Clinical trial NCT04091451
Conditions: Herpes Zoster
Keywords: Shingles Shingles recurrence HZ Vaccine response rate
Sponsor: GlaxoSmithKline
Start date: 2019-09-17; Completion date: 2024-02-15
Enrollment: 1430 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the safety and immunogenicity of GSK Biologicals' HZ/su vaccine when given on a two-dose schedule to adults aged 50 years and above who had a previous episode of Herpes Zoster (HZ).

Detailed description:

Arms: arm 1: Participants with a prior episode of HZ randomized to the HZ/su group were scheduled to receive 2 doses of HZ/su vaccine, one at Day 1 and one at Month 2. arm 2: Participants with a prior episode of HZ randomized to the Placebo group were scheduled to receive 2 doses of placebo, one at Day 1 and one at Month 2.
Interventions: intervention 1: Herpes Zoster subunit (HZ/su) vaccine (GSK1437173A) intervention 2: Placebo
Intervention descriptions: intervention 1: 2 doses of HZ/su vaccine were administered intramuscularly according to a 0,2 months vaccination schedule, at Day 1 and Month 2. intervention 2: 2 doses of Placebo were administered intramuscularly according to a 0,2 months vaccination schedule, at Day 1 and Month 2.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
204939 (ZOSTER-062) 
Protocol Amendment 2 Final 
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1 
 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89, 
1330, Rixensart, Belgium 
Primary Study vaccine and 
number 
GlaxoSmithKline (GSK) Biologicals’ lyophilized 
formulation of the Herpes Zoster subunit vaccine 
(HZ/su) (GSK1437173A) 
Other Study vaccine 
Placebo (Lyophilized sucrose reconstituted with 
saline [NaCl] solution) 
eTrack study number and 
Abbreviated Title 
204939 (ZOSTER-062) 
Investigational New Drug 
(IND) number 
BB-IND-13857 
EudraCT number 
2016-000744-34 
Date of protocol 
Final Version 2: 14 June 2018 
Date of protocol amendment 
Amendment 1 Final: 18 March 2019  
Amendment 2 Final: 14 April 2020 
Title 
Safety and immunogenicity study of GSK 
Biologicals’ Herpes Zoster subunit vaccine (HZ/su) 
GSK1437173A on a two-dose schedule in adults ≥ 50 
years of age with a prior episode of Herpes Zoster  
Detailed Title 
A phase III, randomized, observer-blind, placebo 
controlled, multicenter clinical trial to assess Herpes 
Zoster recurrence and the reactogenicity, safety and 
immunogenicity of GSK Biologicals’ Herpes Zoster 
vaccine (HZ/su) when administered intramuscularly 
on a 0 and 2 month schedule to adults ≥ 50 years of 
age with a prior episode of Herpes Zoster. 
Co-ordinating author 
 and 
, 
Scientific Writer 
Contributing authors 
(Amended 14 April 2020) 
• 
 
Clinical Research and Development Leads 
• 
 Lead Statisticians 
• 
 Statistician 
• 
 Study 
Delivery Leads . 
PPD
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eTrack study number and 
Abbreviated Title 
204939 (ZOSTER-062) 
Investigational New Drug 
(IND) number 
BB-IND-13857 
EudraCT number 
2016-000744-34 
Detailed Title 
A phase III, randomized, observer-blind, placebo 
controlled, multicenter clinical trial to assess Herpes 
Zoster recurrence and the reactogenicity, safety and 
immunogenicity of GSK Biologicals’ Herpes Zoster 
vaccine (HZ/su) when administered intramuscularly 
on a 0 and 2 month schedule to adults ≥ 50 years of 
age with a prior episode of Herpes Zoster. 
Contributing authors 
(Amended 14 April 2020) 
• 
 
 Clinical Safety Representatives 
• 
 Oversight Data Manager 
• 
 Global Regulatory Affairs 
• 
 US Regulatory Affairs 
• 
 Clinical Trial 
Supply Manager 
• 
 Global Patents 
• 
 Clinical 
Laboratory Science Readout Team Leaders 
• 
 Clinical 
Laboratory Science Study Managers 
• 
 ACE and 
Local Delivery Leads 
• 
 Clinical and Epidemiology 
Project Lead (CEPL) for ZOSTER, Clinical 
R&D. 
GSK Biologicals’ Protocol DS v15.0 
©2018 GSK group of companies or its licensor.  
PPD
PPD
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204939 (ZOSTER-062) 
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Protocol Amendment 2 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
204939 (ZOSTER-062) 
IND number 
BB-IND-13857  
EudraCT number 
2016-000744-34  
Date of protocol amendment  
Amendment 2 Final: 14 April 2020 
Detailed Title  
A phase III, randomized, observer-blind, placebo 
controlled, multicenter clinical trial to assess Herpes 
Zoster recurrence and the reactogenicity, safety and 
immunogenicity of GSK Biologicals’ Herpes Zoster 
vaccine (HZ/su) when administered intramuscularly 
on a 0 and 2 month schedule to adults ≥50 years of 
age with a prior episode of Herpes Zoster.  
Sponsor signatory 
Anne Schuind,  
Clinical and Epidemiology Project Lead (CEPL) for 
ZOSTER, Clinical R&D 
 
 
Signature 
 
Date 
 
 
 


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204939 (ZOSTER-062) 
Protocol Amendment 2 Final 
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Protocol Amendment 2 Rationale 
Amendment number: 
Amendment 2 
Rationale/background for changes: 
This protocol amendment 2 outlines measures that may be applicable during special 
circumstances (e.g., during COVID-19 pandemic). The purpose of the amendment is to 
introduce measures that may allow protection of subject’s welfare and safety, as well as 
maintaining the integrity of the study. 
This amendment is considered substantial based on the criteria defined in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it significantly impacts the safety of subjects or/nor the scientific value 
of the study.  
As much as possible all study specified visits and procedures should be completed 
according to the protocol, taking into account clinical judgment and local public health 
guidance to protect the safety of staff and subjects. 
Section 6.7 outlines the measures which include allowing flexibility in schedule and 
procedures to optimize site staff safety, patient safety and to preserve study integrity  
Other change includes: 
• 
 
Please refer to Appendix C for a list of all the changes. 
 
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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 (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study vaccines and other study-related duties and functions as 
described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative.  
• 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).  
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements. 
Hence I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.  
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 


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eTrack study number and 
Abbreviated Title 
204939 ((ZOSTER-062))  
IND number  
BB-IND-13857  
EudraCT number 
2016-000744-34  
Date of protocol amendment 
Amendment 2 Final: 14 April 2020 
Detailed Title 
A phase III, randomized, observer-blind, placebo 
controlled, multicenter clinical trial to assess Herpes 
Zoster recurrence and the reactogenicity, safety, and 
immunogenicity of GSK Biologicals’ Herpes Zoster 
vaccine (HZ/su) when administered intramuscularly 
on a 0 and 2 month schedule to adults ≥50 years of 
age with a prior episode of Herpes Zoster.  
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 


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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4.2. 


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SYNOPSIS 
Detailed Title 
A phase III, randomized, observer-blind, placebo controlled, 
multicenter clinical trial to assess Herpes Zoster recurrence 
and the reactogenicity, safety and immunogenicity of GSK 
Biologicals’ Herpes Zoster vaccine (HZ/su) when 
administered intramuscularly on a 0 and 2 month schedule to 
adults ≥ 50 years of age with a prior episode of Herpes 
Zoster.  
Indication 
Worldwide, indications for Shingrix include the prevention 
of herpes zoster (HZ) and the prevention of HZ-related 
complications, such as postherpetic neuralgia (PHN), in 
adults 50 years of age (YOA) or older.  
Rationale for the 
study and study 
design 
• 
Rationale for the study 
GlaxoSmithKline Biologicals SA (GSK) vaccine for the 
prevention of HZ is a recombinant subunit (su) vaccine 
consisting of Varicella Zoster Virus (VZV) glycoprotein E 
(gE) as antigen and the adjuvant system AS01B. The final 
vaccine formulation (HZ/su) has been evaluated in several 
studies in healthy elderly adults (≥ 50 YOA) and 
immunocompromised (IC) adults (≥18 YOA). In these 
studies, it was shown to be efficacious and elicit strong 
cellular and humoral immune responses. Furthermore, the 
safety and reactogenicity profile of the vaccine was 
acceptable.  
Two large pivotal Phase III trials, ZOSTER-006 [also 
referred to as ZOE-50] enrolled subjects ≥ 50 YOA and 
ZOSTER-022 [also referred to as ZOE-70] enrolled subjects 
≥ 70 YOA, evaluated the vaccine efficacy and safety of 
HZ/su. These trials enrolled more than 30,000 subjects who 
either received HZ/su or placebo on a 0, 2-month schedule. 
Results from ZOSTER-006 and ZOSTER-022 showed a 
vaccine efficacy of 97.2% and 89.8% against HZ in adults 
≥ 50 YOA and ≥ 70 YOA, respectively. In addition, the 
second primary objective of pre-specified pooled analysis of 
ZOSTER-006 and ZOSTER-022 demonstrated that HZ/su 
effectively prevents PHN with an efficacy of 88.8% in 
people ≥ 70 YOA. No safety concerns have been raised. 
An indication in adults ≥ 50 YOA was filed for registration. 
HZ/su (trade name Shingrix) was first approved in Canada 
and the United States in October 2017. 
The majority of completed HZ/su studies in older adults 
excluded people with a history of HZ in order to avoid 


CONFIDENTIAL 
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introducing bias in efficacy, immunogenicity or safety 
evaluations. In an open label, single arm (uncontrolled) study 
(ZOSTER-033) conducted in adults  50 YOA with a history 
of previous HZ, 6 participants (6.3%) reported a total of 9 
suspected HZ cases. This observation was unexpected, 
assuming a recurrence rate of HZ is <1% per year and the 
efficacy of HZ/su shown in the ZOSTER-006 and ZOSTER-
022 studies.  
Study ZOSTER-062 is an observer-blind, randomized, 
placebo-controlled study to assess the rate of HZ-recurrence 
as well as the reactogenicity, safety and immunogenicity of 
HZ/su in a population with a history of HZ. In contrast to the 
ZOSTER-033 study, the study design incorporates a placebo 
arm to better understand the rate of HZ recurrence in this 
population, 
 
 as well as HZ case 
ascertainment using the procedures applied in the ZOSTER-
006 and ZOSTER-022 efficacy studies. 
• 
Rationale for the study design 
Study ZOSTER-062 will evaluate HZ recurrence and the 
reactogenicity, safety and immunogenicity of HZ/su in 
subjects ≥ 50 YOA with a prior episode of HZ. Subjects will 
be randomized (1:1) to the HZ/su or placebo arm and will be 
followed in an observer-blind design. Recruitment will be 
stratified by age, including a minimum of subjects in each 
age category to ensure recruitment of a broad age range of 
adults ≥ 50 YOA. A stratified enrolment, including a 
minimum of subjects in each category, will also be used to 
account for ‘time since previous HZ episode’ (≤ 4 years ago, 
5-9 years ago, ≥ 10 years ago). Additional minimization 
factors include: center, (female) gender, family (first degree 
blood relative) history of HZ, history of PHN and a 
combined minimization factor to reflect the presence of any 
of the following conditions: type 2 diabetes mellitus, asthma, 
chronic obstructive pulmonary disease, chronic kidney 
disease and depression.  
The placebo-control design and rigorous HZ case 
ascertainment aligned with previous HZ/su studies provides 
study design elements not present in the prior ZOSTER-033 
study, that will support the assessment of HZ recurrence in 
the ZOSTER-062 study population. In addition to humoral 
immunity in all subjects, 
 
 
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• 
Rationale for the use of placebo 
A lyophilized sucrose cake reconstituted with saline (NaCl) 
solution is included as a control (placebo) in this study 
evaluating the rate of HZ recurrence, reactogenicity, safety 
and immunogenicity of HZ/su in people with a history of 
HZ. Use of the placebo control and the observer-blind, 
randomized study design, aims to minimize potential bias in 
study results. 
Objectives 
Primary 
To compare the incidence of HZ recurrence in the HZ/su 
group to the placebo group.  
A formal non-inferiority analysis with non-inferiority margin 
of 5 will be performed. 
− 
Criterion: The objective is met if the upper limit 
(UL) of the 95% CI of the ratio of the incidence of 
HZ recurrence (HZ/su versus placebo) is below 5. 
Secondary 
• 
To evaluate the rate of HZ recurrence in HZ/su and 
placebo groups during the entire study period. 
• 
To evaluate safety and reactogenicity following 
administration of HZ/su vaccine or placebo within 30 
days after each dose.  
• 
To evaluate safety following administration of HZ/su 
vaccine or placebo during the entire study period. 
• 
To characterize the anti-gE humoral immunogenicity 
response prior to the first vaccination (Day 1), at two 
months post first vaccination (Month 2) and at one 
month post last vaccination (Month 3) in both groups.  
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• 
• 
 
Study design 
• 
Experimental design: Phase III, observer-blind, 
randomized, placebo controlled, multicenter, multi-
country study with two parallel groups. 
• 
Duration of the study: The duration of the study will 
vary for each subject. The duration of the study will be 
up to the study conclusion contact that occurs within 30 
days of the projected study conclusion date of the last 
enrolled subject, that is, 26 months (790 days) from the 
enrolment date. Therefore, subjects enrolled early in the 
trial could be followed for longer duration than the 
subjects who enrol later in the trial. 
− 
Epoch 001: Starting at Visit 1 (Day 1), followed by 
Visit 2 at two months post first vaccination (Month 
2), and then Visit 3 at one month post last 
vaccination (Month 3). 
− 
Epoch-002: Starting with monthly contact after 
Visit 3 (Month 3) and ending at the monthly contact 
that occurs within 30 days of the projected study 
conclusion date of the last enrolled subject, that is, 
26 months (790 days) from the enrolment date.  
• 
Primary completion Date (PCD): The primary 
completion date will be when the last subject completes 
their study conclusion contact (within 30 days of the 
projected study conclusion date of the last enrolled 
subject, that is, 26 months [790 days] from the 
enrolment date).  
• 
End of Study (EoS): 1) After all the subjects complete 
their study conclusion contact, occurring within 30 days 
of the projected study conclusion date of the last 
enrolled subject, that is, 26 months (790 days) from the 
enrolment date and 2) the release of all polymerase 
chain reaction (PCR) test results for the HZ rash lesion 
samples collected. 
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• 
Study groups: 
Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of 
eligible subjects 
Age (years) 
Epochs 
Epoch 001 
Epoch 002 
HZ/su 
713 
50 years  
● 
● 
Placebo 
713 
50 years  
● 
● 
Synopsis Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Groups 
HZ/su 
Placebo 
HZ/su  
VZV gE 
● 
 
AS01B 
● 
 
Placebo 
Lyophilised sucrose  
 
● 
Saline (NaCl) solution for 
reconstitution 
 
● 
 
• 
Control: placebo control. 
• 
Vaccination schedule: 0 and 2 months. 
 
• 
Treatment allocation: Eligible subjects will be 
randomized (1:1) to the HZ/su or placebo group. The 
randomization algorithm will use a stratification 
procedure accounting for age (50-59 YOA; 60-69 YOA 
and 70 YOA) and also a stratification procedure 
accounting for ‘time since previous HZ episode’ (≤ 4 
years ago, 5-9 years ago, ≥ 10 years ago). Additional 
minimization factors include: (female) gender, center, 
family (first degree blood relative) history of HZ, history 
of PHN and a combined minimization factor to reflect 
the presence of any of the following conditions- type 2 
diabetes mellitus, asthma, chronic obstructive 
pulmonary disease, chronic kidney disease and 
depression 
• 
Blinding:  
Synopsis Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch-002 
observer-blind 


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• 
Sampling schedule: 
− 
Blood samples for humoral immunity (approximately 
5 ml per visit) will be collected from all subjects at 
Visit 1 (Day 1), Visit 2 (Month 2), and Visit 3 (Month 
3). 
− 
− 
Clinical specimens of HZ lesions will be collected 
from all subjects who are clinically diagnosed with a 
suspected case of HZ. 
− 
A urine specimen will be collected from all female 
subjects of child-bearing potential at Visit 1 (Day 1) 
and Visit 2 (Month 2). Please refer to glossary of 
terms for definition of woman of child bearing 
potential. If a serum pregnancy test instead of a urine 
pregnancy test is required by country, local or ethics 
committee regulations, a blood sample will be 
collected from women of child-bearing potential at 
Visit 1 (Day 1) and Visit 2 (Month 2) and used for the 
test as per local guidance. 
Note: The result of the pregnancy test must be obtained 
before any study vaccination and must be negative. 
• 
Type of study: self-contained 
• 
Data collection: eCRF (electronic Case Report Form)  
• 
Safety monitoring: An internal GSK Safety Review Team 
(SRT) will oversee the safety of the ZOSTER-062 study. 
Serious adverse events (SAEs), adverse events (AEs) 
including potential immune mediated diseases (pIMDs) 
and accrual of HZ cases will be reviewed in a blinded 
manner by the SRT at regular intervals. Any potential 
safety concern related to conduct of the study will be 
escalated to higher governing bodies as per internal GSK 
process. 
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Case definition 
• 
Suspected HZ 
A suspected case of HZ is defined as a new unilateral rash 
accompanied by pain (broadly defined to include allodynia, 
pruritus or other sensations) and no alternative diagnosis. 
Subjects clinically diagnosed as having a suspected case of HZ 
by the investigator will be referred to as a case of ‘suspected 
HZ’ and followed up. If a case is not clinically diagnosed as 
suspected HZ, the investigator should not progress further with 
evaluation of the case. 
The HZ onset date is the earlier of the following two events: 1) 
the HZ rash start date; or 2) the date on which pain at the site of 
a subsequent HZ rash is first noted. 
• 
Confirmed HZ 
A suspected case of HZ can be confirmed in two ways by GSK: 
− 
By PCR; 
− 
By the HZ Ascertainment Committee (HZAC). 
Number of subjects 
Target enrolment is 1426 eligible subjects (713 per treatment 
group) with a previous HZ episode to reach approximately 606 
evaluable subjects per group. 
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Endpoints 
Primary 
Occurrence of confirmed HZ episodes from 30 days post 
second vaccination until study end. 
 
Secondary 
• 
Occurrence of confirmed HZ episodes from first study 
vaccination until study end. 
• 
Reactogenicity and safety, in all subjects 
− 
Occurrence, intensity and duration of each solicited 
local AE within 7 days (Day 1-7) after each 
vaccination. 
− 
Occurrence, intensity, duration and relationship to 
vaccination of each solicited general AE within 7 days 
(Days 1-7) after each vaccination.  
− 
Occurrence, intensity, duration and relationship to 
vaccination of unsolicited AEs within 30 days (Days 
1-30) after each vaccination, according to the Medical 
Dictionary for Regulatory Activities (MedDRA) 
classification.  
− 
Occurrence and relationship to vaccination of all SAEs 
from dose 1 up to 30 days post last vaccination.  
− 
Occurrence and relationship to vaccination of any 
pIMDs from dose 1 up to 30 days post last 
vaccination.  
− 
Occurrence and relationship to vaccination of all SAEs 
within the period starting after 30 days post last 
vaccination until 1 year post last vaccination. 
− 
Occurrence and relationship to vaccination of any 
pIMDs within the period starting after 30 days post 
last vaccination until 1 year post last vaccination. 
− 
Occurrence of SAEs related to investigational vaccine, 
related to study participation or to GSK concomitant 
medication/vaccine during the entire study period. 


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• 
Immunogenicity, in all subjects 
− 
Vaccine response for anti-gE humoral immunogenicity 
as determined by ELISA at Month 2 and Month 3.  
− 
Anti-gE antibody concentrations as determined by 
ELISA at Day 1, Month 2 and Month 3.  
 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION .............................................................................................. 7 
SYNOPSIS ........................................................................................................................ 8 
LIST OF ABBREVIATIONS ............................................................................................. 27 
GLOSSARY OF TERMS ................................................................................................. 31 
TRADEMARKS ............................................................................................................... 36 
1. 
INTRODUCTION ..................................................................................................... 37 
1.1. 
Background .................................................................................................. 37 
1.2. 
Rationale for the study and study design ..................................................... 38 
1.2.1. 
Rationale for the study .................................................................. 38 
1.2.2. 
Rationale for the study design ...................................................... 39 
1.2.3. 
Rationale for the use of placebo ................................................... 39 
1.3. 
Benefit : Risk Assessment ............................................................................ 39 
1.3.1. 
Risk Assessment .......................................................................... 40 
1.3.2. 
Benefit Assessment ...................................................................... 42 
1.3.3. 
Overall Benefit: Risk Conclusion ................................................... 42 
2. 
OBJECTIVES ........................................................................................................... 42 
2.1. 
Primary objective .......................................................................................... 42 
2.2. 
Secondary objectives ................................................................................... 42 
2.3. 
...................................................................................... 43 
3. 
STUDY DESIGN OVERVIEW .................................................................................. 43 
4. 
CASE DEFINITION .................................................................................................. 46 
4.1. 
Suspected HZ............................................................................................... 46 
4.2. 
Confirmed HZ ............................................................................................... 46 
4.3. 
...................................................................... 47 
4.4. 
...................................................................... 47 
4.5. 
Evaluation and confirmation of suspected HZ cases ................................... 48 
4.5.1. 
Definitions ..................................................................................... 48 
4.5.2. 
Evaluation of suspected cases of HZ ............................................ 49 
4.5.2.1. 
Evaluation of severity of HZ-associated pain 
using the Zoster Brief Pain Inventory .......................... 51 
4.5.2.2. 
Confirmation of a suspected case of HZ ..................... 51 
4.5.2.2.1. 
Confirmation of suspected HZ by 
PCR......................................................... 51 
4.5.2.2.2. 
Confirmation of suspected HZ by 
the HZAC ................................................ 52 
4.5.3. 
Follow up of suspected HZ cases and HZ-associated pain .......... 52 
5. 
STUDY COHORT .................................................................................................... 53 
5.1. 
Number of subjects/centers .......................................................................... 53 
5.2. 
Inclusion criteria for enrolment ..................................................................... 54 
5.3. 
Exclusion criteria for enrolment .................................................................... 55 
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6. 
CONDUCT OF THE STUDY .................................................................................... 57 
6.1. 
Regulatory and ethical considerations, including the informed 
consent process ........................................................................................... 57 
6.2. 
Subject identification and randomization ...................................................... 58 
6.2.1. 
Subject identification ..................................................................... 58 
6.2.2. 
Randomization of treatment .......................................................... 58 
6.2.2.1. 
Randomization of supplies .......................................... 58 
6.2.2.2. 
Treatment allocation to the subject ............................. 58 
6.2.2.2.1. 
Study group and treatment 
number allocation .................................... 58 
6.2.2.2.2. 
Treatment number allocation for 
es ................................... 59 
...................................... 59 
6.3. 
Method of blinding ........................................................................................ 59 
6.4. 
General study aspects.................................................................................. 60 
6.4.1. 
Diary cards and questionnaires .................................................... 60 
6.4.2. 
Monthly contacts ........................................................................... 60 
6.5. 
Outline of study procedures ......................................................................... 61 
6.6. 
Detailed description of study procedures ..................................................... 65 
6.6.1. 
Informed consent .......................................................................... 65 
6.6.2. 
Check inclusion and exclusion criteria .......................................... 65 
6.6.3. 
Collect demographic data ............................................................. 65 
6.6.4. 
Medical history .............................................................................. 65 
6.6.5. 
History directed physical examination ........................................... 66 
6.6.6. 
Pregnancy test .............................................................................. 66 
6.6.7. 
Check contraindications, warnings and precautions to 
vaccination .................................................................................... 66 
6.6.8. 
Assess pre-vaccination body temperature .................................... 66 
6.6.9. 
Study group and treatment number allocation .............................. 67 
6.6.10. 
Sampling ....................................................................................... 67 
6.6.10.1. Blood sampling for immune response 
assessments ............................................................... 67 
6.6.10.2. Clinical specimens of HZ lesions for PCR 
analysis ....................................................................... 67 
6.6.11. 
Study vaccine administration ........................................................ 67 
6.6.12. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ..................................................... 68 
6.6.13. 
Training on self-reporting by subjects ........................................... 68 
6.6.14. 
Recording of AEs, SAEs, pregnancies and pIMDs ....................... 68 
6.6.15. 
Monthly contact ............................................................................. 69 
6.6.16. 
Study conclusion ........................................................................... 69 
6.7. 
Study procedures during special circumstances (Amended 14 April 
2020) ............................................................................................................ 69 
6.8. 
Biological sample handling and analysis ...................................................... 71 
6.8.1. 
Use of specified study materials ................................................... 72 
6.8.2. 
Biological samples ........................................................................ 72 
6.8.3. 
Laboratory assays ......................................................................... 72 
6.8.4. 
Biological samples evaluation ....................................................... 74 
6.8.4.1. 
Immunological read-outs ............................................. 74 
6.8.5. 
Immunological correlates of protection ......................................... 74 
7. 
STUDY VACCINES AND ADMINISTRATION ......................................................... 75 
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7.1. 
Description of study vaccine ......................................................................... 75 
7.2. 
Storage and handling of study vaccines....................................................... 75 
7.3. 
Dosage and administration of study vaccine/placebo .................................. 76 
7.4. 
Replacement of unusable vaccine doses ..................................................... 76 
7.5. 
Contraindications to subsequent vaccination ............................................... 77 
7.6. 
Warnings and precautions............................................................................ 77 
7.7. 
Concomitant medications/products and concomitant vaccinations .............. 77 
7.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations .............................................................. 78 
7.7.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analysis ............. 78 
7.8. 
Intercurrent medical conditions (IMC) that may lead to elimination of 
a subject from per-protocol analyses ........................................................... 79 
8. 
HEALTH ECONOMICS ............................................................................................ 79 
9. 
SAFETY ................................................................................................................... 80 
9.1. 
Safety definitions .......................................................................................... 80 
9.1.1. 
Definition of an adverse event ...................................................... 80 
9.1.2. 
Definition of a serious adverse event ............................................ 81 
9.1.3. 
Solicited adverse events ............................................................... 82 
9.1.3.1. 
Solicited local (injection-site) adverse events .............. 82 
9.1.3.2. 
Solicited general adverse events ................................ 82 
9.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events .............................................................................. 83 
9.1.5. 
Adverse events of specific interest ............................................... 83 
9.1.5.1. 
Potential immune-mediated diseases ......................... 83 
9.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ............................................................................................. 86 
9.2.1. 
Pregnancy ..................................................................................... 86 
9.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ........................................................................................... 87 
9.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 87 
9.3.2. 
Post-Study adverse events and serious adverse events .............. 89 
9.3.3. 
Evaluation of adverse events and serious adverse events ........... 89 
9.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 89 
9.3.3.2. 
Assessment of adverse events ................................... 90 
9.3.3.2.1. 
Assessment of intensity .......................... 90 
9.3.3.2.2. 
Assessment of causality .......................... 92 
9.3.3.3. 
Assessment of outcomes ............................................ 93 
9.3.3.4. 
Medically attended visits ............................................. 93 
9.4. 
Reporting of serious adverse events, pregnancies, and other events ......... 93 
9.4.1. 
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals ............................................ 93 
9.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs ................................................................ 94 
9.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ..................................................................................... 94 


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9.4.3.1. 
Back-up system in case the electronic 
reporting system does not work .................................. 95 
9.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ..................................................................................... 95 
9.4.5. 
Reporting of pIMDs to GSK Biologicals ........................................ 95 
9.4.6. 
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF ............................. 96 
9.4.7. 
Regulatory reporting requirements for serious adverse 
events ........................................................................................... 96 
9.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies .................................................................................................. 96 
9.5.1. 
Follow-up of adverse events and serious adverse events ............ 96 
9.5.1.1. 
Follow-up during the study .......................................... 96 
9.5.1.2. 
Follow-up after the subject is discharged from 
the study ...................................................................... 97 
9.5.2. 
Follow-up of pregnancies .............................................................. 97 
9.6. 
Treatment of adverse events........................................................................ 97 
9.7. 
Emergency unblinding .................................................................................. 97 
9.8. 
Subject card ................................................................................................. 98 
10. SUBJECT COMPLETION AND WITHDRAWAL ...................................................... 98 
10.1. 
Subject completion ....................................................................................... 98 
10.2. 
Subject withdrawal ....................................................................................... 99 
10.2.1. 
Subject withdrawal from the study ................................................ 99 
10.2.2. 
Subject withdrawal from study vaccine ....................................... 100 
11. STATISTICAL METHODS ..................................................................................... 101 
11.1. 
Primary endpoint ........................................................................................ 101 
11.2. 
Secondary endpoints.................................................................................. 101 
11.3. 
....................................................................................... 101 
11.4. 
Determination of sample size ..................................................................... 103 
11.4.1. 
............. 103 
11.4.2. 
............. 103 
11.5. 
Cohorts for Analyses .................................................................................. 104 
11.5.1. 
Exposed Set ................................................................................ 104 
11.5.1.1. Modified Exposed Set ............................................... 104 
11.5.2. 
Per Protocol Set for immunogenicity ........................................... 104 
11.6. 
Derived and transformed data .................................................................... 104 
11.6.1. 
Handling of missing data ............................................................. 104 
11.7. 
Analysis of demographics .......................................................................... 105 
11.8. 
Analysis of incidence rate of Herpes Zoster recurrence ............................. 105 
11.9. 
Analysis of immunogenicity ........................................................................ 106 
11.9.1. 
Humoral immune response ......................................................... 106 
11.9.1.1. 
 ............................... 107 
11.10. Analysis of safety ....................................................................................... 108 
11.11. Interpretation of analyses ........................................................................... 109 
11.11.1. Conduct of analyses ................................................................... 109 
11.11.2. Sequence of analyses ................................................................. 109 
11.11.3. Statistical considerations for interim analyses ............................ 110 
12. ADMINISTRATIVE MATTERS ............................................................................... 110 
12.1. 
electronic Case Report Form instructions .................................................. 110 
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12.2. 
Study Monitoring by GSK Biologicals ......................................................... 110 
12.3. 
Record retention ......................................................................................... 111 
12.4. 
Quality assurance ...................................................................................... 111 
12.5. 
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 112 
12.6. 
Provision of study results to investigators .................................................. 112 
12.7. 
Data Sharing .............................................................................................. 112 
13. COUNTRY SPECIFIC REQUIREMENTS .............................................................. 112 
14. REFERENCES ...................................................................................................... 113 
15. APPENDICES ........................................................................................................ 115 
 


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LIST OF TABLES 
PAGE 
Table 1 
Study groups and epochs foreseen in the study ..................................... 44 
Table 2 
Study groups and treatment foreseen in the study .................................. 44 
Table 3 
Blinding of study epochs .......................................................................... 45 
Table 4 
Expected enrolment based on overall age stratification .......................... 53 
Table 5 
Expected enrolment based on time from previous HZ case .................... 53 
Table 6 
 
 ................................................................ 54 
Table 7 
List of study procedures .......................................................................... 61 
Table 8 
Study procedures to be performed during the follow-up period for 
each suspected HZ case ......................................................................... 63 
Table 9 
Intervals between study visits .................................................................. 64 
Table 10 
Intervals between visits/contacts for subjects in case of 
suspected HZ .......................................................................................... 64 
Table 11 
Intervals between study visits during special circumstances 
(Amended 14 April 2020) ......................................................................... 70 
Table 12 
Biological samples ................................................................................... 72 
Table 13 
Humoral Immunity (Antibody determination) ........................................... 73 
Table 14 
 73 
Table 15 
Molecular Biology (PCR tests) ................................................................. 73 
Table 16 
Immunological read-outs ......................................................................... 74 
Table 17 
Study vaccine and Placebo ..................................................................... 75 
Table 18 
Dosage and administration ...................................................................... 76 
Table 19 
Solicited local adverse events ................................................................. 82 
Table 20 
Solicited general adverse events ............................................................. 82 
Table 21 
List of potential immune-mediated diseases ........................................... 84 
Table 22 
Reporting periods for collecting safety information .................................. 88 
Table 23 
Intensity scales for solicited AEs in adults ............................................... 90 
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Table 24 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................. 94 
Table 25 
GSK Biologicals’ laboratories ................................................................ 119 
Table 26 
Outsourced laboratories ........................................................................ 119 
 


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LIST OF FIGURES 
PAGE 
Figure 1 
Overview of Study Design ....................................................................... 43 
Figure 2 
Algorithm for HZ case definition by PCR ............................................... 118 
 


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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ....................................................................... 115 
APPENDIX B CLINICAL LABORATORIES ................................................................. 119 
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL .......................................................................................... 120 
 


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LIST OF ABBREVIATIONS 
Ab: 
Antibody 
AE: 
Adverse event 
AS01B: 
MPL, QS21, liposome based Adjuvant System (50 μg 
MPL and 50 μg QS21) 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
CMI: 
Cell-Mediated Immunity 
COVID-19 
Coronavirus Disease 2019 (Amended 14 April 2020) 
CRO: 
Contract Research Organization 
eCRF: 
electronic Case Report Form  
(e)TDF: 
Electronic Temperature excursion Decision Form 
DNA: 
Deoxyribonucleic acid 
ELISA: 
Enzyme Linked Immunosorbent Assay 
EoS: 
End of Study 
ES: 
Exposed Set 
gE: 
VZV glycoprotein E 
GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration  
GSK: 
GlaxoSmithKline 
HIV: 
Human Immunodeficiency Virus 
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HZ: 
Herpes Zoster 
HZAC: 
Herpes Zoster Ascertainment Committee  
HZ/su: 
Herpes Zoster subunit vaccine 
IB: 
Investigator Brochure 
IC: 
Immunocompromised 
ICF: 
Informed Consent Form 
IgG: 
Immunoglobulin class G 
IM: 
Intramuscular/Intramuscularly 
IMC: 
Intercurrent Medical Condition 
IND: 
Investigational New Drug 
LAR 
Legally Acceptable Representative 
LL: 
Lower Limit 
LMP: 
Last Menstrual Period 
LOD 
Limit of Detection 
M: 
Month 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mES 
modified Exposed Set 
mIU: 
Milli-International Unit 
ml: 
Millilitre 
MPL: 
3-O-desacyl-4’-Monophosphoryl Lipid A 
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NA: 
Not Applicable 
NaCl: 
Sodium Chloride (saline) 
PBMC: 
Peripheral Blood Mononuclear Cells 
PCD: 
Primary Completion Date 
PCR: 
Polymerase Chain Reaction 
PHN: 
Postherpetic Neuralgia 
PI: 
Prescribing Information 
PPS: 
Per Protocol Set 
pIMD: 
Potential Immune-Mediated Disease 
Pre-Vacc: 
Pre-Vaccination 
Post-Vacc: 
Post-Vaccination 
QS21: 
Quillaja saponaria Molina, fraction 21 (Licensed by 
GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation) 
SAP: 
Statistical Analysis Plan 
SAS: 
Statistical Analysis System 
SAE: 
Serious Adverse Event 
SBIR: 
Source data Base for Internet Randomization 
SD: 
Standard Deviation 
SDV: 
Source Data Verification 
SmPC: 
Summary of Product Characteristics 
SMS: 
Short Message Service 
SPM: 
Study Procedures Manual 
SRT: 
Safety Review Team 
su: 
Subunit 
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VRR: 
Vaccine Response Rate 
VZV: 
Varicella-Zoster Virus 
YOA: 
Years of Age 
ZBPI: 
Zoster Brief Pain Inventory 


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GLOSSARY OF TERMS 
Adequate contraception: 
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:  
• 
abstinence from penile-vaginal intercourse, when 
this is their preferred and usual lifestyle, 
• 
Oral Contraceptive, either combined or progestogen 
alone. 
• 
injectable progestogen, 
• 
implants of etenogestrel or levonorgestrel, 
• 
Contraceptive vaginal ring, 
• 
percutaneous contraceptive patches, 
• 
intrauterine device or intrauterine system, 
• 
male partner sterilization prior to the female 
subject’s entry into the study, and this male is the 
sole partner for that subject, 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her 
medical history. 
• 
male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive. 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered 
related to the medicinal product. 
An adverse event (AE) can therefore be any 
unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new 
or exacerbated) temporally associated with the use of a 
medicinal product. For marketed medicinal products, 
this also includes failure to produce expected benefits 
(that is, lack of efficacy), abuse or misuse. 


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Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
trial, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. In an observer-blind study, the subject and the site 
and sponsor personnel involved in the clinical evaluation 
of the subjects are blinded while other study personnel 
may be aware of the treatment assignment.  
Caregiver: 
Someone who lives in the close surroundings of a 
subject having a continuous caring role or may be 
someone having substantial periods of contact with a 
subject and is engaged in his/her daily health care (e.g. a 
relative of the subject, a nurse who helps with daily 
activities in case of residence in a nursing home). In a 
context of a clinical study, a caregiver could include an 
individual appointed to oversee and support the subject's 
compliance with protocol specified procedures. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study (EoS):  
(Synonym of End of Trial) 
For studies without collection of human biological 
samples or imaging data, EoS is the Last Subject Last 
Visit (LSLV).  
For studies with collection of Human Biological 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV. 
Epoch: 
Interval of time in the planned conduct of a study. An 
epoch is associated with a purpose (e.g. screening, 
randomization, treatment, follow-up), which applies 
across all arms of a study. NOTE: Epoch is intended as a 
standardized term to replace: period, cycle, phase, stage. 
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. 


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Immunological correlate 
of protection: 
The defined immune response above which there is a 
high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the 
infectious agent. 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use.  
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 a qualified 
individual or party to perform those trial-related duties 
and functions. 
Legally acceptable 
representative (LAR): 
(The terms legal 
representative or legally 
authorized representative 
are used in some settings.) 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial. 
Menopause: 
Menopause is the age associated with complete 
cessation of menstrual cycles, menses, and implies the 
loss of reproductive potential by ovarian failure. A 
practical definition accepts menopause after 1 year 
without menses with an appropriate clinical profile at the 
appropriate age e.g. > 45 years. 
Potential Immune-
Mediated Disease: 
Potential immune-mediated diseases (pIMDs) are a 
subset of AEs that include autoimmune diseases and 
other inflammatory and/or neurologic disorders of 
interest which may or may not have an autoimmune 
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Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated. 
Randomization: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period. 
Study vaccine: 
Any investigational vaccine being tested and/or any 
authorized use of a vaccine/ product /placebo as a 
reference or administered concomitantly, in a clinical 
trial that evaluates the use of an investigational 
vaccine/product. 
Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,) at the time of enrolment. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient 
of the vaccine or as a control. 
Treatment number: 
A number identifying a treatment to a subject, according 
to the treatment allocation. 
Treatment: 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
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 
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Woman of child bearing 
potential (WOCBP): 
A woman is considered fertile following menarche and 
until becoming post-menopausal unless permanently 
sterile (see below) 
Women in the following categories are not considered 
WOCBP: 
• 
Premenarchal: Menarche is the onset of menses for 
the first time in a young female and is preceded by 
several changes associated with puberty including 
breast development and pubic hair growth. 
Menarche usually occurs within 1-2 years of breast 
development, thelarche. However, a young female 
can become pregnant before her first menses. Thus, 
a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young 
female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue). 
• 
Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
− 
Documented tubal ligation 
Note: Documentation can come from the site 
personnel’s: review of subject’s medical records, 
medical examination, or medical history interview. 
• 
Postmenopausal female: A postmenopausal state is 
defined as no menses for 12 months without an 
alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is 
insufficient.  
Females on HRT and whose menopausal status is in 
doubt will be required to use 1 of the non-hormonal 
highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 


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TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the protocol (including the synopsis), the names of the 
vaccines/products and/or medications will be written without the superscript symbol ™ 
or ® and in italics. 
Trademarks of the GSK group of companies 
 
Generic description 
Shingrix 
 
Herpes Zoster vaccine non-live 
recombinant, AS01B adjuvanted 
 
Trademarks not owned by the GSK group of 
companies 
 
Generic description 
Zostavax (Merck & Co., Inc.) 
 
Herpes Zoster vaccine consisting of high-
titer live attenuated Varicella-Zoster Virus 
(Oka strain) 


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1. 
INTRODUCTION 
1.1. 
Background 
Varicella-Zoster Virus (VZV) causes two distinct diseases. Varicella (chickenpox) occurs 
shortly after primary VZV infection and is characterised by systemic illness and a widely 
disseminated rash. Herpes Zoster (HZ), commonly called shingles, occurs when VZV 
reactivates from latency and typically manifests as a localized, dermatomal rash. 
The typical HZ rash usually lasts 2 to 4 weeks and is typically accompanied by pain that 
is often described as burning, shooting, or stabbing. In some patients, even touching the 
affected area lightly may cause pain, a phenomenon known as allodynia. This HZ-
associated pain may be severe, and pruritus, which can also be severe, may be as 
common as pain. 
The most common complication of HZ is postherpetic neuralgia (PHN). PHN is defined 
as pain that persists after the resolution of the HZ rash. Affected patients typically report 
constant burning, throbbing, intermittent sharp or electric shock-like pain, or allodynia 
[Dworkin, 2007]. Other complications of HZ include ophthalmologic, neurological, 
cutaneous and visceral disease, which can result in severe disability. The most common 
ocular complications of HZ are keratitis and uveitis; other ophthalmologic complications 
include ptosis, episcleritis/scleritis, retinitis, secondary glaucoma and cataract [Schmader, 
2008; Carter, 2008]. Neurologic complications associated with HZ include myelitis, 
motor neuropathy, ischaemic infarction of the brain and spinal cord, aneurysm, and 
subarachnoid and cerebral haemorrhage [Gilden, 2009; Schmader, 2008]. 
Age is the most common risk factor for developing HZ. The incidence of HZ is relatively 
constant at 2-3 cases per 1000 persons per year until age 40, and then increases 
progressively with age: at 50-59 years of age (YOA) the incidence is about 5 cases per 
1000 persons per year, and it increases to 10 cases per 1000 persons per year in people 
≥ 60 YOA [CDC, 2008; Oxman, 2005]. 
Half of all HZ cases occur in patients over the age of 60, and individuals who reach 85 
years of age have a 50% chance of having HZ during their lifetime [Oxman, 2005]. 
Patients with impaired cell-mediated immunity (CMI) due to disease, drug treatment, 
medical interventions or advanced age are at an increased risk of developing HZ [Cohen, 
2007]. Since the loss of VZV-specific T cell responses as a result of aging or 
immunosuppression leads to heightened susceptibility to HZ, vaccination is considered as 
a means to reduce the risk of HZ in older adults and immunocompromised (IC) persons 
[Oxman, 2005; Sperber, 1992]. 
GlaxoSmithKline Biologicals SA (GSK) vaccine for the prevention of HZ is a 
recombinant subunit (su) vaccine consisting of VZV glycoprotein E (gE) as antigen and 
the adjuvant system AS01B. The vaccine referred to as HZ/su, was shown to be 
efficacious and elicit strong cellular and humoral immune responses in several studies in 
healthy elderly adults (≥ 50 YOA) and IC adults (≥ 18 YOA), HZ/su. Furthermore, the 
safety and reactogenicity profile of the vaccine was acceptable.  


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Two large pivotal Phase III trials, ZOSTER-006 [also referred to as ZOE-50] enrolled 
subjects ≥ 50 YOA [Lal, 2015] and ZOSTER-022 [also referred to as ZOE-70] enrolled 
subjects ≥ 70 YOA [Cunningham, 2016], evaluated the vaccine efficacy and safety of 
HZ/su. These trials enrolled more than 30,000 subjects who either received HZ/su or 
placebo on a 0, 2-month schedule. Results from ZOSTER-006 and ZOSTER-022 showed 
a vaccine efficacy of 97.2% and 89.8% against HZ in adults ≥ 50 YOA and ≥ 70 YOA, 
respectively. In addition, the second primary objective of pre-specified pooled analysis of 
ZOSTER-006 and ZOSTER-022 demonstrated that HZ/su effectively prevents PHN with 
an efficacy of 88.8% in people ≥ 70 YOA. No safety concerns have been raised. 
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name Shingrix) 
was first approved in Canada and the United States in October 2017. 
Please refer to the current Investigator Brochure (IB) for information regarding the pre-
clinical and clinical studies of HZ/su.  
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
The majority of previously completed HZ/su studies in older adults excluded people with 
a history of HZ to avoid introducing bias in efficacy, immunogenicity or safety 
evaluations. However, in an open label, single arm (uncontrolled) study (ZOSTER-033) 
conducted in adults  50 YOA with a history of previous HZ, 6 participants (6.3%) 
reported a total of 9 suspected HZ cases [Godeaux, 2017]. Given the recurrence rate of 
HZ reported in this population is <1% per year [Tseng, 2012; Yawn, 2011] and the 
known efficacy of HZ/su in the ZOSTER-006 and ZOSTER-022 studies, this observation 
was unexpected. 
Study ZOSTER-062 is an observer-blind, randomized, placebo-controlled study to assess 
the rate of HZ-recurrence as well as the reactogenicity, safety and immunogenicity of 
HZ/su in a population with a history of HZ. In contrast to the ZOSTER-033 study, the 
study design will incorporate inclusion of a placebo arm to better understand the rate of 
recurrence,
 of subjects as well as more 
rigorous HZ case ascertainment (in line with the diagnostic approach used in the 
ZOSTER-006 and ZOSTER-022 efficacy studies). 
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1.2.2. 
Rationale for the study design 
Study ZOSTER-062 will be conducted to evaluate HZ recurrence and the safety, 
reactogenicity and immunogenicity of HZ/su in subjects ≥ 50 YOA with a prior episode 
of HZ. Subjects will be randomized 1:1 to the HZ/su or placebo arm and will be followed 
in an observer-blind design. Recruitment will be stratified by age, including a minimum 
of subjects in each age category to ensure recruitment of a broad age range of adults ≥ 50 
YOA. A stratified enrolment, including a minimum of subjects in each category will be 
used to account for ‘time since previous HZ episode’ (≤ 4 years ago, 5-9 years ago, ≥ 10 
years ago). Additional minimization factors include: (female) gender, center, family (first 
degree blood relative) history of HZ, history of PHN and a combined minimization factor 
to reflect the presence of any of the following conditions: type 2 diabetes mellitus, 
asthma, chronic obstructive pulmonary disease, chronic kidney disease and depression.  
The placebo-control design and rigorous HZ case ascertainment aligned with previous 
HZ/su studies provides study design elements not present in the earlier ZOSTER-033 
study that will support the assessment of HZ recurrence in the ZOSTER-062 study 
population. In addition to humoral immunity in all subjects, 
 
 
. 
1.2.3. 
Rationale for the use of placebo 
A lyophilized sucrose cake reconstituted with saline (NaCl) solution is included as a 
control (placebo) in this study evaluating the rate of HZ recurrence, reactogenicity, safety 
and immunogenicity of HZ/su in people with a history of HZ. Use of the placebo control 
and the observer-blind, randomized study design aims to minimize the potential biases in 
study results. 
1.3. 
Benefit : Risk Assessment 
Please refer to the current IB and/or the Prescribing Information (PI) for information 
regarding the summary potential risks and benefits of HZ/su vaccine. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
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1.3.1. 
Risk Assessment 
Important Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Study vaccine: HZ/su 
Risk of potential immune 
mediated diseases (pIMDs) 
following the HZ/su vaccination 
Based on the theoretical 
concern that vaccination with 
an adjuvanted vaccine 
containing potent 
immunostimulants may 
interfere with immunological 
self-tolerance, pIMDs are 
adverse events of special 
interest undergoing special 
safety monitoring for all GSK 
vaccines containing Adjuvant 
Systems. pIMDs are a subset 
of adverse events that include 
autoimmune diseases and 
other inflammatory and/or 
neurological disorders of 
interest which may or may not 
have an autoimmune aetiology. 
Close monitoring of pIMDs as per 
study protocol and analysis of 
safety data generated through 
clinical trials and other sources. 
The potential risk of events of 
possible autoimmune aetiology to 
occur is mentioned in the Informed 
Consent Form (ICF). In addition, 
the ICF advises subjects to contact 
the study doctor or the study staff 
immediately, should they get any 
symptoms that they feel may be 
serious. 
Hypersensitivity reactions 
(including anaphylaxis) 
Hypersensitivity reactions, may 
occur following exposure to 
allergens from a variety of 
sources including food, 
aeroallergens, venom, drugs, 
and immunisations. Vaccines 
are a mixture of compounds 
and allergic sensitisation can 
occur to any component. While 
cutaneous reactions, such as 
rash or urticaria, are common, 
anaphylactic reactions are very 
rare. 
Administration of the study 
vaccination is to be preceded by a 
review of the subjects’ medical 
history (especially with regard to 
previous vaccination and possible 
occurrence of undesirable events) 
and a clinical examination. 
As with all injectable vaccines, 
appropriate medical treatment and 
supervision should always be 
readily available in case of an 
anaphylactic event following the 
administration of the vaccine. 
Virus reactivation in 
immunocompetent individuals 
with a history of Herpes Zoster 
Following the ZOSTER-033 
results, EU Authorities 
requested to add this as a 
potential risk. ZOSTER-033 
was a phase III, open-label, 
uncontrolled study which 
evaluated the safety and 
immunogenicity of Shingrix 
when administered 
intramuscularly on a 0, 2-month 
schedule to 96 subjects with a 
prior physician-documented 
history of HZ. The occurrence 
of HZ was not an endpoint of 
This potential risk will be assessed 
in this randomized, placebo-
controlled study. 


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Important Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
the study. Six subjects (6.3%), 
two of whom had reported 
more than one prior episode of 
HZ (1 participant with 2 
episodes and 1 participant with 
3 episodes), reported nine 
episodes of unconfirmed HZ 
during the study period of M0 – 
M14. 
Risk of serious ocular 
complications that may be due 
to vasculitis (such as temporal 
arteritis) or inflammation, e.g. 
optic ischemic neuropathy and 
inflammatory (non-infective) 
ocular disease. 
Clinical data from pooled 
analysis of safety reported 3 
events of optic ischemic 
neuropathy (OIN) temporally 
associated with vaccination in 
Shingrix and none in the 
Placebo group. Based on this 
observation, US authorities 
requested to add this as 
potential risk.  
Close monitoring and analysis of 
safety data generated through 
clinical trials and other sources, 
with focus in identifying serious 
ocular complications that may be 
due to vasculitis (such as temporal 
arteritis) or inflammation, e.g. optic 
ischemic neuropathy and 
inflammatory (non-infective) ocular 
disease.  
Study Procedures 
Risk from blood sampling. 
Blood sampling associated risk 
of discomfort, syncope, 
dizziness, infection at the site 
after or during venipuncture. 
Blood samples will be obtained by 
a trained professional and medical 
assistance will be available. 
The potential risk of feeling faint, or 
experiencing mild local pain, 
bruising, irritation or redness at the 
site where blood was taken, is 
mentioned in the ICF. The amount 
of blood to be taken for sampling 
will not be harmful to the subject’s 
health. 
Risk from lesion sampling. 
Swab/needle sampling of 
lesions/crusts associated risk of 
secondary infection, and 
discomfort related to the 
procedure. 
Lesion samples will be obtained by 
a trained professional and anti-
bacterial ointment may be applied 
to minimize the potential for 
secondary infection. 
The potential risk of some 
temporary discomfort during the 
sampling procedure and the 
precautionary use of an anti-
bacterial ointment to reduce the 
risk of infection are mentioned in 
the ICF. 


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1.3.2. 
Benefit Assessment 
Benefits include: 
•
The subjects receiving the HZ/su during the study may have reduced risk of HZ
recurrence.
•
Medical evaluation/assessments associated with study procedures (e.g. physical
examination, HZ case ascertainment).
1.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks in association with HZ/su and study procedures are 
offset by the potential benefits (prevention of HZ and related complications) that may be 
afforded to subjects receiving HZ/su. 
2.
OBJECTIVES
2.1. 
Primary objective
•
To compare the incidence of HZ recurrence in the HZ/su group to the placebo group.
A formal non-inferiority analysis with non-inferiority margin of 5 will be performed.
−
Criterion: The objective is met if the upper limit (UL) of the 95% CI of the ratio
of the incidence of HZ recurrence (HZ/su versus placebo) is below 5.
Refer to Section 11.1 for the definition of the primary endpoint. 
2.2. 
Secondary objectives 
•
To evaluate the rate of HZ recurrence in HZ/su and placebo groups during the entire
study period.
•
To evaluate safety and reactogenicity following administration of HZ/su vaccine or
placebo within 30 days after each dose.
•
To evaluate safety following administration of HZ/su vaccine or placebo during the
entire study period.
•
To characterize anti-gE humoral immunogenicity response prior to the first
vaccination (Day 1), at two months post first vaccination (Month 2) and at one
month post last vaccination (Month 3) in both groups.
Refer to Section 11.2 for the definition of the secondary endpoints. 


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3. 
STUDY DESIGN OVERVIEW  
Figure 1 
Overview of Study Design 
 
BS= Blood sampling; HZ= Herpes Zoster; N= number of subjects planned to be enrolled; Vacc= Vaccination 
*A blood sample (approx. 5ml per visit) will be collected from all subjects at Visits 1, 2 and 3. 
 
 
 
‡ The duration of the study will vary for each subject. Study conclusion will be scheduled based on the projected date 
of the last contact of the last enrolled subject, that is 26 months (790 days) from the enrolment date. The study 
conclusion visit/ contact for subjects with an ongoing episode of HZ will occur after a 4-week pain-free period is 
documented OR after Day HZ-92 follow-up has been completed.  
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 6.5), are essential 
and required for study conduct. Refer to Section 6.7 for study procedures to be 
considered during special circumstances (Amended 14 April 2020). 
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• 
Experimental design: Phase III, observer-blind, randomized, placebo controlled, 
multicenter, multi-country study with two parallel groups. 
• 
Duration of the study: The duration of the study will vary for each subject. The 
duration of the study will be up to the study conclusion contact that occurs within 30 
days of the projected study conclusion date of the last enrolled subject, that is, 26 
months (790 days) from the enrolment date. Therefore subjects enrolled early in the 
trial could be followed for longer duration than the subjects who enrol later in the 
trial. The study conclusion visit/ contact for subjects with an ongoing episode of HZ 
at the time of LSLV will occur after a 4-week pain-free period is documented OR 
after Day HZ-92 follow-up has been completed. 
− 
Epoch 001: Starting at Visit 1 (Day 1) followed by Visit 2 at two months post 
first vaccination (Month 2), Visit 3 at one month post last vaccination (Month 
3). 
− 
Epoch-002: Starting with monthly contact after Visit 3 (Month 3) and ending at 
the monthly contact that occurs within 30 days of the projected study conclusion 
date of the last enrolled subject, that is, 26 months (790 days) from the 
enrolment date. 
• 
Primary completion Date (PCD): The primary completion date will be when the 
last subject completes their study conclusion contact (within 30 days of the projected 
study conclusion date of the last enrolled subject, that is, 26 months [790 days] from 
the enrolment date. 
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): 1) After all the subjects complete their study conclusion 
contact, occurring within 30 days of the projected study conclusion date of the late 
enrolled subject, that is, 26 months (790 days) from the enrolment date of the last 
subject and 2) the release of all polymerase chain reaction (PCR) test results for the 
HZ rash lesion samples  
Refer to glossary of terms for the definition of EoS. 
• 
Study groups: 
Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of 
eligible subjects 
Age (years) 
Epochs 
Epoch 001 
Epoch 002 
HZ/su 
713 
50 years  
● 
● 
Placebo 
713  
50 years  
● 
● 
Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Groups 
HZ/su 
Placebo 
HZ/su  
VZV gE 
● 
 
AS01B 
● 
 
Placebo 
Lyophilised sucrose 
 
● 
Saline (NaCl) solution for reconstitution 
 
● 


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• 
Control: placebo controlled  
• 
Vaccination schedule: 0 and 2 months. 
• 
Treatment allocation: Eligible subjects will be randomized (1:1) to HZ/su group or 
placebo group. The randomization algorithm will use a stratification procedure 
accounting for age (50-59 YOA; 60-69 YOA and  70 YOA) and also a stratification 
procedure accounting for ‘time since previous HZ episode’ (≤ 4 years ago, 5-9 years 
ago, ≥ 10 years ago). Additional minimization factors include: (female) gender, 
center, family (first degree blood relative) history of HZ, history of PHN and a 
combined minimization factor to reflect the presence of any of the following 
conditions: type 2 diabetes mellitus, asthma, chronic obstructive pulmonary disease, 
chronic kidney disease and depression.  
• 
Blinding: 
Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch-002 
observer-blind 
• 
Sampling schedule:  
− 
Blood samples for humoral immunity (approximately 5 ml per visit) will be 
collected from all subjects at Visit 1 (Day 1), Visit 2 (Month 2), and Visit 3 
(Month 3). 
− 
− 
Clinical specimens of HZ lesions will be collected from all subjects who are 
clinically diagnosed with a suspected case of HZ (Section 4.1). 
− 
A urine specimen will be collected from all female subjects of child-bearing 
potential (see glossary of terms for definition of woman of child bearing 
potential) at Visit 1 (Day 1) and Visit 2 (Month 2). If a serum pregnancy test 
instead of a urine pregnancy test is required by country, local or ethics 
committee regulations, a blood sample will be collected from women of child-
bearing potential at Visit 1 (Day 1) and Visit 2 (Month 2) and used for the test as 
per local guidance. 
Note: The result of the pregnancy test must be obtained before any study vaccination 
and must be negative. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
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• 
Safety monitoring: An internal GSK Safety Review Team (SRT) will oversee the 
safety of the ZOSTER-062 study. Serious adverse events (SAEs), adverse events 
(AEs) including potential immune mediated diseases (pIMDs) and accrual of HZ 
cases will be reviewed in a blinded manner by the SRT at regular intervals. Any 
potential safety concern related to conduct of the study will be escalated to higher 
governing bodies as per internal GSK process. 
4. 
CASE DEFINITION 
4.1. 
Suspected HZ 
A suspected case of HZ is defined as a new unilateral rash accompanied by pain (broadly 
defined to include allodynia, pruritus or other sensations) and no alternative diagnosis. 
If a case is not clinically diagnosed as suspected HZ, the investigator should not progress 
further with evaluation of the case. Subjects with ‘suspected HZ’ should be further 
evaluated, as below (also refer to Section 4.5). 
The HZ onset date is the earlier of the following two events: 1) the HZ rash start date; or 
2) the date on which pain at the site of a subsequent HZ rash is first noted. 
The end date of a HZ episode is defined as the first time at which a subject had no rash 
(papules, vesicles, ulcers or crusts) present. This end date will be recorded in the eCRF. 
The occurrence of HZ will be recorded in HZ-specific eCRF screens. The reporting 
period for cases of HZ will be from Day 1 to study end. Refer to Section 4.5 for more 
details on the evaluation and confirmation of suspected HZ cases. 
4.2. 
Confirmed HZ 
A suspected case of HZ can be confirmed by GSK in two ways: 
• 
By PCR: 
Rash lesion samples will be collected from subjects clinically diagnosed as having a 
suspected case of HZ. The samples will be transferred to GSK Biologicals or a 
validated laboratory designated by GSK Biologicals and analyzed using standardized 
and validated procedures for laboratory diagnosis of HZ by PCR (see Section 
4.5.2.2.1). 
• 
By the HZ Ascertainment Committee (HZAC): 
All suspected HZ cases will be referred to the HZAC. The HZAC will classify all 
referred cases as either “HZ” or “not HZ” or “not able to decide” (see Section 
4.5.2.2.2). 


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4.5. 
Evaluation and confirmation of suspected HZ cases 
4.5.1. 
Definitions 
Refer to Sections 4.1, 4.2, 4.3 and 4.4 for definitions of suspected HZ, confirmed HZ, 
PHN and other HZ complications, respectively. 
For all subjects in case of a suspected or confirmed case of HZ: 
HZ-specific diary card: To be completed by subjects (or subject’s LAR/caregiver) who 
develop symptoms suggestive of HZ beginning immediately upon development of these 
symptoms and prior to visiting the study site for evaluation of the suspected HZ. 
ZBPI questionnaire: To be completed by subjects (or subject’s LAR/caregiver) with 
suspected HZ on Day HZ-1(Visit HZ-1) and daily from Day HZ-1 up to Day HZ-29, and 
weekly from Day HZ-30 onwards until a 4-week pain-free period is documented. For all 
subjects with ongoing HZ-associated pain at the time of last subject last contact, ZBPI 
data will be collected until a 4-week pain-free period is documented OR until at least Day 
HZ-92 (Refer to Section 4.5.2 for more details). 
Please refer to Table 7 and Table 8 for information on when diary cards and 
questionnaires are dispensed to the subjects. 
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4.5.2. 
Evaluation of suspected cases of HZ 
All suspected HZ cases that occur during the study period will be followed and evaluated. 
Any symptom/sign suggestive of HZ must be evaluated. At Visit 1 (Day 1), all subjects 
(and subject’s LAR/caregiver, if applicable) will be educated with regard to the signs and 
symptoms of HZ. The subjects are also given a HZ-specific diary card that they would 
complete with the date of onset of rash and/or pain. Subjects will be instructed to contact 
their study site immediately and visit the study site (within 48 hours if possible) for 
evaluation of the suspected case of HZ. The subject will be asked to bring the completed 
HZ-specific diary card when he/she visits the study site for evaluation of the suspected 
HZ. The investigator or delegate will perform a clinical examination when the subject 
visits the study site for the first evaluation of the suspected case of HZ [Visit HZ-1 at Day 
HZ-1]. If it is not considered a suspected HZ diagnosis, further evaluation of this event 
should not progress for the purpose of this study. However, the case should be handled as 
AE/SAE, if applicable (Section 9.3). 
The schedule of visits/contacts that will take place for follow-up of clinically diagnosed 
suspected HZ cases is presented in Table 8. 
For clinically diagnosed suspected HZ cases, the following will take place at Visit HZ-1: 
• 
The investigator or their delegate will verify the completed HZ-specific diary card 
returned by the subject (or the subject’s LAR/caregiver, if applicable). The 
information from the diary card will be transcribed into the eCRF. The investigator 
or their delegate will record relevant information regarding the HZ episode in the 
eCRF (such as date of onset of pain and/or rash, date of clinical diagnosis of HZ, 
location and nature of HZ lesions, HZ-related complications if any); 
• 
The rash will be documented by digital photography. Please refer to the study 
procedures manual (SPM) for specific instructions; 
• 
The study staff/investigator will record concomitant medication/vaccination, 
including concomitant medication for HZ treatment or any HZ-related complications 
(Section 7.7), and record any other intercurrent medical conditions (IMCs) (Section 
7.8). Concomitant medication the subject has already received and/or will receive for 
HZ treatment will be recorded in the eCRF. The study staff/investigator will check if 
the subject received any medical attention [hospitalization, emergency room visit, or 
a visit to or from medical personnel (medical doctor)] for HZ or any HZ-related 
complication; 
• 
Rash lesion samples (three replicate samples on the same day) will be collected from 
subjects clinically diagnosed as having a suspected case of HZ; 
• 
The subject will be given a supply of ZBPI questionnaires to collect information on 
the severity and duration of HZ-associated pain. The study staff/investigator will 
provide instructions to the subjects for completing the ZBPI questionnaires and 
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• 
The subject/subject’s LAR/caregiver will be asked to complete the ZBPI 
questionnaires on Day HZ-1 (Visit HZ-1) and daily from Day HZ-1 up to Day 
HZ-29 (ZBPI must be completed to Day HZ-29 at minimum) and weekly from Day 
HZ-30 onwards until: 
− 
A 28-day (or 4-week) pain free period is documented (a ‘No’ answer to the 
ZBPI question: ‘Have you had any pain caused by your shingles in the last 24 
hours’ (item 1) at each assessment during that entire period); 
− 
For all subjects with ongoing HZ-associated pain at the time of last subject last 
contact, completion of ZBPI questionnaires will continue until a 4-week pain-
free period is documented OR until at least Day HZ-92. 
• 
After Visit HZ-1 until Visit HZ-7, visits/contacts will take place for follow-up of the 
HZ episode according to the schedule presented in Table 8. Follow-up of HZ-
associated pain and complications will continue irrespective of whether the rash has 
ended in some cases. When a case initially clinically diagnosed as suspected HZ is 
subsequently no longer considered by the investigator as suspected HZ, this will be 
noted in the eCRF. However study procedures to be performed during the follow-up 
period for a suspected HZ case (see Table 8) should be continued. 
• 
If HZ-associated pain ceases (defined as a 28-day [or 4-week] pain free period), the 
study staff/investigator will inform the subject/subject’s LAR/caregiver to stop 
completing the ZBPI questionnaires and will provide instructions for the subject to 
return the completed questionnaires to the study site. 
• 
If a 4-week pain-free period is achieved and the HZ rash resolves, subsequent 
follow-up visits or contacts related to this case of HZ will be cancelled meaning that 
collection of subsequent HZ episode-related information will be stopped and no 
further information on that particular suspected HZ episode will be encoded in the 
clinical database. However, if pain reappears in the same area after a 4-week pain-
free period and is not accompanied by a new HZ rash, it will be assigned to the 
previous HZ-episode. Visits/contacts will restart with Day HZ-1 defined as the first 
visit of the assigned episode, prior to the pain free period. Follow-up of HZ-
associated pain persisting beyond Visit HZ-7 (Day HZ-92) or other complications 
will be done at monthly contacts between the subject and the investigator and/or 
investigator’s delegate. 
• 
HZ related complications if considered as SAE will be followed as appropriate 
(Section 9.3.1). 
The following will take place at each visit or contact that occurs for each episode: 
• 
The study staff/investigator will: 1) record relevant information regarding the 
suspected HZ case (such as the location and nature of HZ lesions, the end date of the 
rash, HZ-related complications, if any); 2) record concomitant 
medications/vaccinations, including concomitant medication the subject has already 
received and/or will receive for HZ treatment or treatment of any HZ-related 
complications (Section 7.7); 3) record any other IMC (Section 7.8); and 4) check if 
the subject received any medical attention [hospitalization, emergency room visit, or 


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a visit to or from medical personnel (medical doctor)] for HZ or any HZ-related 
complication. 
• 
Additional photographs of HZ lesions may be taken after the first visit for the HZ 
episode to help note the progression of the rash. 
• 
If the investigator determines that adequate rash samples are not present at the first 
visit (that is < 3 lesions present or only papules present), the investigator has the 
option of collecting three additional samples prior to or at the second Visit HZ-2. 
• 
The study staff/investigator will remind subjects/subject’s LAR/caregiver to 
complete the ZBPI questionnaires and return the completed ZBPI questionnaires to 
the study site according to the instructions given by the study staff/investigator. Once 
the completed ZBPI questionnaires are available, the investigator will transcribe the 
information into the subject’s eCRF. A new supply of ZBPI questionnaires will be 
provided to the subjects as necessary. 
4.5.2.1. 
Evaluation of severity of HZ-associated pain using the Zoster Brief Pain 
Inventory 
The ZBPI is an assessment tool in the form of a questionnaire completed by the 
subject/subject’s LAR/caregiver that is specifically designed to assess HZ-associated pain 
and discomfort during an HZ episode. 
In each case of suspected HZ, the subjects will be asked to assess their HZ-associated 
pain by completing the ZBPI questionnaire either themselves or assisted by an aide (such 
as a family member or caregiver who is not involved in the study) (Section 6.4.1). At 
each visit, the subject/subject’s LAR/caregiver will be trained (if required) on ways to 
complete the ZBPI questionnaire. 
Information on HZ-associated pain is derived from the ZBPI question: “Please rate your 
pain by circling the one number that best describes your pain at its worst in the last 24 
hours” (item 3), so called “worst pain” in this protocol. 
4.5.2.2. 
Confirmation of a suspected case of HZ 
A suspected case of HZ can be confirmed by GSK in two ways: 
4.5.2.2.1. Confirmation of suspected HZ by PCR 
Rash lesion samples will be collected from subjects clinically diagnosed as having a 
suspected case of HZ. The samples will be transferred to GSK Biologicals or a validated 
laboratory designated by GSK Biologicals and analyzed using standardised and validated 
procedures for laboratory diagnosis of HZ by PCR. Refer to APPENDICES 
APPENDIX A for details of PCR assay to be performed on HZ lesion samples and for 
details of the PCR testing algorithm to classify suspected cases of HZ. 


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4.5.2.2.2. Confirmation of suspected HZ by the HZAC 
All suspected HZ cases will be referred to the HZAC. The HZAC will classify all 
referred cases as either “HZ” or “not HZ” or “not able to decide”. The HZAC 
classification will serve as the final case definition only when the case cannot be 
confirmed or excluded by PCR, e.g., when all samples from a given subject are 
inadequate (as when both VZV and β-actin PCR results are negative), or when no 
samples are available for a given subject. Therefore, definitive PCR results, when 
available, will determine the final HZ case assignment. In such cases, the HZAC 
classification will not contribute to HZ case determination decision. 
The HZAC will consist of three to five physicians with HZ expertise. HZAC members, 
participating as investigators in this study, will not evaluate cases from their own study 
site. HZAC members will be blinded to group assignments. For every case, each 
reviewing HZAC member will be asked to make a clinical determination of whether the 
case is HZ based on review of the available clinical information (e.g., summary of the 
rash and pain evaluations, digital photographs of the subject's rash, and clinical progress 
notes). A suspected case of HZ will be considered as “HZ” if the HZAC members concur 
unanimously; otherwise, it will be classified as “not HZ”. A case of “not able to decide” 
will be classified as “not HZ”. As described above, the HZAC case assignment will only 
be considered as the final case assignment if definitive PCR results are not available. 
Further details will be provided in the HZAC charter. 
4.5.3. 
Follow up of suspected HZ cases and HZ-associated pain 
Data will be collected on all suspected HZ cases that occur from Visit 1 (Day 1) until the 
study conclusion. For each suspected case of HZ that the investigator concludes is 
clinically consistent with HZ, data on HZ-associated pain (using ZBPI questionnaires 
completed by the subject/subject’s LAR/caregiver) will be collected daily until Day- HZ-
29, and weekly from Day HZ-30 until the subject has no HZ-associated pain for 4 
consecutive weeks. For all subjects with ongoing HZ-associated pain at the time of last 
subject last contact, ZBPI data will be collected until a 4-week pain-free period is 
documented OR until Day HZ-92. If pain reappears in the same area after a 4-week pain-
free period and is not accompanied by a new HZ rash, it will be assigned to the previous 
HZ-episode. The completion of the ZBPI questionnaire will resume based upon the 
weekly schedule established at the start of the assigned episode. Visits/contacts will also 
restart according to the schedule in Table 8 with reference to the established Day HZ-1 at 
the start of the assigned episode prior to the pain free period. Follow-up is described in 
Section 4.5.2. 
If during clinical evaluation at Visit HZ-1, the investigator determines that adequate rash 
lesion samples cannot be collected (that is, less than three lesions present, or if only 
papules are present), the investigator has the option of collecting three additional samples 
preferably within 7 days, or at the Visit HZ-2 if there is rash progression (that is, 
appearance of new/additional lesions if originally less than three lesions present, or 
appearance of vesicles if originally only papules present). When the subject returns for 
repeat sample collection, if possible, three samples from separate lesions should be 
collected. Refer to the central lab manual for further details on sample collection. 


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Additional photographs of HZ lesions may be taken after Visit HZ-1 to help note the 
progression of the rash. 
5. 
STUDY COHORT 
5.1. 
Number of subjects/centers 
Target enrolment is 1426 eligible subjects (713 per treatment group) with previous HZ 
episode to reach approximately 606 evaluable subjects per group for statistical analysis 
assuming a 15% drop out rate. Refer to Sections 5.2 and 5.3 for eligibility criteria. 
Subjects will be stratified according to age and time since previous HZ episode. Sample 
size details are given in Table 4, Table 5 and Section 11.4. 
The enrolment strategy will ensure that a minimum of 285 subjects in each of the 50-59 
and 60-69 YOA ranges and at least 143 subjects ≥ 70 YOA are expected to be included in 
the study (Table 4). A minimum of 143 subjects are expected to be enrolled in each sub-
group for ‘time since previous HZ episode (Table 5). Additional minimization factors 
include: (female) gender, center, family (first degree blood relative) history of HZ, 
history of PHN and a combined minimization factor to reflect the presence of any of the 
following conditions: type 2 diabetes mellitus, asthma, chronic obstructive pulmonary 
disease, chronic kidney disease and depression. 
Table 4 
Expected enrolment based on overall age stratification  
Age strata 
Sample size 
Percentage of total 
50-59 YOA 
Min 285 
Min 20 
60-69 YOA 
Min 285 
Min 20 
 70 YOA 
Min 143 
Min 10 
All 
1426 
100.0 
Table 5 
Expected enrolment based on time from previous HZ case 
Sub-group 
Sample size 
Percentage of total 
4 years ago 
Min 143 
Min 10 
5-9 years ago 
Min 143 
Min 10 
 10 years ago 
Min 143 
Min 10 
All 
1426 
100.0 
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Overview of the recruitment plan: 
• 
The target enrolment will be 1426 subjects. 
• 
The study is planned to be conducted at multiple sites in multiple countries. 
• 
The recruitment rate will be monitored using a study-specific central randomization 
system on the internet (SBIR). 
5.2. 
Inclusion criteria for enrolment 
Deviations from the inclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects and/or subject’s LAR(s) who, in the opinion of the investigator, can and 
will comply with the requirements of the protocol (e.g. completion of the diary cards 
and ability to be in regular contact to allow evaluation during the study). 
• 
Written informed consent obtained from the subject/subject’s LAR(s) prior to 
performance of any study specific procedure. 
• 
A male or female ≥ 50 YOA at the time of the first vaccination. 
• 
Subjects with a history of HZ (>6 months prior to enrolment). Confirmation of the 
prior HZ diagnosis can be done by one of the following three methods:  
− 
Clinically diagnosed HZ: The subject is eligible for enrolment if there is 
documentation from a physician or health care provider that establishes a 
diagnosis of HZ and the date of diagnosis. Examples of documentation include a 
physician progress note or a hospital discharge summary. The diagnosing 
physician does not need to be an investigator in the ZOSTER-062 study. Subject 
recall of having a prior HZ episode in the absence of supporting documentation 
is not sufficient to meet inclusion criteria. 
OR 
− 
Laboratory diagnosed HZ: a rash consistent with HZ accompanied by laboratory 
findings (for example, PCR, viral culture, immunohistochemical staining, etc.) 
that indicates the presence of VZV in the rash.  
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OR 
− 
HZ diagnosed by an adjudication committee: HZ diagnosed by an expert 
committee constituted specifically to diagnose HZ during clinical trials such as 
the HZAC from previous HZ/su efficacy studies, or comparable committees 
empanelled during other clinical or epidemiological studies. 
• 
Female subjects of non-childbearing potential may be enrolled in the study.  
− 
Non-childbearing potential is defined as current bilateral tubal ligation or 
occlusion, hysterectomy, bilateral ovariectomy, bilateral salpingectomy or post-
menopause. 
Please refer to the glossary of terms for the definition of menopause. 
• 
Female subjects of childbearing potential may be enrolled in the study if the subject: 
− 
has practiced adequate contraception for 30 days prior to vaccination, and 
− 
has a negative pregnancy test on the day of vaccination, and  
− 
has agreed to continue adequate contraception for 2 months after completion of 
the vaccination series. 
Please refer to the glossary of terms for the definition of adequate contraception. 
5.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity regulatory acceptability of the study, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
• 
Subjects who at time of study entry or during the maximum period of anticipated 
study participation (approximately 4 years) are/will become part of the population 
recommended to receive a zoster vaccine per existing local or national immunization 
practices will be excluded from study participation. 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -30 to Day 1), or planned use during the study period. 
• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
• 
Onset of HZ in the past 6 months or any ongoing symptoms from a prior HZ episode. 
• 
Chronic antiviral use for HZ prophylaxis. 
• 
History of > 1 prior episode of HZ. 


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• 
A history of disseminated HZ, cutaneous or associated with visceral disease (defined 
as an abnormality of one or more internal organs [e.g., hepatitis, pneumonitis, 
gastroenteritis, etc] caused by VZV infection) or associated with neurologic disease 
(defined as cranial or peripheral nerve palsies, myelitis, meningoencephalitis or 
stroke) caused by VZV infection. 
• 
Use or anticipated use of immunosuppressants or immune-modifying drugs during 
the period starting six months prior to study start and during the whole study period. 
This includes chronic administration of corticosteroids (> 14 consecutive days of 
prednisone at a dose of ≥ 20 mg/day [or equivalent]) (intra-articular, inhaled and 
topical steroids are allowed), long-acting immune-modifying agents (e.g., 
infliximab) or immunosuppressive/cytotoxic therapy (e.g., medications used during 
cancer chemotherapy, organ transplantation or to treat autoimmune disorders). 
• 
Administration or planned administration of a vaccine not foreseen by the study 
protocol within the period starting 30 days before the first dose of study vaccine and 
ending 30 days after the last dose of study vaccine. However, licensed pneumococcal 
vaccines and non-replicating vaccines (i.e., inactivated and subunit vaccines, 
including inactivated and subunit influenza vaccines, with or without adjuvant for 
seasonal or pandemic flu) may be administered up until 8 days prior to dose 1 and/or 
dose 2 and/or at least 14 days after any dose of study vaccine. 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device). 
• 
Previous vaccination against VZV or HZ. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required) 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
• 
Acute disease and/or fever at the time of enrolment.  
− 
Fever is defined as temperature 38.0°C/100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity.  
− 
Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator. 
• 
Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the first dose of study vaccine or planned administration 
during the study period. 
• 
Pregnant or lactating female. 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions in the period up to 2 months after completion of the vaccination series. 


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6. 
CONDUCT OF THE STUDY 
6.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the ICH Guideline for good clinical 
practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki.  
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject and/or subject’s LAR(s) informed consent. 
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject and/or subject’s LAR(s) prior to participation in the study.  
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.  
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
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6.2. 
Subject identification and randomization 
6.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre. 
6.2.2. 
Randomization of treatment 
6.2.2.1. 
Randomization of supplies 
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to the 
study centers /warehouses. 
6.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose. 
6.2.2.2.1. Study group and treatment number allocation 
The target will be to enrol approximately 1426 subjects who will be randomly assigned to 
two study groups in a (1:1) ratio (713 subjects in each group). 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR). The randomization algorithm will use a 
stratification procedure accounting for age and ‘time since previous HZ episode’ as 
stratification factors. 
A minimum of 285 subjects in each of the 50-59 and 60-69 YOA ranges and at least 143 
subjects ≥ 70 YOA range are expected to be enrolled. A minimum of 143 subjects are 
expected to be enrolled in each sub-group (≤ 4 years ago, 5-9 years ago, ≥ 10 years ago) 
for ‘time since previous HZ episode’. Additional minimization factors include: (female) 
gender, center, family (first degree blood relative) history of HZ, history of PHN (defined 
as clinically significant pain or painful abnormal sensations [e.g., allodynia or itch] that 
persists 90 days or more after HZ rash onset) and a combined minimization factor to 
reflect the presence of any of the following conditions- type 2 diabetes mellitus, asthma, 
chronic obstructive pulmonary disease, chronic kidney disease and depression. 
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After obtaining the signed and dated ICF from the subject/subject’s LAR and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. Upon providing the subject identification number, the randomization 
system will determine the study group and will provide the treatment number to be used 
for the first dose. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
When SBIR is not available, please refer to the SBIR user guide or the SPM for specific 
instructions. 
6.2.2.2.2. Treatment number allocation for subsequent doses  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
6.3. 
Method of blinding  
This is an observer-blind study. 
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine recipient and those responsible for the 
evaluation of any study endpoint (e.g. HZ recurrence, safety, reactogenicity, and 
immunogenicity) will all be unaware of which vaccine was administered. To do so, 
vaccine preparation and administration will be done by authorized medical personnel 
who will not participate in any of the study clinical evaluation assays. 
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The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample. 
6.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied (refer to Section 6.7 for further details; Amended 
14 April 2020). 
6.4.1. 
Diary cards and questionnaires 
The diary cards and/or questionnaires to be completed by the subject/subject’s 
LAR/caregiver will be distributed and explained by the investigator or delegate. Any 
supplied diary cards or questionnaires should be preferably completed by the subject 
themselves. In case of difficulty in self-completion of the diary cards or questionnaires, a 
caregiver may provide assistance with reading the questions (verbatim) and/or 
transcribing the subject’s responses on the questionnaires and/or diary cards. 
All subjects will receive a diary card on the day of each vaccination. The diary card will 
be completed by the subjects (or subjects’ LAR/caregiver) after each vaccination to 
record solicited AEs (from Day 1 to Day 7), unsolicited AEs (from Day 1 to Day 30) and 
any concomitant medication and vaccination taken from Day 1 to Day 30 (Table 7 and 
Table 22). 
In addition, HZ-specific diary card will also be dispensed to be completed by subjects (or 
subject’s LAR/caregiver) who develop symptoms suggestive of HZ, prior to visiting the 
study site for evaluation of the suspected HZ.  
When the completed diary cards and/or questionnaires are returned to the study staff, the 
study staff will ask the subject (at the time of return or at subsequent contact) if he/she 
received any assistance in completing diary cards or questionnaires. If the subject had 
assistance completing the diary card and/or questionnaires (e.g., by a caregiver), it should 
be noted in the eCRF.  
6.4.2. 
Monthly contacts 
After Visit 3 (Month 3), monthly contacts between the subjects/ subject’s LAR/caregiver 
and the investigator or delegate will take place to collect information on any event of 
interest that may have occurred [see Section 6.6.13 for details]. Also, subjects with 
suspected HZ will be contacted as outlined in Table 8 . The contacts will take place using 
the most convenient method suited for the sites (e.g., telephone calls by site staff or 


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designee, or Short Message Service (SMS) text messages through a call centre, or visit by 
the study staff to the subject's home). A guidance document outlining the information that 
needs to be collected at each contact will be provided to each country and will serve as a 
guidance to develop the local script (Refer to the SPM). The logistic details on the set-up 
of the contacts will be documented by each site/country. At each contact, the 
subject/subject’s LAR/caregiver will respond to a standard set of questions in a language 
that is understandable to them. The investigator or delegate will transcribe the relevant 
information on any event of interest in the appropriate language of the subject’s eCRF to 
English. In case of an ongoing HZ case, subjects/subjects’ LAR/caregiver will also be 
reminded to complete ZBPI questionnaires and visit the site (refer to section 4.5.2.1). 
6.5. 
Outline of study procedures 
Table 7 presents the list of study procedures and Table 8 presents procedures to be 
performed for each suspected HZ case. 
Table 7 
List of study procedures 
Epoch 
Epoch 001 
Epoch-002 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Contact 
Monthly 
Contact until 
study end6 
Timepoints 
Day 1 Month 2 Month 3 Month 14 
Month 26* 
Sampling timepoints 
Pre-
vacc 1 
Pre-
vacc 2 
Post-
vacc 2 
 
 
Informed consent 
● 
 
 
 
 
Check inclusion/exclusion criteria 
● 
 
 
 
 
Collect demographic data 
● 
 
 
 
 
Medical history including previous HZ history (Section 
6.6.4) 
● 
 
 
 
 
History directed physical examination 
O 
O 
 
 
 
Pregnancy test if applicable1  
● 
● 
 
 
 
Check contraindications and warnings and precautions to 
vaccination  
O 
O 
 
 
 
Pre-vaccination body temperature (oral route preferred)  
● 
● 
 
 
 
Study group and treatment number allocation 
O 
 
 
 
 
Treatment number allocation for subsequent doses  
 
O 
 
 
 
Recording of administered treatment number  
● 
● 
 
 
 
Vaccine administration 5 
● 
● 
 
 
 
Blood sampling for antibody determination (~5 ml) from 
all subjects 4 
● 
● 
● 
 
 
Post-vaccination observation (30 minutes minimum)  
O 
O 
 
 
 
Distribution of diary cards2  
O 
O 
 
 
 
Training on self-reporting by subjects 3  
O 
O 
O 
O 
O 
Training on completion of diary cards  
O 
O 
 
 
 
Training on signs/symptoms of typical HZ  
O 
O 
O 
O 
O 
Reminder for follow-up contact  
O 
O 
O 
O 
O 
Recording of solicited AEs (Days 1–7 post-vaccination) 
by subjects on diary cards  
O 
O 
 
 
 
Recording of unsolicited AEs within 30 days (Days 1-30 
post-vaccination) by subjects on diary cards  
O 
O 
 
 
 
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Epoch 
Epoch 001 
Epoch-002 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Contact 
Monthly 
Contact until 
study end6 
Timepoints 
Day 1 Month 2 Month 3 Month 14 
Month 26* 
Sampling timepoints 
Pre-
vacc 1 
Pre-
vacc 2 
Post-
vacc 2 
 
 
Return of diary cards  
 
O 
O 
 
 
Diary card transcription by study staff/investigator  
 
● 
● 
 
 
Record any intercurrent medical conditions (excluding 
HZ)  
● 
● 
● 
● 
● 
Record and follow-up of HZ cases 7  
● 
● 
● 
● 
● 
Record any concomitant medications/vaccinations  
● 
● 
● 
● 
● 
Recording of SAEs, pregnancies, pIMDs  
● 
● 
● 
● 
 
Recording of AE/SAEs leading to withdrawal 
● 
● 
● 
● 
● 
Recording of SAEs related to study participation, or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
● 
● 
Study Conclusion 
 
 
 
 
● 
AE: Adverse Event;
HZ: Herpes Zoster; M: Month; pIMD: potential Immune Mediated 
Disease; Pre-Vacc: Pre-Vaccination; Post-Vacc: Post-Vaccination; SAE: Serious Adverse Event; VZV: Varicella Zoster 
Virus 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1 Only for women of child bearing potential. Please refer to glossary of terms for definition of woman of child bearing 
potential. 
2 Diary card to collect solicited and unsolicited AEs following each vaccination and HZ specific diary card. 
3 Subjects will be instructed to contact their study site immediately if he/she manifests any symptoms he/she perceives 
as serious and in case of pregnancy or HZ symptoms.  
4 Before vaccine administration  
5 Any subject with a clinically diagnosed suspected HZ episode between Visit 1 (Day 1) and Visit 2 (Month 2) is not to 
receive the second dose. 
6 The duration of the study will vary for each subject. Study conclusion will be scheduled based on the projected date of 
the last contact of the last enrolled subject, that is 26 months (790 days) from the enrolment date. The study 
conclusion visit/ contact for subjects with an ongoing episode of HZ will occur after a 4-week pain-free period is 
documented OR after Day HZ-92 follow-up has been completed. 
7 Refer to Section 4.5 and Table 8 for the brief evaluation and study procedures to be followed in case of suspected 
HZ. 
* For the last enrolled subject only 
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Table 8 
Study procedures to be performed during the follow-up period for 
each suspected HZ case 
Type of contact 
Visit 
HZ-1 
Visit 
HZ-2 
Contact 
HZ-3 
Contact 
HZ-4 
Visit HZ-
5 
Contact 
HZ-6 
Visit 
HZ-7 
Timepoints 
Day HZ-
1 
Day 
HZ-8 
Day HZ-
15 
Day HZ-
22 
Day HZ-
29 
Day HZ-
57 
Day HZ-
92 
Perform clinical examination 
O 
 
 
 
 
 
 
Return HZ-specific diary cards to study 
staff/investigator 
O 
 
 
 
 
 
 
Transcription of the HZ-specific diary card by 
study staff/investigator 
● 
 
 
 
 
 
 
Take digital photographs of HZ rash  
● 
 
 
 
 
 
 
Recording of the HZ onset date by study 
staff/investigator 
● 
 
 
 
 
 
 
Collect HZ lesion samples (3 replicate samples) 
for confirmation by PCR of a case of clinically 
diagnosed suspected HZ as specified in Section 
4.5.2* 
● 
 
 
 
 
 
 
Record relevant information regarding HZ in 
eCRF by study staff/investigator as specified in 
4.5.2 
● 
● 
● 
● 
● 
● 
● 
Record information regarding HZ related 
complications 
● 
● 
● 
● 
● 
● 
● 
Record concomitant medication/vaccination 
according to guidelines in Section 7.7 
● 
● 
● 
● 
● 
● 
● 
Record any other IMCs according to guidelines in 
Section 7.8 
● 
● 
● 
● 
● 
● 
● 
Record any medical attention received for HZ or 
any HZ-related complication 
● 
● 
● 
● 
● 
● 
● 
Dispense ZBPI questionnaires to subjects ‡ 
O 
O 
 
 
O 
 
O 
Training on completion of ZBPI questionnaires 
O 
O 
 
 
O 
 
O 
Completion of ZBPI questionnaires by the 
subjects (refer to section 4.5.2.1) 
O 
O 
O 
O 
O 
O 
O 
Return completed ZBPI questionnaires to study 
staff/investigator  
 
O 
O 
O 
O 
O 
O 
Transcription of ZBPI questionnaires by study 
staff/investigator 
● 
● 
● 
● 
● 
● 
● 
● 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. 
HZ = Herpes Zoster; PCR = Polymerase Chain Reaction; eCRF = electronic Case Report Form; IMC = Intercurrent 
Medical Condition; ZBPI = Zoster Brief Pain Inventory. 
 Additional photographs of HZ lesions may be taken after Visit HZ-1 to help note the progression of the rash. 
* If during clinical evaluation at Visit HZ-1, the investigator determines that adequate rash samples are not present (that 
is <3 lesions present or only papules), the investigator has the option of collecting three additional samples prior 
to or at Visit HZ-2 (preferably within 7 days).  
‡ The study staff/investigator will dispense additional questionnaires and provide instructions for the subject to return 
the completed questionnaires to the study site until the subject has a 4-week pain free or at least Day HZ-92 (for 
subjects with ongoing pain at the time of last subject last contact). 


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Time intervals between study visits/contacts related to study procedures performed in 
subjects participating in the study are provided below. Whenever possible, the 
investigator should arrange study visits within the interval described in Table 9. 
Table 9 
Intervals between study visits 
Interval 
Optimal length of interval 1 
Allowed interval 2 
Visit 1→Visit 2 
60 days (2 months) 
49 days - 83 days  
Visit 2→Visit 3 
30 days (1 month) 
28 days- 48 days 
Between Monthly Contacts* 
30 days (1 month) 
20 – 40 days 
Visit 2→Month 26 Contact (for the 
last enrolled subject only)  
730 days (24 months) 
730- 760 days 
*including first contact post Visit 3 (Month 3) 
1 Whenever possible the investigator should arrange study visits according to this interval. 
2 Except the intervals between the Monthly Contacts post Visit 3 (Month 3), subjects may not be eligible for inclusion in 
the Per Protocol Set if study visits occur outside the allowed interval. 
Time intervals between study visits/contacts to be performed for follow-up of HZ are 
presented in Table 10. 
Table 10 
Intervals between visits/contacts for subjects in case of suspected 
HZ 
Interval between Visits/ Contacts 
Length of 
interval 
Optimal Timing of contact 
(range of days) 
Visit HZ-1 (Day HZ-1) → Visit HZ-2 (Day HZ-8) 
7 days 
Day HZ-8 (+/- 3 days)* 
Visit HZ-2 (Day HZ-8) → Contact HZ-3 (Day HZ-15) 
7 days 
Day HZ-15 (+/- 3 days)* 
Contact HZ-3 (Day HZ-15) → Contact HZ-4 (Day HZ-22) 
7 days 
Day HZ-22 (+/- 3 days)* 
Contact HZ-4 (Day HZ-22) → Visit HZ-5 (Day HZ-29)  
7 days 
Day HZ-29 (+/- 3 days)* 
Visit HZ-5 (Day HZ-29) → Contact HZ-6 (Day HZ-57) 
28 days 
Day HZ-57 (+/- 7 days)* 
Visit HZ-1 (Day HZ-1) → Visit HZ-7 (Day HZ-92) 
91 days 
Day HZ-92 (+ 7 days) 
Note: The date of the previous visit/contact is used as reference date to define the interval between the subsequent 
study visits/contacts. 
Note: If HZ-associated pain ceases (that is, after a 4-week pain-free period is documented) and the HZ rash resolves, 
subsequent follow-up HZ visits or contacts will be cancelled (see Section 4.5.2). At the time of last subject last 
contact, follow-up of HZ-associated pain persisting beyond Visit HZ-7 (Day HZ-92) or other complications will end 
for study purposes and the subject will be followed as per the investigators discretion. 
* If contacted early in the window, then remaining days in the interval will need to be captured with the next contact. 
Refer to Section 6.7 for study procedures to be considered during special 
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6.6. 
Detailed description of study procedures 
6.6.1. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject/subject’s LAR(s) 
must be obtained before study participation. Refer to Section 6.1 for the requirements on 
how to obtain informed consent. 
When a subject needs the assistance of a caregiver in completing study procedures, this 
will be confirmed during informed consent by the subject. In addition, the caregiver will 
also provide his/her agreement to be involved in the study and express willingness to act 
in a support role during the conduct of study specific procedures. The agreement of the 
caregiver to participate to the study will be included in the subject’s ICF in a separate 
dedicated paragraph/annex. The role of the caregiver will be fully explained in the ICF or 
annex where the subject and the caregiver will confirm their involvement in the study. 
The caregiver can stop participation in the study for any reason at any time, and he/she 
should be replaced by another caregiver. The former caregiver must not be involved in 
the consent process and the appointment of a new caregiver. The new caregiver will 
confirm his/her participation following the same process: by having both subject and 
him/her-self (re-)signing the annex part of the ICF. 
6.6.2. 
Check inclusion and exclusion criteria 
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment. 
6.6.3. 
Collect demographic data 
Record demographic data such as year of birth, sex, race and ethnicity in the subject’s 
eCRF. 
6.6.4. 
Medical history 
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF.  
Clinically relevant prior medical history is defined as: chronic disease or medical 
conditions requiring continued or chronic treatment (e.g., diabetes, psoriasis), any 
previous malignant cancer, acute disease resolved with sequelae (e.g., hemiplegia due to 
cerebrovascular accident), any pIMDs (see Table 21). 
Excluded from recording are: acute infections that have resolved (e.g. lobar pneumonia, 
influenza), medical events that have resolved (e.g. hip fracture with replacement, cataract 
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In addition, history of the prior HZ episode must be recorded. Any available information 
for the diagnosis of HZ episode (clinical diagnosis, PCR, laboratory methods, etc.) must 
be recorded. 
6.6.5. 
History directed physical examination 
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled. 
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
6.6.6. 
Pregnancy test  
Female subjects of childbearing potential (refer to glossary of terms for definition) are to 
have a urine/blood pregnancy test prior to any study vaccine administration. The study 
vaccine may only be administered if the pregnancy test is negative.  
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit. 
A urine pregnancy test is sufficient. A serum pregnancy test instead of a urine pregnancy 
test should only be considered if required by country, local or ethics committee 
regulations. 
6.6.7. 
Check contraindications, warnings and precautions to 
vaccination  
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Sections 7.5 and 7.6 for more details. 
6.6.8. 
Assess pre-vaccination body temperature 
The body temperature (oral route) of each subject needs to be measured prior to any 
study vaccine administration. If the subject has fever (fever is defined as temperature 
 38.0°C/100.4°F regardless the location of measurement) on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit  
(see Table 9). 
In rare situations when there is no other alternative, the temperature may be recorded by 
other route. If the temperature is taken by another route (axillary, rectal or tympanic), the 
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6.6.9. 
Study group and treatment number allocation 
Study group and treatment number allocation will be performed as described in Section 
6.2.2. The number of each administered treatment must be recorded in the eCRF. 
6.6.10. 
Sampling 
Refer to the central lab manual for detailed instructions for the collection, handling and 
processing of the samples. 
6.6.10.1. 
Blood sampling for immune response assessments  
Blood samples will be taken during certain study visits as specified in Section 6.5 (List of 
Study Procedures). 
• 
A volume of at least approximately 5 ml of whole blood (to provide at least 1.5 ml of 
serum) should be drawn from all subjects for assessment of humoral immune 
response at each pre-defined timepoint. After centrifugation, serum samples should 
be kept at –20°C/ –4°F or below until shipment. Refer to the central lab manual for 
more details on sample storage conditions. 
• 
6.6.10.2. 
Clinical specimens of HZ lesions for PCR analysis 
Clinical specimens of HZ lesions will be collected from subjects clinically diagnosed as 
having a suspected case of HZ (see Sections 4.5.2.2.1, 4.5.3). Samples for HZ cases 
assessment should be kept at –20°C/ –4°F or –70/80°C (-94/-112°F) until shipment. 
Refer to the central lab manual for more details on sample storage conditions. 
6.6.11. 
Study vaccine administration 
• 
After completing all prerequisite procedures prior to vaccination, the vaccine will be 
administered IM in the deltoid of the arm according to the administration schedule 
(refer to Section 7.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 9).  
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• 
The subjects 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. 
• 
Any subjects with an event of HZ between Visit Day 1 and Visit Month 2 vaccine, 
should not receive the upcoming dose. 
6.6.12. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.7. 
IMCs must be checked and recorded in the eCRF as described in Section 7.8. 
6.6.13. 
Training on self-reporting by subjects 
Subjects/ subject’s LAR/caregiver will be instructed at Visit Day 1 (and will be reminded 
at subsequent visits and phone contacts) to contact their study site immediately: 
• 
should the subject manifest any signs or symptoms he/she perceive as serious; 
• 
should the subject become pregnant (for women of childbearing potential). 
• 
should the subject develop any symptoms suggestive of HZ, the subject should be 
reminded to start completion of the HZ-specific diary card immediately upon 
development of these symptoms prior to visiting the study site for evaluation of the 
suspected HZ. 
6.6.14. 
Recording of AEs, SAEs, pregnancies and pIMDs 
• 
Refer to Section 9.3 for procedures for the investigator to record AEs, SAEs, 
pregnancies and pIMDs. Refer to Section 9.4 for guidelines and how to report SAE, 
pregnancy and pIMD reports to GSK Biologicals. 
• 
The subjects /subject’s LAR(s)/caregiver will be instructed to contact the 
investigator immediately should they manifest any signs or symptoms they perceive 
as serious.  
• 
At each vaccination visit, diary cards will be provided to the subject/subject’s 
LAR/caregiver. The subject will be instructed to measure and record the oral body 
temperature and any solicited local/general AEs (that is, on the day of vaccination 
and during the next 6 days) or any unsolicited AEs (that is, on the day of vaccination 
and during the next 29 days occurring after vaccination). The subject will be 
instructed to return the completed diary card to the investigator at the next study 
visit. 
• 
Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient method.  
• 
The investigator will transcribe the collected information into the eCRF in English. 


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6.6.15. 
Monthly contact 
After Visit 3 (Month 3), all subjects will be contacted by the study staff on a monthly 
basis until the study end (that is, until all the subjects complete their last contact, 
occurring within 30 days of the projected study conclusion date of the last enrolled 
subject, that is, 26 months [790 days] from the enrolment date). Therefore, duration of the 
follow-up will vary for each subject and subjects enrolled early in the trial could be 
followed for longer duration than the subjects who enrol later in the trial. 
6.6.16. 
Study conclusion 
Study conclusion will be scheduled based on the projected date of the last contact of the 
last enrolled subject, that is, 26 months (790 days) from the enrolment date. All sites will 
be notified of this date as to schedule the study conclusion contact for all subjects within 
30 days of that date. 
The study conclusion visit/ contact for subjects with an ongoing episode of HZ will occur 
after a 4-week pain-free period is documented OR after Day HZ-92 follow-up has been 
completed (see Table 8). 
At the study conclusion contact the investigator will: 
• 
review data collected to ensure accuracy and completeness, 
• 
complete the Study Conclusion screen in the eCRF. 
After study conclusion, placebo recipients may be offered cross-over vaccination with 
HZ/su, if supported by study results. 
6.7. 
Study procedures during special circumstances (Amended 
14 April 2020) 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled subjects:   
The impact of COVID-19 to the study conduct will be documented in the clinical study 
report.  
• 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
• 
Diary cards may be transmitted from and to the site by electronic means and/or 
conventional mail.  
• 
Biological samples may be collected at a different location* other than the study 
site or at subject’s home. Biological samples should not be collected if they cannot 
be processed in a timely manner or appropriately stored until the intended use. 


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* It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on subjects by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March, 2020) for more details.  
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 9), then the interval may be extended 
as outlined in Table 11. 
• 
If despite best efforts it is not possible to administer the second dose of study 
intervention as defined in the protocol (see Table 9), a maximum dose interval of 
180 days may be used (see Table 11). 
− 
In case the investigator needs to conduct visits 2 and 3 during the allowed 
extended interval due to the special circumstances, then the best efforts should 
be made to conduct a safety follow-up by telephone contact at the time when  
visits 2 and 3 were initially planned (as close to the optimal window as 
possible) and approximately monthly thereafter until visits 2 and 3 procedures 
can be conducted. 
Table 11 
Intervals between study visits during special circumstances 
(Amended 14 April 2020) 
Interval 
Optimal length of interval 
Allowed interval per 
Protocol 
Allowed interval during 
special circumstances 
Visit 1 →Visit 2  
60 days (2 months) 
49 days - 83 days 
49 days – 180 days 
Visit 2→Visit 3  
30 days (1 month) 
28 days- 48 days 
28 days- 90 days 
Between Monthly 
Contacts*  
30 days (1 month) 
20 – 40 days 
20 – 40 days 
Visit 2→Month 26 Contact 
(for the last enrolled subject 
only)   
730 days (24 months) 
730- 760 days 
730- 760 days 
Note: Investigator should prioritize conducting the visit as close to the optimal window as possible. 
• 
Visits for suspected HZ may take place in a different location* other than the study 
site or at subject’s home. If this is not feasible, then the medical evaluation of 
suspected HZ may take place virtually with documentation of all the signs and 
symptoms as outlined in Table 8 and Table 10. 
− 
If the subject is not able to contact the study staff/investigator to evaluate/ 
clinically diagnose the suspected HZ case, the subject should be encouraged to 
document all the signs and symptoms and record the progression of the rash 
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− 
Digital photographs can be taken by the study staff/investigator at a different 
location* other than the study site or at subject’s home. If this is not feasible, 
subjects might be asked to take photographs of their Hz lesions themselves. 
The photographs will be transferred to the investigator. 
− 
ZBPI questionnaire may be transmitted from and to the site by electronic 
means and/or conventional mail. If feasible the study staff/investigator can 
conduct ZBPI questionnaire by telephone contact. 
Impact on the modified exposed set for HZ recurrence analysis and per protocol set for 
immunogenicity (humoral and 
) will be determined on a case by case basis. 
6.8. 
Biological sample handling and analysis 
Please refer to the central lab manual for details on biospecimen management (handling, 
storage and shipment). 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 
• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research. 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.  
If additional testing is performed, the marker priority ranking given in Section 6.8.4 may 
be changed. 
Any sample testing will be done in line with the consent of the individual 
subject/subject’s LAR(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
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Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
6.8.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the per-protocol analysis (See Section 11.5 for the 
definition of cohorts to be analyzed). The investigator must ensure that his/her personnel 
and the laboratory(ies) under his/her supervision comply with this requirement. However, 
when GSK Biologicals does not provide material for collecting and storing clinical 
samples, appropriate materials from the investigator’s site must be used. Refer to the 
Module on Clinical Trial Supplies in the SPM. 
6.8.2. 
Biological samples 
The biological samples collected in the study, the quantity needed, the unit and the time 
points are described in Table 12. 
Table 12 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Sub-set name* 
Blood-Humoral 
 
approx 5  
ml 
scheduled 
All subjects 
HZ lesion sample 
preferably 
3 samples 
- 
unscheduled 
All subjects with suspected HZ episodes 
during the study 
*Refer to Section 5.1 for sub-cohort description 
Approx= Approximately; 
 HZ= Herpes Zoster; ml= milliliter 
6.8.3. 
Laboratory assays 
Please refer to APPENDICES 
APPENDIX A for a detailed description of the assays performed in the study. Please 
refer to APPENDIX B for the address of the clinical laboratories used for sample 
analysis. 
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Laboratory assays which will be used in this study are summarised in Table 13 (Humoral 
Immunogenicity), Table 14 
 and Table 15 (Molecular Biology), respectively.  
Table 13 
Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit /Manufacturer 
Unit* 
Cut-off 
Laboratory 
SERUM 
Varicella Zoster 
Virus Glycoprotein 
E Ab.IgG 
ELISA 
NA 
mIU/mL 
97 
GSK Biologicals 
Ab: Antibody; ELISA; Enzyme-linked Immunosorbent Assay; IgG: Immunoglobulin class G; mIU: milli-international unit; 
ml= milliliter; NA: Not applicable 
Table 15 
Molecular Biology (PCR tests) 
System 
Component 
Method 
Unit 
Laboratory 
HZ lesion sample 
Varicella Zoster Virus DNA 
PCR 
No unit 
GSK Biologicals 
HZ lesion sample 
Actin Gene DNA  
PCR 
No unit  
GSK Biologicals 
DNA= Deoxyribonucleic Acid; HZ= Herpes Zoster; PCR= Polymerase Chain Reaction 
Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol. 
The GSK Biologicals’/contract research organization’s (CRO) clinical laboratories have 
established a Quality System supported by procedures. The activities of GSK 
Biologicals’/CRO’s 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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6.8.4. 
Biological samples evaluation 
6.8.4.1. 
Immunological read-outs 
The plan for immunogenicity testing on samples obtained is shown in Table 16 
Table 16 
Immunological read-outs 
Blood sampling timepoint 
Sub-cohort Name  
Number of 
targeted 
subjects 
Component 
Type of contact and 
timepoint 
Sampling timepoint 
Day 1 (Visit 1) 
Pre-vacc 1 
All subjects 
1426  
Ab gE ELISA 
Month 2 (Visit 2) 
Pre-vacc 2 
All subjects 
1426  
Ab gE ELISA 
Month 3 (Visit 3) 
Post-vacc 2 
All subjects 
1426  
Ab gE ELISA 
Ab: Antibody;
 ELISA: Enzyme-linked Immunosorbent Assay; gE: recombinant purified 
Glycoprotein E; 
; Pre-Vacc: pre-vaccination; Post-Vacc: post-vaccination; 
6.8.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection against HZ has been 
demonstrated so far for the gE antigen used in the HZ/su study vaccine. 
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7. 
STUDY VACCINES AND ADMINISTRATION 
7.1. 
Description of study vaccine 
The study vaccine to be used has been developed and manufactured by GSK Biologicals. 
The Quality Control Standards and Requirements for the vaccine are described in 
separate Quality Assurance documents (e.g. release protocols, certificate of analysis) and 
the required approvals have been obtained.  
The vaccine/placebo are labelled and packed according to applicable regulatory 
requirements. 
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics. 
Table 17 
Study vaccine and Placebo 
Treatment 
name 
Vaccine name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of doses 
HZ/su 
VZV gE 
gE=50µg 
(50g gE per 0.5ml of 
reconstituted vaccine) 
Lyophilized pellet 
in a monodose 
vial 
 
0.5 ml 
2 
AS01B 
MPL=50µg; QS21=50µg; 
Liposomes per 0.5 ml of 
reconstituted vaccine 
Liquid in a 
monodose vial 
Placebo 
Lyophilised 
sucrose  
Sucrose=20mg 
(20mg sucrose per 0.5ml of 
reconstituted placebo) 
Lyophilized 
pellet in a 
monodose vial  
 
0.5 ml 
2 
Saline (NaCl) 
solution 
NaCl=150mM 
(150mM NaCl solution [salt 
water for injection]) 
Liquid in a 
monodose vial 
AS01B= Adjuvant System 01B; gE= recombinant purified Glycoprotein E; MPL= 3-O-desacyl-4’-monophosphoryl lipid A; 
NaCl= Sodium Chloride; QS21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a 
wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation) 
7.2. 
Storage and handling of study vaccines 
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine. 
Temperature excursions must be reported in degree Celsius. 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 


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The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor. 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion. 
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take. 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
7.3. 
Dosage and administration of study vaccine/placebo 
After removal of the vaccine components from the temperature monitored refrigerator, 
the vaccine should be reconstituted and administered within 6 hours, and should be kept 
at room temperature (not to exceed the range of 2°C/36°F and 30°C/86°F). 
Vaccine will be administered as indicated in Table 18. 
The reconstituted vaccine (0.5 ml) should be administered by intra-muscular (IM) 
injection into the deltoid muscle of the non-dominant arm using a standard aseptic 
technique. 
Refer to the SPM for more details on vaccine reconstitution and administration. 
Table 18 
Dosage and administration 
Type of contact and 
timepoint 
Volume to be 
administered 
 Study 
group 
Treatment 
name 
Route 
Site 
Side1 
Visit 1 (Day 1) 
0.5 ml 
HZ/su  
HZ/su 
IM 
Deltoid 
Non-dominant 
Visit 2 (Month 2) 
Visit 1 (Day 1) 
0.5 ml 
Placebo 
Placebo 
Visit 2 (Month 2) 
IM: Intramuscular; ml= milliliter 
1 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. 
7.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 5% additional vaccine doses will be 
supplied to replace those that are unusable.  


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7.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
study vaccine. If any of these events occur during the study, the subject must not receive 
additional doses of vaccine but may continue other study procedures at the discretion of 
the investigator (see Section 9.5).  
• 
Anaphylaxis following the administration of vaccine 
• 
Pregnancy (see Section 9.2.1)  
• 
Any SAE judged to be vaccine-related by the investigator. 
• 
Occurrence of HZ between the first and second vaccine dose. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including Human Immunodeficiency Virus (HIV) infection. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, expose the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine. Refer to Section 9.1.5.1 for the 
definition of pIMDs. 
The following events constitute contraindications to administration of study vaccine at 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 6.5), or the subject may be withdrawn from vaccination at the 
discretion of the investigator (see Section 9.5).  
• 
Acute disease and/or fever at the time of vaccination.  
− 
Fever is defined as temperature  38.0°C / 100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered study vaccines. 
7.6. 
Warnings and precautions 
Refer to the approved product label/package insert, if applicable 
7.7. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit/contact, the investigator or delegate should question the 
subject/subject’s LAR/caregiver about any medications/products taken and vaccinations 
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7.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the 30 day period following each dose of study vaccine (Day 1 
to Day 30). 
• 
Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and ending at Visit 3 (Day -30 to Day 90 [that is, 30 days 
post last vaccination]). 
• 
Prophylactic medication (that is, medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring.  
• 
Any medication used to treat HZ or its complications during the study period. 
• 
Any concomitant medications/products/vaccines listed in Section 7.7.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE /pIMD. In addition, concomitant medications relevant to SAEs 
and pIMD need to be recorded on the expedited Adverse Event report. 
7.7.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analysis 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 11.5 for cohorts to be analyzed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period.  
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(that is, more than 14 days in total) during the study period. For corticosteroids, this 
will mean prednisone  20 mg/day or equivalent. Inhaled, topical and intra-articular 
corticosteroids are allowed.  
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 


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• 
A vaccine not foreseen by the study protocol administered during the period starting 
30 days before and ending 30 days after the last dose of study vaccine 
administration* with the exception of licensed pneumococcal vaccines and non-
replicating vaccines (that is, inactivated and subunit vaccines, including inactivated 
and subunit influenza vaccines, with or without adjuvant for seasonal or pandemic 
flu) which may be administered up until 8 days prior to either dose and/or at least 14 
days after either dose of study vaccine. 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organized by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine, provided it is licensed and used according to its Summary of 
Product Characteristics (SmPC) or PI and according to the local governmental 
recommendations and provided a written approval of the Sponsor is obtained. 
• 
Immunoglobulins and/or any blood products administered during the study period. 
• 
Administration of cytotoxic chemotherapy at any time during the study period. 
• 
Receipt of a vaccine against HZ or VZV vaccine other than the study vaccine during 
the study period. 
7.8. 
Intercurrent medical conditions (IMC) that may lead to 
elimination of a subject from per-protocol analyses 
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any IMC. If it is the case, the condition(s) 
must be recorded in the eCRF (Table 22). 
An IMC is defined as a condition that has the capability of confounding the immune 
response to the study vaccine or its interpretation of HZ recurrence. Subjects may be 
eliminated from the per protocol set (PPS) for immunogenicity if they incur an IMC 
between dose 1 and one month post last vaccination. 
Examples of IMCs include cases of HZ or a confirmed or suspected immunosuppressive 
or immunodeficient condition resulting from disease (e.g., malignancy, HIV infection). 
8. 
HEALTH ECONOMICS 
Not applicable 


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9. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.  
Each subject/subject’s LAR(s)/caregiver will be instructed to contact the investigator 
immediately should they/the subject manifest any signs or symptoms they perceive as 
serious. 
9.1. 
Safety definitions 
9.1.1. 
Definition of an adverse event 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (that is lack of efficacy), abuse or misuse.  
Examples of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study vaccine 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 or a concurrent medication (overdose per se should not be reported as an 
AE/SAE). 
• 
Signs, symptoms temporally associated with study vaccine administration. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(that is invasive procedures, modification of subject’s previous therapeutic regimen). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 9.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 


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Examples of an AE DO NOT include: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.  
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.  
9.1.2. 
Definition of a serious adverse event  
A SAE is a subset of AEs and is any untoward medical occurrence that: 
• 
Results in death, 
• 
Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
• 
Results in disability/incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, 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. 
• 
Is a congenital anomaly/birth defect in the offspring of a study subject. 


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Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
9.1.3. 
Solicited adverse events 
9.1.3.1. 
Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 19 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
Injection site pruritus 
9.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: 
Table 20 
Solicited general adverse events 
Fatigue 
Fever 
Gastrointestinal symptoms † 
Headache 
Myalgia 
Shivering 
Malaise 
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
Note: Subjects/subject’s LAR (s)/caregiver will be instructed to measure and record the 
oral temperature in the evening. Should additional temperature measurements be 
performed at other times of day, subjects/subject’s LAR (s)/caregiver will be instructed to 
record the highest temperature in the diary card. 


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9.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events  
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. imaging studies) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. 
The investigator will exercise their medical and scientific judgement in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant. 
9.1.5. 
Adverse events of specific interest 
9.1.5.1. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 21. 
However, the investigator will exercise their medical and scientific judgement in deciding 
whether other diseases have an autoimmune origin (that is pathophysiology involving 
systemic or organ-specific pathogenic autoantibodies) and should also be recorded as a 
pIMD. 


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Table 21 
List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and paresis 
(e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome, 
including Miller Fisher syndrome 
and other variants. 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants e.g.: non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic inflammatory 
demyelinating polyneuropathy,  
- 
Multifocal motor neuropathy  
- 
Polyneuropathies associated 
with monoclonal gammopathy. 
• 
Narcolepsy. 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma (Systemic 
sclerosis), including: 
- 
Diffuse Scleroderma 
- 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis  
- 
Polymyositis  
• 
Anti-synthetase syndrome. 
• 
Rheumatoid Arthritis and 
associated conditions including:  
- 
Juvenile Idiopathic Arthritis 
- 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, including:  
- 
Ankylosing Spondylitis,  
- 
Reactive Arthritis (Reiter's 
Syndrome), 
- 
Undifferentiated 
Spondyloarthritis, 
- 
Psoriatic Arthritis, 
- 
Enteropathic arthritis. 
• 
Relapsing Polychondritis. 
• 
Mixed Connective Tissue 
disorder. 
• 
Gout. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous 
skin diseases 
(including pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localised Scleroderma 
(Morphoea). 
 


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Vasculitis 
Blood disorders 
Others 
• 
Large vessels vasculitis including:  
- 
Giant Cell Arteritis (Temporal Arteritis), 
- 
Takayasu's Arteritis.  
• 
Medium sized and/or small vessels 
vasculitis including:  
- 
Polyarteritis nodosa, 
- 
Kawasaki's disease,  
- 
Microscopic Polyangiitis,  
- 
Wegener's Granulomatosis 
(granulomatosis with polyangiitis),  
- 
Churg–Strauss syndrome (allergic 
granulomatous angiitis or eosinophilic 
granulomatosis with polyangiitis),  
- 
Buerger’s disease (thromboangiitis 
obliterans),  
- 
Necrotizing vasculitis (cutaneous or 
systemic),  
- 
anti-neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), 
- 
Henoch-Schonlein purpura (IgA 
vasculitis),  
- 
Behcet's syndrome, 
- 
Leukocytoclastic vasculitis. 
• 
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. 
• 
Idiopathic pulmonary fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel 
disease, including: 
- 
Crohn’s disease,  
- 
Ulcerative colitis,  
- 
Microscopic colitis,  
- 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave's or Basedow’s 
disease. 
• 
Diabetes mellitus type 
I. 
• 
Addison’s disease. 
• 
Polyglandular 
autoimmune syndrome. 
• 
Autoimmune 
hypophysitis. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
designate) must complete, date and sign an electronic Expedited Adverse Events Report. 


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9.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events  
9.2.1. 
Pregnancy 
Female subjects who are pregnant or lactating may not receive additional doses of study 
vaccine but may continue other study procedures at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE. 
Note: The pregnancy itself should always be recorded on an electronic pregnancy report. 
The following should always be considered as SAE and will be reported as described in 
Sections 9.4.1 and 9.4.3: 
• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different. 
• 
Any early neonatal death (that is death of a live born infant occurring within the first 
7 days of life).  
• 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion. 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 9.4.3. While the investigator is not obligated to 
actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting. 


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9.3. 
Detecting and recording adverse events, serious adverse 
events and pregnancies 
9.3.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
All AEs starting within 30 days following administration of each dose of study vaccine 
(Day 1 to Day 30) must be recorded in the Adverse Event screen in the subject’s eCRF, 
irrespective of intensity or whether or not they are considered vaccination-related. 
The standard time period for collecting and recording SAEs will begin at the first receipt 
of study vaccine and will end at Month 14 contact (that is, approximately 12 months 
following administration of the last dose of the study vaccine for each subject). See 
Section 9.4 for instructions on reporting of SAEs.  
SAEs that are related to the investigational product will be collected and recorded from 
the time of the first receipt of study vaccine/placebo until the subject is discharged from 
the study. 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (that is, 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine or any fatal SAE will be collected and 
recorded from the time the subject consents to participate in the study until she/he is 
discharged from the study 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first study visit until she/he is discharged from the study. 
The standard time period for collecting and recording pregnancies will begin at the first 
receipt of study vaccine and will end at Month 14 contact (that is, approximately 12 
months following administration of the last dose of the study vaccine for each subject). 
See section 9.4 for instructions on reporting of pregnancies. 
The standard time period for collecting and recording of pIMDs will begin at the first 
receipt of study vaccine and will end at Month 14 contact (that is, approximately 12 
months following administration of the last dose of the study vaccine for each subject). 
See section 9.4 for instructions on reporting of pIMDs. 
The time period for collecting and recording of IMCs (including HZ) will begin at the 
first receipt of study vaccine and will end at the end of the study. 
An overview of the protocol-required reporting periods for AEs, SAEs, IMCs and 
pregnancies is given in Table 22. 


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Table 22 
Reporting periods for collecting safety information 
Events 
Dose 1 
(Visit 1) 
7 
days 
Post 
first 
Dose 
30 
days 
Post 
first 
Dose 
 
Dose 2 
(Visit 
2) 
7 days 
Post 
last 
vaccinat
ion 
30 days 
Post last 
vaccination 
(Visit 3) 
One year 
Post last 
vaccination 
Monthly 
contact 
until study 
end* 
Day 1 
 
 
 
Month 
2 
 
Month 3 
Month 14 
 
Timing of 
reporting 
Day 1 
Day 7 Day 30 
 
Day 1 
Day 7 
Day 30 
 
 
Solicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs 
leading to 
withdrawal from 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
the study 
vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study 
participation or 
concurrent GSK 
medication/ 
vaccine a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMCs (excluding 
HZ episodes)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HZ episodes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HZ related 
complication 
(including SAE 
information) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE= Adverse event; HZ= Herpes Zoster; IMC= Intercurrent medical condition; pIMDs= potential immune mediated 
diseases; SAE= serious adverse event 
Note: For each solicited and unsolicited AEs the subject experiences, the subject will be asked if he/she received 
medical attention defined as hospitalization, an emergency room visit or a visit to or from medical personnel (medical 
doctor) for any reason and this information will be recorded in the eCRF. 


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a SAEs related to study participation or GSK concomitant medication/vaccine are to be recorded from the time the 
subject consents to participate in the study. All other SAEs are to be reported after administration of the first dose of 
vaccine. 
* Study conclusion will be scheduled based on the projected date of the last contact of the last enrolled subject, that is 
26 months (790 days) from the enrolment date. 
9.3.2. 
Post-Study adverse events and serious adverse events 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 22. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study vaccine the investigator will promptly notify the 
Study Contact for Reporting SAEs. 
9.3.3. 
Evaluation of adverse events and serious adverse events 
9.3.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject or the subject’s LAR/caregiver 
should be asked a non-leading question such as: 
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 


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9.3.3.2. 
Assessment of adverse events 
9.3.3.2.1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 23 
Intensity scales for solicited AEs in adults  
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing normal every 
day activities. 
2 
Moderate: Painful when limb is moved and interferes with every day 
activities. 
3 
Severe: Significant pain at rest. Prevents normal every day 
activities. 
Redness at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Pruritus at injection site 
0 
None 
1 
Mild: Itchy sensation that neither interferes with nor prevents normal 
activities 
2 
Moderate: Itchy sensation that interferes with normal activity 
3 
Severe: Itchy sensation that prevents normal activity 
Fever* 
Record temperature in °C 
Headache 
0 
None 
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 
Gastrointestinal symptoms 
(nausea, vomiting, diarrhoea 
and/or abdominal pain) 
0 
None 
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 
Myalgia 
0 
None  
1 
Mild: Myalgia that is easily tolerated 
2 
Moderate: Myalgia that interferes with normal activity 
3 
Severe: Myalgia that prevents normal activity 
Shivering 
0 
None 
1 
Shivering that is easily tolerated 
2 
Shivering that interferes with normal activity 
3 
Shivering that prevents normal activity 
Malaise 
0 
None 
1 
Malaise that is easily tolerated 
2 
Malaise that interferes with normal activity 
3 
Malaise that prevents normal activity 
*Fever is defined as temperature  38.0°C / 100.4°F. The preferred route for measuring temperature in this study will 
be the oral cavity. If the temperature is taken by another route (axillary, rectal or tympanic), the route should be 
documented. 


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The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows using GSK Biologicals’ standard grading scale based on the US 
Food and Drug Administration (FDA) guidelines for Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers enrolled in Preventive Vaccine Clinical Trials [FDA, 
2007]: 
0 
: 
< 20 mm diameter 
1 
: 
 20 mm to  50 mm diameter 
2 
: 
> 50 mm to  100 mm diameter 
3 
: 
> 100 mm diameter 
Fever will be graded as: 
0 
: 
<38.0°C 
1 
: 
38.0°C – 38.4°C 
2 
: 
38.5°C – 39.0°C  
3 
: 
>39.0°C 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
The intensity should be assigned to one of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
In adults, such an AE would, for example, prevent attendance at 
work and would necessitate the administration of corrective 
therapy. 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2. 


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9.3.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement.  
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 will be considered and investigated. The investigator will also consult the 
IB and/or SmPC and/or Prescribing Information for marketed products to determine 
his/her assessment. 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES 
: 
There is a reasonable possibility that the study vaccine contributed to the 
AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have 
contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 


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9.3.3.3. 
Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
9.3.3.4. 
Medically attended visits 
For each solicited and unsolicited AE/SAE the subject experiences, the subject/subject’s 
LAR/caregiver will be asked if he/she /the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit by medical personnel for any reason, 
including emergency room visits. This information will be recorded in the eCRF 
(Amended 14 April 2020). 
9.4. 
Reporting of serious adverse events, pregnancies, and 
other events 
9.4.1. 
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals 
SAEs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 24, once the investigator determines that 
the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 9.3 will be reported promptly 
to GSK within the timeframes described in Table 24, once the investigator becomes 
aware of the pregnancy.  
pIMDs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 24, once the investigator determines that 
the event meets the protocol definition of a pIMD. 


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Table 24 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Pregnancies  
2 weeks* 
electronic pregnancy report  
2 weeks* 
electronic pregnancy 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. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD  
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD. 
9.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs 
Study Contact for Reporting SAEs, pIMDs and pregnancies  
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs, pIMDs and pregnancies  
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
9.4.3. 
Completion and transmission of SAE reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 


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9.4.3.1. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
9.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS. 
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
9.4.5. 
Reporting of pIMDs to GSK Biologicals 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
designate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
event, in accordance with the pIMD standard questionnaire provided. Even if the 
investigator does not have all information regarding a pIMD, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD. 
Refer to Section 9.4.3.1 for back-up system in case the electronic reporting system does 
not work. 


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9.4.6. 
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF 
When additional SAE, pregnancy, or pIMD information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 24. 
9.4.7. 
Regulatory reporting requirements for serious adverse events 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccine and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation. 
9.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
9.5.1. 
Follow-up of adverse events and serious adverse events  
9.5.1.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals. (within 24 hours of receipt of information regarding the SAEs; refer to Table 
24). 
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
last visit of the subject. 


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9.5.1.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
• 
With SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilized, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up. 
• 
With other non-serious AEs until they are resolved/until study end or they are lost to 
follow-up. If the investigator receives additional relevant information on a previously 
reported SAE, he/she will provide this information to GSK Biologicals using a 
paper/ electronic Expedited Adverse Events Report and/or pregnancy report as 
applicable. 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
9.5.2. 
Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE. 
9.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE / pIMDs 
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 7.7). 
9.7. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency when knowledge of the treatment is essential for the clinical 
management or welfare of the subject. 
The emergency unblinding process consists of the automated Internet-based system 
(SBIR) that allows the investigator to have unrestricted, immediate and direct access to 
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As back up process, the investigator has the option of contacting a GSK Helpdesk if 
he/she needs support to perform the unblinding (i.e. he/she cannot access the automated 
Internet-based system). 
Non-investigator physician (e.g. physician from emergency room) or subject/care 
giver/family member can also request emergency unblinding either via the investigator 
(preferred option) or via the GSK Helpdesk (back up process). Contact details of 
investigator and GSK Helpdesk are reported in the patient/subject card. 
GSK Helpdesk 
24/24 hour and 7/7 day availability 
The Helpdesk is available by phone, fax and email 
Phone: +32.2.656.68.04 
Fax: +32.2.401.25.75 
email: rix.ugrdehelpdesk@gsk.com 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician, but can still be followed-up for safety. The relevant 
event or condition will be recorded in the eCRF. 
GSK Vaccines Clinical Safety and Pharmacovigilance (VCSP) staff may unblind the 
treatment assignment for any subject in case of Suspected Unexpected Serious Adverse 
Reaction (SUSAR) as well as in case of fatal or life threatening cases. If the SAE requires 
that an expedited regulatory report be sent to 1 or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
9.8. 
Subject card 
Study subjects/subjects’ LAR/caregiver must be provided with the address and telephone 
number of the main contact for information about the clinical study. 
The investigator (or designate) must therefore provide a “subject card” to each 
subject/subject’s LAR/caregiver. In an emergency situation this card serves to inform the 
responsible attending physician that the subject is in a clinical study and that relevant 
information may be obtained by contacting the investigator. 
Subjects / subjects’ LAR/caregiver must be instructed to keep subject cards in their 
possession at all times during the study duration. 
10. 
SUBJECT COMPLETION AND WITHDRAWAL 
10.1. 
Subject completion 
A subject who is available for the concluding contact foreseen in the protocol is 
considered to have completed the study. 


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10.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
10.2.1. 
Subject withdrawal from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol.  
All data collected until the date of last contact of the subject will be used for the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, by the subject’s LAR/caregiver or by the investigator, as well 
as which of the following possible reasons was responsible for withdrawal: 
• 
SAE. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE 
• 
HZ episode 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an AE*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because he/she/the subject’s caregiver has 
withdrawn consent, the investigator will document the reason for withdrawal of consent, 
if specified by the subject/subject’s LAR/caregiver, in the eCRF. 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.5.1.2). 


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10.2.2. 
Subject withdrawal from study vaccine 
A ‘withdrawal’ from the study vaccine refers to any subject who does not receive the 
complete treatment, that is when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol.  
Information relative to premature discontinuation of the study vaccine should be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject himself/herself , by the subject’s LAR(s) , or by the investigator, as well as which 
of the following possible reasons was responsible for withdrawal: 
• 
SAE. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE 
• 
Not willing to be vaccinated 
• 
HZ 
• 
Other (specify). 


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11. 
STATISTICAL METHODS 
11.1. 
Primary endpoint 
Occurrence of confirmed HZ episodes from 30 days post second vaccination until study 
end.  
11.2. 
Secondary endpoints 
• 
Occurrence of confirmed HZ episodes from first study vaccination until study end. 
• 
Reactogenicity and safety, in all subjects  
− 
Occurrence, intensity and duration of each solicited local AE within 7 days 
(Days 1-7) after each vaccination. 
− 
Occurrence, intensity, duration and relationship to vaccination of each solicited 
general AE within 7 days (Days 1-7) after each vaccination.  
− 
Occurrence, intensity, duration and relationship to vaccination of unsolicited 
AEs within 30 days (Days 1-30) after each vaccination, according to the 
Medical Dictionary for Regulatory Activities (MedDRA) classification.  
− 
Occurrence and relationship to vaccination of all SAEs from dose 1 up to 30 
days post last vaccination.  
− 
Occurrence and relationship to vaccination of any pIMDs from dose 1 up to 30 
days post last vaccination.  
− 
Occurrence and relationship to vaccination of all SAEs within the period starting 
after 30 days post last vaccination until 1 year post last vaccination. 
− 
Occurrence and relationship to vaccination of any pIMDs within the period 
starting after 30 days post last vaccination until 1 year post last vaccination. 
− 
Occurrence of SAEs related to investigational vaccine, related to study 
participation or to GSK concomitant medication/vaccine during the entire study 
period.  
• 
Immunogenicity, in all subjects 
− 
Vaccine response for anti-gE humoral immunogenicity as determined by ELISA 
at Month 2 and Month 3.  
− 
Anti-gE antibody concentrations as determined by ELISA at Day 1, Month 2 
and Month 3.  
CCI


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CCI


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11.4. 
Determination of sample size 
The sample size determination enables the evaluation of the non-inferiority of HZ 
recurrence incidence rate, and to rule out a 5-fold increased risk of HZ recurrence in the 
HZ/su group compared to the placebo group. The following assumptions were made: 
• 
Incidence rate of HZ recurrence in the placebo group= 0.55% per year. 
• 
Incidence rate of HZ recurrence in the HZ/su group= 0.275% per year, assuming a 
50% vaccine efficacy. 
• 
Power of 90% and Type I error of 0.025 (one-sided). 
• 
Criterion for non-inferiority = 5-fold; the 5-fold criterion has been selected as 
acceptable for ruling out a moderate increased risk of HZ in a clinical trial setting. 
Let π be the ratio of incidence rate of HZ recurrence in HZ/su group vs the placebo 
group, then null hypothesis H0: π ≥ 5 vs. alternative hypothesis Ha: π < 5. With the 
assumption that the number of HZ recurrence cases in HZ/su and placebo group follows 
Poisson distribution independently, conditioning on the total number of cases, the number 
of cases in HZ/su group would follow the binomial distribution [Lehmann, 1959]. With 
1:1 randomization, the parameter p in the binomial distribution (that is, the probability of 
HZ recurrence in HZ/su group) is expected to be p=π/(1+π). Therefore, the above 
hypotheses becomes: H0: p ≥0.8333 vs. Ha: p < 0.8333. Under the assumption of VE of 
50%, a total number of 10 HZ recurrence cases is needed (PASS 12: Tests for One 
Proportion using proportions (Exact Test)). With incidence rate of 0.55% per year and 
two year follow up, 606 evaluable subjects per group are needed. Further assuming a 
dropout rate of 15% during the 2 year follow up period, 713 subjects per group (a total of 
1426 subjects) need to be enrolled.  
11.4.2. 
Time since previous HZ sub-groups and age category 
• 
To allow a descriptive analysis of the results the target will be to enrol a minimum 
of: 
• 
143 subjects in each (≤ 4 years ago, 5-9 years ago, ≥ 10 years ago) “time since 
previous HZ episode” category. 
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• 
285 subjects in 50-59 and 60-69 YOA category and 143 subjects in 70 YOA 
category. 
11.5. 
Cohorts for Analyses 
11.5.1. 
Exposed Set 
The exposed set (ES) will include all vaccinated subjects with at least one study vaccine 
administered.  
The ES for analysis of immunogenicity will include all vaccinated subjects for whom 
data related to immunogenicity endpoints are available. 
The ES for analysis of reactogenicity will include all subjects with at least one vaccine 
administration documented. 
11.5.1.1. 
Modified Exposed Set 
The modified exposed set (mES) is the primary population for HZ recurrence analysis. 
The mES excludes subjects in the ES who were not administered the second dose of the 
study vaccine or who developed a confirmed case of HZ prior to 30 days after the second 
vaccination. 
11.5.2. 
Per Protocol Set for immunogenicity  
The per protocol set (PPS) for immunogenicity will be defined by time-point (Month 2 
and Month 3) and will include evaluable subjects from the ES: 
• 
who meet all eligibility criteria. 
• 
who received 2 doses of the HZ/su study vaccine or placebo according to their 
random assignment.  
• 
who did not receive forbidden medications as defined in the protocol. 
• 
who had no IMC which may influence immune response. 
• 
who complied with the vaccination schedule as specified in Table 9. 
• 
who complied with the blood sample schedule as specified in Table 9. 
• 
for whom data concerning immunogenicity endpoint measures are available. 
11.6. 
Derived and transformed data 
11.6.1. 
Handling of missing data 
For the analysis of solicited AEs, missing or non-evaluable measurements will not be 
replaced. Therefore, the analysis of the solicited AEs based on the ES will include only 
subjects/doses with documented safety data (that is symptom screen/sheet completed). 


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For the analysis of HZ recurrence/unsolicited AEs/SAEs/pIMDs/concomitant medication, 
all vaccinated subjects will be considered and subjects who did not report an event will 
be considered as subjects without an event. 
For a given subject and a given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. Therefore, an analysis will exclude subjects with 
missing or non-evaluable measurements. 
11.7. 
Analysis of demographics 
Demographic characteristics (age at first study vaccination in years, gender and 
ethnicity), ‘time since previous HZ episode’, age stratum and withdrawal status will be 
summarized by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as age stratum, ‘time 
from previous HZ episode’ and gender. 
• 
Mean, median, Standard Deviation (SD) will be provided for continuous data such as 
age. 
• 
The analysis will be based on ES. 
11.8. 
Analysis of incidence rate of Herpes Zoster recurrence 
For each group, the number of subjects, person-time, number of confirmed HZ cases and 
incidence rate will be tabulated. 
A formal non-inferiority analysis with a non-inferiority margin of 5 will be performed in 
the final analysis. Non-inferiority assessment will be carried out based on the fact that the 
distribution of two Poisson variates conditional on their sum is binomial [Lehmann, 
1959]. Let n1 and n0 be the number of HZ recurrence cases, T1 and T0 (years) be total 
follow up, and r1 and r0 be the incidence rate in HZ/su group and placebo group 
respectively. It is assumed that ni ~ Poisson(λi) (i=0,1) and λi=Ti×ri, and condition on 
n=n0+n1, n1 ~ binomial(n, p), where p=λ1/(λ1+λ0). A 95% exact CI for p can be derived 
by using Clopper-Pearson approach, through which a 95% exact CI for π=r1/r0 (that is, 
the ratio of incidence rate of HZ recurrence (HZ/su versus placebo)) can be derived. Non-
inferiority is met if the upper limit of the 95% CI for π is below 5. 
In addition to performing a formal non-inferiority analysis, to further quantify the 
likelihood of the risk increase of HZ following Shingrix vaccination, a probability curve 
that the ratio of incidence of HZ recurrence (HZ/su versus placebo) is higher than x-fold 
(x varying from 1 to 5) will be estimated by Bayesian methodology. It will be assumed 
that the number of HZ cases in the HZ/su and in placebo groups follows Poisson 
distribution with rate (incidence rate) of λHZ and λp respectively. We further assume that 
λHZ and λp are random variables both with non-informative Gamma prior distribution: 
Gamma(0.001, 0.001). Based on the posterior distribution of λHZ and λp, the probability 
curve of the ratio of incidence of HZ recurrence (HZ/su versus placebo), that is, 
Pr(λHZ/λp>x| data, prior), can be calculated for each given value of x. This will be further 
detailed in the statistical analysis plan (SAP). 


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The primary analysis of incidence rate of HZ recurrence will be based on the mES. The 
analysis will be repeated for the ES. 
11.9. 
Analysis of immunogenicity 
The primary analysis will be based on the PPS for analysis of immunogenicity. If, in any 
group, the percentage of vaccinated subjects with serological results excluded from the 
PPS for analysis of immunogenicity is 5% or more, a second analysis based on the ES 
will be performed to complement the PPS analysis. 
11.9.1. 
Humoral immune response 
A seronegative subject is a subject whose Ab concentration is below the cut-off value. 
A seropositive subject is a subject whose Ab concentration is greater than or equal to the 
cut-off value. 
The seropositivity rate is defined as the percentage of seropositive subjects. 
The vaccine response rate (VRR) for anti-gE is defined as the percentage of subjects who 
have at least: 
• 
a 4-fold increase in the post last vaccination anti-gE Ab concentration as compared 
to the pre-vaccination anti-gE Ab concentration, for subjects who are seropositive at 
baseline, or,  
• 
a 4-fold increase in the post last vaccination anti-gE Ab concentration as compared 
to the anti-gE Ab cut-off value for seropositivity, for subjects who are seronegative 
at baseline. 
The geometric mean concentration (GMC) calculations are performed by taking the 
anti-log of the mean of the log concentration transformations. For descriptive statistics 
only, Ab concentrations below the cut-off of the assay will be given an arbitrary value 
equal to half the cut-off for the purpose of GMC calculation. 
Within groups assessment 
The following descriptive analyses will be performed for each group and by age stratum 
(50-59 YOA; 60-69 YOA and ≥70 YOA) and by ‘time since previous HZ episode’ (≤4 
years ago, 5-9 years ago, ≥10 years ago): 
• 
Seropositivity rate at Day 1, Month 2 and Month 3 with exact 95% CI 
• 
GMC at Day 1, Month 2 and Month 3 with 95% CI 
• 
VRR at Month 2 and Month 3 with exact 95% CI 
• 
Descriptive statistics of the fold over pre-vaccination at Month 2 and Month 3 
(Mean, SD, Min, Q1, Median, Q3, Max). 


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11.10. 
Analysis of safety 
The analysis will be performed on the ES. When appropriate, tabulations will be 
presented overall and by time of occurrence relative to last vaccination (e.g., using 
windows such as Days 1-7, Days 1-30 and more than 30 days post-vaccination). Safety 
analyses will also be performed by age stratum (50-59 YOA; 60-69 YOA and ≥70 YOA) 
and by ‘time since previous HZ episode’ (≤4 years ago, 5-9 years ago, ≥10 years ago). 
The results for the analysis of safety will be tabulated as: 
• 
The proportion of subjects with at least one local AE (solicited or unsolicited), with 
at least one general AE (solicited or unsolicited) and with any AE (solicited or 
unsolicited) during the solicited 7-day follow-up period will be tabulated with exact 
95% CI after each vaccine dose and overall. 
• 
The proportion of subjects with at least one local AE (solicited only), with at least 
one general AE (solicited only) and with any AE (solicited only) during the solicited 
7-day follow-up period will be tabulated with exact 95% CI after each vaccine dose 
and overall. 
• 
The proportion of subjects reporting each individual solicited local and general AE 
during the solicited 7-day-follow-up period will be tabulated with exact 95% CI. 
• 
For all solicited AEs, the same tabulation will be performed for grade 3 solicited AEs 
and for solicited general AEs with relationship to vaccination  
• 
The proportion of solicited AEs resulting in a medically attended visit will be 
tabulated. 
• 
Total duration of each individual solicited local and general AE will be tabulated. 
• 
The proportion of subjects reporting temperature by half degree (°C) cumulative 
increments. Similar tabulations will be performed for any fever with a causal 
relationship to vaccination and for any fever resulting in a medically attended visit. 
• 
The proportion of subjects with at least one report of unsolicited AE classified by the 
MedDRA system organ class (SOC) and preferred term (PT) and reported up to 30 
days after each vaccination will be tabulated with exact 95% CI. 
• 
The same tabulation will be performed for grade 3 unsolicited AEs and for 
unsolicited AEs with a relationship to vaccination. The proportion of AEs resulting 
in a medically attended visit will also be tabulated. 
• 
Total number/percentages of doses (per dose and overall) followed by AEs will be 
tabulated. 
• 
All pIMDs and related pIMDs occurring from first vaccination up to 30 days post 
last vaccination will be tabulated. 
• 
All pIMDs and related pIMDs occurring after 30 days post last vaccination until 1 
year post last vaccination will be tabulated. 
• 
All SAEs, related SAEs occurring from first vaccination up to 30 days post last 
vaccination will be tabulated. 


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• 
All SAEs, related SAEs occurring after 30 days post last vaccination until one year 
post last vaccination will be tabulated. 
• 
Fatal SAEs will be tabulated using date of onset of SAE in the following manner – 
within Day 1-Month 3 (30 days post last vaccination), Day 1 to Month 14 (one year 
post last vaccination) and Month 3 till study end. Fatal SAEs will also be tabulated 
using the date of death within the same time periods. 
• 
All SAE related to investigational vaccine, related to study participation or to GSK 
concomitant medication/vaccine occurring during the entire study period will be 
tabulated.  
• 
AEs/SAEs leading to withdrawal from the study will be tabulated. 
11.11. 
Interpretation of analyses 
The primary objective of non-inferiority of the incidence of HZ recurrence in the HZ/su 
and placebo groups is considered met if the upper limit of the 95% CI of the ratio of the 
incidence of HZ recurrence (HZ/su versus placebo) is below 5. For all secondary 
objectives, analyses will be descriptive with the aim to characterize the differences in 
reactogenicity, safety and immunogenicity between groups. 
11.11.1. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
11.11.2. 
Sequence of analyses 
There will be only one final analysis following end of the study.  
A clinical study report containing all data will be written and made available to the 
investigators. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These data will be documented in annex(es) to the 
study report. 
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11.11.3. 
Statistical considerations for interim analyses 
No interim analyses are planned. 
12. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.  
12.1. 
electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.  
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data.  
The investigator will be provided with a validated GSK system to download the final 
version of the data generated at the investigational site. 
12.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst other items, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.  
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we verify eCRF entries by comparing them with the source 
data that will be made available by the investigator for this purpose.  


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The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.  
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP and GSK procedures. 
12.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.  
12.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 


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12.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol. 
As per EU regulation, summaries of the results of GSK interventional studies (phase I-
IV) in adult populations conducted in at least one EU member state will be posted on 
publicly available EMA registers within 12 months of EoS (as defined in the protocol) in 
the concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification 
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors. 
12.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
12.7. 
Data Sharing 
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions. 
13. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable 


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14. 
REFERENCES 
Carter WP, Germann CA, Baumann MR. Ophthalmic diagnoses in the ED: herpes zoster 
ophthamicus. Am. J. Ophthalmol. 2008; 612– 617. 
CDC. Prevention of herpes zoster. Recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. 2008; 57: 1-30. 
Centres for Disease Control (CDC) and Prevention Metropolitan Atlanta Congenital 
Defects Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-
digit code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf. 
Cohen JI, Straus SE, Arvin AM. Varicella zoster virus and its replication. 2007; p. 2774-
2818. In D. M. Knipe and P. M. Howley (ed.), Fields virology, 5th ed. Lippincott/The 
Williams & Wilkins Co., Philadelphia, PA. 
Cunningham AL, Lal H, Kovac M, et al., Efficacy of the Herpes Zoster Subunit Vaccine 
in Adults 70 Years of Age or Older. N Engl J Med. 2016; 375(11): 1019-32. 
Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of 
herpes zoster. Clin Infect Dis. 2007;44 Suppl 1:S1–26. 
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006); 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf. 
FDA, U.S. Department of Health and Human Services, Center for Biologics Evaluation 
and Research. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Version of 
September 2007. 
Gilden D, Cohrs RJ, Mahalingam R, et al. Varicella zoster virus vasculopathies: diverse 
clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet 
Neurology. 2009;8(8):731–740. 
Godeaux O, Kovac M, Shu D, et al., Immunogenicity and safety of an adjuvanted herpes 
zoster subunit candidate vaccine in adults ≥ 50 years of age with a prior history of herpes 
zoster: A phase III, non-randomized, open-label clinical trial. Hum Vaccin Immunother. 
2017; 13(5): 1051-58 
Lal H, Cunningham AL, Godeaux O et al. Efficacy of an Adjuvanted Herpes Zoster 
Subunit Vaccine in Older Adults. N Engl J Med. 2015: DOI: 10.1056/NEJMoa1501184. 
Lehmann, E.L. (1959) Testing Statistical Hypotheses, New York, Wiley 


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Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine 
to prevent herpes zoster and post-herpetic neuralgia in older adults. N Engl J Med. 2005; 
352: 2271-84. 
Schmader KE, Dworkin RH. Natural history and treatment of herpes zoster. The Journal 
of pain. 2008;9(1):S3–S9. 
Sperber SJ, Smith BV, Hayden FG. Serologic response and reactogenicity to booster 
immunization of healthy seropositive adults with live or inactivated varicella vaccine. 
Antiviral Res. 1992; 17: 213-22. 
Tseng HF, Chi M, Smith N, et al., Herpes Zoster Vaccine and the Incidence of Recurrent 
Herpes Zoster in an Immunocompetent Elderly Population, J Infect Dis, 2012, 
206(2):190-6: 190–196 
Yawn BP, Wollan PC, Kurland MJ et al., Herpes zoster recurrences more frequent than 
previously reported, Mayo Clin Proc, 2011, vol. 86 (pg. 88-93). 


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15. 
APPENDICES 
APPENDIX A 
LABORATORY ASSAYS 
Specific Ab (anti-gE) measurements: 
Anti-gE ELISA: Anti-gE Ab concentrations will be measured using an anti-gE ELISA. 
Diluted blood serum samples of study subjects will be added to microtiter wells pre-
coated with gE antigen. Secondary peroxidase-conjugated anti-human Abs will be added, 
which bind to the primary human anti-gE Abs. After incubation of the microtiter wells 
with a chromogen substrate solution, the enzymatic reaction will be stopped. Optical 
densities will be recorded and anti-gE Ab concentrations are calculated from a standard 
curve. The assay cut-off is 97 mIU/ml. 
PCR assay for confirmation of suspected case of HZ: HZ cases will be confirmed by a 
PCR based algorithm that assesses the presence of VZV Deoxyribonucleic Acid (DNA) 
in samples, and the adequacy of the samples (by assessing the presence of β-actin DNA). 
VZV and β-actin DNA in HZ clinical specimens will be assessed using real-time PCR 
detection by the 5’ nuclease assay based on the Taqman probe technology. If the VZV 
PCR is negative, β-actin PCR will be performed to assess adequacy of the sample and if a 
specimen is found to be VZV–PCR negative and β-actin–PCR negative, it is considered 
to be inadequate. 
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In the Taqman-based PCR experiments, the formation of a PCR product is monitored in 
real-time during amplification by means of fluorogenic probes that bind specifically to 
the amplified product. The reporter fluorophore is at the 5’ end of the Taqman probe and 
the quencher is at the 3’ end. As long as the probe is intact, no fluorescence is produced 
by the fluorophore. During the PCR polymerization step, the Taq DNA polymerase 
displaces the Taqman probe by 3-4 nucleotides, and the 5’ nuclease activity of the DNA 
polymerase separates the fluorophore from the quencher, and a measurable fluorescent 
signal proportional to the DNA copy number is produced. 
As mentioned above, the 5' nuclease-based PCR assay allows the determination of the 
DNA copy number within samples, but in the present study the VZV and β-actin DNA 
PCR data on samples from suspected HZ lesions (swabs of vesicles, papules and crusts, 
and crusts themselves) will be used qualitatively only according to the above mentioned 
approach. 
• 
Ascertainment of HZ cases including the PCR testing algorithm to classify HZ 
suspected cases 
A suspected case of HZ will be documented by digital photography of the rash (if rash is 
present) and by collecting any relevant information as described in the clinical protocol. 
To classify the suspected case of HZ, the samples from the rash lesions (if available) will 
be collected for laboratory testing by PCR (3 samples, collected on the same day, per 
subject). If during clinical evaluation at Visit HZ-1, the investigator determines that 
adequate rash lesion samples cannot be collected (that is, less than three lesions present, 
or if only papules are present), the investigator has the option of collecting three 
additional samples preferably within 7 days, or at the Visit HZ-2 if there is rash 
progression (that is, appearance of new/additional lesions if originally less than three 
lesions present, or appearance of vesicles if originally only papules present). When the 
subject returns for repeat sample collection, if possible, three samples from separate 
lesions should be collected. Refer to the central lab manual for further details on sample 
collection. 
Each rash lesion will be tested using standardised and validated molecular assays 
according to the PCR testing algorithm described below. 
A hierarchical case definition algorithm used in GSK’s Phase III efficacy trials, similar to 
the algorithm used by Merck in their Shingle Prevention Study (Zostavax efficacy study) 
[Oxman, 2005] will be used to classify each suspected case of HZ as a confirmed HZ 
case or not. 
• 
If at least 1 sample coming from a given subject is “VZV positive” by PCR (as 
defined below), the PCR algorithm will classify the “suspected HZ case” as a 
“confirmed case of HZ”. 
• 
If all the samples coming from a given subject are “VZV negative” (as defined 
below), then β-actin PCR will be performed. If one or more “VZV negative” samples 
are “β-actin positive”, this means that the sampling procedure is valid and that the 
“suspected HZ case” will be classified as “not a case of HZ.” 


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• 
If PCR results for a particular subject do not confirm or exclude a “suspected HZ 
case” (that is, samples coming from a given subject are considered as “inadequate” 
as both VZV and β-actin PCR results are negative, or no samples are available for 
the subject), only then will the classification by the HZAC be used to confirm or 
exclude the suspected HZ case. The HZAC will consist of physicians with HZ 
expertise. For every suspected HZ case, each HZAC member will be asked to make a 
clinical determination of whether the case is HZ based on review of the available 
clinical information. A “suspected HZ case” will be considered as “HZ” if all HZAC 
members concur (unanimous decision); otherwise, it will be classified as “not HZ”. 
This algorithm includes the following steps (see Figure 2): 
1. DNA extraction from the rash lesion. 
2. VZV real-time PCR assay (PCR) targeting the orf62 gene is performed to detect 
VZV in the rash lesion: 
• 
If the VZV PCR signal is ≥ the cut-off level, that is, the technical limit of detection 
(LOD) of the assay (10 VZV DNA copies), the sample will be considered as “VZV 
positive”. 
• 
If the VZV PCR signal is above 0 copy/PCR but below the cut-off level of the assay, 
it will be considered as “VZV borderline” and will be re-tested twice in order to 
obtain 3 results per sample. The sample will be considered as “VZV positive” if at 
least 2 results out of the three obtained are ≥ the cut-off level of the assay and it will 
be considered “VZV negative” if fewer than 2 samples are ≥ the cut-off level of the 
assay. 
• 
If the VZV PCR signal is equal to 0 copies/PCR, the sample will be considered as 
“VZV negative”. If every sample is VZV negative, then extracted DNA from the 
samples will be assessed for the presence of β-actin DNA to confirm the validity of 
the rash lesion sampling procedure (see step 3). 
3. As described above, if all the samples are VZV negative for a given subject, then β-
actin PCR will be performed on “VZV negative” samples to confirm the validity of 
the sampling procedure. 
• 
If the β-actin PCR signal is below the cut-off level of the assay (β-actin Negative), 
the sample will be considered as “inadequate” as no β-actin DNA from human cells 
is detected within the rash lesion sample. If all samples are β-actin Negative, then the 
classification by the HZAC will be used to confirm or exclude the HZ case. 
• 
If the β-actin PCR signal is ≥ the cut-off level of the assay (β-actin Positive), the 
sample will be considered as “valid” but without any VZV DNA. If at least one 
sample is β-actin Positive, then the HZAC classification of a suspected HZ case, will 
not be part of the decision-making process for HZ case confirmation. 
Note: The cut-off level of the VZV PCR and β-actin PCR assays is defined as the 
technical limit of detection of these assays (LOD; that is, lowest concentration that can be 
detected by PCR in at least 95% of the tests). 


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Figure 2 
Algorithm for HZ case definition by PCR 
 
VZV: Varicella Zoster Virus; PCR: real-time Polymerase Chain Reaction; DNA: Deoxyribonucleic Acid; ORF: Open 
Reading Frame; HZAC: Herpes Zoster Ascertainment Committee. 
* If the VZV PCR signal is above 0 copy/PCR but below the cut-off level of the assay, it will be considered as “VZV 
borderline” and will be re-tested twice in order to obtain 3 results per sample. The sample will be considered as “VZV 
positive” if at least 2 results out of the three obtained are ≥ the cut-off level of the assay and it will be considered “VZV 
negative” if fewer than 2 results are ≥ the cut-off level of the assay. See then below ‘All samples are VZV Negative’. 
Note: The cut-off level of the VZV PCR assay was defined as the technical limit of detection of the assay (LOD of 10 
VZV DNA copies; that is, lowest concentration that can be detected by PCR in at least 95% of the tests) 


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APPENDIX B 
CLINICAL LABORATORIES 
Table 25 
GSK Biologicals’ laboratories 
Laboratory 
Address 
GSK Biologicals Clinical Laboratory Sciences, Rixensart 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Clinical Laboratory Sciences, Wavre-Nord Noir 
Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
Table 26 
Outsourced laboratories 
Laboratory 
Address 
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APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 1 
eTrack study number 
and Abbreviated Title 
204939 (ZOSTER-062) 
IND number 
BB-IND-13857 
EudraCT number 
2016-000744-34 
Amendment number: 
Amendment 1 
Amendment date: 
18 March 2019 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes:  
This protocol amendment incorporates feedback from regulatory authorities with the 
following changes: 
• 
The primary objective has been revised to a formal non-inferiority analysis with 
revised success criterion for non-inferiority. Consequently, the sample size was 
adjusted from 986 to 1426 subjects. 
• 
To capture
episodes developing after Day HZ-92 according to the protocol 
definition, the time frame for completing the Zoster Brief Pain Inventory (ZBPI) 
questionnaire has been clarified. Subjects with suspected herpes zoster (HZ) are 
required to complete the questionnaire until a 4-week pain-free period is 
documented. This amendment clarifies procedures for monitoring
in subjects 
who have ongoing symptoms beyond Day HZ-92. 
• 
In the tabulation of safety analyses, the collection period for fatal serious adverse 
events (SAEs) is updated. 
Other changes include: 
• 
The timeframe for primary endpoint (confirmed HZ episodes) is corrected to 30 
days post second vaccination instead of 30 days post last vaccination. 
• 
Grading of fever is added to Section 9.3.3. 
• 
The definition of modified exposed set (mES) is clarified. 
• 
Section 9.7 on “Emergency Unblinding” is added as per requirement of new 
process for observer-blind studies. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Title Page: 
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Contributing authors 
• 
 Clinical 
Research and Development Lead 
• 
 
Study Delivery Leads 
• 
 Lead Statistician 
• 
 Oversight Data Manager 
• 
 Clinical 
Laboratory Science Study Managers 
• 
 Clinical and Epidemiology 
Project Lead, Zoster Program, US RDC (CEPL) 
for ZOSTER, Clinical R&D. 
©2018 GSK group of companies or its licensor. ©2018-2019 GSK group of companies or its licensor. 
Glossary of terms 
Adequate contraception: Oral Contraceptive, either combined or progestogen alone. 
Combined estrogen and progesterone oral contraceptives, 
• 
Woman of child bearing potential (WOCBP): Premenopausal female with ONE of 
the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
− 
Documented tubal ligation 
Synopsis and Introduction  
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name Shingrix) 
was first approved in Canada and in the United States and Canada in October 2017. and 
in the European Union and in Japan in March 2018. 
Primary Objective (Synopsis and Section 2.1) 
To compare the incidence of HZ recurrence in the HZ/su group to the placebo group.  
The methodology will depend on the number of confirmed HZ cases accrued from one 
month post last vaccination to study end. If at least 7 confirmed HZ cases are accrued, a 
A formal non-inferiority analysis with non-inferiority margin of 5 will be performed. 
− 
Criterion: The objective is met if the upper limit (UL) of the 95% CI of the ratio 
of the incidence of HZ recurrence (HZ/su versus placebo) is below 5 10.  
If less than 7 confirmed HZ cases are accrued over the study period, the analysis will 
be descriptive:  
− 
Ratio of the incidence of HZ recurrence (HZ/su versus placebo) and its 95% CI 
will be provided. 
PPD
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− 
A probability curve that the ratio of incidence of HZ recurrence (HZ/su versus 
placebo) is higher than x-fold (x varying from 1 to 5 10) may be estimated by 
Bayesian methodology. 
Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of 
eligible subjects 
Age (years) 
Epochs 
Epoch 001 
Epoch 002 
HZ/su 
493 713 
50 years  
● 
● 
Placebo 
493 713 
50 years  
● 
● 
Number of subjects 
Target enrolment is 986 1426 eligible subjects (493 713 per 
treatment group) with a previous HZ episode to reach 
approximately 606 419 evaluable subjects per group. 
Endpoints 
Primary 
Occurrence of confirmed HZ episodes from 30 days post 
second last vaccination until study end. 
− Section 3: Study design overview 
 
 
Duration of the study: The duration of the study will vary for each subject. The duration 
of the study will be up to the study conclusion contact that occurs within 30 days of the 


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projected study conclusion date of the last enrolled subject, that is, 26 months (790 days) 
from the enrolment date. Therefore subjects enrolled early in the trial could be followed 
for longer duration than the subjects who enrol later in the trial. The study conclusion 
visit/ contact for subjects with an ongoing episode of HZ at the time of LSLV will occur 
after a 4-week pain-free period is documented OR after Day HZ-92 follow-up has been 
completed. 
Table 1: Study groups and epochs foreseen in the study 
Study groups 
Number of 
eligible subjects 
Age (years) 
Epochs 
Epoch 001 
Epoch 002 
HZ/su 
493 713 
50 years  
●  
● 
Placebo 
493 713 
50 years  
● 
● 
Section 4.2: Confirmed HZ 
Rash lesion samples will be collected from subjects clinically diagnosed as having a 
suspected case of HZ. The samples will be transferred to GSK Biologicals or a validated 
laboratory designated by GSK Biologicals and analyzed using standardized and validated 
procedures for laboratory diagnosis of HZ by PCR (see Section 4.5.2.2.1). 
Section 4.5.1: Definitions 
ZBPI questionnaire: To be completed by subjects (or subject’s LAR/caregiver) with 
suspected HZ on Day HZ-1(Visit HZ-1) and daily from Day HZ-1 up to Day HZ-29, and 
weekly from Day HZ-29 30 onwards until a 4-week pain-free period is documented or 
until Day HZ-92. For all subjects with ongoing HZ-associated pain at the time of last 
subject last contact, ZBPI data will be collected until a 4-week pain-free period is 
documented OR until at least Day HZ-92 (Refer to Section 4.5.2 for more details). 
Section 4.5.2: Evaluation of suspected case of HZ 
The schedule of visits/contacts that will take place for follow-up of clinically diagnosed 
suspected HZ cases is presented in Table 8. 
• 
The subject/subject’s LAR/caregiver will be asked to complete the ZBPI 
questionnaires on Day HZ-1 (Visit HZ-1) and daily from Day HZ-1 up to Day HZ-
29 (ZBPI must be completed to Day HZ-29 at minimum) and weekly from Day HZ-
30 onwards until: 
− 
A 28-day (or 4-week) pain free period is documented (a ‘No’ answer to the 
ZBPI question: ‘Have you had any pain caused by your shingles in the last 24 
hours’ (item 1) at each assessment during that entire period) or until Day HZ-92; 
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− 
For all subjects with ongoing HZ-associated pain at the time of last subject last 
contact, completion of ZBPI questionnaires will continue until a 4-week pain-
free period is documented OR until at least Day HZ-92. 
− 
If HZ-associated pain ceases (defined as a 28-day [or 4-week] pain free period), 
or until Day HZ-92, the study staff/investigator will inform the subject/subject’s 
LAR/caregiver to stop completing the ZBPI questionnaires and will provide 
instructions for the subject to return the completed questionnaires to the study 
site.  
− 
If a 4-week pain-free period is achieved and the HZ rash resolves, subsequent 
follow-up visits or contacts related to this case of HZ will be cancelled meaning 
that collection of subsequent HZ episode-related information will be stopped 
and no further information on that particular suspected HZ episode will be 
encoded in the clinical database. However, if pain reappears in the same area 
after a 4-week pain-free period and is not accompanied by a new HZ rash, it 
will be assigned to the previous HZ-episode. Visits/contacts will restart with 
Day HZ-1 defined as the first visit of the assigned episode, prior to the pain 
free period. Follow-up of HZ-associated pain persisting beyond Visit HZ-7 
(Day HZ-92) or other complications will be done at monthly contacts between 
the subject and the investigator and/or investigator’s delegate. If pain 
continues beyond Day HZ-92, and rash has resolved, collection of information 
on pain will end for study purposes and the subject will be followed as per the 
investigator’s discretion. Once a pain free period of 4 weeks has been 
documented or information on pain till Day HZ-92 has been collected, subjects 
with ongoing symptoms related to suspected HZ episode including ongoing pain 
will be followed as per the investigator discretion. 
The study staff/investigator will remind subjects/subject’s LAR/caregiver to complete the 
ZBPI questionnaires and return the completed ZBPI questionnaires to the study site 
according to the instructions given by the study staff/investigator. Once the completed 
ZBPI questionnaires are available, the investigator will transcribe the information into the 
subject’s eCRF. A new supply of ZBPI questionnaires will be provided to the subjects as 
necessary. 
Section 4.5.2.2.1: Confirmation of suspected HZ by PCR 
The samples will be transferred to GSK Biologicals or a validated laboratory designated 
by GSK Biologicals and analyzed using standardised and validated procedures for 
laboratory diagnosis of HZ by PCR. 
Section 4.5.3: Follow up of suspected HZ cases and HZ-associated pain 
Data will be collected on all suspected HZ cases that occur from Visit 1 (Day 1) until the 
study conclusion. For each suspected case of HZ that the investigator concludes is 
clinically consistent with HZ, data on HZ-associated pain (using ZBPI questionnaires 
completed by the subject/subject’s LAR/caregiver) will be collected daily until Day- HZ-
29, and weekly from Day HZ-30 until the subject has no HZ-associated pain for 4 


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consecutive weeks, or until Day HZ-92. For all subjects with ongoing HZ-associated pain 
at the time of last subject last contact, ZBPI data will be collected until a 4-week pain-
free period is documented OR until Day HZ-92. If pain reappears in the same area after a 
4-week pain-free period and is not accompanied by a new HZ rash, it will be assigned to 
the previous HZ-episode. The completion of the ZBPI questionnaire will resume based 
upon the weekly schedule established at the start of the assigned episode. Visits/contacts 
will also restart according to the schedule in Table 8 with reference to the established 
Day HZ-1 at the start of the assigned episode prior to the pain free period. Follow-up will 
end at Day HZ-92 as is described in Section 4.5.2. 
When the subject returns for repeat sample collection, if possible, three samples from 
separate lesions should be collected. Refer to the SPM central lab manual for further 
details on sample collection. 
Section 5.1: Number of subjects/centers 
Target enrolment is 986 1426 eligible subjects (493 713 per treatment group) with 
previous HZ episode to reach approximately 419 606 evaluable subjects per group for 
statistical analysis assuming a 15% drop out rate. 
The enrolment strategy will ensure that a minimum of 285 197 subjects in each of the 50-
59 and 60-69 YOA ranges and at least 143 98 subjects ≥ 70 YOA are expected to be 
included in the study (Table 4). A minimum of 143 98 subjects are expected to be 
enrolled in each sub-group for ‘time since previous HZ episode (Table 5). 


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Table 4: Expected enrolment based on overall age stratification 
Age strata 
Sample size 
Percentage of total 
50-59 YOA 
Min 285 197 
Min 20 
60-69 YOA 
Min 285 197 
Min 20 
 70 YOA 
Min 143 98 
Min 10 
All 
986 1426 
100.0 
Table 5: Expected enrolment based on time from previous HZ case 
Sub-group 
Sample size 
Percentage of total 
4 years ago 
Min 143 98 
Min 10 
5-9 years ago 
Min 143 98 
Min 10 
 10 years ago 
Min 143 98 
Min 10 
All 
1426 986 
100.0 
Overview of the recruitment plan: 
• 
The target enrolment will be 986 1426 subjects. 
Section 5.2: Inclusion criteria for enrolment 
• 
Female subjects of non-childbearing potential may be enrolled in the study.  
− 
Non-childbearing potential is defined as current bilateral tubal ligation or 
occlusion, hysterectomy, bilateral ovariectomy, bilateral salpingectomy or post-
menopause. 
Section 5.3: Exclusion criteria for enrolment 
• 
Use or anticipated use of immunosuppressants or immune-modifying drugs during 
the period starting six months prior to study start and during the whole study period. 
This includes chronic administration of corticosteroids (> 14 consecutive days of 
prednisone at a dose of ≥ 20 mg/day [or equivalent]) (intra-articular, inhaled and 
topical steroids are allowed), long-acting immune-modifying agents (e.g., 
infliximab). 
• 
Acute disease and/or fever at the time of enrolment.  
− 
Fever is defined as temperature 38.0°C/100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity. 
Section 6.2.2.2.1: Study group and treatment number allocation 
• 
The target will be to enrol approximately 986 1426 subjects who will be randomly 
assigned to two study groups in a (1:1) ratio (493 713 subjects in each group). 
• 
A minimum of 285 197 subjects in each of the 50-59 and 60-69 YOA ranges and at 
least 143 98 subjects ≥ 70 YOA range are expected to be enrolled. A minimum of 
143 98 subjects are expected to be enrolled in each sub-group (≤ 4 years ago, 5-9 
years ago, ≥ 10 years ago) for ‘time since previous HZ episode’. 


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Section 6.4.1: Diary cards and questionnaires 
All subjects will receive 2 a dairy diary cards- 7-day and 30-day diary card on the day of 
each vaccination to be completed by the subjects/ subjects’ LAR/caregiver. The diary 
card will be completed by the subjects (or subjects’ LAR/caregiver) after each 
vaccination to record 7-day diary cards will be completed for solicited AEs (from Day 1 
to Day 7) , after each vaccination) and the 30-day diary cards will be completed for 
unsolicited AEs (from Day 1 to Day 30 after each vaccination) and any concomitant 
medication and vaccination taken from Day 1 to Day 30 after each vaccination (Table 7 
and Table 21). 
Section 6.4.2: Monthly contacts 
After Visit 3 (Month 3), monthly contacts between the subjects/ subject’s LAR/caregiver 
and the investigator or delegate will take place to collect information on any event of 
interest that may have occurred [see Section 6.6.13 for details] 
Footnote to Table 7: List of study procedures 
2 One diary Diary card to collect solicited and unsolicited AEs following each 
vaccination for solicited AEs (Days 1-7) and one for unsolicited AEs (Days 1-30) post 
each vaccination and HZ specific diary card. 
Table 8: Study procedures to be performed during the follow-up period for each 
suspected HZ case 
Type of contact 
Visit HZ-1 Visit HZ-2 
Contact 
HZ-3 
Contact HZ-
4 
Visit HZ-5 Contact HZ-
6 
Visit HZ-7 
Timepoints 
Day HZ-1 
Day HZ-8 Day HZ-15 Day HZ-22 Day HZ-29 Day HZ-57 
Day HZ-92 
Dispense ZBPI 
questionnaires to 
subjects‡ 
O 
O 
 
 
O 
 
O 
‡ The study staff/investigator will dispense additional questionnaires and provide instructions for the subject to return 
the completed questionnaires to the study site until the subject has a 4-week pain free or at least Day 92 (for 
subjects with ongoing pain at the time of last subject last contact). 
Footnote to Table 10: Intervals between visits/contacts for subjects in case of 
suspected HZ 
Note: If HZ-associated pain ceases (that is, after a 4-week pain-free period is documented) and the HZ rash resolves, 
subsequent follow-up HZ visits or contacts will be cancelled (see Section 4.5.2). At the time of last subject last 
contact, follow-up of HZ-associated pain persisting beyond Visit HZ-7 (Day HZ-92) or other complications will end for 
study purposes and the subject will be followed as per the investigators discretion. 
Section 6.6.10: Sampling 
Refer to the Module on Biospecimen Management in the central lab manual SPM for 
detailed instructions for the collection, handling and processing of the samples. 


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Section 6.6.10.1: Blood sampling for immune response assessments 
• 
A volume of at least approximately 5 ml of whole blood (to provide at least 1.5 ml of 
serum) should be drawn from all subjects for assessment of humoral immune 
response at each pre-defined timepoint. After centrifugation, serum samples should 
be kept at –20°C/ –4°F or below until shipment. Refer to the central lab manual 
SPM for more details on sample storage conditions. 
• 
Section 6.6.10.2: Clinical specimens of HZ lesions for PCR analysis 
Samples for HZ cases assessment should be kept at –20°C/ –4°F or –70/80°C (-94/-
112°F) until shipment. 
Refer to the SPM central lab manual for more details on sample storage conditions. 
Section 6.7: Biological sample handling and analysis 
Please refer to the central lab manual SPM for details on biospecimen management 
(handling, storage and shipment). 
Table 15: Immunological read-outs 
Blood sampling timepoint 
Sub-cohort Name  
Number of 
targeted 
subjects 
Component 
Type of contact and 
timepoint 
Sampling timepoint 
Day 1 (Visit 1) 
Pre-vacc 1 
All subjects 
1426 986 
Ab gE ELISA 
Month 2 (Visit 2) 
Pre-vacc 2 
All subjects 
1426 986 
Ab gE ELISA 
Month 3 (Visit 3) 
Post-vacc 2 
All subjects 
1426 986 
Ab gE ELISA 
Section 7.7.2: Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analysis 
• 
Administration of cytotoxic chemotherapy at any time during the study period. 
Section 9.3.1: Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
The standard time period for collecting and recording pregnancies will begin at the first 
receipt of study vaccine and will end at study end at Month 14 contact (that is, 
approximately 12 months following administration of the last dose of the study vaccine 
for each subject). 
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The standard time period for collecting and recording of pIMDs will begin at the first 
receipt of study vaccine and will end at study end at Month 14 contact (that is, 
approximately 12 months following administration of the last dose of the study vaccine 
for each subject). 
Section 9.3.3.2.1: Assessment of intensity 
The preferred route for recording temperature in this study is oral. Fever is defined as 
temperature  38.0°C / 100.4°Grade 3 fever will be defined as temperature > 39.0C.  
Fever will be graded as: 
0 
: 
<38.0°C 
1 
: 
38.0°C – 38.4°C 
2 
: 
38.5°C – 39.0°C  
3 
: 
>39.0°C 
Section 9.7 Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency when knowledge of the treatment is essential for the clinical 
management or welfare of the subject. 
The emergency unblinding process consists of the automated Internet-based system 
(SBIR) that allows the investigator to have unrestricted, immediate and direct access to 
the subject’s individual study treatment. 
As back up process, the investigator has the option of contacting a GSK Helpdesk 
(refer to Table 24) if he/she needs support to perform the unblinding (i.e. he/she 
cannot access the automated Internet-based system). 
Non-investigator physician (e.g. physician from emergency room) or subject/care 
giver/family member can also request emergency unblinding either via the investigator 
(preferred option) or via the GSK Helpdesk (back up process). Contact details of 
investigator and GSK Helpdesk are reported in the patient/subject card. 
Table 24 Contact information for emergency unblinding 
GSK Helpdesk 
24/24 hour and 7/7 day availability 
The Helpdesk is available by phone, fax and email 
Phone: +32.2.656.68.04 
Fax: +32.2.401.25.75 
email: rix.ugrdehelpdesk@gsk.com 


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A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician, but can still be followed-up for safety. The relevant 
event or condition will be recorded in the eCRF. 
GSK Vaccines Clinical Safety and Pharmacovigilance (VCSP) staff may unblind the 
treatment assignment for any subject in case of Suspected Unexpected Serious Adverse 
Reaction (SUSAR) as well as in case of fatal or life threatening cases. If the SAE 
requires that an expedited regulatory report be sent to 1 or more regulatory agencies, a 
copy of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy. 
Section 10.2.2.: Subject withdrawal from study vaccine 
• 
SAE. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE 
• 
Not willing to be vaccinated 
• 
HZ 
• 
Other (specify). 
Section 11.1: Primary Endpoint 
• 
Occurrence of confirmed HZ episodes from 30 days post second last vaccination 
until study end. 
Section 11.4: Determination of sample size 
The sample size determination enables the evaluation of the non-inferiority of HZ 
recurrence incidence rate, and to rule out a 5 10-fold increased risk of HZ recurrence in 
the HZ/su group compared to the placebo group. The following assumptions were made: 
• 
Criterion for non-inferiority = 10 5-fold; the 10 5-fold criterion has been selected as 
acceptable for ruling out a moderate increased risk of HZ in a clinical trial setting. 
Let π be the ratio of incidence rate of HZ recurrence in HZ/su group vs the placebo 
group, then null hypothesis H0: π ≥ 5 vs. alternative hypothesis Ha: π < 5. With the 
assumption that the number of HZ recurrence cases in HZ/su and placebo group 
follows Poisson distribution independently, conditioning on the total number of cases, 
the number of cases in HZ/su group would follow the binomial distribution (Lehmann, 
1959). With 1:1 randomization, the parameter p in the binomial distribution (that is, 
the probability of HZ recurrence in HZ/su group) is expected to be p=π/(1+π). 
Therefore, the above hypotheses becomes: H0: p≥0.8333 vs. Ha: p < 0.8333. Under the 
assumption of VE of 50%, a total number of 10 HZ recurrence cases is needed (PASS 
12: Tests for One Proportion using proportions (Exact Test)). With incidence rate of 
0.55% per year and two year follow up, 606 evaluable subjects per group are needed. 
Further assuming a dropout rate of 15% during the 2 year follow up period, 713 
subjects per group (a total of 1426 subjects) need to be enrolled.  


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Sample size calculations were done using PASS 12 (non-inferiority for two proportions 
using ratios). 
• 
Assuming a dropout rate of 15% during the 2-year follow up period, 493 subjects are 
to be enrolled in each group to reach 419 evaluable subjects. Based on the above 
assumptions, this sample size and a follow-up of at least 2 years will yield 7 
confirmed HZ cases which will be needed for final analysis. 
Section 11.4.2: Time since previous HZ sub-groups and age category 
• 
To allow a descriptive analysis of the results the target will be to enrol a minimum 
of: 
• 
143 98 subjects in each (≤ 4 years ago, 5-9 years ago, ≥ 10 years ago) “time since 
previous HZ episode” category. 
• 
285 197 subjects in 50-59 and 60-69 YOA category and 143 98 subjects in 70 YOA 
category. 
Section 11.5.1.1: Modified Exposed Set 
• 
The modified exposed set (mES) is the primary population for HZ recurrence 
analysis. The mES excludes subjects in the ES who were not administered the 
second dose of the study vaccine , which excludes subjects in the ES who did not 
receive the 2 doses of the study vaccine according to protocol or who developed a 
confirmed case of HZ prior to 30 days after the second vaccination. 
Section 11.5.2: Per Protocol Set for Immunogenicity 
• 
who complied with the vaccination schedule as specified in Table 10 Table 9 
• 
who complied with the blood sample schedule as specified in Table 10 Table 9. 
Section 11.8: Analysis of incidence rate of Herpes Zoster recurrence 
A formal non-inferiority analysis with a non-inferiority margin of 5 assessment will be 
performed if the number of accrued confirmed HZ cases (from both study groups 
combined) is at least 7 in the final analysis (in the mES). Non-inferiority is met if the 
upper limit of the 95% CI for the ratio of the incidence of HZ recurrence (HZ/su versus 
placebo) is below 10. Non-inferiority assessment, point estimate and 95% CI for the ratio 
of the incidence of HZ recurrence (HZ/su versus placebo) will be carried out based on the 
fact that the distribution of two Poisson variates conditional on their sum is binomial 
(Lehmann, 1959). Let n1 and n0 be the number of HZ recurrence cases, T1 and T0 
(years) be total follow up, and r1 and r0 be the incidence rate in HZ/su group and 
placebo group respectively. It is assumed that ni ~ Poisson(λi) (i=0,1) and λi=Ti×ri, and 
condition on n=n0+n1, n1 ~ binomial(n, p), where p=λ1/(λ1+λ0). A 95% exact CI for p 
can be derived by using Clopper-Pearson approach, through which a 95% exact CI for 
π=r1/r0 (that is, the ratio of incidence rate of HZ recurrence (HZ/su versus placebo)) 
can be derived. Non-inferiority is met if the upper limit of the 95% CI for π is below 5. 


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In addition to performing a formal non-inferiority analysis, to further quantify the 
likelihood of the risk increase of HZ following Shingrix vaccination, a probability 
curve that the ratio of incidence of HZ recurrence (HZ/su versus placebo) is higher 
than x-fold (x varying from 1 to 5) will be estimated by Bayesian methodology. It will 
be assumed that the number of HZ cases in the HZ/su and in placebo groups follows 
Poisson distribution with rate (incidence rate) of λHZ and λp respectively. We further 
assume that λHZ and λp are random variables both with non-informative Gamma prior 
distribution: Gamma(0.001, 0.001). Based on the posterior distribution of λHZ and λp, 
the probability curve of the ratio of incidence of HZ recurrence (HZ/su versus 
placebo), that is, Pr(λHZ/λp>x| data, prior), can be calculated for each given value of x. 
This will be further detailed in the statistical analysis plan (SAP). 
• 
If the number of accrued confirmed cases is below 7 in the mES, the descriptive 
statistics for the incidence ratio will be provided. In addition, the probability that the 
ratio of incidence of HZ recurrence (HZ/su versus placebo) is higher than x-fold 
(varying from 1 to 10) may be estimated using Bayesian methodology with different 
priors. This will be further detailed in the statistical analysis plan (SAP). 
Section 11.10 : Analysis of safety 
• 
All SAEs, related SAEs and fatal SAEs occurring from first vaccination up to 30 
days post last vaccination will be tabulated. 
• 
All SAEs, related SAEs and fatal SAEs occurring after 30 days post last vaccination 
until one year post last vaccination will be tabulated. 
• 
Fatal SAEs will be tabulated using date of onset of SAE in the following manner-
within Day 1- Month 3 (30 days post last vaccination), Day 1 to Month 14 (one 
year post last vaccination) and Month 3 till study end. Fatal SAEs will also be 
tabulated using the date of death within the same time periods. 
Section 11.11: Interpretation of analyses 
• 
If the number of accrued confirmed HZ cases is at least 7 in the mES, The primary 
objective of non-inferiority of the incidence of HZ recurrence in the HZ/su and 
placebo groups is considered met if the upper limit of the 95% CI of the ratio of the 
incidence of HZ recurrence (HZ/su versus placebo) is below 5 10. If the number of 
accrued confirmed cases is below 7 in the mES, a descriptive assessment of the 
incidence of HZ recurrence will be done. For all secondary objectives, analyses will 
be descriptive with the aim to characterize the differences in reactogenicity, safety 
and immunogenicity between groups. 
Section 12.1: Electronic case report form instructions 
• 
The investigator will be provided with a validated GSK system to download CD-
ROM of the final version of the data generated at the investigational site. once the 
database is archived and the study report is complete and approved by all parties 


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Appendix A: Laboratory Assays 
• 
Ascertainment of HZ cases including the PCR testing algorithm to classify HZ 
suspected cases 
• 
To classify the suspected case of HZ, the samples from the rash lesions (if available) 
will be collected for laboratory testing by PCR (3 samples, collected on the same 
day, per subject). If during clinical evaluation at Visit HZ-1, the investigator 
determines that adequate rash lesion samples cannot be collected (that is, less than 
three lesions present, or if only papules are present), the investigator has the option 
of collecting three additional samples preferably within 7 days, or at the Visit HZ-2 
if there is rash progression (that is, appearance of new/additional lesions if originally 
less than three lesions present, or appearance of vesicles if originally only papules 
present). When the subject returns for repeat sample collection, if possible, three 
samples from separate lesions should be collected. Refer to the SPM central lab 
manual for further details on sample collection. 


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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 2 
eTrack study number 
and Abbreviated Title 
204939 (ZOSTER-062) 
IND number 
BB-IND-13857 
EudraCT number 
2016-000744-34 
Amendment number: 
Amendment 2 
Amendment date: 
14 April 2020 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes:  
This protocol amendment 2 outlines measures that may be applicable during special 
circumstances (e.g., during COVID-19 pandemic). The purpose of the amendment is to 
introduce measures that may allow protection of subject’s welfare and safety, as well 
as maintaining the integrity of the study. 
This amendment is considered substantial based on the criteria defined in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it significantly impacts the safety of subjects or/nor the scientific value 
of the study.  
As much as possible all study specified visits and procedures should be completed 
according to the protocol, taking into account clinical judgment and local public health 
guidance to protect the safety of staff and subjects. 
Section 6.7 outlines the measures which include allowing flexibility in schedule 
and procedures to optimize site staff safety, patient safety and to preserve study 
integrity  
Other change includes: 
• 
Clarification on subjects to be enrolled in the
 sub-cohort has been added. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Section 3. Study design overview 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 6.5), are essential 
and required for study conduct. Refer to Section 6.7 for study procedures to be 
considered during special circumstances. 
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Section 6.4. General study aspects 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied (refer to Section 6.7 for further details). 
Section 6.7. Study procedures during special circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled subjects:   
The impact of COVID-19 to the study conduct will be documented in the clinical study 
report.  
• 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
• 
Diary cards may be transmitted from and to the site by electronic means and/or 
conventional mail.  
• 
Biological samples may be collected at a different location* other than the study 
site or at subject’s home. Biological samples should not be collected if they cannot 
be processed in a timely manner or appropriately stored until the intended use. 
* It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on subjects by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March, 2020) for more details.  
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 9), then the interval may be extended 
as outlined in Table 11. 
• 
If despite best efforts it is not possible to administer the second dose of study 
intervention as defined in the protocol (see Table 9), a maximum dose interval of 
180 days may be used (see Table 11). 
• 
In case the investigator needs to conduct visits 2 and 3 during the allowed 
extended interval due to the special circumstances, then the best efforts should 
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be made to conduct a safety follow-up by telephone contact at the time when  
visits 2 and 3 were initially planned (as close to the optimal window as 
possible) and approximately monthly thereafter until visits 2 and 3 procedures 
can be conducted. 
Table 11 
Intervals between study visits during special circumstances 
Interval 
Optimal length of interval 
Allowed interval per 
Protocol 
Allowed interval during 
special circumstances 
Visit 1→Visit 2  
60 days (2 months) 
49 days - 83 days 
49 days – 180 days 
Visit 2→Visit 3  
30 days (1 month) 
28 days- 48 days 
28 days- 90 days 
Between Monthly 
Contacts*  
30 days (1 month) 
20 – 40 days 
20 – 40 days 
Visit 2→Month 26 Contact 
(for the last enrolled subject 
only)   
730 days (24 months) 
730- 760 days 
730- 760 days 
Note: Investigator should prioritize conducting the visit as close to the optimal window as possible. 
• 
Visits for suspected HZ may take place in a different location* other than the study 
site or at subject’s home. If this is not feasible, then the medical evaluation of 
suspected HZ may take place virtually with documentation of all the signs and 
symptoms as outlined in Table 8 and Table 10. 
− If the subject is not able to contact the study staff/investigator to evaluate/ 
clinically diagnose the suspected HZ case, the subject should be encouraged to 
document all the signs and symptoms and record the progression of the rash 
and share it with the investigator when possible. 
− Digital photographs can be taken by the study staff/investigator at a different 
location* other than the study site or at subject’s home. If this is not feasible, 
subjects might be asked to take photographs of their Hz lesions themselves. The 
photographs will be transferred to the investigator. 
− ZBPI questionnaire may be transmitted from and to the site by electronic means 
and/or conventional mail. If feasible the study staff/investigator can conduct 
ZBPI questionnaire by telephone contact. 
Impact on the modified exposed set for HZ recurrence analysis and per protocol set for 
immunogenicity (humoral and 
) will be determined on a case by case basis. 
Section 9.3.3.4. Medically attended visits 
For each solicited and unsolicited AE/SAE the subject experiences, the subject/subject’s 
LAR/caregiver will be asked if he/she /the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit by medical personnel for any reason, 
including emergency room visits. 
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SAP_001.pdf: 
CONFIDENTIAL 
204939 (ZOSTER-062) 
Statistical Analysis Plan Amendment 2 
06 Oct 2023 
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Statistical Analysis Plan 
Detailed Title: 
A phase III, randomized, observer-blind, placebo 
controlled, multicenter clinical trial to assess Herpes 
Zoster recurrence and the reactogenicity, safety and 
immunogenicity of GSK Biologicals’ Herpes Zoster 
vaccine (HZ/su) when administered intramuscularly 
on a 0 and 2 month schedule to adults ≥ 50 years of 
age with a prior episode of Herpes Zoster 
eTrack study number and 
Abbreviated Title 
204939 (ZOSTER-062) 
Scope: 
All data pertaining to the above study. 
Date of Statistical Analysis 
Plan 
Amendment 2: Final 06 Oct 2023 
APP 9000058193 Statistical Analysis Plan Template V4 (Effective date: 3 June 2019) 


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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 7 
1. 
DOCUMENT HISTORY ............................................................................................ 9 
2. 
OBJECTIVES/ENDPOINTS ..................................................................................... 9 
2.1. 
Objectives ..................................................................................................... 9 
2.1.1. 
Primary objectives ......................................................................... 9 
2.1.2. 
Secondary objectives ..................................................................... 9 
2.1.3. 
Tertiary objectives ........................................................................ 10 
2.2. 
Endpoints.................................................................................................... 10 
2.2.1. 
Primary endpoints ........................................................................ 10 
2.2.2. 
Secondary endpoints ................................................................... 10 
...................................................................... 11 
3. 
STUDY DESIGN .................................................................................................... 13 
4. 
ANALYSIS SETS ................................................................................................... 16 
4.1. 
Definition..................................................................................................... 16 
4.1.1. 
Enrolled Set ................................................................................. 16 
4.1.2. 
Randomized Set .......................................................................... 16 
4.1.3. 
Exposed Set ................................................................................ 17 
4.1.4. 
Modified Exposed Set .................................................................. 17 
4.1.5. 
Per Protocol Set for immunogenicity ............................................ 17 
4.2. 
Criteria for eliminating data from Analysis Sets ........................................... 18 
4.2.1. 
Elimination from Enrolled Set ....................................................... 18 
4.2.2. 
Elimination from Randomized Set ................................................ 18 
4.2.3. 
Elimination from Exposed Set (ES) .............................................. 19 
4.2.4. 
Elimination from modified Exposed Set (mES) ............................. 19 
4.2.5. 
Elimination from Per-protocol analysis Set (PPS) ........................ 19 
4.2.5.1. 
Excluded subjects ...................................................... 19 
5. 
STATISTICAL ANALYSES ..................................................................................... 24 
5.1. 
Demography ............................................................................................... 24 
5.1.1. 
Analysis of demographics/baseline characteristics planned 
in the protocol .............................................................................. 24 
5.1.2. 
Additional considerations ............................................................. 24 
5.2. 
Exposure .................................................................................................... 24 
5.2.1. 
Analysis of exposure planned in the protocol ............................... 24 
5.2.2. 
Additional considerations ............................................................. 24 
5.3. 
Analysis of incidence rate of Herpes Zoster recurrence .............................. 25 
5.3.1. 
Analysis of incidence rate of Herpes Zoster recurrence 
planned in protocol ...................................................................... 25 
5.3.1.1. 
Within group ............................................................... 25 
5.3.1.2. 
Between group ........................................................... 25 
5.3.2. 
Additional considerations ............................................................. 25 
5.4. 
Immunogenicity........................................................................................... 27 
5.4.1. 
Analysis of immunogenicity planned in the protocol ..................... 27 
5.4.1.1. 
Humoral immune response ......................................... 27 
5.4.1.1.1. 
Within group assessment ....................... 27 
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................... 27 
................... 27 
5.4.2. 
Additional considerations ............................................................. 28 
5.5. 
Analysis of safety and reactogenicity .......................................................... 28 
5.5.1. 
Analysis of safety and reactogenicity planned in the 
protocol ........................................................................................ 28 
5.5.2. 
Additional considerations ............................................................. 30 
6. 
ANALYSIS INTERPRETATION .............................................................................. 30 
7. 
CONDUCT OF ANALYSES .................................................................................... 31 
7.1. 
Sequence of analyses................................................................................. 31 
7.2. 
Statistical considerations for interim analyses ............................................. 31 
8. 
CHANGES FROM PLANNED ANALYSES ............................................................. 31 
9. 
NON-STANDARD DATA DERIVATION RULES AND STATISTICAL 
METHODS ............................................................................................................. 33 
9.1. 
Data derivation ........................................................................................... 33 
9.1.1. 
Demography ................................................................................ 33 
9.1.2. 
Immunogenicity............................................................................ 33 
9.1.2.1. 
Humoral immune response ......................................... 33 
............................. 34 
9.1.3. 
HZ incidence ................................................................................ 35 
9.1.4. 
Safety .......................................................................................... 36 
9.2. 
Statistical Method ....................................................................................... 37 
9.2.1. 
HZ incidence ................................................................................ 37 
9.2.2. 
Safety .......................................................................................... 38 
10. ANNEXES .............................................................................................................. 39 
10.1. 
Business rules for standard data derivations and statistical methods .......... 39 
10.1.1. 
Attributing events to vaccine doses .............................................. 39 
10.1.2. 
Handling of missing data .............................................................. 39 
10.1.2.1. Dates .......................................................................... 39 
10.1.2.2. Laboratory data .......................................................... 40 
10.1.2.3. Daily recording of solicited adverse events ................. 40 
10.1.2.3.1. Studies with paper diaries ....................... 40 
10.1.2.4. Unsolicited adverse events ......................................... 41 
10.1.3. 
Data derivation ............................................................................ 41 
10.1.3.1. Temperature ............................................................... 41 
10.1.3.2. Numerical serology results ......................................... 41 
10.1.3.3. Geometric mean concentrations (GMCs) .................... 41 
10.1.3.4. Onset day ................................................................... 42 
10.1.3.5. Duration of events ...................................................... 42 
10.1.3.6. Counting rules for combining solicited and 
unsolicited adverse events ......................................... 42 
10.1.3.7. Counting rules for occurrences of solicited 
adverse events ........................................................... 42 
10.1.4. 
Display of decimals ...................................................................... 42 
10.1.4.1. Percentages ............................................................... 42 
10.1.4.2. Differences in percentages ......................................... 43 
10.1.4.3. Serological summary statistics ................................... 43 
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10.1.5. 
Statistical methodology ................................................................ 43 
10.1.5.1. Exact confidence intervals around proportions ........... 43 
10.2. 
TFL TOC..................................................................................................... 44 
11. REFERENCES ....................................................................................................... 44 


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LIST OF TABLES 
PAGE 
Table 1 
Study groups and epochs foreseen in the study ..................................... 14 
Table 2 
Expected enrolment based on overall age stratification .......................... 14 
Table 3 
Expected enrolment based on time from previous HZ case .................... 14 
Table 4 
.......... 15 
Table 5 
Blinding of study epochs ........................................................................ 15 
Table 6 
Group names and description for footnote will be used in the 
Tables, Figures and Listings, in line with the T-domains: ........................ 16 
Table 7 
Sub-group name and definitions to be used for the sub-group 
analysis by age stratum .......................................................................... 16 
Table 8 
Sub-group name and definitions to be used for the sub-group 
analysis by time since previous HZ episode ........................................... 16 
Table 9 
Intervals between study visits ................................................................. 18 
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LIST OF FIGURES 
PAGE 
Figure 1 
Overview of Study design ....................................................................... 13 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
CI 
Confidence Interval 
CMI 
Cell-Mediated Immunity 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTRS 
Clinical Trial Registry Summary 
ELISA 
Enzyme-linked immunosorbent assay 
EoS 
End of study 
ES 
Exposed Set 
gE 
VZV glycoprotein E 
GMC 
Geometric mean antibody concentration 
GSK 
GlaxoSmithKline Biologicals SA 
HI 
Humoral Immunogenicity 
HZ 
Herpes Zoster 
ICF 
Informed consent form 
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IMC 
Intercurrent Medical Condition 
LL 
Lower Limit of the confidence interval 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mES 
Modified Exposed Set 
NA 
Not Applicable 
PBMC 
Peripheral blood mononuclear cells 
PCD 
Primary completion date 
PD 
Protocol Deviation 
PHN 
Postherpetic Neuralgia 
pIMD 
Potential Immune-Mediated Disease 
PPS 
Per-Protocol Set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBIR 
GSK’s Internet Randomization System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
TFL 
Tables Figures and Listings  
TOC 
Table of Content 
UL 
Upper Limit of the confidence interval 
VRR 
Vaccine response rate 
WBR 
Web-based Randomization 
YOA 
Years of Age 
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1. 
DOCUMENT HISTORY 
Date 
Description 
Protocol 
Version 
28 AUGUST 
2019 
First version 
Amendment 1: 
18 MAR 2019 
24 JANUARY 
2020 
Amendment 1: amendment of the SAP definition of enrolled set 
to better align across study documents, specifically the protocol 
and eCRF completion guidelines. None of these modifications 
are major changes to planned analysis. 
Amendment 1: 
18 MAR 2019 
06 Oct 2023 
Amendment 2:  
The protocol was amended to include subjects vaccinated 
beyond the original 2-month dose interval during the special 
circumstances of the COVID-19 pandemic. Per CHMP Scientific 
Advice received on March 24, 2022, the SAP is amended to add 
a sensitivity analysis for non-inferiority after removing the 
participants who received a second dose more than 2 months 
after the first dose (outside of the original scheduled window), a 
stratified analysis for non-inferiority by recruitment interruption, 
and Kaplan-Meier curves to compare the onset time of HZ 
recurrences. 
Added clarifications on how to handle extreme cases, when there 
are no confirmed HZ cases in one of the treatment groups. 
Added analysis to assess the impact of COVID-19 on safety. 
Amendment 2: 
14 APR 2020 
2. 
OBJECTIVES/ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary objectives 
• 
To compare the incidence of Herpes Zoster (HZ) recurrence in the HZ/su group to 
the placebo group 
A formal non-inferiority analysis with non-inferiority margin of 5 will be performed 
− 
Criterion: The objective is met if the upper limit (UL) of the 95% confidence 
interval (CI) of the ratio of the incidence of HZ recurrence (HZ/su versus 
placebo) is below 5. 
2.1.2. 
Secondary objectives 
• 
To evaluate the rate of HZ recurrence in HZ/su and placebo groups during the entire 
study period. 
• 
To evaluate safety and reactogenicity following administration of HZ/su vaccine or 
placebo within 30 days after each dose. 


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• 
To evaluate safety following administration of HZ/su vaccine or placebo during the 
entire study period. 
• 
To characterize anti-gE humoral immunogenicity response prior to the first 
vaccination (Day 1), at two months post first vaccination (Month 2) and at one 
month post last vaccination (Month 3) in both groups. 
2.2. 
Endpoints 
2.2.1. 
Primary endpoints 
• 
Occurrence of confirmed HZ episodes from 30 days post second vaccination until 
study end. 
2.2.2. 
Secondary endpoints 
• 
Occurrence of confirmed HZ episodes from first study vaccination until study end 
• 
Reactogenicity and safety, in all subjects  
− 
Occurrence, intensity and duration of each solicited local adverse event (AE) 
within 7 days (Days 1-7) after each vaccination. 
− 
Occurrence, intensity, duration and relationship to vaccination of each solicited 
general AE within 7 days (Days 1-7) after each vaccination.  
− 
Occurrence, intensity and relationship to vaccination of unsolicited AEs within 
30 days (Days 1-30) after each vaccination, according to the Medical Dictionary 
for Regulatory Activities (MedDRA) classification.  
− 
Occurrence and relationship to vaccination of all serious adverse events (SAEs) 
from dose 1 up to 30 days post last vaccination.  
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− 
Occurrence and relationship to vaccination of any potential immune mediated 
diseases (pIMDs) from dose 1 up to 30 days post last vaccination.  
− 
Occurrence and relationship to vaccination of all SAEs within the period starting 
after 30 days post last vaccination until 1 year post last vaccination. 
− 
Occurrence and relationship to vaccination of any pIMDs within the period 
starting after 30 days post last vaccination until 1 year post last vaccination. 
− 
Occurrence of SAEs related to investigational vaccine, related to study 
participation or to GSK concomitant medication/vaccine during the entire study 
period.  
• 
Immunogenicity, in all subjects 
− 
Vaccine response for Anti-gE humoral immunogenicity as determined by 
Enzyme-linked immunosorbent assay (ELISA) at Month 2 and Month 3.  
− 
Anti-gE antibody concentrations as determined by ELISA at Day 1, Month 2 
and Month 3.  
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3. 
STUDY DESIGN 
Figure 1 
Overview of Study design 
 
BS= Blood sampling; HZ= Herpes Zoster; N= number of subjects planned to be enrolled; Vacc= Vaccination 
*A blood sample (approx. 5ml per visit) will be collected from all subjects at Visits 1, 2 and 3. An additional blood 
sample (approx. 20ml per visit) will be collected from subjects in the cell mediated immunity sub-cohort at Visits 1, 2 
and 3. 
‡The duration of the study will vary for each subject. Study conclusion will be scheduled based on the projected date of 
the last contact of the last enrolled subject, that is 26 months (790 days) from the enrolment date. The study conclusion 
visit/ contact for subjects with an ongoing episode of HZ will occur after a 4-week pain-free period is documented OR 
after Day HZ-92 follow-up has been completed. 
• 
Experimental design: Phase III, observer-blind, randomized, placebo controlled, 
multicenter, multi-country study with two parallel groups. 
• 
Duration of the study: The duration of the study will vary for each subject. The 
duration of the study will be up to the study conclusion contact that occurs within 30 
days of the projected study conclusion date of the last enrolled subject, that is, 26 
months (790 days) from the enrolment date. Therefore, subjects enrolled early in the 
trial could be followed for longer duration than the subjects who enrol later in the 
trial. The study conclusion visit/ contact for subjects with an ongoing episode of HZ 
at the time of last subject last visit (LSLV) will occur after a 4-week pain-free period 
is documented OR after Day HZ-92 follow-up has been completed. 
− 
Epoch 001: Starting at Visit 1 (Day 1) followed by Visit 2 at two months post 
first vaccination (Month 2), Visit 3 at one month post last vaccination (Month 
3). 
− 
Epoch-002: Starting with monthly contact after Visit 3 (Month 3) and ending at 
the monthly contact that occurs within 30 days of the projected study conclusion 
date of the last enrolled subject, that is, 26 months (790 days) from the 
enrolment date. 
• 
Primary completion Date (PCD): The primary completion date will be when the 
last subject completes their study conclusion contact (within 30 days of the projected 
study conclusion date of the last enrolled subject, that is, 26 months [790 days] from 
the enrolment date.  
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• 
End of Study (EoS): 1) After all the subjects complete their study conclusion 
contact, occurring within 30 days of the projected study conclusion date of the late 
enrolled subject, that is, 26 months (790 days) from the enrolment date of the last 
subject and 2) the release of all polymerase chain reaction (PCR) test results for the 
HZ rash lesion sample.  
Refer to the protocol glossary of terms for the definition of EoS. 
• 
Study groups: 
Table 1 
Study groups and epochs foreseen in the study  
Study groups 
Number of eligible 
subjects 
Age (years) 
Epochs 
Epoch 001 
Epoch 002 
HZ/su 
713 
≥50 years  
● 
● 
Placebo 
713  
≥50 years  
● 
● 
• 
Control: placebo controlled 
• 
Vaccination schedule: 0 and 2 months 
• 
Treatment allocation: Eligible subjects will be randomized (1:1) to HZ/su group or 
placebo group. The randomization algorithm will use a stratification procedure 
accounting for age (50-59 years of age [YOA]; 60-69 YOA and ≥ 70 YOA) and also 
a stratification procedure accounting for ‘time since previous HZ episode’ (≤ 4 years 
ago, 5-9 years ago, ≥ 10 years ago). Additional minimization factors include: 
(female) gender, center, family (first degree blood relative) history of HZ, history of 
PHN and a combined minimization factor to reflect the presence of any of the 
following conditions: type 2 diabetes mellitus, asthma, chronic obstructive 
pulmonary disease, chronic kidney disease and depression. 
Table 2 
Expected enrolment based on overall age stratification  
Age stratum 
Sample size 
Percentage of total 
50-59 YOA 
Min 285 
Min 20 
60-69 YOA 
Min 285 
Min 20 
≥70 YOA 
Min 143 
Min 10 
All 
1426 
100.0 
Table 3 
Expected enrolment based on time from previous HZ case 
Sub-group 
Sample size 
Percentage of total 
≤4 years ago 
Min 143 
Min 10 
5-9 years ago 
Min 143 
Min 10 
≥ 10 years ago 
Min 143 
Min 10 
All 
1426 
100.0 
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• 
Blinding: 
Table 5 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch-002 
observer-blind 
• 
Sampling schedule:  
− 
Blood samples for humoral immunity (approximately 5 mL per visit) will be 
collected from all subjects at Visit 1 (Day 1), Visit 2 (Month 2), and Visit 3 
(Month 3). 
− 
Clinical specimens of HZ lesions will be collected from all subjects who are 
clinically diagnosed with a suspected case of HZ (Section 4.1 of the protocol). 
− 
A urine specimen will be collected from all female subjects of child-bearing 
potential (see glossary of terms in protocol for definition of woman of child 
bearing potential) at Visit 1 (Day 1) and Visit 2 (Month 2). If a serum pregnancy 
test instead of a urine pregnancy test is required by country, local or ethics 
committee regulations, a blood sample will be collected from women of child-
bearing potential at Visit 1 (Day 1) and Visit 2 (Month 2) and used for the test as 
per local guidance.  
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• 
Group and sub-group information 
Table 6 
Group names and description for footnote will be used in the Tables, 
Figures and Listings, in line with the T-domains: 
Group order 
in tables 
Group label 
in tables 
Group definition for footnote 
1 
HZ/su 
Subjects receiving HZ/su vaccine 
2 
Placebo 
Subjects receiving Placebo 
The following sub-groups will be used in the Tables Figures and Listings (TFL), in line 
with the T-domains: 
Table 7 
Sub-group name and definitions to be used for the sub-group 
analysis by age stratum  
Sub-group order in tables 
Sub-group label in tables 
Sub-group definition for footnote 
1 
50-59 YOA 
Subjects aged 50-59 years of age 
2 
60-69 YOA 
Subjects aged 60-69 years of age 
3 
≥70 YOA 
Subjects aged ≥70 years of age 
YOA = Years of age 
Table 8 
Sub-group name and definitions to be used for the sub-group 
analysis by time since previous HZ episode  
Sub-group order in 
tables 
Sub-group label in 
tables  
Sub-group definition for footnote 
1 
Previous HZ ≤ 4 Y 
Previous HZ episode was ≤ 4 years prior to enrolment 
2 
Previous HZ ≥ 5 - ≤ 9 Y 
Previous HZ episode was 5-9 years prior to enrolment  
3 
Previous HZ ≥ 10 Y 
Previous HZ episode was ≥ 10 years prior to enrolment  
Y = Year  
4. 
ANALYSIS SETS 
4.1. 
Definition 
4.1.1. 
Enrolled Set 
The enrolled set will include subjects who signed the informed consent form (ICF) and 
were either randomized to receive treatment or have had an invasive procedure (i.e., 
blood draw or vaccine administration). 
4.1.2. 
Randomized Set 
The randomized set will include subjects who signed the inform consent form (ICF) and 
treatment is allocated for them. 


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4.1.3. 
Exposed Set 
The exposed set (ES) will include all subjects with at least one study vaccine 
administered.  
The ES for analysis of immunogenicity will include all vaccinated subjects for whom 
data related to immunogenicity endpoints are available. 
 
 
 
The ES for analysis of reactogenicity (e.g., solicited AEs) will include all subjects with at 
least one vaccine administration documented and who have solicited safety data (i.e., 
symptom screen/sheet completed). 
The ES for analysis of safety (e.g. SAEs) will include all subjects with at least one 
vaccine administered. 
4.1.4. 
Modified Exposed Set 
The modified exposed set (mES) is the primary population for HZ recurrence analysis. 
The mES excludes subjects from the ES who were not administered two doses of the 
study vaccine per protocol, or who developed a confirmed case of HZ prior to 30 days 
after the second vaccination.  
4.1.5. 
Per Protocol Set for immunogenicity  
The per protocol set (PPS) for immunogenicity will be defined by time-point and will 
include evaluable subjects from the ES: 
• 
who meet all eligibility criteria. 
• 
who received 2 doses of the HZ/su study vaccine or placebo according to their 
random assignment.  
• 
who did not receive forbidden medications as defined in the protocol. 
• 
who had no intercurrent medical condition (IMC) which may influence immune 
response. 
• 
who complied with the vaccination schedule as specified in Table 9. 
• 
who complied with the blood sample schedule as specified in Table 9. 
• 
for whom data concerning immunogenicity endpoint measures are available. 
The intervals allowed for the inclusion in the PPS for analysis of immunogenicity are 
defined as follows: 
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Table 9 
Intervals between study visits 
Interval 
Optimal length of interval 1 
Allowed interval 
Allowed interval during 
special circumstances 2 
Visit 1→Visit 2 
60 days (2 months) 
49 days - 83 days  
49 days – 180 days 
Visit 2→Visit 3 
30 days (1 month) 
28 days- 48 days 
28 days- 90 days 
1Whenever possible the investigator should arrange study visits according to this interval. 
2 Refer to protocol Section 6.7 for study procedures to be considered during special circumstances. 
Based on the availability of humoral immune response result and 
, separate 
PPS will be defined for humoral sample and 
: 
• 
PPS-HI - all subjects meeting the criteria described above and have humoral immune 
result available post vaccination 
For the immunogenicity tables where different timepoints are presented, the concept of 
“Adapted PPS for immunogenicity” will be used to denote that for each timepoint, the 
corresponding PPS will be used. 
More specifically, 
• 
The analyses at the Day 1 timepoint will be based on the PPS for immunogenicity 
Day 1; 
• 
The analyses at the Month 2 timepoint will be based on the PPS for immunogenicity 
Month 2; 
• 
The analysis at the Month 3 timepoint will be based on the PPS for immunogenicity 
Month 3; 
4.2. 
Criteria for eliminating data from Analysis Sets 
Elimination codes are used to identify subjects to be eliminated from analysis. Detail is 
provided below for each set.  
4.2.1. 
Elimination from Enrolled Set  
Code 800 (fraudulent data) and code 900 (invalid ICF) will be used for identifying 
subjects eliminated from Enrolled Set. 
4.2.2. 
Elimination from Randomized Set  
Code 800 (fraudulent data), 900 (invalid ICF) and code 1010 (vaccine number not 
allocated) will be used for identifying subjects eliminated from Randomized Set 
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4.2.3. 
Elimination from Exposed Set (ES) 
Code 800 (Fraudulent data) and code 900 (invalid ICF), code 1010 (vaccine number not 
allocated) and code 1030 (Study vaccine not administered at all) will be used for 
identifying subjects eliminated from ES.  
4.2.4. 
Elimination from modified Exposed Set (mES) 
Code 800 (Fraudulent data), code 900 (invalid ICF), code 1010 (vaccine number not 
allocated), code 1030 (Study vaccine not administered at all), code 1050 (Randomization 
failure), code 1070 (Vaccination not according to protocol), code 2500 (Subject who 
didn’t receive two doses) and code 3500 (Subject having confirmed HZ episode prior to 
30 days after the dose 2) will be used for identifying subjects eliminated from mES.  
4.2.5. 
Elimination from Per-protocol analysis Set (PPS) 
4.2.5.1. 
Excluded subjects 
A subject will be excluded from the PPS analysis under the following conditions  
For codes 800, 900, 1010, 1030, 1050, 1060, 2010, 2500: subjects will be eliminated 
from all visits. 
For codes 1040, 1070, 1080, 1090, 2040, 2050, 2080, 3500: subjects will be eliminated 
from a specific visit (at which the condition is met) onwards. 
For code 2090: subjects will be eliminated at the specific visit at which the condition is 
met. 
Additionally, for the PPS-HI, subjects with codes 2020, 2100, 2120 will be eliminated at 
the specific visit at which the condition is met. 
 
 
. 
Code 
Condition under 
which the code is 
used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for 
analysis set 
800 
Fraudulent data 
All 
All 
900 
Invalid ICF 
All 
All 
1010 
Vaccine not allocated 
All 
Randomized set, 
ES, mES, PPS 
1030 
Study vaccine not 
administered at all 
All 
ES, PPS, mES 
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Code 
Condition under 
which the code is 
used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for 
analysis set 
1040* 
Administration of 
concomitant 
vaccine(s) forbidden 
in the protocol 
Any concomitant 
vaccination not 
foreseen by the study 
protocol administered 
in the period starting 
30 days before the 
first dose of study 
vaccine and ending at 
Visit 3 (Day -30 to 
Month 3) 
Day -30 up to Month 
3 
PPS 
1050 
Randomization failure All 
mES, PPS 
1060 
Randomization code 
was broken 
Day 1 to Month 3 
PPS 
1070** 
Vaccination not 
according to protocol 
• 
Subjects got 
vaccinated with 
the correct 
vaccine but 
containing a 
lower volume 
• 
Administration 
not according to 
protocol for 
reason specified 
by the 
investigator, 
other than side, 
site and route 
• 
Site or route of 
study vaccine 
administration 
wrong or 
unknown 
• 
Wrong 
replacement or 
Day 1, Month 2 
mES, PPS 


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Code 
Condition under 
which the code is 
used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for 
analysis set 
study vaccine 
administered (not 
compatible with 
the vaccine 
regimen 
associated to the 
treatment 
number) 
Administered study 
vaccine reported as 
being the correct one 
but is not compatible 
with the vaccine 
regimen associated to 
the treatment number 
1080 
Vaccine temperature 
deviation 
Day 1, Month 2 
PPS 
1090 
Expired vaccine 
administered 
Day 1, Month 2 
PPS 
2010 
Protocol violation 
(inclusion/exclusion 
criteria) 
Day 1 
PPS 
2020 
Unknown antibody 
status at pre timepoint 
for anti-gE humoral 
result (baseline 
sampling missing or 
unable to test because 
of hemolysis, 
insufficient volume) 
Day 1 
PPS-HI 
2040* 
Administration of any 
medication forbidden 
by the protocol 
Day 1 to Month 3 
PPS 
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Code 
Condition under 
which the code is 
used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for 
analysis set 
Any concomitant 
medication or drug 
not foreseen by the 
study protocol (refer 
to section 7.7.2 of the 
protocol) 
administered in the 
period from the first 
dose of study vaccine 
and ending at Visit 3 
(Day -30 to Month 3) 
2050* 
Underlying medical 
condition forbidden 
by the protocol  
Any IMC (refer to 
section 7.8 of the 
protocol) which can 
affect the immune 
response to the study 
vaccine between the 
first dose of study 
vaccine and ending at 
Visit 3 (Day -30 to 
Month 3) 
Day 1 to Month 3 
PPS 
2080 
Subjects who had 
planned study visits 
during special 
circumstances did 
not comply with 
vaccination schedule 
DOSE 1 - DOSE 2 = 
49-180 days  
Other Subjects did 
not comply with 
vaccination schedule 
DOSE 1 - DOSE 2 = 
49-83 days 
Month 2 
PPS 
2090 
Subjects who had 
planned study visits 
during special 
circumstances did 
not comply with 
blood sample 
schedule 
Month 2, Month 3 
PPS 


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Code 
Condition under 
which the code is 
used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for 
analysis set 
DOSE 1 - BS2 = 49-
180 days for PPS at 
Month 2 
DOSE2 - BS2 = 28-
90 days for PPS at 
Month 3  
Other Subjects did 
not comply with 
blood sample 
schedule 
DOSE1 - BS2 = 49-
83days for PPS at 
Month 2 
DOSE2 - BS3 = 28-
48 days for PPS at 
Month 3 
2100 
Serological results of 
anti-gE humoral not 
available post-
vaccination 
Month 2, Month 3 
PPS-HI 
2120 
Obvious incoherence 
or abnormality or 
error in anti-gE 
humoral data 
Day 1, Month 2, 
Month 3 
PPS-HI 
2500 
Subjects who did not 
receive two doses 
Month 2 
mES, PPS 
3500 
Subjects having 
confirmed HZ 
episode prior to 30 
days after the dose 2 
Day 1 to Month 3 
mES, PPS 
 
*Attribution of these elimination codes to subject need CSL review of individual listing 
** Attribution of code 1070 to a subject requires CSL confirmation 
PPS = PPS-HI and 
(until specifically mentioned) 
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5. 
STATISTICAL ANALYSES 
5.1. 
Demography 
5.1.1. 
Analysis of demographics/baseline characteristics planned in the 
protocol 
Demographic characteristics (age at first study vaccination in years, gender and 
Geographic Ancestry/ethnicity), ‘time since previous HZ episode’, age stratum and 
withdrawal status will be summarized by group using descriptive statistics: 
Frequency tables will be generated for categorical variable such as age stratum, ‘time 
since previous HZ episode’ and gender. 
Mean, median, Standard Deviation (SD) will be provided for continuous data such as age. 
The analysis will be based on ES. 
5.1.2. 
Additional considerations 
• 
Demographic characteristics (age at first study vaccination in years, gender, 
ethnicity, and race), ‘time since previous HZ episode’ and age stratum will also be 
generated on mES, PPS-HI and 
 
• 
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal on ES and mES.  
• 
Number of subjects by country and center will be presented on ES. 
The following table will be generated for web disclosure: 
− 
Percentage of Enrolled subjects by country will be tabulated by group, 
− 
Percentage of Enrolled subjects in the following age strata ≤64, 65-84, ≥85 
YOA will be tabulated by group. 
• 
Summary of important protocol deviations leading to elimination will be presented 
from Enrolled Set. 
• 
The number of subjects enrolled into the study as well as the number of subjects 
excluded from PPS analyses will be presented through tables.  
5.2. 
Exposure 
5.2.1. 
Analysis of exposure planned in the protocol 
None  
5.2.2. 
Additional considerations 
The number of doses administered will be tabulated on ES. 
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5.3. 
Analysis of incidence rate of Herpes Zoster recurrence 
5.3.1. 
Analysis of incidence rate of Herpes Zoster recurrence planned 
in protocol 
The primary analysis of incidence rate of HZ recurrence will be based on the mES. The 
same analysis will be performed on ES to complement the mES analysis. 
5.3.1.1. 
Within group  
For each group, the number of subjects, person-time, number of confirmed HZ cases and 
incidence rate will be tabulated from 30 days post the last vaccination until study end and 
from first study vaccination until study end on ES. 
5.3.1.2. 
Between group 
A formal non-inferiority analysis with a non-inferiority margin of 5 will be performed. 
Non-inferiority assessment will be carried out based on the fact that the distribution of 
two Poisson variates conditional on their sum is binomial [Lehmann, 1959]. Let n1 and 
n0 be the number of HZ recurrence cases, T1 and T0 (years) be total follow up, and r1 
and r0 be the incidence rate in HZ/su group and placebo group respectively. It is assumed 
that ni ~ Poisson(λi) (i=0,1) and λi=Ti×ri, and condition on n=n0+n1, n1 ~ Binomial (n, 
p), where p=λ1/(λ1+λ0). A 95% exact CI for p can be derived by using Clopper-Pearson 
approach, through which a 95% exact CI for π=r1/r0 (that is, the ratio of incidence rate of 
HZ recurrence (HZ/su versus placebo)) can be derived. Non-inferiority is met if the upper 
limit of the 95% CI for π is below 5. 
In addition to performing a formal non-inferiority analysis, to further quantify the 
likelihood of the risk increase of HZ following Shingrix vaccination, a probability curve 
that the ratio of incidence of HZ recurrence (HZ/su versus placebo) is higher than x-fold 
(x varying from 1 to 5) will be estimated by Bayesian methodology. It will be assumed 
that the number of HZ cases in the HZ/su and in placebo groups follows Poisson 
distribution with rate (incidence rate) of λHZ and λP respectively. We further assume that 
λHZ and λP are random variables both with non-informative Gamma prior distribution: 
Gamma (0.001, 0.001). Based on the posterior distribution of λHZ and λP, the probability 
curve of the ratio of incidence of HZ recurrence (HZ/su versus placebo), that is, 
Pr(λHZ/λP>x| data, prior), can be calculated for each given value of x. 
5.3.2. 
Additional considerations 
For analysis for non-inferiority, only the first confirmed HZ episode will be considered. 
The non-inferiority will be assessed by following model and fitted via the PROC 
GENMOD procedure according to the following code: 
PROC GENMOD data=XXX;  
 
CLASS group_nb(ref="Placebo") / param=ref; 
 
MODEL nb_cases = group_nb / dist=poisson offset=log_T link=log type3; 


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EXACT group_nb / estimate=odds; 
 
ODS OUTPUT ExpExactParmEst=IRR; 
RUN; 
where, 
nb_case = number of cases 
Group_nb = Group information of the subject (treatment received by subject) 
Log_T = Log of the follow-up time 
Note: variables names may vary as per ADAM variables however their derivations 
remain the same. 
The estimated rate ratio and its 95% CI will be provided in the output dataset IRR.  
In extreme situations, when there are no confirmed HZ cases in the HZ/su group and 
> 0 confirmed HZ cases in the Placebo group, the EXACT computational algorithm 
used in SAS will run into difficulty and cannot provide accurate results. Therefore, the 
rate ratio (HZ/su versus placebo) will be set to 0. When there are no confirmed HZ 
cases in the Placebo group and > 0 confirmed HZ cases in the HZ/su group, the rate 
ratio is not estimable, instead the incidence rate and 95% CI in each treatment group 
will be reported. 
• 
For Bayesian analysis, the number of HZ cases in the HZ/su and in placebo groups 
follows Poisson distribution with rate (incidence rate) of λHZ and λP, respectively. 
We further assume that λHZ and λP are random variables both with non-informative 
Gamma prior distribution: Gamma (0.001, 0.001). The posterior distribution of λHZ 
and λP will be Gamma distribution with parameter  
λHZ ~ Gamma (0.001 + 𝑐𝑎𝑠𝑒𝐻𝑧 , 0.001 + 𝑇𝐻𝑧) and  
λP ~ Gamma (0.001 + 𝑐𝑎𝑠𝑒𝑃, 0.001 + 𝑇𝑃) 
where, 
𝑐𝑎𝑠𝑒𝐻𝑧= number of cases in HZ/su group  
𝑐𝑎𝑠𝑒𝑝= number of cases in placebo group 
𝑇𝐻𝑧= total follow-up time in years in HZ/su group  
𝑇𝑝= total follow-up time in years in placebo group  
To estimate the probability of incidence rate ratio, simulation program will be run to 
generate sample from Gamma distribution using the function above. 
The probability of incidence rate ratio greater than a specified value (e.g., 1, 2, 3, 4, 5) 
will be plotted against incidence rate ratio in graph. 
In extreme situations, when there are no confirmed HZ cases in the HZ/su group or 
the Placebo group, the Gamma prior distribution will be updated to Gamma (0.015, 
0.015), considering the minimum acceptable alpha in SAS is 0.015. 
Considering the enrolment gap due to COVID-19, if data permit, the following 
sensitivity analyses will be conducted to explore between group comparisons to 
complement the analysis of primary endpoint: 


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• 
A sensitivity analysis comparing HZ incidence rates between HZ/su and placebo 
groups on adopted mES removing the participants who received a second dose 
more than 2 months after the first dose (outside of the original scheduled window 
receiving the second dose >83 days after the first dose). 
• 
A sensitivity analysis comparing HZ incidence rates between HZ/su and placebo 
groups stratified by enrolment pre- and post- recruitment interruption, using 
March 14th 2020 (the first day of site closure) as the cut-off date. 
• 
Kaplan-Meier curves to compare the onset time of HZ recurrences since receipt of 
the first and second assigned dose. 
• 
Moreover, if very different distribution between the HZ/su group and placebo 
group is presented, the Kaplan-Meier analysis on appropriate subintervals may 
also be performed. 
5.4. 
Immunogenicity 
5.4.1. 
Analysis of immunogenicity planned in the protocol 
The primary analysis will be based on the PPS for analysis of immunogenicity. If, in any 
group, the percentage of vaccinated subjects with serological results excluded from the 
PPS for analysis of immunogenicity is 5% or more, a second analysis based on the ES 
will be performed to complement the PPS analysis. 
5.4.1.1. 
Humoral immune response 
5.4.1.1.1. Within group assessment 
The following descriptive analyses will be performed for each group and by age stratum 
(50-59 YOA; 60-69 YOA and ≥70 YOA) and by ‘time since previous HZ episode’ (≤4 
years ago, 5-9 years ago, ≥10 years ago): 
• 
Seropositivity rate at Day 1, Month 2 and Month 3 with exact 95% CI 
• 
GMC at Day 1, Month 2 and Month 3 with 95% CI 
• 
VRR (vaccine response rate) at Month 2 and Month 3 with exact 95% CI.  
Descriptive statistics of the fold increase over pre-vaccination for anti-gE antibody 
concentration at Month 2 and Month 3 (Mean, SD, Min, Q1, Median, Q3, Max). 
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5.4.2. 
Additional considerations 
None 
5.5. 
Analysis of safety and reactogenicity 
5.5.1. 
Analysis of safety and reactogenicity planned in the protocol 
The analysis will be performed on the ES. When appropriate, tabulations will be 
presented overall and by time of occurrence relative to last vaccination (e.g., using 
windows such as Days 1-7, Days 1-30 and more than 30 days post-vaccination). Safety 
analyses will also be performed by age stratum (50-59 YOA; 60-69 YOA and ≥70 YOA) 
and by ‘time since previous HZ episode’ (≤4 years ago, 5-9 years ago, ≥10 years ago). 
The results for the analysis of safety will be tabulated as: 
• 
The proportion of subjects with at least one local AE (solicited or unsolicited), with 
at least one general AE (solicited or unsolicited) and with any AE (solicited or 
unsolicited) during the 7-day follow-up period will be tabulated with exact 95% CI 
after each vaccine dose and overall. 
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• 
The proportion of subjects with at least one local AE (solicited only), with at least 
one general AE (solicited only) and with any AE (solicited only) during the solicited 
7-day follow-up period will be tabulated with exact 95% CI after each vaccine dose 
and overall. 
• 
The proportion of subjects reporting each individual solicited local and general AE 
during the solicited 7-day-follow-up period will be tabulated with exact 95% CI. 
• 
For all solicited AEs, the same tabulation will be performed for grade 3 solicited AEs 
and for solicited general AEs with relationship to vaccination  
• 
The proportion of solicited AEs resulting in a medically attended visit will be 
tabulated. 
• 
Total duration of each individual solicited local and general AE will be tabulated. 
• 
The proportion of subjects reporting temperature by half degree (°C) cumulative 
increments. Similar tabulations will be performed for any fever with a causal 
relationship to vaccination and for any fever resulting in a medically attended visit. 
• 
The proportion of subjects with at least one report of unsolicited AE classified by the 
MedDRA system organ class (SOC) and preferred term (PT) and reported up to 30 
days after each vaccination will be tabulated with exact 95% CI. 
• 
The same tabulation will be performed for grade 3 unsolicited AEs (including 
serious AE) and for unsolicited AEs with a relationship to vaccination. The 
proportion of AEs resulting in a medically attended visit will also be tabulated. 
• 
Total number/percentages of doses (per dose and overall) followed by AEs will be 
tabulated. 
• 
All pIMDs and related pIMDs occurring from first vaccination up to 30 days post 
last vaccination will be tabulated. 
• 
All pIMDs and related pIMDs occurring after 30 days post last vaccination until 1 
year post last vaccination will be tabulated. 
• 
All SAEs, related SAEs occurring from first vaccination up to 30 days post last 
vaccination will be tabulated. 
• 
All SAEs, related SAEs occurring after 30 days post last vaccination until one year 
post last vaccination will be tabulated. 
• 
Fatal SAEs will be tabulated using date of onset of SAE in the following manner – 
within Day 1-Month 3 (30 days post last vaccination), Day 1 to Month 14 (one year 
post last vaccination) and during the entire study period. Fatal SAEs will also be 
tabulated using the date of death within the same time periods. 
• 
All SAE related to investigational vaccine, related to study participation or to GSK 
concomitant medication/vaccine occurring during the entire study period will be 
tabulated.  
• 
AEs/SAEs leading to withdrawal from the study will be tabulated. 
• 
• 
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• 
• 
• 
5.5.2. 
Additional considerations 
Following additional tables will be generated: 
• 
Number and percentage of subjects with at least one report of a grade 3 non-serious 
unsolicited AE during the 30-day (Days 1−30) follow-up period after each 
vaccination classified according to the MedDRA SOC and PT will be tabulated, with 
exact 95% CI. The same will be generated for grade 3 non-serious unsolicited AE 
considered related to vaccination. 
• 
Listing of subjects with fatal SAE during the entire study period including the 
associated events will be generated on Enrolled Set. 
• 
Listing of all SAEs up to end of study will be generated on Exposed Set. 
• 
Listing of subjects with a suspected HZ episode, PCR final result and HZAC final 
result from first administered dose up to end of study will be generated on Exposed 
Set.  
• 
Listing of (S)AEs and solicited adverse events leading to study or treatment 
discontinuation up to end of study will be generated on Exposed Set. 
• 
Duration of each individual solicited local and general AE within the solicited 
follow-up period will be tabulated. 
• 
COVID-19 infection cases identified during the study will be assessed as follows: 
• 
Numbers and percentage of subjects with a suspected, probable or confirmed 
COVID-19 infection will be summarized by group based on ES. 
• 
Number and percentage of subjects who had a COVID-19 infection reported 
as an AE or SAE will be summarized by group on ES. 
• 
Number and percentage of subjects who had a COVID-19 infection leading to 
study or treatment discontinuation be summarized by group on ES. 
6. 
ANALYSIS INTERPRETATION 
The primary objective of non-inferiority of the incidence of HZ recurrence in the HZ/su 
and placebo groups is considered met if the upper limit of the 95% CI of the ratio of the 
incidence of HZ recurrence (HZ/su versus placebo) is below 5.  
For all secondary objectives, analyses will be descriptive with the aim to characterize the 
differences in reactogenicity, safety and immunogenicity between groups. 
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The ratio of incidence of HZ recurrence (HZ/su versus Placebo) calculated using 
Bayesian methodology will be a descriptive analysis to provide additional information 
about incidence rate ratio between Hz/su and Placebo based on simulated data with 
assumption provided (sections 5.3.1.2 and 5.3.2) of the SAP. 
7. 
CONDUCT OF ANALYSES 
Any deviation(s) or change(s) from the original statistical plan outlined in the study 
protocol will be described and justified in the final clinical study report (CSR). 
7.1. 
Sequence of analyses 
There will be only one final analysis at the end of the study.  
A CSR containing all data will be written and made available to the investigators. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These data will be documented in annex(es) to the 
study report. 
Description 
Disclosure Purpose 
(CTRS=public posting, SR=study report, internal) 
Final analysis 
CTRS, SR  
7.2. 
Statistical considerations for interim analyses 
No interim analyses are planned. 
8. 
CHANGES FROM PLANNED ANALYSES 
Following are the changes from the planned analysis described in the protocol: 
• 
Two new cohorts – Enrolled Set and Randomized Set have been defined as required 
for web disclosure and SAE tables presentation on Enrolled Set. 
• 
The PPS population has been defined separately for the humoral immune response 
and 
 for each timepoint. 
• 
Evaluation of duration of unsolicited adverse event has been removed from endpoint 
as it is mistakenly added. 
• 
The grading of fever (grade 1 and grade 2) has been changed from protocol to align 
with other studies in Zoster project. Refer to section 9.1.4 for grading of fever.  
• 
Timeframe of fatal SAE reporting from Month 3 to study end is changed to Day 1 to 
study end. 
• 
The definition of modified Exposed Set has been modified to exclude the subjects 
who has not received vaccination per protocol. 
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• 
For the primary endpoint, added a sensitivity analysis on mES after removing the 
participants who received a second dose more than 2 months after the first dose 
(outside of the original scheduled window), added a stratified analysis by 
recruitment interruption, and Kaplan-Meier curves to compare the onset time of 
HZ recurrences if applicable. 
• 
Added analysis to assess the impact of COVID-19 on safety. 


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9. 
NON-STANDARD DATA DERIVATION RULES AND 
STATISTICAL METHODS 
The following sections describe additional derivation rules and statistical methods which 
are not presented in section 10.1. 
9.1. 
Data derivation 
9.1.1. 
Demography 
• 
For computation of age, following rule need to be considered:  
− 
Age will be calculated as the number of years between the date of birth and the 
date of first vaccination. 
− 
To ensure that the collection of date of birth will not jeopardise the privacy of 
Personally Identifiable Information (PII), only a partial date of birth (YYYY) 
will be collected. As the date and month will be missing, the date will be 
replaced by the June 30th of the year.  
9.1.2. 
Immunogenicity 
9.1.2.1. 
Humoral immune response 
• 
A seronegative subject is a subject whose Ab concentration is below the cut-off 
value. 
• 
A seropositive subject is a subject whose Ab concentration is greater than or equal to 
the cut-off value. 
• 
The seropositivity rate is defined as the percentage of seropositive subjects. 
• 
The VRR for anti-gE Ab concentration is defined as the percentage of subjects who 
have at least: 
− 
a 4-fold increase in the post last vaccination anti-gE Ab concentration as 
compared to the pre-vaccination anti-gE Ab concentration, for subjects who are 
seropositive at baseline, or,  
− 
a 4-fold increase in the post last vaccination anti-gE Ab concentration as 
compared to the anti-gE Ab cut-off value for seropositivity, for subjects who are 
seronegative at baseline. 
• 
The GMC calculations are performed by taking the anti-log of the mean of the log 
base 10 concentration transformations. For descriptive statistics only, Ab 
concentrations below the cut-off of the assay will be given an arbitrary value equal to 
half the cut-off for the purpose of GMC calculation. 
• 
To assess the VRR and the percentages of subjects with fold increase for anti-gE 
antibody concentration/ CD4+/CD8+ T-cells at Month 2/Month 3, subjects who are 
part of both PPS immunogenicity (Month 2/Month 3) and PPS immunogenicity at 
Day 1 will be considered. 


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9.1.3. 
HZ incidence 
• 
For the primary analysis of HZ incidence, first confirmed HZ episode will be 
considered.  
• 
The HZ onset date is the earlier of the following two events: 1) the HZ rash start 
date; or 2) the date on which pain at the site of a subsequent HZ rash is first noted. 
• 
A suspected case of HZ can be confirmed by GSK in two ways: 
− 
By PCR: Rash lesion samples will be collected from subjects clinically 
diagnosed as having a suspected case of HZ. The samples will be transferred to 
GSK or a validated laboratory designated by GSK Biologicals and analyzed 
using standardized and validated procedures for laboratory diagnosis of HZ by 
PCR (see Section 4.5.2.2.1 of the protocol).  
− 
By the HZ Ascertainment Committee (HZAC): All suspected HZ cases will 
be referred to the HZAC. The HZAC will classify all referred cases as either 
“HZ” or “not HZ” or “not able to decide” (see Section 4.5.2.2.2 of the protocol). 
The HZAC classification will serve as the final case definition only when the 
case cannot be confirmed or excluded by PCR. Therefore, definitive PCR 
results, when available, will determine the final HZ case assignment. In such 
cases, the HZAC classification will not contribute to HZ case determination 
decision 
• 
For a given subject and for HZ episode, missing or non-evaluable measurements will 
not to be imputed for the primary analysis. The missing endpoint and censoring are 
considered to occur independently, and the pattern being either Missing Completely 
At Random (MCAR) or Missing At Random (MAR) only. 
• 
For HZ recurrence analysis, due to the algorithm used and taking into account both 
laboratory and HZAC results, no imputation and no sensitivity analysis for missing 
data will be performed. 
• 
A 28-day pain-free period is used to confirm cessation of HZ-associated pain 
• 
The “follow-up time at risk” for confirmed HZ is expressed in days and is computed 
according to the following rules: 
− 
The start date of the follow-up time (start) will be computed as follows: 
o 
From the dose 1 administration date for the analysis on the ES; 
o 
From 30 days post-dose 2 date for the analysis on the mES. 
− 
The end date of the follow-up time (stop) will be computed as follows: 
o 
Date of the last visit/contact for subjects who did not have an event; 
o 
Last contact date for subjects dropped out of the study, if not preceded by 
an event; 
o 
Date of the event 
o 
Date of HZ vaccination outside the study, if not preceded by an event 


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• 
The follow-up time at risk is computed using the following formula: 
− 
stop – start +1. 
The time at risk will be expressed in Person-Year and derived from the follow up time 
(follow up time in days/365.25). 
9.1.4. 
Safety 
• 
For the analysis of 
/HZ related complications/solicited AEs/unsolicited 
AEs/SAEs/pIMDs/ concomitant medication, all vaccinated subjects will be 
considered and subjects who did not report an event will be considered as subjects 
without an event. 
• 
AEs that need to be reported as pIMDs are listed in Table 20 of the protocol. 
• 
The maximum intensity of local injection site redness/swelling will be graded as: 
0 
<20 mm diameter 
1 
≥20 mm to – ≤50 mm diameter 
2 
>50 mm to – ≤ 100 mm diameter 
3 
>100 mm diameter 
• 
The fever grading to be considered for analysis will be:  
0 
<38.0°C 
1 
≥38.0°C – ≤38.5°C 
2 
>38.5°C – ≤ 39.0°C  
3 
>39.0°C 
• 
 
. Severe ‘worst’ pain is 
defined as HZ-associated pain rated as 3 or greater on the “worst pain” question on 
the Zoster Brief Pain Inventory (ZBPI) questionnaire (see Sections 6.4.1 and 4.5.2.1 
of the protocol). 
 
. The cases without severe 
“worst” pain (score ≥ 3) were considered as non-event case. 
• 
CCI
CCI
CCI
CCI


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9.2. 
Statistical Method 
9.2.1. 
HZ incidence  
The number of HZ incidence is assumed to follow the Poisson distribution. The estimated 
incidence rate with 95% CI for both groups will be computed using following formula: 
CCI


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Incidence rate (per 1000) = Number of events*1000/Total follow-up period (in days) 
=n*1000/T 
 
 
Where 𝑋𝑣,𝑎
2 is the chi-square distribution quantile for upper tail probability on ν degrees of 
freedom, n is the number of events and T is the total follow-up time [Ulm, 1990]. Rule to 
derive the total follow-up period (in days) is provided in section 9.1.3 of the SAP.  
9.2.2. 
Safety  
The
 and other HZ related complication is assumed to follow 
Poisson distribution and will be estimated for both the groups with 95% CI using the 
formula provided in the section 9.2.1 of the SAP. 
Exact LL of incidence rate = 
𝑋2𝑛,𝛼/2
2
2𝑇
 
Exact UL of incidence rate = 
𝑋2(𝑛+1),(1−𝛼
2)
2
2𝑇
 
CCI


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10. 
ANNEXES 
10.1. 
Business rules for standard data derivations and statistical 
methods 
This section contains GSK Vaccines’ standard rules for data display and derivation for 
clinical and epidemiological studies. These rules will be applied along with those detailed 
in section 9 (additional study-specific rules). 
10.1.1. 
Attributing events to vaccine doses 
The dose relative to an event is the most recent study dose given to a subject prior to the 
start of a given event. For example, if the start date of an AE is between Dose 1 and Dose 
2, the relative dose will be Dose 1. 
If an event starts on the same day as a study dose, the relative dose will be derived from 
the additional information provided in the CRF using the contents of the flag indicating if 
the event occurred before or after vaccination. If ‘after vaccination’ is selected, the 
relative dose for the event will be the one administered on the start day of the event. If 
‘before vaccination’ is selected, the relative dose for the event will be the dose prior to 
this one. 
10.1.2. 
Handling of missing data 
10.1.2.1. 
Dates 
When partially completed dates (i.e. with missing day or month) are used in calculations, 
the following standard rules will be applied: 
• 
A missing day will be replaced by 15 
• 
A missing day and month will be replaced by June 30th. 
The following exceptions apply: 
• 
AE start dates with missing day: 
− 
If the event starts in the same month as at least one of the study doses, the 
contents of AE.AESTRTPT (the flag indicating if the event occurred before or 
after vaccination) will be used to complete the date. If ‘after vaccination’ is 
selected, the imputed start date will match the first (or only) study dose given 
during that month. If ‘before vaccination’ is selected, the imputed date will be 
one day before the first (or only) study dose given during that month. 
• 
AE start dates with missing day and month: 
− 
If the event starts in the same year as at least one of the study doses, the contents 
of AE.AESTRTPT (the flag indicating if the event occurred before or after 
vaccination) will be used to complete the date. If ‘after vaccination’ is selected, 
the imputed start date will match the first (or only) study dose given during that 


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year. If ‘before vaccination’ is selected, the imputed date will be one day before 
the first (or only) study dose given during that year. 
All other cases of incomplete AE or concomitant medication/vaccination start date will 
follow the standard rules above. 
10.1.2.2. 
Laboratory data 
Missing laboratory results (including immunological data) will not be replaced. 
10.1.2.3. 
Daily recording of solicited adverse events 
10.1.2.3.1. Studies with paper diaries 
For studies using paper diaries which have questions in the CRF indicating the presence 
or absence of solicited AEs, the following rules are applicable. 
Denominators for the summary of local (or general) solicited AEs will be calculated 
using the number of subjects who respond “Yes” or “No” to the question concerning the 
occurrence of local (or general) AEs. 
When a specific solicited AE is marked as having not occurred following a specific 
vaccination (i.e. SDTM CE.CEOCCUR=N for the specified post-vaccination period for 
the AE in question), all daily measurements will be imputed as Grade 0. 
When a specific solicited AE is marked as having occurred following a specific 
vaccination (i.e. SDTM CE.CEOCCUR=Y for the specified post-vaccination period for 
the AE in question), any missing daily recordings will be given imputed values to allow 
them to contribute to the ‘Any’ rows but not to specific grade rows of the solicited AE 
summary tables. 
When the occurrence of a specific solicited AE is not present (i.e. SDTM CE.CEOCCUR 
is neither Y nor N for the specified post-vaccination period for the symptom in question) 
but the group of solicited AE (local or general) is marked as having occurred (i.e. SDTM 
CE.CEOCCUR=Y), all missing daily recordings will be given imputed values to allow 
them to contribute to the ‘Any’ rows but not to specific grade rows of the solicited AE 
summary tables. 
The following table shows how subjects contribute to each category for a specific 
solicited AE over the Day X to Day Y post-vaccination period: 


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Solicited adverse 
event category 
Subjects included in the calculation of the numerator 
Any 
All subjects with at least one occurrence of the adverse event at grade 1, grade 2, or grade 
3 between Day X and Day Y or with the adverse event marked as present and at least one 
missing daily recording between Day X and Day Y 
At least grade 1 
All subjects with at least one occurrence of the adverse event at grade 1, grade 2, or grade 
3 between Day X and Day Y 
At least grade 2 
All subjects with at least one occurrence of the adverse event at grade 2 or grade 3 between 
Day X and Day Y 
At least grade 3 
All subjects with at least one occurrence of the adverse event at grade 3 between Day X 
and Day Y 
10.1.2.4. 
Unsolicited adverse events 
Unsolicited AE summaries are including SAEs unless specified otherwise.  
Missing severity, relationship with study vaccine, and outcome of unsolicited adverse 
events will not be replaced and will appear as ‘UNKNOWN’ in all statistical output. 
10.1.3. 
Data derivation 
10.1.3.1. 
Temperature 
Temperatures will be presented in degrees Celsius (°C). Temperatures reported in degrees 
Fahrenheit (°F) will be converted as follows: 
Temperature (Celsius) = ((Temperature (Fahrenheit) - 32) x 5)/9 
10.1.3.2. 
Numerical serology results 
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM 
dataset. For assays with a specific cut-off, the following derivation rules apply: 
IS.ISORRES 
Derived value 
“value” and value is < cut-off 
cut-off/2 
“value” and value is >= cut-off 
value 
All other cases 
missing 
10.1.3.3. 
Geometric mean concentrations (GMCs) 
Geometric Mean Concentration (GMC) calculations are performed by taking the inverse 
logarithm of the mean of the log titre or concentration transformations. Antibody titres or 
concentrations below the cut-off of the assay will be given an arbitrary value of half the 
cut-off of the assay for the purpose of GMC calculation. The cut-off value is defined by 
the laboratory before the analysis and is described in the protocol. 


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10.1.3.4. 
Onset day 
The onset day for an event (e.g. AE, medication, vaccination) is the number of days 
between the last study vaccination and the start date of the event. This is 1 for an event 
occurring on the same day as a vaccination (and reported as starting after vaccination). 
10.1.3.5. 
Duration of events 
The duration of an event with a start and end date will be the number of days between the 
start and end dates plus one day, i.e. an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days. 
The duration of solicited events will be calculated as the sum of the individual days with 
the adverse event reported at grade 1 or higher during the solicited adverse event period. 
10.1.3.6. 
Counting rules for combining solicited and unsolicited adverse events 
For output combining solicited and unsolicited adverse events, all serious adverse events 
will be considered general events since the administration site flag is not included in the 
expedited adverse event CRF pages. 
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence. 
10.1.3.7. 
Counting rules for occurrences of solicited adverse events 
When the occurrences of solicited AEs are summarized, each event recorded as having 
occurred during a specific period will be counted as only one occurrence regardless of the 
number of days on which it occurs. Also, in the case of co-administered study vaccines, 
an injection site reaction recorded for a subject following multiple vaccines will be 
counted as only one occurrence. 
10.1.4. 
Display of decimals 
10.1.4.1. 
Percentages 
Percentages and their corresponding confidence limits will be displayed with: 
• 
no decimals when there are fewer than 50 subjects in each tabulated group 
• 
one decimal when there are at least 50 subjects in at least one tabulated group 
− 
Exceptions will be made for percentages that are not 0% or 100% but appear as 
0% or 100% due to rounding. For these specific cases the number of decimals 
will be increased until the displayed value is no longer 0% or 100%. Examples 
are given in the following table. 


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n/N Displayed percentage 
10/45 22% 
1/45 2% 
10/55 18.2% 
1/55 1.8% 
1/300 0.3% 
1/3000 0.03% 
1/30000 0.003% 
299/300 99.7% 
2999/3000 99.97% 
29999/30000 99.997% 
− 
The display of additional decimals for values close to 0% or 100% will be 
applied only to point estimates and not confidence limits, which can be rounded 
and displayed as 0% or 100%. 
− 
Values of exactly 0% or 100% will be presented with no decimals regardless of 
the number of subjects per tabulated group. 
10.1.4.2. 
Differences in percentages 
Differences in percentages and their corresponding confidence limits will be displayed 
with one more decimal than the maximum number used to display the individual 
percentages, for example the difference between two percentages displayed with one 
decimal will be displayed with two decimals. 
10.1.4.3. 
Serological summary statistics 
The number of decimals used when displaying GMC and their confidence limits is shown 
in the following table: 
GMC value 
Number of decimals to display 
<0.1 
3 
>=0.1 and <10 
2 
>=10 and <1000 
1 
>=1000 
0 
When multiple categories of GMC values are present in the same table, the number of 
decimals displayed should match that of the smallest category (i.e. the one with the 
higher number of decimals). For example, if GMC values of <0.1 appear in the same 
table as values of >=0.1 and <10, 3 decimals should be displayed for both. 
10.1.5. 
Statistical methodology 
10.1.5.1. 
Exact confidence intervals around proportions 
The exact confidence intervals around within-group proportions are derived using the 
method of Clopper and Pearson [Clopper, 1934]. 


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10.2. 
TFL TOC 
The TFL Table Of Content (TOC) which itemizes the planned list of TFL and their 
associated lay-out is developed as a separate document. 
11. 
REFERENCES 
Clopper CJ, Pearson E. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika. 1934;26:404-13. 
Lehmann, E.L. (1959) Testing Statistical Hypotheses, New York, Wiley 
Ulm K. A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology 1990;131(2):373-375.