‘No’, the subject will be considered not having that administration 
site symptom at the injection site after that dose. If the answer to is ‘Yes’, the 
maximum intensity recording over the considered follow-up period will be used for 
the analysis of the percentage of subjects with symptoms.  
Subjects who documented the presence of a symptom but partially recorded daily 
measurement over the solicited period will be included in the summaries and 
classified according to their maximum observed daily recording over the solicited 
period. 
 
Subjects who have documented the presence of a symptom without any recorded 
daily measurement from Day 1 to Day 7 will not be counted in the summary of 
subjects with each grade, however they will be part of the summary 
corresponding to the ‘Any’ category. 
 
 


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4.6 
Analysis Sets 
4.6.1 Enrolled Set 
All participants who agreed to participate in a clinical study after completion of 
the informed consent process. 
4.6.2 Randomized Set 
All participants who were randomized to receive a study vaccine 
4.6.3 Exposed Set 
All participants who received any study vaccination. The allocation in a group is 
done in function of the administered intervention. The analysis of primary and 
secondary safety endpoints will be based on this set. 
4.6.4 Full Analysis Sets (FASx) 
 
Full Analysis Set 1 
• 
All participants in the Exposed Set who have post-vaccination 
immunogenicity data at Visit 3 (Day 43). Participants will be analyzed as 
“randomized” (i.e. according to the vaccine[s] the participant was 
randomized to receive). 
 
Full Analysis Set 2 
• 
All participants in the Exposed Set who have post-vaccination 
immunogenicity data at Visit 2 (Day 22). Participants will be analyzed as 
“randomized” (i.e. according to the vaccine[s] the participant was 
randomized to receive). 
4.6.5 Per Protocol Set (PPSx) 
 
Per Protocol Set 1 
• 
The PPS 1 is a subset of FAS 1. The PPS 1 includes all FAS 1 
participants with no major protocol deviations that lead to exclusion at or 
prior to Visit 3 (Day 43).  Primary immunogenicity data will be evaluated 
based on this set. 
 
Per Protocol Set 2 
• 
The PPS 2 is a subset of FAS 2. The PPS 2 includes all FAS 2 
participants with no major protocol deviations that lead to exclusion at or 
prior to Visit 2 (Day 22). Secondary immunogenicity data will be 
evaluated based on this set. 


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Major protocol deviations leading to exclusion are described in Section 5.2 and 
the Study Deviation Rules document and will be finalized prior to the interim 
analysis defined in Section 10.2. 
 
4.6.6 Modified Per Protocol Set (mPPSx) 
 
Modified Per Protocol Set 1 (mPPS1) 
• 
The mPPS 1 is a subset of FAS 1. The mPPS 1 includes all FAS 1 
participants with no major protocol deviations (check major protocol 
deviations definition in Section 5.2) that lead to exclusion at or prior to 
Visit 3 (Day 43). The time window between Visit 1 and Visit 2 that is 
permitted for inclusion in this analysis set is 18-32 days. The time window 
between Visit 2 and Visit 3 that is permitted for inclusion in this analysis 
set is 14-32 calendar days.  
 
All major protocol deviations which lead exclusion from PPS1 will also lead 
exclusion from mPPS1. Only the major protocol deviations related to sample 
collection date or vaccination date outside to the intervals described above will 
not lead exclusion from mPPS1. 
 
Modified Per Protocol Set 2 (mPPS2) 
• 
The mPPS 2 is a subset of FAS 2. The mPPS 2 includes all FAS 2 
participants with no major protocol deviations that lead to exclusion at or 
prior to Visit 2 (Day 22). The time window between Visit 1 and Visit 2 
that is permitted for inclusion in this analysis set is 18-32 days. 
Major protocol deviations leading to exclusion are described in Section 5.2 and 
the Study Deviation Rules document and will be finalized prior to the interim 
analysis defined in Section 10.2. 
 
4.6.7 Microneutralization Set 
All participants in the Randomized Set who were also selected to the subset of 
MN evaluation. 
4.6.8 Microneutralization Per Protocol Set (MNPPSx) 
 
Microneutralization Per Protocol Set 1 
• 
All participants in the MN Set who are also part of the PPS 1. 
 
Microneutralization Per Protocol Set 2 
• 
All participants in the MN Set who are also part of the PPS 2. 
 


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4.6.9 Microneutralization modified Per Protocol Set (MNmPPSx) 
 
Microneutralization modified Per Protocol Set 1 
• 
All participants in the MN Set who are also part of the mPPS 1. 
 
Microneutralization Per Protocol Set 2 
• 
All participants in the MN Set who are also part of the mPPS 2. 
5 
Participant Disposition 
5.1 
Disposition 
Participant disposition will be summarized as treated for the Exposed Set, and for 
each study group, age group, and overall.  The summary of participant disposition 
as enrolled will include the number and percentage of participants who were 
randomized, screen failures, and major reason for screen failure. The summary of 
participant disposition as treated will include the number of participants in each 
analysis set defined in Section 4.6, the number and percentage of participants who 
received any and each study vaccination, the number and percentage of 
participants who completed the study and the primary reason for withdrawal from 
the study, the number and percentage of participants who completed the study 
vaccinations and the primary reason for withdrawal of study vaccination.   
 
Listings will be provided for disposition data based on the Enrolled Set. 
5.2 
Major Protocol Deviations 
A major protocol deviation leading to exclusion is defined as a protocol deviation 
that is considered to have a significant impact on the immunogenicity results of 
the participant and will cause a participant to be excluded from the per-protocol 
analysis sets (PPSx, mPPSx, MN PPSx and MN mPPSx). The number and 
percentage of participants with each significant protocol deviation leading to 
exclusion from per-protocol analysis sets will be presented for the Exposed Set, 
and a listing will also be provided. Major protocol deviations leading to 
exclusions from PPSx, mPPSx, MN PPSx and MN mPPSx will be summarized by 
study group, age group, and overall for the Exposed Set. 
 
All protocol deviations will be identified prior to the analysis and a clinical 
judgment will be necessary to classify each deviation as “major” or “minor”.  Key 
major deviations are provided below, but not limited to: 
 
• Participants enrolled who did not sign the informed consent 
• Participants enrolled who signed the wrong informed consent version 
• Participants enrolled who included fraudulent data 


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• Participants enrolled who did not meet entry criteria including age at 
enrollment  
• Participants who received incorrect treatment number 
• Participants who were unblinded before end of the study 
• Participants incorrectly vaccinated  
• Participants who did not receive study vaccinations as planned in protocol 
• Participants who did not do the corresponding vaccination visit 
• Participants who did not have blood draws as planned in protocol 
• Participants with a blood draw outside of allowed time window 
• Participants with a vaccination done outside of allowed time window 
• Participants who reported taking any prohibited vaccination/therapy as 
listed in protocol 
These key major deviations will be assessed based on the data collected in the 
eCRFs. The complete list of protocol deviations considered major for this study 
will be reported in the CSR. If a participant incurs a condition that has the 
capability of altering their immune response, this will be recorded as an AE and 
identified as a significant protocol deviation by medical monitoring. 
 
The terms ‘major’ and ‘significant’ for protocol deviations are used 
interchangeably in study documents and have the same meaning. 
 
Significant protocol deviations leading to exclusion in each of the study 
populations is described in Table 9. 
 
 
 


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Table 9 Significant Protocol Deviation that leads in an exclusion 
Protocol Deviation 
Enr 
Rand 
Exp 
FAS1 
FAS2 
PPS1 
PPS2 
mPPS1 
mPPS2 
MNPPS1 
MNPPS2 
MNmPPS1 
MNmPPS2 
Invalid informed consent or fraud in 
data 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Incorrect treatment number provided at 
V2 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Unblinding of subject by sponsor/CRO 
personnel not done per study 
procedures at V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Unblinding of subject by sponsor/CRO 
personnel not done per study 
procedures at V2 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Investigational vaccine administrated at 
V1 Day 1 even though subject met 
exclusion 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Persistent inadequate source documents 
management after re-education** 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Vaccine temperature deviation at V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccine temperature deviation at V2 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Inclusion/Exclusion criteria not meet 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study vaccine dose not administered 
according to protocol for V1: Wrong 
site/route injection/, wrong 
reconstitution, incorrect volume, 
Expired vaccine administered 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study vaccine dose not administered 
according to protocol for V2: Wrong 
site/route injection, wrong 
reconstitution, incorrect volume, 
Expired vaccine administered 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 


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Protocol Deviation 
Enr 
Rand 
Exp 
FAS1 
FAS2 
PPS1 
PPS2 
mPPS1 
mPPS2 
MNPPS1 
MNPPS2 
MNmPPS1 
MNmPPS2 
Subsequent vaccine 
administered while 
contraindicated at V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subsequent vaccine 
administered while 
contraindicated at V2 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Incomplete treatment course V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Incomplete treatment course V2 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vaccination date at V2 done 
outside of the interval between 
V1 and V2 of 18-25 Days 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Vaccination date at V2 done 
outside of the interval between 
V1 and V2 of 18-32 Days 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Serological results collected but 
not available at V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample at V1: not taken, 
not available, low serum 
volume, Lab error (spinning 
…), temperature deviation  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample at V2: not taken, 
not available, low serum 
volume, Lab error (spinning 
…), temperature deviation 
 
 
 
 
X* 
 
X 
 
X 
 
X 
 
X 
Blood sample at V3: not taken, 
not available, low serum 
volume, Lab error (spinning 
…), temperature deviation 
 
 
 
X* 
 
X 
 
X 
 
X 
 
X 
 
Blood sample collection at V2 
done outside of the interval 
between V1 and V2 of 18-25 
Days 
 
 
 
 
 
 
X 
 
 
 
X 
 
 


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Protocol Deviation 
Enr 
Rand 
Exp 
FAS1 
FAS2 
PPS1 
PPS2 
mPPS1 
mPPS2 
MNPPS1 
MNPPS2 
MNmPPS1 
MNmPPS2 
Blood sample collection at V2 
done outside of the interval 
between V1 and V2 of 18-32 
Days 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Blood sample collection done at 
V3 outside of the interval 
between V2 and V3 of 14 - 32 
calendar Days 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Blood sample collection at V3 
done outside of the interval 
between 38 - 46 Study Days 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Subjects MN1 and MN2, who 
were randomized to MN set but 
were not included 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Temperature deviations from 
range defined in protocol and/or 
SPM for vaccine stored in 
fridge (0-8C; site level) at V1 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
* Subject elimination from FAS 1 or FAS 2 must only take place in cases where blood sample results are not available for any reason above described  
** Elimination will be based on case-by-case bases 
Enr = Enrolled set; Exp = Exposed set; Rand = Randomized set; FAS = Full Analysis Set; PPS = Per Protocol Set; mPPS = modified Per Protocol Set; 
MNPPS = Microneutralization per protocol set; MNmPPS = Microneutralization modified per protocol set. 
X = Exclusion from the study population set 


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6 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the Exposed 
Set, Enrolled Set, PPS1, PPS 2, mPPS1, mPPS2, presented by study group, age 
group, and overall.  Participant demographic and baseline characteristics will also 
be presented in a listing for the Enrolled Set. 
6.1 
Demographics 
The demographic characteristics consist of gender, race, ethnicity, and center.  
The number and percentage of participants by gender (Male, Female), race 
(American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, and Other), ethnicity (Hispanic or 
Latino, Not Hispanic or Latino) and center, will be reported.   
Demographics will be summarized using frequency counts and percentages. 
6.2 
Baseline Characteristics 
The baseline characteristics consist of age (years), age group, baseline height 
(cm), baseline weight (kg), and baseline body mass index (BMI) (kg/m2). Age 
group will be based on the age recorded on the eCRF. BMI is calculated as (body 
weight in kilograms) / (height in meters)2 and will be calculated to 2 decimal 
places.   
Age (years, as recorded on the eCRF), baseline height (cm), baseline weight (kg), 
and baseline BMI (kg/m2) will be summarized using descriptive statistics.  
Additionally, for web disclosure requirement, the number and percentage of 
subjects in the following age categories will be presented for the Enrolled Set: 18-
64 years, 65-84 years, ≥85 years.  
6.3 
Medical History  
Medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version to be delineated in the CSR. The number and 
percentage of participants with any medical history will be summarized overall 
and for each system organ class and preferred term by study group. Percentages 
will be calculated based on number of participants in the Exposed Set by study 
group, age group, and overall. 
 
Participant medical history data will also be presented in a listing for the Exposed 
Set. 


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6.4 
Inclusion and Exclusion Criteria 
Participants who did not meet inclusion criteria or met exclusion criteria will be 
presented in a listing for the Enrolled Set.  Inclusion and exclusion criteria are 
listed in the protocol sections 5.1 and 5.2. 
7 
Treatments and Medications 
7.1 
Vaccination History, Concomitant Vaccinations, and Concomitant 
Medications 
All vaccinations and medications will be coded according to the GSK Drug 
dictionary (GSKDrug), version to be delineated in the CSR. Concomitant 
medications are also collected for any SAE and pIMD per protocol section 6.5. 
7.1.1 Vaccination History and Concomitant Vaccinations 
The number and percentage of participants with any prior and concomitant 
vaccinations recorded on the eCRF will be summarized by study group, age 
group, and overall.  A concomitant vaccination is defined as a vaccination 
administered in the period starting from the first dose of study vaccine(s) and 
ending at the last study visit (Day 43). Prior and concomitant vaccinations will be 
displayed in a listing. All summaries and listings will be performed using the 
Exposed Set.  
7.1.2 Concomitant Medications 
Concomitant medications are defined as any medications/products, except 
vitamins and dietary supplements, associated with an AE administered through 
EOS.  
 
The number and percentage of participants with at least one concomitant 
medication will be summarized by study group, age group, and overall and the 
number and percentage of participants taking each medication will be presented 
by preferred term.  Concomitant medications will be displayed in a listing. All 
summaries and listings will be performed using the Exposed Set.  Participants 
with missing concomitant medication data will be handled as described in Section 
4.5.   
 
 


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7.2 
Extent of Exposure 
Extent of exposure will be based on the Exposed Set and will be presented by 
study group, age group, and overall. 
7.2.1 Compliance 
The number and percentage of participants who received any study vaccination 
will be presented, as well as the number and percentage of participants who 
received all expected vaccinations during the study and the number and 
percentage of participants who withdrew from study vaccine.  A participant has 
withdrawn from study vaccine if vaccination was administered at Visit 1, no 
vaccination was administered at Visit 2 and the participant has data recorded for 
at least one of the following: Telephone Contact Day 8 or Visit 2. 
 
In addition, the number and percentage of participants who did not receive all 
vaccinations with reason (including participants who received a partial 
vaccination) will be displayed by visit.  All study groups and age group are 
expected to receive 2 vaccinations; one at Visit 1 and one at Visit 2.   
7.2.2 Visit Attendance 
The number and percentage of participants who attended a visit or received a 
safety call within the interval described in Table 3 and per the naming 
conventions in Table 8 will be presented for the following visits: 
 
• Visit 1 Day 1 
• Telephone Contact 1 Day 8 
• Visit 2 Day 22 
• Telephone Contact 2 Day 29 
• Visit 3 Day 43 
• Telephone Contact 3 Month 4 
• Telephone Contact 4 Month 7 
• Telephone Contact 5 Month 10 
• Telephone Contact 6 Month 13 
The number and percentage of participants with attendance at each study visit will 
be summarized by study group, age group, and overall for the Exposed Set. 
Listings will be provided for the Exposed Set to provide details of visit 
attendance, safety calls, and blood samples. 
An additional table with the number and percentage of participants with a 
deviation from the study and with the minimum and maximum days deviated will 
be generated by treatment group and overall.  
 


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The deviation intervals included in this table for the PPSx and MNPPSx will be: 
- Between 18 – 25 days from Visit 1 to Visit 2 
- Between 38 – 46 days from Visit 2 to Visit 3 
The deviation intervals included in this table for the mPPSx and mMNPPSx will 
be: 
- Between 18 – 32 days from Visit 1 to Visit 2 
- Between 14 – 32 days from Visit 2 to Visit 3 
A table with all deviations from intervals according to Table 3 will be added in 
the final analysis. 
8 
Immunogenicity Analysis 
 
The primary immunogenicity objective of this study is to evaluate whether the 
vaccine with monovalent H7N9 virus containing 1.9 µg, 3.75 µg, or 7.5 µg of HA 
adjuvanted with AS03A or AS03B elicits a HI antibody response to the vaccine-
homologous virus that meets or exceeds the US FDA, CBER immunogenicity 
criteria at the Day 43 visit.  Section 4.3 defines the conditions under which the 
observed immune responses will meet the guidelines. 
 
The secondary immunogenicity objectives of this study are to describe the 
vaccine homologous H7N9 HI and MN antibody profiles at Days 1, 22, and 43. 
 
The primary and secondary H7N9 HI immunogenicity analyses will be based on 
the applicable PPSx as described in section 4.6. Supplementary analyses for 
primary and secondary HI immunogenicity analyses will be based on the 
applicable mPPSx. Results for baseline values will be presented using PPS2 and 
mPPS2 accordingly. If the difference between PPS 1 and FAS 1 is greater than 
10%, a second analysis based on the applicable FASx will be performed to 
complement the PPSx analysis. 
 
The H7N9 MN immunogenicity analyses will be based on the applicable 
MNPPSx as described in section 4.6. Supplementary analyses for MN 
immunogenicity analyses will be based on the applicable MN mPPSx.  
 
For a given participant and a given immunogenicity measurement, missing or 
non-evaluable measurements will not be replaced. 
 
Titers below cut-off will be handled as described in Section 4.5.   
 
 


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H7N9 HI titer results will be listed for the Exposed Set and the listing will 
indicate participants included in each of PPSx, mPPSx and FASx. The listing will 
also indicate participants with HI titers ≥ cut-off and participants who experienced 
a 4-fold increase in HI titers since baseline. A similar listing will also be prepared 
for the H7N9 MN titer results for the MN Set and the listing will indicate 
participants included in each of MNPPSx and MNmPPSx. 
 
For the remainder of Section 8 the Analysis Visit names defined in Table 8 will 
be used. 
 
The primary and secondary immunogenicity analyses will be presented in the 
same outputs. 
8.1 
Seroconversion Rate (SCR) and Seroprotection Rate (SPR) 
 
The percentage of participants with seroconversion (SCR) and seroprotection 
(SPR) will be calculated along with Clopper-Pearson exact two-sided CIs by 
intervention group, age group, and post-baseline visit.  For Day 43 only, the CIs 
will be 99.17% for the antigen/adjuvant groups and will allow testing of the 
statistical hypotheses. For Day 1 (SPR only) and Day 22 (SCR and SPR) and 
Placebo (including Day 43), the CIs will be 95% and are provided for descriptive 
purposes only. 
 
The SCR and SPR will be analyzed for H7N9 HI antibody titer only.  
8.2 
Geometric Mean Titer 
 
Titer results are not normally distributed so summary statistics will be calculated 
using log-transformed titer results.  The anti-logarithm of the summary statistics 
will be presented.  Titer results will be summarized by study group, age group, 
visit. Missing titer results and results below the cut-off will be handled as 
described in Section 4.5.   
In addition, the distribution of antibody titers for each intervention group and age 
group will be displayed using reverse cumulative distribution curves.  The x-axis 
of the reverse cumulative distribution curves will be presented on a log scale. A 
reference line will be included to show the cut-off.  All study groups for a single 
visit will be displayed on the same page, and visits will be displayed on separate 
pages. 
 
 
 


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Summaries will include the number of participants with non-missing titer results, 
GMT, geometric standard deviation (GSD), 95% CI for GMT, minimum and 
maximum.   
  
GMT will be calculated as the anti-logarithm of the mean of the log-transformed 
titer values i.e. anti-logarithm of ∑(𝑙𝑜𝑔10(𝑡𝑖𝑡𝑒𝑟))/𝑛 where n is the number of 
participants with non-missing titer results.  GSD will be calculated as the anti-
logarithm of the standard deviation (SD) of the log-transformed data.  The 95% 
CI for GMT will be calculated as the anti-logarithm of the endpoints of the 95% 
CI for the mean of the log-transformed data.  The anti-logarithm is calculated as 
10𝑥 where x is the statistic of interest calculated from the log-transformed data 
(e.g. mean, SD, 95% CI endpoints).   
 
No adjustment will be made for multiplicity in GMT and CIs are provided for 
descriptive purposes only.  The GMT will be analyzed for both H7N9 HI and MN 
antibody titers. 
8.3 
Mean Geometric Increases (MGIs) 
 
MGI for HI will be summarized by study group, age group, and post-baseline 
visit.  Missing titer results and results below the cut-off will be handled as 
described in Section 4.5. 
MGI will be calculated as the anti-logarithm of the mean of the change from 
baseline of log-transformed titer values at Post-Baseline and Baseline i.e. anti-
logarithm of ∑(𝑙𝑜𝑔10(𝑡𝑖𝑡𝑒𝑟𝑃𝑜𝑠𝑡−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐴𝑉𝐼𝑆𝐼𝑇) −𝑙𝑜𝑔10(𝑡𝑖𝑡𝑒𝑟𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒))/𝑛  where 
n is the number of participants with non-missing titer results at Baseline and 
Post-Baseline AVISIT. 
Summaries will include the number of participants with non-missing titer results 
at each post-baseline AVISIT, MGI, GSD of the difference in log-transformed 
titer results at post-baseline AVISIT and Baseline, 95% CI for MGI, minimum 
and maximum. 
 
GSD will be calculated as the anti-logarithm of the SD of the change from 
baseline of the log-transformed data.  The 95% CI for MGI will be calculated as 
the anti-logarithm of the endpoints of the 95% CI for the mean MGI.  The 
anti-logarithm is calculated as 10𝑥 where x is the statistic of interest calculated 
from the log-transformed data (e.g. mean, SD, 95% CI endpoints). 
 
No adjustment will be made for multiplicity in MGI and CIs are provided for 
descriptive purposes only.  The MGI will be analyzed for H7N9 HI antibody titers 
only. 


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8.4 
Seropositivity 
 
The percentage of seropositive participants for HI and MN as well as the 
associated Clopper-Pearson exact 2-sided 95% CIs will be computed by study 
group, age group and visit.  
 
No adjustment will be made for multiplicity in seropositivity and CIs are provided 
for descriptive purposes only. Seropositivity will be analyzed for both H7N9 HI 
and MN antibody titers. 
8.4.1 Vaccine Response Rate (VRR) 
 
The VRR for MN as well as the associated Clopper-Pearson exact 2-sided 95% 
CIs will be computed by study group, age group and post-baseline visit.  
 
No adjustment will be made for multiplicity in VRR and CIs are provided for 
descriptive purposes only. The VRR will be analyzed for H7N9 MN antibody 
titers only. 
9 
Safety Analysis 
Safety summaries and listings will be based on the Exposed Set.  
9.1 
Adverse Events 
Solicited events, unsolicited AEs, SAEs, medically attended AEs, AEs leading to 
withdrawal from intervention or from the study, and pIMDs that occur post-
vaccination will be summarized and also presented in listings. AEs occurring 
prior to a participant receiving any study vaccine will be listed only.   
 
The definitions for SAEs and medically attended AEs can be found in protocol 
sections 10.3.2 and 10.3.9.3 respectively.  Further information about pIMDs can 
be found in protocol section 10.3.5.1. 
 
Incomplete onset dates and end dates for any AEs will be imputed to determine if 
the event occurred within the time period specified for AE summaries that are 
described in sections 0 and 9.1.2.  Actual dates recorded will be presented in 
listings, imputed dates will not be presented.  Incomplete dates will be imputed as 
follows: 
 
Missing onset dates (where UK and UKN indicate unknown or missing day and 
month respectively):  
 


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• 
If the response to “If exact start date is unknown, or is on the same day as 
any study vaccination, please confirm whether it occurred before or after 
vaccination:” is “After vaccination 1” or “After vaccination 2” then 
assume the start date is the date of the first and second dose of study 
vaccine, respectively.  
• 
If the response is “Before vaccination” assume the following: 
• 
UK-MMM-YYYY: If the month and year are different from the 
month and year of the first dose of study vaccine, assume 01-
MMM-YYYY. If the month and year are the same as the first dose 
of study vaccine month and year, and the end date (after any 
imputation) is on or after the first dose of study vaccine, then 
assume the date of the first dose of study vaccine. If the month and 
year are the same as the first dose of study vaccine month, and year 
and the end date (after any imputation) is prior to the first dose of 
study vaccine, then assume the end date for the onset date.  
• 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is before the year 
of first dose of study vaccine, assume DD-JAN-YYYY/01-JAN-
YYYY of the collected year. If the year is after the first dose and 
the same as the second dose, assume DD-JAN-YYYY/01-JAN-
YYYY.  If the year is the same as the first dose of study vaccine 
year, and the end date (after any imputation) is on or after the first 
dose of study vaccine, then assume the date of the first dose of 
study vaccine. If the year is the same as the first dose of study 
vaccine, and the end date (after any imputation) is prior to the first 
dose of study vaccine, then assume the end date for the onset date.  
 
Missing end dates (where UK and UKN indicate unknown or missing day and 
month respectively):  
• UK-MMM-YYYY: Assume the last day of the month. 
• DD-UKN-YYYY: Assume DD-DEC-YYYY. 
• UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 
 


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9.1.1 Solicited Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited 
events”) occurring in the hours and days following a vaccination.  Participants 
will be assessed for reactogenicity, to be collected for 7 days following each 
vaccination (the day of vaccination and the following 6 days), using a paper diary 
(pDiary).  Solicited events will be recorded in the eDiary for the periods Day 1 to 
Day 7 and Day 22 to Day 28.   
 
Solicited administration site events 
Solicited administration site events for this study are pain, redness, and swelling.  
Solicited administration site events will be recorded according to the vaccine that 
was administered most recently. 
 
Solicited systemic events 
Solicited systemic events for this study are fatigue, fever, nausea, vomiting, 
diarrhea, abdominal pain, headache, muscle ache, joint pain, shivering (chills), 
sweating.  The preferred location for measuring temperature in this study is oral. 
Solicited events will be summarized according to the defined severity grading 
scales in Table 10. Fever will be considered as a body temperature value ≥38°C. 


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Table 10 Solicited Event Intensity Grades 
Adults (18 years) 
Event 
Intensity grade 
Parameter 
Pain at administration 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. 
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. 
Muscle ache 
0 
Normal 
 
1 
Mild: Muscle aches that are easily tolerated. 
 
2 
Moderate: Muscle aches that interfere with normal 
activity. 
 
3 
Severe: Muscle aches that prevent normal activity. 
Joint pain 
0 
Normal 
 
1 
Mild: Joint pain that is easily tolerated. 
 
2 
Moderate: Joint pain that interferes with normal activity. 
 
3 
Severe: Joint pain that prevents normal activity. 
Shivering (chills) 
0 
Normal 
 
1 
Mild: Shivering (chills) that is easily tolerated. 
 
2 
Moderate: Shivering (chills) that interferes with normal 
activity. 
 
3 
Severe: Shivering (chills) that prevents normal activity. 
Sweating 
0 
Normal 
 
1 
Mild: Sweating that is easily tolerated. 
 
2 
Moderate: Sweating that interferes with normal activity. 
 
3 
Severe: Sweating that prevents normal activity. 
Gastrointestinal symptoms: nausea, 
vomiting, diarrhea and/or abdominal 
pain 
0 
Normal 
 
1 
Mild: Gastrointestinal symptoms that are easily tolerated. 
 
2 
Moderate: Gastrointestinal symptoms that interfere with 
normal activity. 
 
3 
Severe: Gastrointestinal symptoms that prevent normal 
activity. 
Redness at administration site 
Record greatest surface diameter in mm 
Swelling at administration site 
Record greatest surface diameter in mm 
Temperature* 
 
Record temperature in °F 
* Refer to the Protocol Schedule of Assessments for the definition of fever and the preferred location 
for temperature measurement. 


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The maximum intensity of local injection site redness/swelling will be scored at 
GSK as follows: 
0: 
≤ 20 mm 
1: 
> 20 to 50 mm 
2: 
> 50 to 100 mm 
3: 
> 100 mm 
 
The maximum intensity of fever will be scored at GSK as follows: 
0: 
< 38.0°C (< 100.4°F) 
1: 
≥ 38.0 – 38.4°C (≥100.4 – 101.2°F) 
2: 
≥ 38.5 – 38.9°C (≥ 101.3 – 102.1°F) 
3: 
≥ 39.0 – 40.0°C (≥ 102.2 – 104.0°F) 
4: 
> 40.0°C (>104.0°F) 
 
1. Participants with solicited events will be counted based on actual 
intervention received for each study group and age group.  Solicited 
events will also be presented by individual vaccine received (dose 1 and 
dose 2).  The following categories will be included in the summary table 
for solicited events and will be generated on subjects who has filled in 
solicited symptom in the eDiary: Participants who experienced any 
solicited event within 7 days of vaccination 
2. Participants who experienced any systemic solicited event within 7 days 
of vaccination 
3. Participants who experienced any administration site solicited event 
within 7 days of vaccination 
A summary table containing the number and percentage of participants showing 
the occurrence of any solicited event will be presented by study group, age group, 
visit, and timepoint. The duration of solicited events will also be summarized by 
study group, age group and vaccination. 
The duration (in days) of a solicited event will be calculated as: 
Date of last report of a solicited event after the respective vaccination 
administration date within 7 days of vaccination – date of first report of a 
solicited event after the respective vaccination administration date + 1 
The duration (in days) of an ongoing solicited event after the 7 days of 
vaccination will be calculated as: 
Date of last report of a solicited event after the respective vaccination 
administration date – date of first report of a solicited event after the 
respective vaccination administration date + 1 
A similar calculation will be made for the second vaccination. Duration will be 
calculated for each solicited event separately.  


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A summary table for duration of solicited events within 7 days post-vaccination 
and a frequency table of solicited event after the 7 days of vaccination will be 
presented. 
The number and percentage of participants experiencing each solicited event will 
be presented for each symptom maximal severity (defined in Table 10) by study 
group, age group, visit, and time point.  If a solicited event occurs more than once 
for a participant within a time point, it will be counted in the summary only once, 
according to the maximal severity.   
Solicited events will be listed.  
9.1.2 Unsolicited Adverse Events 
An unsolicited AE is an AE that was not solicited using a participant Diary and 
that was spontaneously communicated by the participants or a solicited 
administration site or systemic event that meets the criteria described in Section 0. 
Solicited events lasting more than 7 days after vaccination (including the day of 
vaccination) are also recorded as unsolicited AEs. 
 
The original verbatim terms used by investigators to identify AEs in the Adverse 
Events page of the eCRF will be mapped to preferred terms (PT) using MedDRA, 
version to be delineated in the CSR.  The AEs will then be grouped by MedDRA 
according to system organ class (SOC). 
The following summaries will present the event count, number and percentage of 
participants reporting each AE and will be presented by SOC, PT, and maximum 
relationship to study intervention for each study group, grouped by 21 days post-
vaccination at any visit and then by 2 time points (at the final analysis): 21 days 
post-vaccination at Visit 1, and 21 days post-vaccination at Visit 2: 
• Any unsolicited AE  
• Any severe unsolicited AE (grade 3) 
• Any related unsolicited AE 
• Any severe related unsolicited AE (grade 3 related) 
• Unsolicited MAEs 
• Any AEs with MAEs 
• Any related AEs with MAEs 


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Additional summaries will present the number and percentage of participants 
reporting AEs in the following categories and will be presented by SOC and PT 
for each study group and age group from Day 1 through the Day 43 visit and from 
Day 1 through the end of study: 
• SAEs 
• AEs leading to withdrawal from study drug (through Day 22 only 
• AEs leading to withdrawal from study 
• MAEs (within 21 days post each vaccination) 
• pIMDs 
Data listings of all AEs will be provided by participant. In addition, AEs in the 
categories above will be provided as listed data.  
 
Missing data will be handled as described in Section 4.5. 
 
9.2 
COVID-19 Assessments 
Frequencies and percentages of participants with suspected, probable, or 
confirmed COVID-19 cases will be summarized for the Exposed Set for each 
study group, age group, and overall. 
 
In addition, a summary of the following COVID-19 additional assessments will 
be produced on all assessments reported. with the denominator being subject (i.e. 
if more than one per subject, counted only once): 
• Does the subject have a history of travel to or residence in a location 
reporting community transmission of COVID-19 disease during the 14 
days prior to symptom onset? 
• Did the subject visit any health care facility in the 14 days prior to 
symptom onset? 
• Did the subject have contact with a confirmed or probable case in the 14 
days prior to symptom onset? 
• Were any concomitant medications taken by the subject, including 
experimental medications, to treat COVID-19? 
Additional COVID-19 case details will be produced. The listing will include: 
• 
Site Identifier 
• 
Treatment 
• 
Period 
• 
Unique Subject Identifier 
• 
Subject Identifier 


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• 
COVID-19 case diagnosis 
• 
COVID-19 test performed 
• 
Result of the COVID-19 test 
• 
Assessments and Symptom Assessments performed 
• 
Results of the Assessments and Symptom Assessments 
Participants with COVID-19 cases or who take COVID-19 vaccine may be 
excluded from the per protocol analysis depending on timing of the infection or 
the vaccination. For example, if a participant has COVID-19 infection between 
Day 22 and Day 43, the participant may be excluded from analysis of Day 43 data 
but still be included in the analysis for Day 22 data. 
 
The COVID-19 related protocol deviations (e.g. blood draw outside of allowed 
time window due to COVID-19 related restrictions of movement) will be 
reviewed together with other protocol deviations. Participants with major protocol 
deviations may be excluded from per protocol analysis sets, as described in 
Section 5.2. 
 
If study procedures are modified due to special circumstances, there may be a 
requirement to conduct analyses that separately describe the data collected during 
the period of modified study procedures.  If required, these analyses will be 
described in a separate analysis plan. 
9.3 
Clinical Laboratory Evaluations 
 
Clinical laboratory measurements (e.g. clinical chemistry, hematology, and 
urinalysis) are not scheduled to be taken during the study; however, clinical 
laboratory tests may be done and the results obtained as part of critical care or 
follow-up due to the occurrence of MAEs, SAEs, or pIMDs during the study. The 
investigator must review the laboratory report, document that he/she did so, and 
record any clinically relevant changes occurring during the study in the eCRF. 
Clinically significant abnormal laboratory findings are those which are associated 
with an underlying disease judged by the investigator to be more severe than 
expected for the participant's condition. 
 
Should any clinical laboratory tests be performed during the study for a 
participant, abnormal laboratory findings or other abnormal assessments that are 
judged by the investigator to be clinically significant will be recorded as an AE or 
SAE if they meet the definition of an AE or SAE and will be included in AE/SAE 
summaries.   
 


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9.4 
Physical Examination and Vital Signs 
 
At a minimum, temperature and vital signs (e.g. heart rate and respiratory rate, 
blood pressure) must be collected. Participants will undergo a physical 
examination and vital signs are to be taken prior to the first vaccination and will 
consist of 1 pulse and 1 blood pressure measurement. Blood pressure and pulse 
measurements will be assessed by a completely automated device on Day 1 only. 
Manual techniques will be used only if an automated device is not available. 
Collected information will be recorded in the eCRF.  Blood pressure and pulse 
measurements will be listed only. 
 
Summary statistics (mean, SD, minimum and maximum) for pre-vaccination body 
temperature at each visit will be presented by study group and age group for the 
Exposed Set.  Pre-vaccination vital signs and body temperature will be listed for 
the Exposed Set.    
9.5 
Pregnancy 
Female participants of childbearing potential will have a urine pregnancy test 
prior to any study vaccine(s) administration.   
 
Pregnancy test results will be displayed in a listing for the Exposed Set. Listings 
of pregnancy will also be generated. 
 
10 
Sequence of Analyses 
10.1 
iSRC Review 
At least 2 iSRC reviews are planned, as described in Section 3.1. For each iSRC 
review, a subset of unblinded Tables, Listings and Figures (TLFs) from the main 
analysis will be generated by PPD and delivered to the iSRC team at GSK for 
their review. The TLFs required for these reviews are detailed separately in the 
TLF Table of Contents (ToC). Details regarding the timing and scope of iSRC 
reviews will be provided in the iSRC charter. 
 
The iSRC will review the following data:  
1. Participant demographic data 
2. Adverse Events (AEs) / Serious Adverse Events (SAEs), including Council 
for International Organizations of Medical Sciences (CIOMS) reports, 
including listings for: 
• All AEs 
• Potential immune-mediated diseases (pIMDs) 


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• Fatal SAEs 
• AEs/SAEs/pIMDs leading to permanent discontinuation from study 
treatment or withdrawal from the study 
• AE/SAEs/pIMDs causally related to study vaccine 
3. Participant Disposition listing (number of subjects vaccinated, withdrew from 
the study, withdrawal reasons) 
4. Other information as deemed necessary by the study team/iSRC 
The Safety Review Team (SRT) will review the same safety data, but in a blinded 
manner. 
10.2 
Analysis at Day 43 
An interim analysis will be performed on data collected through the Day 43 visit. 
This interim analysis will provide intervention-level unblinded summaries for 
GSK, Biomedical Advanced Research and Development Authority, and 
regulatory agency review, and no individual unblinding data will be provided. 
 
An analysis will be performed on data collected through the Day 43 visit. 
Elements will include: 
• Analyses of cleaned immunogenicity data through the Day 43 visit will be 
conducted. 
• Analyses of cleaned solicited administration site events and solicited 
systemic events data collected during a 7-day follow-up period (Day 1 to 
Day 7) after each vaccination will be conducted. 
• Analyses of unsolicited AEs and MAEs up to 21 days post each 
vaccination presented overall per subject on as clean as possible data. 
• Analyses of SAEs, pIMDs, pregnancies and withdrawals due to AEs 
collected up to the Day 43 post-vaccination visit will be carried out. 
• Blinded listing of pregnancies and withdrawals due to AEs collected up to 
the Day 43 post-vaccination visit will be presented. 
• Results will be presented in a Day 43 statistical report. Access to 
individual intervention codes will be restricted to the designated unblinded 
statisticians in charge of the analysis. No individual listings or data with 
the participants’ identifying information will be disseminated. Listings of 
final data will be provided with the Month 13 report. 
All analyses will be performed on data that has been cleaned and locked. The 
possibility of post-analysis changes to data evaluated at Day 43 exists, since data 


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collection and data entry may continue through Month 13. All final data will be 
presented in the listings provided at Month 13. 
10.3 
Final Analysis at Month 13 
A final data analysis will be performed at the end of study (Month 13) of all 
primary and secondary endpoints based on the clean data, including evaluations 
of: 
• Immunogenicity at all measured time points (Days 1, 22 and 43). 
• Solicited administration site events and solicited systemic events data 
reported 7 days after each vaccination (Day 1 to Day 7 and Day 22 to Day 
28). 
• Unsolicited AEs and MAEs reported up to 21 days after each vaccination. 
• Concomitant medications reported up to 21 days after each vaccination. 
• SAEs, pIMDs and withdrawals due to AEs collected throughout the entire 
study. 
• Pregnancies throughout the entire study. 
An integrated CSR containing all data will be written and made available to the 
investigators. 
10.4 
Statistical Considerations for the Analysis at Day 43 
Since the primary immunogenicity endpoints for the study will be complete by the 
Day 43 visit (collection past Day 43 includes only assessments for unsolicited 
AEs leading to study withdrawal, SAEs and pIMDs), no statistical consideration 
for multiplicity will be given to account for changes in the results reported at the 
interim analysis compared to the final analysis. For the primary immunogenicity 
analysis, which will be reported at Day 43 the overall type I error rate is fixed at 
5% (two-sided intervals) and a Bonferroni adjustment will be applied to allow 
simultaneous multiple comparisons of each antigen/adjuvant group. No further 
adjustment is needed since sequential testing will be used for each 
antigen/adjuvant group related to the two endpoints and to the two age categories.  
For the secondary immunogenicity and primary safety analyses no adjustment for 
multiple comparisons will be made in each antigen/adjuvant group as the CIs are 
provided for descriptive purposes only. No adjustment is applied for the Placebo 
group. 
11 
Changes to the Protocol Planned Analysis 
The duration of solicited events will also be summarized by study group, age 
group and vaccination. 


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12 
References 
Center for Biologics Evaluation and Research (CBER). Guidance for Industry. 
Clinical data needed to support the licensure of pandemic influenza vaccines. May 
2007. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-data-needed-support-licensure-pandemic-influenza-vaccines. 
 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika. 1934; 26: 404-413. 
 
Food and Agriculture Organization of the United Nations (FAO). Agriculture and 
Consumer Protection Department. Animal Production and Health. H7N9 situation 
update. Avian Influenza A (H7N9) 4 September 2019. 
http://www.fao.org/ag/againfo/programmes/en/empres/h7n9/situation_update.htm
l. Accessed 2 October 2019. 
 
World Health Organization (WHO). Avian Influenza Weekly Update Number 
694. 20 September 2019. https://www.who.int/docs/default-source/wpro---
documents/emergency/surveillance/avian-influenza/ai-
20190920.pdf?sfvrsn=30d65594_36. Accessed: 2 October 2019 
 
Xiang N, Li X, Ren R, Wang D, Zhou S, Greene CM, et al. Assessing change in 
avian influenza A(H7N9) virus infections during the fourth epidemic - China, 
September 2015-August 2016. MMWR Morb Mortal Wkly 
Rep.2016;65(49):1390-94.  
 
Zhou L, Ren R, Yang L, Bao C, Wu J, Wang D, et al. Sudden increase in human 
infection with avian influenza A(H7N9) virus in China, September-December 
2016. Western Pac Surveill Response J. 2017;8(1):6-14. 


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13 
Appendices 
13.1 
Schedule of Study Events 
Table 11 List of Study Procedures  
 
Primary 
Follow-up 
Type of contact 
Visit 1  
TC1  
Visit 2  
TC2  
Visit 3  
TC3  
TC4  
TC5  
TC6  
Time points 
Day 1  
Day 8  
Day 22  
Day 29  
Day 43  
Month 4 Month 7  Month 10 Month 13  
Sampling time points 
Pre-Vacc I  
 
Pre-Vacc II  
 
Post-Vacc 
II 
Informed consent  
●  
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
 
 
 
 
 
Collect demographic data 
●  
 
 
 
 
 
 
 
 
Vaccine/Product 
Study group and intervention number allocation 
O 
 
 
 
 
 
 
 
 
Intervention number allocation for subsequent dose 
 
 
O 
 
 
 
 
 
 
Recording of administered intervention number 
● 
 
● 
 
 
 
 
 
 
Vaccine administration 
●  
 
●  
 
  
 
 
 
 
Clinical specimens for laboratory assays 
Blood sampling for antibody determination (25 mL) 
●  
 
● 
 
●  
 
 
 
 
Safety assessments 
Medical history1 
● 
 
 
 
 
 
 
 
 
Physical examination2 
● 
 
 
 
 
 
 
 
 
History of administration of adjuvanted vaccine and 
influenza vaccine 
● 
 
 
 
 
 
 
 
 
Urine pregnancy test3 
●  
 
●  
 
 
 
 
 
 
Check warnings and precautions to vaccination 
● 
 
● 
 
 
 
 
 
 
Pre-vaccination body temperature4 
●  
 
●  
 
 
 
 
 
 
Record any concomitant medication/vaccination 
●  
 
●  
 
●  
 
 
 
 
Distribution of diary cards and COVID-19 assessment 
cards5 
O 
 
O 
 
 
 
 
 
 


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Primary 
Follow-up 
Type of contact 
Visit 1  
TC1  
Visit 2  
TC2  
Visit 3  
TC3  
TC4  
TC5  
TC6  
Time points 
Day 1  
Day 8  
Day 22  
Day 29  
Day 43  
Month 4 Month 7  Month 10 Month 13  
Sampling time points 
Pre-Vacc I  
 
Pre-Vacc II  
 
Post-Vacc 
II 
Telephone contact  
 
● 
 
● 
 
● 
● 
● 
● 
Recording of solicited administration site and systemic 
events (Days 1-7 after each vaccination)6 
●  
 
●  
 
 
 
 
 
 
Recording of unsolicited adverse events and MAEs 
(Days 1-21 after each vaccination)6  
●  
● 
● 
● 
● 
 
 
 
 
Occurrence of urticaria/rash within 30 minutes 
post-vaccination observation 
●  
 
●  
 
 
 
 
 
 
Return of diary cards and COVID-19 assessment 
cards5 
 
 
O 
 
O 
 
 
 
 
Diary card transcription by investigator or delegate6 
 
 
● 
 
● 
 
 
 
 
Reporting of pIMDs 
●  
● 
●  
● 
●  
●  
● 
● 
● 
Reporting of SAEs, pregnancies  
●  
● 
●  
● 
●  
●  
●  
●  
●  
Study Conclusion  
 
 
 
 
 
 
 
 
●  
Note: The double-line borders indicate analyses which will be performed on all data obtained up to those time points. 
Note: Participants who discontinue or withdraw from the study should be followed with telephone contacts at Months 4, 7, 10, and 13 (as applicable) for safety follow-
up. 
MAEs: medically attended adverse events; Pre-Vacc: pre-vaccination; pIMDs: potential immune-mediated diseases; Post-Vacc: post-vaccination; SAEs: serious 
adverse events; TC:  telephone contact 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
O is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1. 
Medical history data should include the presence or absence of risk factors for complications associated with influenza. Influenza vaccination history covers 
influenza vaccines administered in the previous 3 influenza seasons (if any). Clinically significant abnormalities are to be captured in the eCRF as adverse events. 
2. 
At a minimum, temperature and vital signs (e.g. heart rate and respiratory rate, blood pressure) must be collected. 
3. 
Urine pregnancy test to be performed for women of child-bearing potential; a negative result must be obtained prior to each vaccination. 
4. 
Fever is defined as temperature  38.0°C/100.4°F. The preferred location for measuring temperature in this study will be oral. Participants with a minor illness 
(such as mild diarrhea, mild upper respiratory infection) without fever may be enrolled and/or vaccinated at the discretion of the investigator. 
5. 
Diary cards used to capture both solicited administration site and systemic events (Days 1-7 after each vaccination) and unsolicited adverse events (Days 1-21 
after each vaccination) and COVID-19 assessment cards are provided at the time of each vaccination and collected at the next visit following each vaccination 


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(solicited administration site and systemic events portion of card) and at the subsequent visit (unsolicited adverse events portion of card) or by mail using the pre-
stamped envelope received at the site. 
6. 
Participant records intensity and duration of solicited administration site events and occurrence, intensity and duration, of each solicited systemic event and 
unsolicited adverse event. Investigator or delegate later assesses and records relationship of each solicited administration site and systemic event and unsolicited 
adverse event to vaccination.