Efficacy, Safety and Immunogenicity of GSK Biologicals' HZ/su Vaccine GSK1437173A in a Phase IIIb, Open-label, Long-term Follow-up Study (ZOE-LTFU) of Studies 110390/113077 (ZOSTER-006/022) and Assessment of Additional Doses in Older Adults
Phase: PHASE3
Conditions: Herpes Zoster, Herpes Zoster Vaccine
Sponsor: GlaxoSmithKline

Protocol Amendment 5
Study ID:  201190
Official Title of Study: A phase IIIb, open-label, multi-country, multi-centre, long-
term follow-up study (ZOE-LTFU) of studies 110390 and 113077 (ZOSTER-006/022) 
to assess the prophylactic efficacy, safety, and immunogenicity persistence of GSK 
Biologicalsâ€™ Herpes Zoster subunit (HZ/su) vaccine and assessment of 1 or 2 
additional doses on a 0 or 0, 2-month schedule in two subgroups of older adults.
NCT number: NCT02723773
Date of Document: 14 May 2020

CONFIDENTIAL 
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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
Primary Study vaccine 
(and number) 
GlaxoSmithKline (GSK) Biologicals’ lyophilised 
formulation of the Herpes Zoster subunit (HZ/su) vaccine 
(GSK1437173A) 
eTrack study number 
and Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
Investigational New 
Drug (IND) number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Date of protocol 
Final Version 1: 11 December 2015 
Date of protocol 
amendment/adminis-
trative change 
Amendment 1 Final: 19 February 2016 
Amendment 2 Final: 19 January 2017 
Administrative Change 1 Final: 05 May 2017 
Amendment 3 Final: 16 March 2018 
Amendment 4 Final: 23 October 2018
Administrative Change 2 Final: 11 February 2019 
Amendment 5 Final: 11 May 2020 
Title 
Efficacy, safety and immunogenicity of GSK Biologicals’ 
HZ/su vaccine GSK1437173A in a phase IIIb, open-label, 
long-term follow-up study (ZOE-LTFU) of studies 
110390/113077 (ZOSTER-006/022) and assessment of 
additional doses in older adults 
Detailed Title 
A phase IIIb, open-label, multi-country, multi-centre, long-
term follow-up study (ZOE-LTFU) of studies 110390 and 
113077 (ZOSTER-006/022) to assess the prophylactic 
efficacy, safety, and immunogenicity persistence of GSK 
Biologicals’ Herpes Zoster subunit (HZ/su) vaccine and 
assessment of 1 or 2 additional doses on a 0 or 0, 2-month 
schedule in two subgroups of older adults. 
Co-ordinating author 
(Amended 11 May 
2020) 
, 
 and 
, 
Scientific Writer 
Contributing authors 
(Amended 11 May 
2020) 
•
, 
 and 
Clinical Research and Development Leads
•
, 
, 
,
Study Delivery Leads
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eTrack study number 
and Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
Investigational New 
Drug (IND) number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Detailed Title 
A phase IIIb, open-label, multi-country, multi-centre, long-
term follow-up study (ZOE-LTFU) of studies 110390 and 
113077 (ZOSTER-006/022) to assess the prophylactic 
efficacy, safety, and immunogenicity persistence of GSK 
Biologicals’ Herpes Zoster subunit (HZ/su) vaccine and 
assessment of 1 or 2 additional doses on a 0 or 0, 2-month 
schedule in two subgroups of older adults. 
Contributing authors 
(continued)  
(Amended 11 May 
2020) 
•
 and 
, Clinical
Laboratory Sciences Clinical readout Team Leader
•
 and 
, Clinical
Laboratory Sciences Study Manager
•
, Vaccine Supply Coordinator
•
, 
 and 
, Clinical Safety representatives
•
, Clinical Safety Physician
•
 and 
, Oversight
Data Managers
•
, 
 and 
 (USA), Global Regulatory Affairs
•
, Local delivery Lead
•
, Global Patent
•
 and 
, Lead Statisticians
•
, Project Statistician
•
, Project Statistician
•
, Clinical and Epidemiology Project
Lead for Zoster, GlaxoSmithKline Biologicals, US
RDC
GSK Biologicals’ Protocol DS v14.1.1 
©2015 GSK group of companies or its licensor 
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Protocol Amendment 5 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Date of protocol amendment 
Amendment 5 Final: 11 May 2020 
Detailed Title 
A phase IIIb, open-label, multi-country, multi-
centre, long-term follow-up study (ZOE-LTFU) of 
studies 110390 and 113077 (ZOSTER-006/022) to 
assess the prophylactic efficacy, safety, and 
immunogenicity persistence of GSK Biologicals’ 
Herpes Zoster subunit (HZ/su) vaccine and 
assessment of 1 or 2 additional doses on a 0 or 0, 2-
month schedule in two subgroups of older adults. 
Sponsor signatory 
Anne Schuind, Clinical and Epidemiology Project 
Lead for Zoster, GlaxoSmithKline Biologicals, US 
RDC 
 
 
Signature 
 
 
 
Date 
 
 
 
 
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Protocol Amendment 5 Rationale 
Amendment number 
5 
Rationale/background for changes: 
This protocol amendment 5 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 6.6 outlines the measures which include allowing flexibility in schedule and 
procedures to optimize site staff safety, patient safety and to preserve study integrity. 
Other changes include, 
• 
The classification of HZ cases by HZAC has been clarified with the addition of 
“not able to decide” to be classified as “not HZ” to Section 4.5.2.4.2 for 
confirmation of suspected HZ by the HZAC. 
• 
The timelines concerning data entry into the eCRF for France in Section 13.1 have 
been updated to align with the timelines presented in the data management plan. 
Please refer to Appendix C for a list of all the changes. 
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Protocol Amendment 5 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’ investigational 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 vaccines, and more generally about his/her 
financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 
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eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number  
BB-IND 13857 
EudraCT number 
2015-001778-17 
Date of protocol amendment 
Amendment 5 Final: 11 May 2020 
Detailed Title 
A phase IIIb, open-label, multi-country, multi-
centre, long-term follow-up study (ZOE-LTFU) of 
studies 110390 and 113077 (ZOSTER-006/022) to 
assess the prophylactic efficacy, safety, and 
immunogenicity persistence of GSK Biologicals’ 
Herpes Zoster subunit (HZ/su) vaccine and 
assessment of 1 or 2 additional doses on a 0 or 0, 2-
month schedule in two subgroups of older adults. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 name, function and 
title 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
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eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number  
BB-IND 13857 
EudraCT number 
2015-001778-17 
Date of protocol amendment 
Amendment 5 Final: 11 May 2020 
Detailed Title 
A phase IIIb, open-label, multi-country, multi-
centre, long-term follow-up study (ZOE-LTFU) of 
studies 110390 and 113077 (ZOSTER-006/022) to 
assess the prophylactic efficacy, safety, and 
immunogenicity persistence of GSK Biologicals’ 
Herpes Zoster subunit (HZ/su) vaccine and 
assessment of 1 or 2 additional doses on a 0 or 0, 2-
month schedule in two subgroups of older adults. 
GSK Japan representative 
name, function and title 
 
 
 
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 IIIb, open-label, multi-country, multi-centre, long-term 
follow-up study (ZOE-LTFU) of studies 110390 and 113077 
(ZOSTER-006/022) to assess the prophylactic efficacy, safety, 
and immunogenicity persistence of GSK Biologicals’ Herpes 
Zoster subunit (HZ/su) vaccine and assessment of 1 or 2 
additional doses on a 0 or 0, 2-month schedule in two subgroups 
of older adults. 
Indication 
Prevention of Herpes Zoster (HZ) and related complications in 
adults aged 50 years and older and in immunocompromised (IC) 
adults aged 18 years and older. 
Rationale for the 
study and study 
design 
•
Rationale for the study
GlaxoSmithKline (GSK) Biologicals’ study vaccine for the 
prevention of HZ, is a recombinant subunit (su) vaccine 
consisting of Varicella Zoster Virus (VZV) glycoprotein E (gE) 
as antigen and an adjuvant system (AS01), has been and is being 
evaluated in several studies in older adults and 
immunocompromised adults. In these studies, it was shown to 
elicit strong cellular and humoral immune responses. 
Furthermore, the safety and reactogenicity profile of the study 
vaccine was clinically acceptable. Based on phase II data from 
the antigen dose-ranging study, ZOSTER-003, and the adjuvant 
dose comparison study, ZOSTER-010, a gE antigen dose of 50 
g and the adjuvant system AS01B were selected for the final 
vaccine formulation. Henceforth, the final vaccine formulation 
will be referred to as HZ/su. The results of the previous studies in 
older adults demonstrated strong vaccine-induced immune 
responses following HZ/su administration at 0 and 2 months, 
supporting the selection of a 2-dose vaccine schedule. 
Two large pivotal phase III trials ZOE-50 and ZOE-70 that 
enrolled subjects  50 and  70 years of age (YOA) respectively, 
evaluated the vaccine efficacy (VE), immunogenicity and safety 
of GSK Biologicals’ HZ/su vaccine. These trials, hereafter 
referred to as ZOSTER-006 and ZOSTER-022, respectively and 
collectively referred to as the ZOSTER-006/022 studies, enrolled 
more than 30,000 subjects who either received the HZ/su vaccine 
or placebo on a 0, 2-month schedule. 
The final HZ/su VE results from the ZOSTER-006 phase III trial 
demonstrated the HZ/su vaccine to be highly efficacious in the 
prevention of HZ overall and in all age strata and available safety 
data until the data lock point raised no safety concerns in this 
population of subjects  50 YOA. The results for the ZOSTER-
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022 study demonstrated that the HZ/su vaccine reduced the risks 
of HZ and PHN among adults  70 YOA. 
Since the mean follow-up period for VE at the time of the final 
analysis in the ZOSTER-006/022 studies was about four years, 
further follow-up for long term efficacy assessment is needed, in 
order to establish that the HZ/su vaccine provides not only strong, 
but also persistent protection. 
This study will also assess the immunogenicity responses of 1 or 
2 additional doses in two subgroups of older adults who 
previously received two doses of the HZ/su vaccine in the 
ZOSTER-006/022 studies. If over time, VE of HZ/su wanes, 
additional vaccination with HZ/su could be needed to prevent HZ 
and its complications. Knowing if 1 or 2 additional doses of 
HZ/su vaccine can stimulate the immune response again, could 
support the concept of providing additional doses with the 
expectation that this may translate into preserving VE. 
•
Rationale for the study design
The primary objective of this study is to assess the efficacy of the 
HZ/su vaccine in the prevention of HZ. The data from this study 
will also be analysed combined with ZOSTER-006/022 data 
(analysis over the full duration of the follow-up in the primary 
ZOSTER-006/022 studies and the ZOSTER-049 study). 
Persistence of immunogenicity and long-term safety of the HZ/su 
vaccine administered in ZOSTER-006/022 will also be evaluated. 
Safety, reactogenicity, and immunogenicity one month after 1 or 
2 additional doses of the HZ/su vaccine in subjects who 
previously received 2 doses of the vaccine in the primary 
ZOSTER-006/022 studies will also be assessed to further support 
evaluation of additional vaccination if it is determined VE wanes 
over time. 
Due to the high VE observed in the ZOSTER-006/022 studies, it 
was considered that subjects having received placebo during both 
studies should be offered cross-vaccination with HZ/su vaccine as 
soon as possible. Since they will be enrolled in a separate cross-
vaccination study, no placebo recipients will be available for this 
study and historic controls will be used for assessment of VE. 
All subjects that were previously vaccinated with at least one 
dose of the HZ/su vaccine in the ZOSTER-006/022 primary 
studies, and confirmed their interest to enrol in the study at 
participating centres, will be considered for entry in study 
ZOSTER-049, after they have completed all study-related 
activities in the ZOSTER-006 or ZOSTER-022 studies and when 
their treatment assignment can be released without compromising 
the integrity of the ZOSTER-006/022 data. Since the interval 
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between the end of the ZOSTER-006/022 studies and the start of 
study ZOSTER-049 will vary per subject and is dependent on 
receipt of approval or implementing the study in the different 
participating countries/centres, the study will analyze the annual 
LTFU data from Year 5 up to Year 10 and annually beyond Year 
10 after the primary vaccination in the ZOSTER-006/022 studies 
(in case samples from these timepoints are collected). 
The study will be comprised of four study groups as follows: 
LTFU Group: Subjects from this group [N ≤ 14,000] will be 
followed for VE and safety. In addition, immunogenicity will be 
followed in subjects that were part of the immunogenicity subset 
(HI) in the ZOSTER-006/022 studies and Cell-Mediated 
Immunity (CMI) subset from the ZOSTER-006 study; 
1-Additional Dose Group: Subjects from this group [N = 60] 
will receive 1 additional dose of the HZ/su vaccine, at the time of 
enrolment, to assess the immunogenicity, reactogenicity and 
safety of 1 additional dose;  
Revaccination Group: Subjects from this group [N = 60] will be 
revaccinated with 2 additional doses of the HZ/su vaccine, on a 0, 
2-month schedule from the time of enrolment, to assess the 
immunogenicity, reactogenicity and safety of 2 additional doses; 
Control Group: Subjects from this group [N = 120] will not be 
vaccinated but will serve as a control to assess immunogenicity 
and safety compared to the two vaccinated groups 1-Additional 
Dose and Revaccination. This Control group will also be used to 
evaluate the VE, safety and immunogenicity. 
Subjects (N, to be determined) who developed HZ during the 
ZOSTER-006/022 studies (confirmed HZ) and/or during the 
interval between the end of the ZOSTER-006/022 studies and 
beginning of the ZOSTER-049 study, and/or during the 
ZOSTER-049 study (suspected HZ) will be part of the HZ 
subset. 
Subjects from the 1-Additional Dose and Revaccination groups 
who will develop HZ cases during the ZOSTER-049 study will 
follow the sampling schedule as per their original group and will 
not be part of the HZ subset. 
Note: Subjects from the immunogenicity subset of studies 
ZOSTER-006/022 are not allocated to the 1-Additional Dose, 
Revaccination and Control groups. Subjects in these three groups 
will be enrolled amongst subjects who received 2 doses of the 
HZ/su vaccine and were part of the ATP cohort for analysis of 
efficacy in the previous studies ZOSTER-006/022. In order not to 
confound immune responses, subjects who developed HZ prior to 
enrolment in the ZOSTER-049 study (confirmed HZ during the 
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ZOSTER-006/022 studies or suspected HZ during the interval 
between the end of the ZOSTER-006/022 studies and beginning 
of the ZOSTER-049 study), will not be enrolled in the 1-
Additional Dose, Revaccination and Control groups. 
Objectives 
Primary 
• 
To assess the VE in the prevention of HZ over the total 
duration of the ZOSTER-049 study as measured by the 
reduction in HZ risk in subjects ≥ 50 YOA overall at the time 
of first vaccination in the ZOSTER-006/022 studies.  
 
Secondary 
• 
To assess the VE in the prevention of HZ over the total 
duration of the ZOSTER-049 study as measured by the 
reduction in HZ risk in subjects within each of the age 
ranges* at the time of first vaccination in the ZOSTER-
006/022 studies; 
• 
To assess the VE in the prevention of HZ from one month 
post dose 2 in the ZOSTER-006/022 studies until the end of 
the ZOSTER-049 study as measured by the reduction in HZ 
risk in subjects  50 YOA overall and within each of the 
specified age ranges* at the time of first vaccination in the 
ZOSTER-006/022 studies;  
• 
To assess the VE in the prevention of HZ over each year of 
follow-up from one month post dose 2 in the ZOSTER-
006/022 studies as measured by the reduction in HZ risk in 
subjects  50 YOA overall and within each of the specified 
age ranges* at the time of first vaccination in the ZOSTER-
006/022 studies;  
• 
To assess the VE over the total duration of the ZOSTER-049 
study in prevention of PHN in subjects  50 YOA overall 
and within each of the specified age ranges* at the time of 
first vaccination in the ZOSTER-006/022 studies; 
• 
To assess the VE in the prevention of PHN from one month 
post dose 2 in the ZOSTER-006/022 studies until the end of 
the ZOSTER-049 study in subjects  50 YOA overall and 
within each of the specified age ranges* at the time of first 
vaccination in the ZOSTER-006/022 studies;  
• 
To assess the VE over the total duration of the ZOSTER-049 
study in prevention of HZ related complications (other than 
PHN) in subjects ≥ 50 YOA overall and within each of the 
specified age ranges* at the time of first vaccination in the 
ZOSTER-006/022 studies;  
• 
To assess the VE in the prevention of HZ related 
complications (other than PHN) from one month post dose 2 
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in the ZOSTER-006/022 studies until the end of the 
ZOSTER-049 study in subjects ≥ 50 YOA overall and within 
each of the specified age ranges* at the time of first 
vaccination in the ZOSTER-006/022 studies;  
• 
To assess persistence of humoral immune responses at Year 
5, 6, 7, 8, 9 and 10 and beyond after the primary vaccination 
in the ZOSTER-006/022 studies in the HI subset in subjects 
 50 YOA overall and within each of the specified age 
ranges* at the time of first vaccination, in the ZOSTER-
006/022 studies;  
• 
To assess persistence of vaccine induced cell-mediated 
immune responses at Year 5, 6, 7, 8, 9 and 10 and beyond 
after the primary vaccination in the ZOSTER-006/022 
studies in the CMI subset in subjects  50 YOA overall and 
within each of the specified age ranges* at the time of first 
vaccination, in the ZOSTER-006 study;  
• 
To assess humoral immune responses at Year 5, 6, 7, 8, 9 and 
10 and beyond after the primary vaccination in the ZOSTER-
006/022 studies in subjects ≥ 50 YOA at the time of first 
vaccination, in the ZOSTER-006/022 studies, who had a 
confirmed HZ episode previously for the timepoint 
considered; 
• 
To assess vaccine induced cell-mediated immune responses 
at Year 5, 6, 7, 8, 9 and 10 and beyond after the primary 
vaccination in the ZOSTER-006/022 studies in the CMI 
subset in subjects ≥ 50 YOA at the time of first vaccination, 
in the ZOSTER-006 study, who had a confirmed HZ episode 
previously for the timepoint considered; 
• 
To assess humoral immune responses one month after the 
first additional HZ/su vaccine dose (1-Additional Dose and 
Revaccination groups) and at the same timepoint in the 
Control group; 
• 
To assess vaccine induced cell-mediated immune responses 
one month after the first additional HZ/su vaccine dose (1-
Additional Dose and Revaccination groups) and at the same 
timepoint in the Control group; 
• 
To assess humoral immune responses one month after the 
second additional HZ/su vaccine doses (Revaccination group 
and at the same timepoint in the Control group); 
• 
To assess vaccine induced cell-mediated immune responses 
one month after the second additional HZ/su vaccine doses 
(Revaccination group and at the same timepoint in the 
Control group); 
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•
To assess persistence of humoral immune responses at Year
1, 2, 3, 4, 5 and 6 timepoints of this study in subjects from
the 1-Additional Dose, Revaccination and Control groups;
•
To assess persistence of vaccine induced cell-mediated
immune responses at Year 1, 2, 3, 4, 5 and 6 timepoints of
this study in subjects from the 1-Additional Dose,
Revaccination and Control groups;
•
To assess vaccine safety and reactogenicity in the 1-
Additional Dose and Revaccination groups
•
To assess vaccine safety in the LTFU and Control groups.
* Specified age range: 50-59 YOA, 60-69 YOA,  60 YOA and
 70 YOA at time of primary vaccination in ZOSTER-006/022.
Tertiary 
Study design 
•
Experimental design: Phase IIIb, open-label, multi-centre,
multi-country study with 4 groups.
•
Duration of the study: Each subject will be followed for
approximately 6 years.
•
Epoch 001: LTFU of studies ZOSTER-006/022 starting at
Visit Month 0 and ending at Visit Year 6 (Month 72) and
assessment of 1 or 2 additional doses in two groups of
subjects.
•
Study groups:
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Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Epochs 
From ZOSTER-006 
primary study 
From ZOSTER-022 
primary study 
Total 
Epoch 001 
ZOSTER-049 Total 
≤ 7698 
≤ 6750 
≤ 14448 * 
 
LTFU 
 
 
≤ 14208 ** 
x 
1-Additional Dose 
 
 
60 
x 
Revaccination 
 
 
60 
x 
Control 
 
 
120 
x 
* Maximum number of subjects expected for ZOSTER-049 based on the number of subjects in the ZOSTER-006/022 
studies. 
** All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 0. For 
subjects in the LTFU group, who do not belong to any subset, these samples will be stored and tested for HI only 
if the subject develops HZ during the ZOSTER-049 study or if there are other reasons requiring the HI testing of 
these samples. 
Synopsis Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Product name 
Study groups 
LTFU 
1-Additional Dose 
Revaccination 
Control 
HZ/su 
VZV gE 
None 
x 
x 
None 
AS01B 
 
• 
Control: historical control. 
• 
Vaccination schedule: Two groups of subjects (1-Additional Dose 
and Revaccination) will receive 1 or 2 additional doses of HZ/su 
vaccine at Month 0 or Months 0 and 2, respectively. 
 
• 
Treatment allocation: Randomised to treatment schedule 
accounting for age at primary vaccination in studies ZOSTER-
006/022 (50-59, 60-69 and ≥ 70 YOA) and countries for the three 
groups 1-Additional Dose, Revaccination and Control. 
• 
Blinding: Open-label. 
Synopsis Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
open-label 
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• 
Sampling schedule: 
All subjects (N ≤ 14,448) entering the study will have a HI 
blood sample (approximately 5 mL) at Visit Month 0. 
For subjects in the LTFU group, who do not belong to any 
subset, these samples will be stored and tested for HI only if 
the subject develops HZ during the ZOSTER-049 study or if 
there are other reasons requiring the HI testing of these 
samples. 
LTFU Group (HI subset): Subjects (N ≤ 1,729) who were in 
the immunogenicity subset during studies ZOSTER-006/022 
and continue participation in this study. Blood samples 
(approximately 5 mL) will be collected and tested from Visit 
Month 0 to Visit Year 6, on a yearly basis, to assess HI 
responses. 
LTFU Group (CMI subset): Subjects (N ≤ 234) who were in 
the CMI subset during study ZOSTER-006 and continue 
participation in this study. Blood samples (approximately 
20 mL) will be collected and tested from Visit Month 0 to 
Visit Year 6 on a yearly basis to assess CMI responses. 
HZ subset: Subjects (N to be determined) who developed 
confirmed HZ during ZOSTER-006 or ZOSTER-022, or who 
develop HZ during the interval between the end of the 
ZOSTER-006/022 and the beginning of ZOSTER-049, or 
who develop suspected HZ during ZOSTER-049 will be part 
of the HZ subset. Blood sampling for subjects in the HZ 
subset is described below. 
Subjects who develop HZ at any time after enrolment in 
ZOSTER-006 or ZOSTER-022 and who are already part of 
the HI subset in ZOSTER-006 or ZOSTER-022 will provide 
blood samples to assess HI responses (approximately 5 mL) 
from Visit Month 0 to Visit Year 6 irrespective of when the 
HZ episode occurs. If these subjects are part of the ZOSTER-
006 CMI subset, then they will also continue to provide blood 
to assess CMI responses (approximately 20 mL). 
Subjects who develop HZ at any time after enrolment in 
ZOSTER-006 or ZOSTER-022 and who were NOT part of 
the HI or CMI subsets in these studies, will provide blood 
samples to assess HI responses (approximately 5 mL) 
beginning at the annual visit in the ZOSTER-049 study 
subsequent to the occurrence of the HZ episode. The blood 
sample taken upon enrolment at Visit Month 0 will be tested 
and included in the analyses for these subjects. 
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1-Additional Dose Group: Subjects (N = 60) to be 
administered HZ/su vaccine on a 1-dose schedule at Visit 
Month 0. Blood samples (approximately 5 and 20 mL) will be 
collected at Visit Month 0, Visit Month 1, and from Visit 
Year 1 to Visit Year 6 on a yearly basis to assess HI and CMI 
responses. 
Revaccination Group: Subjects (N = 60) to be administered 
HZ/su vaccine on a 2-dose schedule at Visit Month 0 and 
Visit Month 2. Blood samples (approximately 5 and 20 mL) 
will be collected at Visit Month 0, Visit Month 1, Visit Month 
3 and from Visit Year 1 to Visit Year 6 on a yearly basis to 
assess HI and CMI responses. 
Control Group: Subjects (N = 120) in the non-vaccinated 
control group. Blood samples (approximately 5 and 20 mL) 
will be collected at Visit Month 0, Visit Month 1, Visit 
Month 3 and from Visit Year 1 to Visit Year 6 on a yearly 
basis to assess HI and CMI responses. 
Specimens of HZ lesions will be collected from subjects 
clinically diagnosed as having a suspected case of HZ. 
Refer to Section 6.6 for study procedures to be considered during 
special circumstances (Amended 11 May 2020). 
• 
Type of study: extension of other protocol(s), i.e., 110390 
(ZOSTER-006) and 113077 (ZOSTER-022). 
• 
Data collection: Electronic Case Report Form (eCRF). 
Case definition 
• 
Suspected HZ 
A suspected case of HZ is defined as 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 Polymerase Chain Reaction (PCR); 
− 
By the HZ Ascertainment Committee (HZAC). 
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• 
Postherpetic neuralgia (PHN) 
PHN is defined by the presence of HZ-associated severe ‘worst’ 
pain persisting or appearing more than 90 days after onset of the 
HZ rash. 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. 
• 
HZ complications 
Any HZ complications will be recorded by the investigator in HZ-
specific eCRF screens, and on the AE/SAE reporting screens as 
appropriate. The reporting period for HZ complications will be 
from Month 0 to study end. If a recorded complication is 
associated with a case of suspected HZ, and that case is finally not 
considered to be a confirmed case, the associated complication 
will not be considered as a complication of HZ. 
Number of 
subjects 
Expected number of subjects for enrolment will be up to 14,448 
potentially eligible subjects. 
Endpoints 
Primary 
• 
Confirmed HZ cases (LTFU and Control groups); 
− 
Confirmed HZ cases during the ZOSTER-049 study.  
 
Secondary 
• 
Confirmed HZ cases; 
− 
Confirmed HZ cases since one month post dose 2 in the 
previous ZOSTER-006/022 studies; 
• 
PHN cases; 
− 
PHN cases during the ZOSTER-049 study and since one 
month post dose 2 in the previous ZOSTER-006/022 
studies;  
• 
HZ related complications (other than PHN); 
− 
HZ related complications (other than PHN) during the 
ZOSTER-049 study and since one month post dose 2 in 
the previous ZOSTER-006/022 studies; 
• 
Antigen-gE humoral immunogenicity at Months 0, 12, 24, 36, 
48, 60 and 72 (LTFU HI subset, 1-Additional Dose, 
Revaccination and Control groups), at Month 1 (1-Additional 
Dose, Revaccination and Control groups), and at Month 3 
(Revaccination and Control groups); 
− 
Anti-gE Ab concentrations as determined by ELISA; 
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• 
CMI in terms of frequencies of antigen-specific CD4+ T cells 
at Months 0, 12, 24, 36, 48, 60 and 72 (LTFU CMI subset, 1-
Additional Dose, Revaccination and Control groups), at 
Month 1 (1-Additional Dose, Revaccination and Control 
groups), and at Month 3 (Revaccination and Control groups); 
− 
Frequencies of CD4+ T cells with antigen-specific 
Interferon gamma (IFN-γ) and/or Interleukin-2 (IL-2) 
and/or Tumour Necrosis Factor alpha (TNF-α) and/or 
CD40 Ligand (CD40L) secretion/expression to gE as 
determined by ICS; 
• 
Solicited local and general symptoms in subjects administered 
with 1 or 2 additional doses of HZ/su vaccine (1-Additional 
Dose and Revaccination groups); 
− 
Occurrence, intensity and duration of each solicited local 
symptom within 7 days (Days 0 − 6) after each 
vaccination; 
− 
Occurrence, intensity, duration and relationship to 
vaccination of each solicited general symptom within 7 
days (Days 0 − 6) after each vaccination; 
• 
Unsolicited AEs in subjects administered with 1 or 2 
additional doses of HZ/su vaccine (1-Additional Dose and 
Revaccination groups); 
− 
Occurrence, intensity and relationship to vaccination of 
unsolicited AEs during 30 days (Days 0 − 29) after each 
vaccination, according to the Medical Dictionary for 
Regulatory Activities (MedDRA) classification; 
• 
Serious AEs; 
− 
Occurrence and relationship to vaccination of all SAEs; 
− 
from Visit Month 0 until 12 months: for Control and 1-
Additional Dose groups; 
− 
from Visit Month 0 until 12 months after last HZ/su 
vaccination: for the Revaccination group; 
− 
Occurrence of SAEs related to investigational vaccine, 
related to study participation or to GSK concomitant 
medication/vaccine during the entire study period in all 
subjects; 
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• 
Occurrence of AEs of specific interest: Potential immune-
mediated diseases (pIMDs) (1-Additional Dose, 
Revaccination and Control groups); 
− 
Occurrence and relationship to vaccination of all pIMDs; 
− 
from Visit Month 0 until 12 months: for Control and 1-
Additional Dose groups; 
− 
from Visit Month 0 until 12 months after last HZ/su 
vaccination: for the Revaccination group. 
Tertiary 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 8 
SYNOPSIS ...................................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................... 30 
GLOSSARY OF TERMS ............................................................................................... 34 
TRADEMARKS ............................................................................................................. 38 
1. 
INTRODUCTION .................................................................................................... 39 
1.1. 
Background ................................................................................................ 39 
1.2. 
Rationale for the study and study design .................................................... 41 
1.2.1. 
Rationale for the study ................................................................. 41 
1.2.2. 
Rationale for the study design ...................................................... 41 
1.3. 
Benefit : Risk Assessment .......................................................................... 43 
1.3.1. 
Risk Assessment ......................................................................... 43 
1.3.2. 
Benefit Assessment ..................................................................... 44 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 44 
2. 
OBJECTIVES ......................................................................................................... 44 
2.1. 
Primary objective ........................................................................................ 44 
2.2. 
Secondary objectives .................................................................................. 44 
2.3. 
Tertiary Objectives ...................................................................................... 46 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 47 
4. 
CASE DEFINITION ................................................................................................ 52 
4.1. 
Suspected HZ ............................................................................................. 52 
4.2. 
Confirmed HZ ............................................................................................. 52 
4.3. 
Postherpetic neuralgia (PHN) ..................................................................... 52 
4.4. 
HZ complications ........................................................................................ 53 
4.5. 
Evaluation and confirmation of suspected HZ cases ................................... 54 
4.5.1. 
Definitions .................................................................................... 54 
4.5.2. 
Evaluation of suspected case of HZ ............................................. 54 
4.5.2.1. 
For clinically diagnosed suspected HZ cases, 
the following will take place at Visit HZ-1: ................... 55 
4.5.2.2. 
The following will take place at each visit or 
contact that occurs for each episode: ......................... 56 
4.5.2.3. 
Evaluation of severity of HZ-associated pain 
using the Zoster Brief Pain Inventory .......................... 57 
4.5.2.4. 
Confirmation of a suspected case of HZ ..................... 57 
4.5.2.4.1. 
Confirmation of suspected HZ by 
PCR ........................................................ 57 
4.5.2.4.2. 
Confirmation of suspected HZ by 
the HZAC ................................................ 57 
4.5.3. 
Follow up of suspected HZ cases and HZ-associated pain .......... 58 
5. 
STUDY COHORT ................................................................................................... 59 
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5.1. 
Number of subjects/centres ........................................................................ 59 
5.2. 
Inclusion criteria for enrolment .................................................................... 60 
5.3. 
Exclusion criteria for enrolment ................................................................... 61 
6. 
CONDUCT OF THE STUDY .................................................................................. 63 
6.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 63 
6.1.1. 
Subject identification and randomisation of treatment .................. 64 
6.1.1.1. 
Randomisation of supplies .......................................... 64 
6.1.1.2. 
Randomisation of treatment ........................................ 64 
6.1.1.2.1. 
Treatment allocation to the subject 
for the 1-Additional Dose, 
Revaccination and Control groups .......... 64 
6.1.1.2.2. 
Treatment number allocation for 
subsequent doses .................................. 65 
6.1.2. 
Allocation of subjects to assay subsets ........................................ 65 
6.2. 
Method of blinding ...................................................................................... 66 
6.3. 
General study aspects ................................................................................ 66 
6.3.1. 
Data collection ............................................................................. 66 
6.3.1.1. 
Monthly contacts ........................................................ 66 
6.3.1.2. 
Diary cards and questionnaires .................................. 66 
6.4. 
Outline of study procedures ........................................................................ 67 
6.5. 
Detailed description of study procedures .................................................... 76 
6.5.1. 
Informed consent ......................................................................... 76 
6.5.2. 
Check inclusion and exclusion criteria ......................................... 76 
6.5.3. 
Medical history ............................................................................. 76 
6.5.4. 
Physical examination ................................................................... 77 
6.5.5. 
Pregnancy test ............................................................................. 77 
6.5.6. 
Check contraindications, warnings and precautions to 
vaccination ................................................................................... 77 
6.5.7. 
Training on self-reporting by subjects .......................................... 77 
6.5.7.1. 
Reminder for monthly follow-up contacts/yearly 
follow-up visits ............................................................ 78 
6.5.8. 
Sampling...................................................................................... 78 
6.5.8.1. 
Blood sampling for immune response 
assessments .............................................................. 78 
6.5.8.2. 
Clinical specimens of HZ lesions for PCR 
analysis ...................................................................... 79 
6.5.9. 
Check and record concomitant medication/vaccination and 
IMCs ............................................................................................ 79 
6.5.10. 
Recording of AEs and SAEs ........................................................ 80 
6.5.11. 
Study conclusion .......................................................................... 80 
6.6. 
Study procedures during special circumstances (Amended 11 May 
2020) .......................................................................................................... 81 
6.7. 
Biological sample handling and analysis ..................................................... 83 
6.7.1. 
Use of specified study materials .................................................. 84 
6.7.2. 
Biological samples ....................................................................... 84 
6.7.3. 
Laboratory assays ....................................................................... 85 
6.7.4. 
Biological samples evaluation ...................................................... 86 
6.7.4.1. 
Immunological read-outs ............................................ 86 
6.7.4.2. 
Test for laboratory diagnosis of HZ ............................. 87 
6.7.5. 
Immunological correlates of protection ......................................... 87 
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7. 
STUDY VACCINE AND ADMINISTRATION ........................................................... 87 
7.1. 
Description of study vaccine ....................................................................... 87 
7.2. 
Storage and handling of study vaccine ....................................................... 88 
7.3. 
Dosage and administration of study vaccine ............................................... 88 
7.4. 
Replacement of unusable vaccine doses .................................................... 89 
7.5. 
Contraindications to subsequent vaccination .............................................. 89 
7.6. 
Concomitant medications/products and concomitant vaccinations .............. 90 
7.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 90 
7.6.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses ........................ 91 
7.7. 
Intercurrent medical conditions (IMCs) that may lead to elimination 
of a subject from ATP analyses .................................................................. 92 
8. 
HEALTH ECONOMICS .......................................................................................... 92 
9. 
SAFETY ................................................................................................................. 92 
9.1. 
Safety definitions ........................................................................................ 92 
9.1.1. 
Definition of an adverse event ...................................................... 92 
9.1.2. 
Definition of a serious adverse event ........................................... 93 
9.1.3. 
Solicited adverse events .............................................................. 94 
9.1.3.1. 
Solicited local (injection-site) adverse events .............. 94 
9.1.3.2. 
Solicited general adverse events ................................ 94 
9.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 95 
9.1.5. 
Medically attended visits .............................................................. 95 
9.1.6. 
Adverse events of specific interest ............................................... 95 
9.1.6.1. 
Potential immune-mediated diseases ......................... 95 
9.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ........................................................................................... 97 
9.2.1. 
Pregnancy ................................................................................... 97 
9.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 98 
9.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 98 
9.3.2. 
Post-Study adverse events and serious adverse events ............ 102 
9.3.3. 
Evaluation of adverse events and serious adverse events ......... 102 
9.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ...................................... 102 
9.3.3.2. 
Assessment of adverse events ................................. 103 
9.3.3.2.1. 
Assessment of intensity ........................ 103 
9.3.3.2.2. 
Assessment of causality ....................... 104 
9.3.3.3. 
Assessment of outcomes.......................................... 105 
9.4. 
Reporting of serious adverse events, pregnancies and other events ........ 106 
9.4.1. 
Prompt reporting of serious adverse events, pregnancies 
and other events to GSK Biologicals .......................................... 106 
9.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs ............................................................. 106 
9.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................. 107 
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9.4.3.1. 
Back-up system in case the electronic 
reporting system does not work ................................ 107 
9.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................. 107 
9.4.5. 
Reporting of pIMDs to GSK Biologicals ...................................... 108 
9.4.6. 
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF ........................... 108 
9.4.7. 
Regulatory reporting requirements for serious adverse 
events ........................................................................................ 108 
9.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies .............................................................................................. 109 
9.5.1. 
Follow-up of adverse events and serious adverse events .......... 109 
9.5.1.1. 
Follow-up during the study ........................................ 109 
9.5.1.2. 
Follow-up after the subject is discharged from 
the study ................................................................... 109 
9.5.2. 
Follow-up of pregnancies ........................................................... 110 
9.6. 
Treatment of adverse events .................................................................... 110 
9.7. 
Subject card .............................................................................................. 110 
10. SUBJECT COMPLETION AND WITHDRAWAL ................................................... 110 
10.1. 
Subject completion ................................................................................... 110 
10.2. 
Subject withdrawal .................................................................................... 110 
10.2.1. 
Subject withdrawal from the study ............................................. 110 
10.2.2. 
Subject withdrawal from investigational vaccine......................... 111 
11. STATISTICAL METHODS .................................................................................... 112 
11.1. 
Primary endpoint ....................................................................................... 112 
11.2. 
Secondary endpoints ................................................................................ 112 
11.3. 
Tertiary endpoints ..................................................................................... 113 
11.4. 
Determination of sample size .................................................................... 113 
11.4.1. 
VE assessment .......................................................................... 114 
11.5. 
Cohorts for Analyses ................................................................................ 115 
11.5.1. 
Total vaccinated cohort .............................................................. 115 
11.5.2. 
Modified Total Vaccinated cohort (LTFU and Control 
group) ........................................................................................ 115 
11.5.3. 
According To Protocol cohort for analysis of efficacy 
(LTFU and Control groups) ........................................................ 116 
11.5.4. 
According To Protocol cohort for analysis of 
immunogenicity (1-Additional Dose, Revaccination and 
Control groups) .......................................................................... 116 
11.5.5. 
According To Protocol cohort for analysis of persistence of 
immunogenicity (LTFU group) .................................................... 117 
11.5.6. 
According To Protocol cohort for analysis of persistence of 
immunogenicity (1-Additional Dose, Revaccination and 
Control groups) .......................................................................... 117 
11.6. 
Derived and transformed data ................................................................... 118 
11.6.1. 
Handling of missing data ............................................................ 118 
11.6.2. 
Humoral immune response ........................................................ 118 
11.6.3. 
CMI response ............................................................................ 119 
11.7. 
Statistical analyses ................................................................................... 120 
11.7.1. 
Analysis of demographics (for each of the four groups of 
the study) ................................................................................... 120 
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11.7.2. 
Analysis of efficacy (LTFU and Control groups) ......................... 120 
11.7.3. 
Analysis of immunogenicity ........................................................ 121 
11.7.3.1. Assessment for 1-Additional Dose, 
Revaccination and Control groups ............................ 122 
11.7.3.1.1. Humoral immune response ................... 122 
11.7.3.1.2. Cell-mediated immune response .......... 123 
11.7.3.2. Analysis on subjects with HZ cases .......................... 123 
11.7.3.3. Analysis of persistence (immune subset of 
LTFU group) ............................................................. 123 
11.7.3.3.1. Humoral immune response ................... 124 
11.7.3.3.2. Cell-mediated immune response .......... 124 
11.7.4. 
Analysis of safety ....................................................................... 125 
11.8. 
Interpretation of analyses .......................................................................... 126 
11.9. 
Conduct of analyses ................................................................................. 126 
11.9.1. 
Sequence of analyses................................................................ 126 
11.9.2. 
Statistical considerations for interim analyses ............................ 127 
12. ADMINISTRATIVE MATTERS ............................................................................. 127 
12.1. 
electronic Case Report Form instructions ................................................. 127 
12.2. 
Study Monitoring by GSK Biologicals ........................................................ 127 
12.3. 
Record retention ....................................................................................... 128 
12.4. 
Quality assurance ..................................................................................... 129 
12.5. 
Posting of information on publicly available clinical trial registers and 
publication policy ...................................................................................... 129 
12.6. 
Provision of study results to investigators ................................................. 129 
13. COUNTRY SPECIFIC REQUIREMENTS ............................................................. 130 
13.1. 
Requirements for France .......................................................................... 130 
13.2. 
Requirements for Germany ....................................................................... 134 
13.3. 
Requirements for Japan ............................................................................ 135 
14. REFERENCES ..................................................................................................... 138 
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LIST OF TABLES 
PAGE 
Table 1 
Study groups and epochs foreseen in the study ..................................... 50 
Table 2 
Study groups and treatment foreseen in the study ................................. 50 
Table 3 
Blinding of study epochs ........................................................................ 50 
Table 4 
Subsets .................................................................................................. 59 
Table 5 
List of study procedures (for the LTFU group) ........................................ 68 
Table 6 
List of study procedures (for the 1-Additional Dose, 
Revaccination and Control groups) ........................................................ 69 
Table 7 
Study procedures to be performed during the follow-up period for 
each suspected HZ case ........................................................................ 72 
Table 8 
Intervals between study visits for the LTFU group .................................. 74 
Table 9 
Intervals between study visits for the 1-Additional Dose and 
Control groups ....................................................................................... 74 
Table 10 
Intervals between study visits for the Revaccination group ..................... 75 
Table 11 
Intervals between visits/contacts for subjects in case of 
suspected HZ ......................................................................................... 75 
Table 12 
Intervals for blood sampling for the LTFU group during special 
circumstances (Amended 11 May 2020) ................................................ 81 
Table 13 
Intervals for blood sampling for the 1-Additional Dose and 
Control groups during special circumstances (Amended 11 May 
2020) ...................................................................................................... 82 
Table 14 
Intervals for blood sampling for the Revaccination group during 
special circumstances (Amended 11 May 2020) .................................... 82 
Table 15 
Biological samples ................................................................................. 84 
Table 16 
Humoral Immunity (Antibody determination) ........................................... 85 
Table 17 
Cell-Mediated Immunity (CMI) ................................................................ 85 
Table 18 
Molecular Biology (PCR tests) ................................................................ 85 
Table 19 
Immunological read-outs ........................................................................ 86 
Table 20 
Study vaccine ......................................................................................... 87 
Table 21 
Dosage and administration ..................................................................... 89 
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Table 22 
Solicited local adverse events ................................................................ 94 
Table 23 
Solicited general adverse events ............................................................ 94 
Table 24 
List of potential immune-mediated diseases ........................................... 96 
Table 25 
Reporting periods for collecting safety information (for the LTFU 
group) .................................................................................................... 99 
Table 26 
Reporting periods for collecting safety information (for the 1-
Additional Dose, Revaccination and Control groups) ............................ 100 
Table 27 
Intensity scales for solicited symptoms in adults................................... 103 
Table 28 
Timeframes for submitting serious adverse events, pregnancy 
and other event reports to GSK Biologicals .......................................... 106 
Table 29 
Probability to get a Lower Limit (LL) of 95% CI (95%LL) of the VE 
above 0% every year considering a VE of 80% .................................... 114 
Table 30 
Probability to get a Lower Limit (LL) of 95% CI (95%LL) of the VE 
above 0% every year considering a VE of 65% .................................... 115 
Table 31 
GSK Biologicals’ laboratories ............................................................... 144 
Table 32 
Outsourced laboratories ....................................................................... 144 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 47 
Figure 2 
Detailed overview of the 1-Additional Dose, Revaccination and 
Control groups (Year 1 only) .................................................................. 48 
Figure 3 
Algorithm for HZ case definition by PCR .............................................. 143 
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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ..................................................................... 140 
APPENDIX B CLINICAL LABORATORIES ................................................................ 144 
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 145 
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LIST OF ABBREVIATIONS 
Ab: 
Antibody 
AE: 
Adverse event 
ANCOVA: 
Analysis of Covariance 
AS01B: 
MPL, QS21, liposome based Adjuvant System (50 μg MPL and 
50 μg QS21) 
ATP: 
According-To-Protocol 
CD40 L: 
CD40 Ligand 
CDC: 
Centres for Disease Control (and Prevention) 
CEVAC: 
Centre for Vaccination 
CI: 
Confidence Interval 
CMI: 
Cell-Mediated Immunogenicity/Immunity 
COVID-19: 
Coronavirus Disease 2019 (Amended 11 May 2020) 
CT: 
Computerised Tomography 
CVA: 
Cerebrovascular Accident 
DNA: 
Deoxyribonucleic Acid 
eCRF: 
electronic Case Report Form 
EDD: 
Estimated Date of Delivery 
EGA: 
Estimated Gestational Age 
ELISA: 
Enzyme Linked Immunosorbent Assay 
EMA: 
European Medicines Agency  
(e)TDF: 
Electronic Temperature excursion Decision Form 
FDA: 
Food and Drug Administration, United States 
FSFV: 
First Subject First Visit 
GCP: 
Good Clinical Practice 
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gE: 
VZV glycoprotein E 
GMC: 
Geometric Mean Concentration 
GSK: 
GlaxoSmithKline 
HI: 
Humoral Immunogenicity 
HZ/su: 
Herpes Zoster subunit vaccine 
HZ: 
Herpes Zoster 
HZAC: 
Herpes Zoster Ascertainment Committee 
IB: 
Investigator Brochure 
IC: 
Immunocompromised 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 
ICS: 
Intracellular Cytokine Staining 
IEC: 
Independent Ethics Committee 
IFN-: 
Interferon Gamma 
IgG: 
Immunoglobulin class G 
IL-2: 
Interleukin-2 
IM: 
Intramuscular 
IMC: 
Intercurrent Medical Condition 
IMP: 
Investigational Medicinal Product 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
LL: 
Lower Limit 
LLL: 
Lower Limit of Linearity 
LMP: 
Last Menstrual Period 
LOD: 
Limit of Detection 
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LSLV/C: 
Last Subject Last Visit/Contact 
LSLV: 
Last Subject Last Visit 
LTFU: 
Long-Term Follow-up 
MACDP: 
Metropolitan Atlanta Congenital Defects Program 
MAR: 
Missing At Random 
MATEX: 
MATerial EXcellence 
MCAR: 
Missing Completely At Random 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MGI: 
Mean Geometric Increase 
mIU: 
Milli-International Unit 
mL: 
Millilitre 
MRI: 
Magnetic Resonance Imaging 
mTVc: 
Modified Total Vaccinated cohort 
ORF: 
Open Reading Frame 
PBMC: 
Peripheral Blood Mononuclear Cells 
PCR: 
Polymerase Chain Reaction 
PHN: 
Postherpetic Neuralgia 
pIMD: 
Potential Immune-Mediated Disease 
Post-Vacc: 
Post-Vaccination 
Pre-Vacc: 
Pre-Vaccination 
PT: 
Preferred Term 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan 
SAS: 
Statistical Analysis System 
SBIR: 
Randomisation System on Internet 
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SD: 
Standard Deviation 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SMS: 
Short Message Service 
SPM: 
Study Procedures Manual 
su: 
Subunit 
TNF-: 
Tumour Necrosis Factor Alpha 
TVc: 
Total Vaccinated cohort 
UL: 
Upper Limit 
VE: 
Vaccine Efficacy 
VRR: 
Vaccine Response Rate 
VZV: 
Varicella-Zoster Virus 
YOA: 
Years of age 
ZBPI: 
Zoster Brief Pain Inventory 
μg: 
Microgram 
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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 contraceptives, either combined or progestogen 
alone, 
• 
injectable progestogen, 
• 
implants of etenogestrel or levonorgestrel, 
• 
estrogenic vaginal ring, 
• 
percutaneous contraceptive patches, 
• 
intrauterine device or intrauterine system, 
• 
male partner sterilisation prior to the female 
subject’s entry into the study, and this male is the 
sole partner for that subject, 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her 
medical history. 
• 
male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), 
• 
male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, 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 
(i.e., 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 (SAE). In an open-label study, no blind is used. 
Both the investigator and the subject know the identity 
of the treatment assigned. 
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. 
Epoch: 
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety. 
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 according-to-protocol (ATP) analysis. 
Intercurrent Medical 
Condition: 
It is defined as a condition with onset during the study 
period that has the capability of confounding the 
immune response to the study vaccine or its 
interpretation. Examples of other IMCs include a 
confirmed or suspected immunosuppressive or 
immunodeficient condition resulting from disease (e.g., 
HIV infection, malignancy). Occurrence of HZ during 
this study will be considered an intercurrent medical 
condition (IMC). 
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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/product: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical 
trial, including a product with a marketing authorisation 
when used in a way different from the approved form, or 
when used for an unapproved indication, or when used 
to gain further information about an approved use. 
Menarche: 
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development 
and pubic hair growth. Menarche usually occurs within 
1-2 years of breast development, thelarche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non-
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue). 
Menopause: 
Menopause is the age associated with complete 
cessation of menstrual cycles, menses, and implies the 
loss of reproductive potential by ovarian failure. A 
practical definition accepts menopause after 1 year 
without menses with an appropriate clinical profile at the 
appropriate age e.g., > 45 years. 
Potential Immune-
Mediated Disease: 
Potential immune-mediated diseases (pIMDs) are a 
subset of AEs that include autoimmune diseases and 
other inflammatory and/or neurologic disorders of 
interest which may or may not have an autoimmune 
aetiology. 
Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated. 
Protocol amendment: 
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of 
subjects, scope of the investigation, study design, or 
scientific integrity of the study. 
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Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.  
Randomisation: 
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. 
Site Monitor: 
An individual assigned by the sponsor who is 
responsible for assuring proper conduct of clinical 
studies at one or more investigational sites. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient 
of the vaccine(s)/product(s) or as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
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, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 
Treatment number: 
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 
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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 not owned by the 
GlaxoSmithKline group of companies 
 
Generic description 
Varivax (Merck & Co., Inc.) 
 
Varicella vaccine consisting of live 
attenuated varicella-zoster virus (Oka strain) 
Zostavax (Merck & Co., Inc.) 
 
Herpes zoster vaccine consisting of high-
titre live attenuated Varicella-zoster virus 
(Oka strain) 
 
Trademarks of the GSK group of 
companies  
 
Generic description 
Shingrix 
 
Herpes zoster vaccine non-live 
recombinant, AS01B adjuvanted 
 
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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 localised, 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. 
Older age is a clear risk factor for PHN. Other risk factors may include a severe HZ rash 
and a painful HZ prodrome. PHN tends to improve over a period of months. About 70-
80% of cases resolve within 1 year, however, in some persons PHN persists for many 
years [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]. While most HZ incidence data come from the 
United States (US) and Europe, available data indicate similar incidences of HZ in other 
parts of the world including Japan, Korea, Australia and Latin America [Araújo, 2007; 
Garcia, 2008; Kang, 2008; Toyama, 2009]. 
Half of all HZ cases occur in patients over the age of 60, and individuals who reach 85 
years old have a 50% chance of having HZ during their lifetime [Oxman, 2005]. The risk 
for PHN is also highest in older people with HZ, occurring in 18-50% of those aged 70 
years and older [Oxman, 2005; Scott, 2006]. Patients with impaired cell-mediated 
immunity (CMI) due to disease, drug treatment, medical interventions or advanced age 
are at increased risk for the development of 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 persons [Oxman, 2005; Sperber, 1992]. 
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The potential of vaccination to protect against HZ was evaluated in a large efficacy study 
in which Zostavax (a live attenuated HZ vaccine that is a high titre preparation of the 
varicella vaccine, Varivax [both manufactured by Merck & Co., Inc.]) partially protected 
immunocompetent older adults against HZ [Oxman, 2005]. In the overall population 
(≥ 60 YOA), Zostavax reduced the incidence of HZ by 51.3% (p-value < 0.001), although 
its efficacy decreased with the age of the vaccinee. In particular, vaccine efficacy (VE) 
diminished to 37.6% among persons in older age groups (≥ 70 YOA) [Oxman, 2005]. 
Based on the data from this study, Zostavax was licensed in the US and other countries. 
In the US, Zostavax is indicated for prevention of HZ in individuals ≥ 50 YOA and older 
[Zostavax Prescribing information, 2011]. In Australia, Zostavax is indicated for the 
prevention of HZ, PHN and for reduction of acute and chronic HZ-associated pain in 
individuals ≥ 60 YOA, and for the prevention of HZ in individuals 50-59 YOA [TGA, 
2015]. In Europe, Zostavax is indicated for prevention of HZ and PHN in individuals 
≥ 50 YOA [EMEA, 2011]. Zostavax is contraindicated in persons with 
immunodeficiency due to malignancy, human immunodeficiency virus (HIV) infection or 
immunosuppressive medical therapy. 
In a short term persistence sub-study of the large efficacy trial (Shingles Prevention 
Study) it was reported that Zostavax continued to reduce the incidence of HZ and PHN in 
subjects evaluated from 3.3 to 7.8 years after vaccination [Schmader, 2012]. However, 
the recent long-term persistence study of Zostavax showed that the VE for three 
outcomes (1. HZ burden of illness [a severity-by-duration measure of HZ pain and 
discomfort]; 2. incidence of PHN; and 3. incidence of HZ) declined from year 7 through 
year 11 post vaccination [Morrison, 2015]. 
GlaxoSmithKline (GSK) Biologicals’ study vaccine (Shingrix) for the prevention of HZ, 
is a recombinant subunit (su) vaccine consisting of Varicella Zoster Virus (VZV) 
glycoprotein E (gE) as antigen and an adjuvant system (AS01), has been and is being 
evaluated in several studies in older adults and immunocompromised adults. In these 
studies it was shown to elicit strong cellular and humoral immune responses. 
Furthermore, the safety and reactogenicity profile of the study vaccine was clinically 
acceptable.  Based on phase II data from the antigen dose-ranging study, ZOSTER-003, 
and the adjuvant dose comparison study, ZOSTER-010, a gE antigen dose of 50 g and 
the adjuvant system AS01B were selected for the final vaccine formulation. Henceforth, 
the final vaccine formulation will be referred to as HZ/su. The results of the previous 
studies in older adults demonstrated strong vaccine-induced immune responses following 
HZ/su administration at 0 and 2 months, supporting the selection of a 2-dose vaccine 
schedule. 
Two large pivotal phase III trials ZOE-50 and ZOE-70 that enrolled subjects  50 and 
 70 years of age (YOA) respectively, evaluated the vaccine efficacy (VE), 
immunogenicity and safety of GSK Biologicals’ HZ/su vaccine. These trials, hereafter 
referred to as ZOSTER-006 and ZOSTER-022, respectively and collectively referred to 
as the ZOSTER-006/022 studies, enrolled more than 30,000 subjects who either received 
the HZ/su vaccine or placebo on a 0, 2-month schedule. 
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The final HZ/su VE results from the ZOSTER-006 phase III trial demonstrated the HZ/su 
vaccine to be highly efficacious in the prevention of HZ overall and in all age strata and 
available safety data until the data lock point raised no safety concerns in this population 
of subjects  50 YOA [Lal, 2015]. The results for the ZOSTER-022 study demonstrated 
that the HZ/su vaccine reduced the risks of HZ and PHN among adults  70 YOA 
[Cunningham, 2016]. 
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 vaccine. 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
Since the mean follow-up period for VE at the time of the final analysis in the ZOSTER-
006/022 studies was about four years, further follow-up for long term efficacy assessment 
is needed in order to establish that the HZ/su vaccine provides not only strong, but also 
persistent protection. 
This study will also assess the immunogenicity responses of 1 or 2 additional doses in 
two subgroups of older adults who previously received two doses of the HZ/su vaccine in 
the ZOSTER-006/022 studies. If over time, VE of HZ/su wanes, additional vaccination 
with HZ/su could be needed to prevent HZ and its complications. Knowing if 1 or 2 
additional doses of HZ/su vaccine can stimulate the immune response again, could 
support the concept of providing additional doses with the expectation that this may 
translate into preserving VE. 
1.2.2. 
Rationale for the study design 
The primary objective of this study is to assess the efficacy of the HZ/su vaccine in the 
prevention of HZ. The data from this study will also be analysed combined with 
ZOSTER-006/022 data (analysis over the full duration of the follow-up in the primary 
ZOSTER-006/022 studies and the ZOSTER-049 study). Persistence of immunogenicity 
and long-term safety of the HZ/su vaccine administered in ZOSTER-006/022 will also be 
evaluated. Safety, reactogenicity, and immunogenicity one month after 1 or 2 additional 
doses of the HZ/su vaccine in subjects who previously received 2 doses of the vaccine in 
the primary ZOSTER-006/022 studies will also be assessed to further support evaluation 
of additional vaccination if it is determined VE wanes over time. 
Due to the high VE observed in the ZOSTER-006/022 studies, it was considered that 
subjects having received placebo during both of the studies should be offered cross-
vaccination with HZ/su vaccine as soon as possible. Since they will be enrolled in a 
separate cross-vaccination study, no placebo recipients will be available for this study 
and historic controls will be used for assessment of VE. 
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All subjects that were previously vaccinated with at least one dose of the HZ/su vaccine 
in the ZOSTER-006/022 primary studies, and confirmed their interest to enrol in the 
study at participating centres, will be considered for entry in study ZOSTER-049, after 
they have completed all study-related activities in the ZOSTER-006 or ZOSTER-022 
studies and when their treatment assignment can be released without compromising the 
integrity of the ZOSTER-006/022 data. Since the interval between the end of the 
ZOSTER-006/022 studies and the start of study ZOSTER-049 will vary per subject and is 
dependent on receipt of approval or implementing the study in the different participating 
countries/centres, the study will analyze the annual LTFU data from Year 5 up to Year 10 
and annually beyond Year 10 after the primary vaccination in the ZOSTER-006/022 
studies (in case samples from these timepoints are collected). 
The study will be comprised of four study groups as follows: 
LTFU Group: Subjects from this group [N ≤ 14,000] will be followed for VE and 
safety. In addition, immunogenicity will be followed in subjects that were part of the 
immunogenicity subset (HI) in the ZOSTER-006/022 studies and Cell-Mediated 
Immunity (CMI) subset from the ZOSTER-006 study; 
1-Additional Dose Group: Subjects from this group [N = 60] will receive 1 additional 
dose of the HZ/su vaccine, at the time of enrolment, to assess the immunogenicity, 
reactogenicity and safety of 1 additional dose; 
Revaccination Group: Subjects from this group [N = 60] will be revaccinated with 2 
additional doses of the HZ/su vaccine, on a 0, 2-month schedule from the time of 
enrolment, to assess the immunogenicity, reactogenicity and safety of 2 additional doses; 
Control Group: Subjects from this group [N = 120] will not be vaccinated but will serve 
as a control to assess immunogenicity and safety compared to the two vaccinated groups 
1-Additional Dose and Revaccination. This Control group will also be used to evaluate 
the long-term VE, safety and immunogenicity. 
Subjects (N, to be determined) who developed HZ during the ZOSTER-006/022 studies 
(confirmed HZ) and/or during the interval between the end of the ZOSTER-006/022 
studies and beginning of the ZOSTER-049 study, and/or during the ZOSTER-049 study 
(suspected HZ) will be part of the HZ subset. 
Subjects from the 1-Additional Dose and Revaccination groups who will develop HZ 
cases during the ZOSTER-049 study will follow the sampling schedule as per their 
original group and will not be part of the HZ subset. 
Note: Subjects from the immunogenicity subset of studies ZOSTER-006/022 are not 
allocated to the 1-Additional Dose, Revaccination and Control groups. Subjects in these 
three groups will be enrolled amongst subjects who received 2 doses of the HZ/su 
vaccine and were part of the ATP cohort for analysis of efficacy in the previous studies 
ZOSTER-006/022. In order not to confound immune responses, subjects who developed 
HZ prior to enrolment in the ZOSTER-049 study (confirmed HZ during the ZOSTER-
006/022 studies or suspected HZ during the interval between the end of the ZOSTER-
006/022 studies and beginning of the ZOSTER-049 study), will not be enrolled in the 1-
Additional Dose, Revaccination and Control groups (Refer to Table 4 and Section 6.1.2). 
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1.3. 
Benefit : Risk Assessment 
Please refer to the current IB for the summary of potential risks and benefits of HZ/su 
vaccine. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
1.3.1. 
Risk Assessment 
Important Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational HZ/su vaccine 
Theoretical risk of acquiring a 
vaccine induced autoimmune 
disease after vaccination  
(1-Additional Dose and 
Revaccination groups only). 
No confirmed signals related to 
this potential risk have been 
identified during the clinical 
program. Available clinical data 
do not highlight any concern. 
Close monitoring of pIMDs as per study 
protocol. 
The potential risk of events of possible 
autoimmune aetiology to occur is 
mentioned in the 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 maybe serious. 
Hypersensitivity reactions (including 
anaphylaxis) 
No confirmed signals related to 
this potential risk have been 
identified during the clinical 
program. Available clinical data 
do not highlight any concern. 
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. 
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 minimise 
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: 
• 
Potential benefit of receiving the study vaccine that may provide a clinical benefit in 
case the VE of HZ/su vaccine wanes over time (for the vaccinated groups 1-
Additional Dose and Revaccination). 
• 
Medical evaluations/assessments associated with study procedures [e.g., physical 
examination]. 
1.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures to minimise risk to subjects participating in this study, 
the potential or recognised risks identified in association with the investigational HZ/su 
vaccine and study procedures are offset by the potential benefits (prolonged prevention of 
HZ and related complications in case of waning VE for subjects in the 1-Additional Dose 
and Revaccination groups, and additional medical follow-up and assessments) that may 
be afforded to the subject(s). 
2. 
OBJECTIVES 
The statistical analyses to be performed for the study objectives described in Sections 2.1 
and 2.2 will be descriptive. No success criteria have been defined. 
2.1. 
Primary objective 
• 
To assess the VE in the prevention of HZ over the total duration of the ZOSTER-049 
study as measured by the reduction in HZ risk in subjects ≥ 50 YOA overall at the 
time of first vaccination in the ZOSTER-006/022 studies.  
Refer to Section 11.1 for the definition of the primary endpoint. 
2.2. 
Secondary objectives 
• 
To assess the VE in the prevention of HZ over the total duration of the ZOSTER-049 
study as measured by the reduction in HZ risk in subjects within each of the age 
ranges* at the time of first vaccination in the ZOSTER-006/022 studies; 
• 
To assess the VE in the prevention of HZ from one month post dose 2 in the 
ZOSTER-006/022 studies until the end of the ZOSTER-049 study as measured by 
the reduction in HZ risk in subjects  50 YOA overall and within each of the 
specified age ranges* at the time of first vaccination in the ZOSTER-006/022 
studies; 
• 
To assess the VE in the prevention of HZ over each year of follow-up from one 
month post dose 2 in the ZOSTER-006/022 studies as measured by the reduction in 
HZ risk in subjects  50 YOA overall and within each of the specified age ranges* at 
the time of first vaccination in the ZOSTER-006/022 studies;  
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• 
To assess the VE over the total duration of the ZOSTER-049 study in prevention of 
PHN in subjects  50 YOA overall and within each of the specified age ranges* at 
the time of first vaccination in the ZOSTER-006/022 studies;  
• 
To assess the VE in the prevention of PHN from one month post dose 2 in the 
ZOSTER-006/022 studies until the end of the ZOSTER-049 study in subjects 
 50 YOA overall and within each of the specified age ranges* at the time of first 
vaccination in the ZOSTER-006/022 studies;  
• 
To assess the VE over the total duration of the ZOSTER-049 study in prevention of 
HZ related complications (other than PHN) in subjects ≥ 50 YOA overall and within 
each of the specified age ranges* at the time of first vaccination in the ZOSTER-
006/022 studies;  
• 
To assess the VE in the prevention of HZ related complications (other than PHN) 
from one month post dose 2 in the ZOSTER-006/022 studies until the end of the 
ZOSTER-049 study in subjects ≥ 50 YOA overall and within each of the specified 
age ranges* at the time of first vaccination in the ZOSTER-006/022 studies;  
• 
To assess persistence of humoral immune responses at Year 5, 6, 7, 8, 9 and 10 and 
beyond after the primary vaccination in the ZOSTER-006/022 studies in the HI 
subset in subjects  50 YOA overall and within each of the specified age ranges* at 
the time of first vaccination, in the ZOSTER-006/022 studies;  
• 
To assess persistence of vaccine induced cell-mediated immune responses at Year 5, 
6, 7, 8, 9 and 10 and beyond after the primary vaccination in the ZOSTER-006/022 
studies in the CMI subset in subjects  50 YOA overall and within each of the 
specified age ranges* at the time of first vaccination, in the ZOSTER-006 study;  
• 
To assess humoral immune responses at Year 5, 6, 7, 8, 9 and 10 and beyond after 
the primary vaccination in the ZOSTER-006/022 studies in subjects ≥ 50 YOA at the 
time of first vaccination, in the ZOSTER-006/022 studies, who had a confirmed HZ 
episode previously for the timepoint considered; 
• 
To assess vaccine induced cell-mediated immune responses at Year 5, 6, 7, 8, 9 and 
10 and beyond after the primary vaccination in the ZOSTER-006/022 studies in the 
CMI subset in subjects ≥ 50 YOA at the time of first vaccination, in the ZOSTER-
006 study, who had a confirmed HZ episode previously for the timepoint considered; 
• 
To assess humoral immune responses one month after the first additional HZ/su 
vaccine dose (1-Additional Dose and Revaccination groups) and at the same 
timepoint in the Control group; 
• 
To assess vaccine induced cell-mediated immune responses one month after the first 
additional HZ/su vaccine dose (1-Additional Dose and Revaccination groups) and at 
the same timepoint in the Control group; 
• 
To assess humoral immune responses one month after the second additional HZ/su 
vaccine doses (Revaccination group and at the same timepoint in the Control group); 
• 
To assess vaccine induced cell-mediated immune responses one month after the 
second additional HZ/su vaccine doses (Revaccination group and at the same 
timepoint in the Control group); 
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• 
To assess persistence of humoral immune responses at Year 1, 2, 3, 4, 5 and 6 
timepoints of this study in subjects from the 1-Additional Dose, Revaccination and 
Control groups; 
• 
To assess persistence of vaccine induced cell-mediated immune responses at Year 1, 
2, 3, 4, 5 and 6 timepoints of this study in subjects from the 1-Additional Dose, 
Revaccination and Control groups; 
• 
To assess vaccine safety and reactogenicity in the 1-Additional Dose and 
Revaccination groups; 
• 
To assess vaccine safety in the LTFU and Control groups. 
* Specified age range: 50-59 YOA, 60-69 YOA,  60 YOA and  70 YOA at time of 
primary vaccination in ZOSTER-006/022. 
Refer to Section 11.2 for the definition of the secondary endpoints. 
2.3. 
Tertiary Objectives  
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3. 
STUDY DESIGN OVERVIEW 
Figure 1 
Study design overview 
 
§ N = Maximum number of subjects expected for ZOSTER-049 based on the number of subjects in the ZOSTER-
006/022 studies. 
Note: The interval between the end of ZOSTER-006/022 studies and start of study ZOSTER-049 is depicted by the 
gray inverted triangle. There is to be a database freeze and unblinding of subjects at the end of the ZOSTER-
006/022 studies and before ZOSTER-049 begins. The interval between the end of the ZOSTER-006/022 studies 
and start of study the ZOSTER-049 will vary per subject and is dependent on receipt of approval or implementing 
the study in the different participating countries/centres. 
1 A new reference timepoint Visit Month 0 is set for the first visit in ZOSTER-049. 
2 From Visit Month 0 onwards, yearly visits/contacts occur at Months 12, 24, 36, 48, 60 and 72 (Refer to Section 6.4). 
3 Study conclusion takes place at the last yearly visit/ contact (Refer to Section 6.5.11). 
† Monthly phone contacts will be done to assess HZ cases and safety follow up for all study groups and will NOT occur 
when subjects have a scheduled visit (see Table 5 and Table 6). 
¥ R= Randomisation 1:1:2. 
See Figure 2 for study activities up to Year 1 for the 1-Additional Dose, Revaccination and Control groups. 
Note: In case of suspected HZ, there are additional visits and phone contacts for follow-up of the HZ episode (see 
Table 7). 
Visit 1
Month 0
Month 0
HZ/su Group (gE/AS01B ) 
(ZOSTER-006: N ≤7698; 
ZOSTER-022: N  ≤6750) §
ZOSTER-006/022
ZOSTER-049
Visit/ Contact 2
Year 1
Month 12 
Visit/ Contact 3
Year 6
Month 72
Conclusion
Monthly contacts after Visit Month 0 until the subject’s last visit †
Epoch 001: Primary
Month 0, 1 & 3
Blood Samples
Visit/ Contact 2
Year 2
Month 24 
Visit/ Contact 2
Year 3
Month 36
Visit/ Contact 2
Year 4
Month 48 
Visit/ Contact 2
Year 5
Month 60
Blood Samples from ALL subjects at Visit Month 0 and yearly from subjects in the HI, CMI and HZ subsets
Visit 1
Month 0
Month 0
Visit 2
Year 1
Month 12 
Visit 3
Year 6
Month 72
Conclusion
Visit 2
Year 2
Month 24 
Visit 2
Year 3
Month 36
Visit 2
Year 4
Month 48 
Visit 2
Year 5
Month 60
Yearly Post-Dose Blood Samples (HI and CMI)
LTFU Group (No Vaccination)
Control Group (No Vaccination) [N = 120]
R¥
*       1-Additional Dose Group (1 Dose) [N = 60]
*  *    Revaccination Group
(2 Doses) [N = 60]
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Figure 2 
Detailed overview of the 1-Additional Dose, Revaccination and 
Control groups (Year 1 only) 
 
§ N = Maximum number of subjects expected for ZOSTER-049 based on the number of subjects in the ZOSTER-
006/022 studies. 
* The two groups (1-Additional Dose and Revaccination, only) will have a HZ/su vaccination (Vacc 1) at Visit Month 0 
and the Revaccination group will have a second dose (Vacc 2) at Visit Month 2 (see Table 6 and Table 21). 
** Blood sampling (BS) as in the Sampling schedule in Section 3, Table 4, Table 15 and Table 19. 
Refer to Figure 1 for study activities beyond Year 1 and to Table 9 and Table 10 for the intervals between study visits 
for the 1-Additional Dose and Control groups and for the Revaccination group, respectively. 
† Monthly phone contacts will be done to assess HZ cases and safety follow up for all study groups and will NOT occur 
when subjects have a scheduled visit (see Table 5 and Table 6). 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.4), are essential and required for 
study conduct. Refer to Section 6.6 for study procedures to be considered during special 
circumstances (Amended 11 May 2020). 
• 
Experimental design: Phase IIIb, open-label, multi-centre, multi-country study with 4 
groups. 
• 
Duration of the study: Each subject will be followed for approximately 6 years. 
• 
Epoch 001: LTFU of studies ZOSTER-006/022 starting at Visit Month 0 and ending 
at Visit Year 6 (Month 72) and assessment of 1 or 2 additional doses in two groups 
of subjects. 
HZ/su Group (gE/AS01B ) 
(ZOSTER-006: N ≤7698; 
ZOSTER-022: N ≤6750) §
ZOSTER-006/022
Visit
Month 0
(BS)**
Visit
Month 1
(BS)**
Visit
Month 2
Visit
Month 3
(BS)**
Monthly 
Contacts †
Visit
Year 1
(BS)**
Randomisation
1:1:2
Vacc 1 *
Vacc 2 *
LTFU Group (No Vaccination)
*     1-Additional Dose Group (1 Dose) [N = 60]
*     Revaccination Group (2 Doses) [N = 60]
Control  Group (No Vaccination) [N = 120]
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• 
Study groups: 
The study will be comprised of four study groups as follows: 
LTFU Group: Subjects from this group [N ≤ 14,000] will be followed for VE and 
safety. In addition, immunogenicity will be followed in subjects that were part of the 
immunogenicity subset (HI) in the ZOSTER-006/022 studies and Cell-Mediated 
Immunity (CMI) subset from the ZOSTER-006 study; 
1-Additional Dose Group: Subjects from this group [N = 60] will receive 1 additional 
dose of the HZ/su vaccine, at the time of enrolment, to assess the immunogenicity, 
reactogenicity and safety of 1 additional dose; 
Revaccination Group: Subjects from this group [N = 60] will be revaccinated with 2 
additional doses of the HZ/su vaccine, on a 0, 2-month schedule from the time of 
enrolment, to assess the immunogenicity, reactogenicity and safety of 2 additional doses; 
Control Group: Subjects from this group [N = 120] will not be vaccinated but will serve 
as a control to assess immunogenicity and safety compared to the two vaccinated groups 
1-Additional Dose and Revaccination. This Control group will also be used to evaluate 
the VE, safety and immunogenicity. 
Subjects (N, to be determined) who developed HZ during the ZOSTER-006/022 studies 
(confirmed HZ) and/or during the interval between the end of the ZOSTER-006/022 
studies and beginning of the ZOSTER-049 study, and/or during the ZOSTER-049 study 
(suspected HZ) will be part of the HZ subset. 
Subjects from the 1-Additional Dose and Revaccination groups who will develop HZ 
cases during the ZOSTER-049 study will follow the sampling schedule as per their 
original group and will not be part of the HZ subset. 
Note: Subjects from the immunogenicity subset of studies ZOSTER-006/022 are not 
allocated to the 1-Additional Dose, Revaccination and Control groups. Subjects in these 
three groups will be enrolled amongst subjects who received 2 doses of the HZ/su 
vaccine and were part of the ATP cohort for analysis of efficacy in the previous studies 
ZOSTER-006/022. In order not to confound immune responses, subjects who developed 
HZ prior to enrolment in the ZOSTER-049 study (confirmed HZ during the ZOSTER-
006/022 studies or suspected HZ during the interval between the end of the ZOSTER-
006/022 studies and beginning of the ZOSTER-049 study), will not be enrolled in the 1-
Additional Dose, Revaccination and Control groups (Refer to Table 4 and Section 6.1.2). 
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Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Epochs 
From ZOSTER-006 
primary study 
From ZOSTER-022 
primary study 
Total 
Epoch 001 
ZOSTER-049 Total 
≤ 7698 
≤ 6750 
≤ 14448 * 
 
LTFU 
 
 
≤ 14208 ** 
x 
1-Additional Dose 
 
 
60 
x 
Revaccination 
 
 
60 
x 
Control 
 
 
120 
x 
* Maximum number of subjects expected for ZOSTER-049 based on the number of subjects in the ZOSTER-006/022 
studies. 
** All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 0. For 
subjects in the LTFU group, who do not belong to any subset, these samples will be stored and tested for HI only 
if the subject develops HZ during the ZOSTER-049 study or if there are other reasons requiring the HI testing of 
these samples (see Section 6.5.8.1). 
Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Product name 
Study groups 
LTFU 
1-Additional Dose 
Revaccination 
Control 
HZ/su 
VZV gE 
None 
x 
x 
None 
AS01B 
• 
Control: historical control. 
• 
Vaccination schedule: Two groups of subjects (1-Additional Dose and 
Revaccination) will receive 1 or 2 additional doses of HZ/su vaccine at Month 0 or 
Months 0 and 2, respectively. 
• 
Treatment allocation: Randomised to treatment schedule accounting for age at 
primary vaccination in studies ZOSTER-006/022 (50-59, 60-69 and ≥ 70 YOA) and 
countries for the three groups 1-Additional Dose, Revaccination and Control. 
• 
Blinding: Open-label. 
Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
open-label 
• 
Sampling schedule: 
All subjects (N ≤ 14,448) entering the study will have a HI blood sample 
(approximately 5 mL) at Visit Month 0. 
For subjects in the LTFU group, who do not belong to any subset, these samples will 
be stored and tested for HI only if the subject develops HZ during the ZOSTER-049 
study or if there are other reasons requiring the HI testing of these samples. 
LTFU Group (HI subset): Subjects (N ≤ 1,729) who were in the immunogenicity 
subset during studies ZOSTER-006/022 and continue participation in this study. 
Blood samples (approximately 5 mL) will be collected and tested from Visit Month 0 
to Visit Year 6, on a yearly basis, to assess HI responses. 
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LTFU Group (CMI subset): Subjects (N ≤ 234) who were in the CMI subset 
during study ZOSTER-006 and continue participation in this study. Blood samples 
(approximately 20 mL) will be collected and tested from Visit Month 0 to Visit 
Year 6 on a yearly basis to assess CMI responses. 
HZ subset: Subjects (N to be determined) who developed confirmed HZ during 
ZOSTER-006 or ZOSTER-022, or who develop HZ during the interval between the 
end of the ZOSTER-006/022 and the beginning of ZOSTER-049, or who develop 
suspected HZ during ZOSTER-049 will be part of the HZ subset. Blood sampling for 
subjects in the HZ subset is described below. 
Subjects who develop HZ at any time after enrolment in ZOSTER-006 or ZOSTER-
022 and who are already part of the HI subset in ZOSTER-006 or ZOSTER-022 will 
provide blood samples to assess HI responses (approximately 5 mL) from Visit 
Month 0 to Visit Year 6 irrespective of when the HZ episode occurs. If these subjects 
are part of the ZOSTER-006 CMI subset, then they will also continue to provide 
blood to assess CMI responses (approximately 20 mL). 
Subjects who develop HZ at any time after enrolment in ZOSTER-006 or ZOSTER-
022 and who were NOT part of the HI or CMI subsets in these studies, will provide 
blood samples to assess HI responses (approximately 5 mL) beginning at the annual 
visit in the ZOSTER-049 study subsequent to the occurrence of the HZ episode. The 
blood sample taken upon enrolment at Visit Month 0 will be tested and included in 
the analyses for these subjects. 
1-Additional Dose Group: Subjects (N = 60) to be administered HZ/su vaccine on a
1-dose schedule at Visit Month 0. Blood samples (approximately 5 and 20 mL) will
be collected at Visit Month 0, Visit Month 1, and from Visit Year 1 to Visit Year 6
on a yearly basis to assess HI and CMI responses.
Revaccination Group: Subjects (N = 60) to be administered HZ/su vaccine on a 2-
dose schedule at Visit Month 0 and Visit Month 2. Blood samples (approximately 5 
and 20 mL) will be collected at Visit Month 0, Visit Month 1, Visit Month 3 and 
from Visit Year 1 to Visit Year 6 on a yearly basis to assess HI and CMI responses. 
Control Group: Subjects (N = 120) in the non-vaccinated control group. Blood 
samples (approximately 5 and 20 mL) will be collected at Visit Month 0, Visit 
Month 1, Visit Month 3 and from Visit Year 1 to Visit Year 6 on a yearly basis to 
assess HI and CMI responses. 
Specimens of HZ lesions will be collected from subjects clinically diagnosed as 
having a suspected case of HZ. 
•
Type of study: extension of other protocols, i.e., 110390 (ZOSTER-006) and 113077
(ZOSTER-022).
•
Data collection: Electronic Case Report Form (eCRF).
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4. 
CASE DEFINITION 
4.1. 
Suspected HZ 
A suspected case of HZ is defined as 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. 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 Month 0 to study end. Refer to Section 4.5 for more 
details on the evaluation and confirmation of suspected HZ cases. 
Subjects who developed confirmed HZ during ZOSTER-006 or ZOSTER-022, or who 
develop HZ during the interval between the end of the ZOSTER-006/022 and the 
beginning of ZOSTER-049, or who develop suspected HZ during ZOSTER-049 will be 
part of the HZ subset (Table 4 and Section 6.5.8.1). 
4.2. 
Confirmed HZ 
A suspected case of HZ can be confirmed in two ways: 
• 
By Polymerase Chain Reaction (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 using standardised and validated 
procedures for laboratory diagnosis of HZ by PCR (see Section 4.5.2.4.1). 
• 
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” (see Section 4.5.2.4.2). 
4.3. 
Postherpetic neuralgia (PHN) 
PHN is defined by the presence of HZ-associated severe ‘worst’ pain persisting or 
appearing more than 90 days after onset of the HZ rash. 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 6.3.1.2 and 4.5.2.3). 
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Cessation of pain to assess duration of HZ-associated pain: A 28-day pain-free period is 
used to confirm cessation of HZ-associated pain.  
Acute pain is defined as pain measured during the 4-week period following the onset of 
confirmed HZ. 
4.4. 
HZ complications 
Any HZ complications listed below will be recorded by the investigator in HZ-specific 
eCRF screens, and on the AE/SAE reporting screens. The reporting period for HZ 
complications will be from Month 0 to study end. Any HZ complications, according to 
the definitions below, will be recorded by the investigator. If a recorded complication is 
associated with a case of suspected HZ, and that case is finally not considered to be a 
confirmed case, the associated complication will not be considered as a complication of 
HZ. 
HZ vasculitis  
Vasculopathy or vasculitis (based on clinical, laboratory or 
radiologic findings) that is temporally associated with an 
episode of HZ and, in the opinion of the investigator, was 
caused directly by the VZV infection arising from the HZ 
episode. 
Disseminated disease  
Defined as ≥ 6 HZ lesions outside the primary dermatome as per 
the investigator’s judgment. 
Ophthalmic disease  
Defined as HZ affecting any eye structure as per investigator’s 
judgment. 
Neurologic disease  
Defined as cranial or peripheral nerve palsies, myelitis, 
meningoencephalitis, stroke, etc. that is temporally associated 
with an episode of HZ and, in the opinion of the investigator, 
was caused directly by VZV infection arising from the HZ 
episode. 
Visceral disease  
Defined as an abnormality of one or more internal organs (e.g., 
hepatitis, pneumonitis, gastroenteritis, etc.) that is temporally 
associated with an episode of HZ and, in the opinion of the 
investigator, was caused directly by VZV infection arising from 
the HZ episode. 
Stroke A 
 diagnosis of stroke requires that criteria 1, 2 and 3 are fulfilled 
or criteria 1 and 4 and in the opinion of the investigator is 
temporally associated with an episode of HZ  
 
Criterion 1: Rapid onset of localising neurological deficit and/or 
change in level of consciousness; 
 
Criterion 2: Localising neurological deficit or change in level of 
consciousness that lasts greater than 24 hours; 
 
Criterion 3: No other cerebral process, peripheral lesion, or other 
disorder is the cause of the localising neurological deficit or 
change in level of consciousness; 
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Criterion 4: Computerised Tomography (CT) scan or Magnetic 
Resonance Imaging (MRI) scan evidence of an acute thrombotic 
or hemorrhagic lesion. 
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 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 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. 
Zoster Brief Pain Inventory (ZBPI) questionnaire: To be completed by subjects with 
suspected HZ (or subject’s caregiver) on Day HZ-0 (Visit HZ-1) and daily from Day HZ-
1 (day after the Visit HZ-1) up to Day HZ-28, and weekly from Day HZ-29 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 visit/contact (LSLV/C), ZBPI data will be collected 
until a 4-week pain-free period is documented OR until at least Day HZ-91 (Refer to 
Section 4.5.2 for more details).  
Please refer to Table 5, Table 6 and Table 7 for information on when diary cards and 
questionnaires are dispensed to the subjects. 
4.5.2. 
Evaluation of suspected case of HZ 
All HZ cases that occur during the study period up to the LSLV/C will be followed and 
evaluated as was done for the previous ZOSTER-006/022 studies. Any symptom/sign 
suggestive of HZ must be evaluated. At Visit Month 0, all subjects (and subject’s 
caregiver if applicable) will be re-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 that rash and/or pain began. Subjects will be instructed to contact their study site 
immediately, and start completing the HZ-specific diary card (with the help of the subject 
caregiver if applicable) if he/she develops any symptoms suggestive of HZ. The subjects 
will be asked to 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 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-0]. If not 
considered a suspected HZ diagnosis, the investigator should not progress further with 
evaluation of this event as a HZ case for the purpose of this study. However, if meeting 
the definition of an AE/SAE (Section 9.1), the case should be handled as applicable 
(Section 9.3). 
The schedule of visits/contacts that will take place for follow-up of suspected HZ cases is 
presented in Table 7. 
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4.5.2.1. 
For clinically diagnosed suspected HZ cases, the following will take 
place at Visit HZ-1: 
• 
The investigator or his delegate will verify the completed HZ-specific diary card 
returned by the subject and the subject’s caregiver if applicable. The information 
from the diary card will be transcribed into the eCRF. The investigator or his 
delegate will record relevant information regarding the HZ episode in the eCRF 
(such as date of onset of pain and rash, date of clinical diagnosis of HZ, location and 
nature of HZ lesions, HZ-related complications if any); 
• 
The study staff/investigator will ask the subject (with the help of subject’s caregiver 
if necessary) to complete a ZBPI questionnaire at Visit HZ-1 to rate HZ-associated 
pain within the last 24 hours. If the time between the HZ onset and clinical 
evaluation at Visit HZ-1 is greater than 24 hours, the subject will be asked to 
complete a second ZBPI also for the elapsed time between the HZ onset and 24 
hours before Visit HZ-1; 
• 
The rash will be documented by digital photography. Please refer to the 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 7.6), and record intercurrent medical conditions (Section 7.7). If antiviral 
therapy is needed, it is recommended to use valacyclovir, acyclovir or famciclovir. 
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 (Section 4.5.3); 
• 
The subject will be given a supply of ZBPI questionnaires. The ZBPI questionnaires 
will be used 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 explain the importance of completing and 
returning the questionnaires to the site in order to provide more information on HZ. 
• 
The subject/subject’s caregiver will be asked to complete the ZBPI questionnaires on 
Day HZ-0 (Visit HZ-1) and daily from Day HZ-1 (day after the Visit HZ-1) up to 
Day 28 (ZBPI must be completed to Day HZ-28 at minimum) and weekly from Day 
HZ-29 onwards until:  
− 
28 days after HZ-associated pain ceases. The subject/ subject’s caregiver should 
continue to complete the ZBPI questionnaires weekly 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); 
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− 
For all subjects with ongoing HZ-associated pain at the time of LSLV/C, 
completion of ZBPI questionnaires will continue until a 4-week pain-free period 
is documented OR until at least Day HZ-91. 
• 
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 7. 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 7) 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 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-0 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-91) 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.  
4.5.2.2. 
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 7.6); 3) record intercurrent medical conditions (Section 7.7); 
and 4) 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. 
• 
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 (i.e., <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 (see 
Section 4.5.3). 
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•
The study staff/investigator will remind subjects/subject’s 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.
4.5.2.3. 
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 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 6.3.1.2, see 
also further details in Section 4.5.2). 
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. 
4.5.2.4. 
Confirmation of a suspected case of HZ 
A suspected case of HZ can be confirmed in two ways: 
4.5.2.4.1. 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 using standardised and validated procedures 
for laboratory diagnosis of HZ by PCR. Refer to 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. 
4.5.2.4.2. 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”. However, 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 (Amended 11 May 
2020). 
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The HZAC will consist of three to five physicians with HZ expertise. HZAC members, 
participating as investigator 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 (Amended 11 May 2020). 
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 Month 0 until the 
study conclusion Visit. 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) will be collected daily until Day- HZ-28, and weekly from Day 
HZ-29 until the subject has no HZ-associated pain for 4 consecutive weeks. 
For all subjects with ongoing HZ-associated pain at the time of LSLV/C, ZBPI data will 
be collected until a 4-week pain-free period is documented OR until Day HZ-91. 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 7 
with Day HZ-0 defined as the first visit of the assigned episode, prior to the pain free 
period. Follow-up is described in Section 4.5.2. 
At the first HZ evaluation visit (Visit HZ-1 at Day HZ-0 – the visit at which the 
suspected case of HZ is first evaluated by the investigator), rash lesion samples will be 
collected from the subject if the investigator considers the symptoms/signs to be 
consistent with HZ. Three replicate rash lesion samples (see Table 15) should be 
collected on the same day. If during clinical evaluation at Visit HZ-1, the investigator 
determines that adequate rash lesion samples cannot be collected (i.e., 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 (i.e., 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 for further details on sample collection. 
At Visit HZ-1, the rash will be documented by digital photography. Additional 
photographs of HZ lesions may be taken after Visit HZ-1 to help note the progression of 
the rash. 
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5. 
STUDY COHORT 
5.1. 
Number of subjects/centres 
Subjects who received at least 1 dose of HZ/su vaccine in study ZOSTER-006 or study 
ZOSTER-022, and confirmed their interest to enrol in the study at participating centres, 
will be considered for entry in study ZOSTER-049. Refer to Sections 5.2 and 5.3 for 
inclusion/exclusion criteria, respectively. 
The subsets foreseen for HI analysis and for CMI analyses as well as the 1-Additional 
Dose, Revaccination and Control groups are described in Table 4. Refer to Section 11.4 
for details regarding the estimation of sample size for the LTFU study group. 
Table 4 
Subsets 
Subset name 
Description 
Estimated 
maximum 
number of 
subjects 
All subjects 
All subjects entering the study will have a HI blood sample (approximately 5 
mL) at Visit Month 0. For subjects in the LTFU group, who do not belong to 
any subset, these samples will be stored and tested for HI only if the subject 
develops HZ during the ZOSTER-049 study or if there are other reasons 
requiring the HI testing of these samples. 
≤ 14448 
LTFU Group HI 
subset 
Subjects in the LTFU group who were in the immunogenicity subset during 
studies ZOSTER-006/022 and continue participation in this study. Blood 
samples (approximately 5 mL) will be collected and tested from Visit Month 0 
to Visit Year 6, on a yearly basis, to assess HI responses. 
≤ 1740 
LTFU Group CMI 
subset 
Subjects in the LTFU group who were in the CMI subset during study 
ZOSTER-006 and continue participation in this study. Blood samples 
(approximately 20 mL) will be collected and tested from Visit Month 0 to Visit 
Year 6 on a yearly basis to assess CMI responses. 
≤ 234 
HZ subset 
Subjects who developed confirmed HZ during ZOSTER-006 or ZOSTER-022, 
or who develop HZ during the interval between the end of the ZOSTER-
006/022 and the beginning of ZOSTER-049, or who develop suspected HZ 
during ZOSTER-049 will be part of the HZ subset. 
Subjects who develop HZ at any time after enrolment in ZOSTER-006 or 
ZOSTER-022 and who are already part of the HI subset in ZOSTER-006 or 
ZOSTER-022 will provide blood samples to assess HI responses 
(approximately 5 mL) from Visit Month 0 to Visit Year 6 irrespective of when 
the HZ episode occurs. If these subjects are part of the ZOSTER-006 CMI 
subset, then they will also continue to provide blood to assess CMI responses 
(approximately 20 mL). 
Subjects who develop HZ at any time after enrolment in ZOSTER-006 or 
ZOSTER-022 and who were NOT part of the HI or CMI subsets in these 
studies, will provide blood samples to assess HI responses (approximately 5 
mL) beginning at the annual visit in the ZOSTER-049 study subsequent to the 
occurrence of the HZ episode. The blood sample taken upon enrolment at 
Visit Month 0 will be tested and included in the analyses for these subjects. 
TBD 
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Subset name 
Description 
Estimated 
maximum 
number of 
subjects 
1-Additional Dose  
Group 
Subjects to be administered HZ/su vaccine on a 1-dose schedule at Visit 
Month 0. Blood samples (approximately 5 and 20 mL) will be collected at Visit 
Month 0, Visit Month 1, and from Visit Year 1 to Visit Year 6 on a yearly basis 
to assess HI and CMI responses. 
60 
Revaccination  
Group 
Subjects to be administered HZ/su vaccine on a 2-dose schedule at Visit 
Month 0 and Visit Month 2. Blood samples (approximately 5 and 20 mL) will 
be collected at Visit Month 0, Visit Month 1, Visit Month 3 and from Visit Year 
1 to Visit Year 6 on a yearly basis to assess HI and CMI responses. 
60 
Control Group 
Subjects in the non-vaccinated control group. Blood samples (approximately 5 
and 20 mL) will be collected at Visit Month 0, Visit Month 1, Visit Month 3 and 
from Visit Year 1 to Visit Year 6 on a yearly basis to assess HI and CMI 
responses. 
120 
HI = Humoral Immunogenicity; mL = Millilitre; LTFU = Long-Term Follow-Up; CMI = Cell-Mediated Immunity; HZ= 
Herpes Zoster; TBD = To Be Determined. 
Overview of the recruitment plan: 
Potentially eligible subjects from centres who participated and received HZ/su vaccine in 
ZOSTER-006/022 studies will be contacted and considered for entry in the ZOSTER-049 
study. The rationale for not enrolling any of these subjects will be recorded in the site’s 
screening log. This study is planned to be conducted in multiple countries worldwide at 
centres which participated in the ZOSTER-006/022 studies. 
5.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., completion of the diary cards, return for follow-up 
visits, ability to have scheduled contacts to allow evaluation during the study). Or 
subjects with a caregiver who, in the opinion of the investigator, can and will comply 
with the requirements of the protocol (e.g., completion of the diary cards, availability 
for follow-up contacts); 
• 
Written informed consent obtained from the subject prior to performance of any 
study specific procedure; 
• 
Subject who participated in ZOSTER-006 or ZOSTER-022 studies and received at 
least one dose of HZ/su vaccine.1 
                                                 
1 HZ/su vaccine is referred to as gE/AS01B vaccine in ZOSTER-006/022 protocols. 
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Note: Subjects from the immunogenicity subset of studies ZOSTER-006/022 are not 
allocated to the 1-Additional Dose, Revaccination and Control groups. Subjects in these 
three groups will be enrolled amongst subjects who received 2 doses of the HZ/su 
vaccine and were part of the ATP cohort for analysis of efficacy in the previous studies 
ZOSTER-006/022. In order not to confound immune responses, subjects who developed 
HZ prior to enrolment in the ZOSTER-049 study (confirmed HZ during the ZOSTER-
006/022 studies or suspected HZ during the interval between the end of the ZOSTER-
006/022 studies and beginning of the ZOSTER-049 study), will not be enrolled in the 1-
Additional Dose, Revaccination and Control groups (Refer to Table 4 and Section 6.1.2). 
Additional inclusion criteria for the 1-Additional Dose, Revaccination and Control 
groups, ONLY: 
• 
Female subjects of non-childbearing potential may be enrolled. 
− 
Non-childbearing potential is defined as pre-menarche, current tubal ligation, 
hysterectomy, ovariectomy or post-menopause. 
Please refer to the glossary of terms for the definition of menarche and menopause. 
• 
Female subjects of childbearing potential may be enrolled 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 during the entire treatment period 
and 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 
jeopardise the scientific integrity of the study, regulatory acceptability 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: 
• 
Use of any investigational or non-registered product (pharmaceutical product or 
device) at the time of enrolment or planned use during the study period; 
• 
Previous vaccination against VZV or HZ and/or planned administration during the 
study of a VZV or HZ vaccine (including an investigational or non-registered 
vaccine other than the HZ/su vaccine administered in studies ZOSTER-006/022); 
• 
Chronic administration (defined as > 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to Visit Month 0 of study ZOSTER-049 or expected administration at 
any time during the study period. For corticosteroids, this will mean prednisone 
≥ 20 mg/day or equivalent. A prednisone dose of < 20 mg/day is allowed. Inhaled, 
topical and intra-articular corticosteroids are allowed; 
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• 
Administration of long-acting immune-modifying drugs (e.g., infliximab, rituximab) 
within 6 months prior to Visit Month 0 of study ZOSTER-049 or expected 
administration at any time during the study period; 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
resulting from disease (e.g., malignancy, human immunodeficiency virus [HIV] 
infection) or immunosuppressive/cytotoxic therapy (e.g., medications used during 
cancer chemotherapy, organ transplantation or to treat autoimmune disorders); 
• 
Administration of immunoglobulins and/or any blood products within 3 months prior 
to Visit Month 0 of study ZOSTER-049 or planned administration during the study 
period; 
• 
Prolonged use (> 14 consecutive days) of oral and/or parenteral antiviral agents that 
are active against VZV (acyclovir, valacyclovir, famciclovir, etc. ) and planned to be 
used during the study period for an indication other than to treat suspected or 
confirmed HZ or an HZ-related complication (topical use of these antiviral agents is 
allowed). 
• 
Important underlying illness that in the opinion of the investigator would be expected 
to interfere significantly during the study; 
Additional exclusion criteria for the 1-Additional Dose, Revaccination and Control 
groups, ONLY: 
• 
Subjects who experienced an SAE from first vaccination in the previous ZOSTER-
006/022 studies to enrolment in study ZOSTER-049 that was considered related to 
study vaccine by either the investigator or the sponsor; 
• 
Subjects with a new onset of a pIMD or exacerbation of a pIMD from first 
vaccination in the previous ZOSTER-006/022 studies to enrolment in study 
ZOSTER-049; 
• 
Use of any investigational or non-registered product (pharmaceutical product or 
device) within 30 days preceding the first dose of study vaccine or planned use 
during the study period; 
• 
Administration or planned administration of any other immunizations within 30 days 
before the first study vaccination or scheduled within 30 days after study 
vaccination. However, licensed non-replicating vaccines (i.e., inactivated and subunit 
vaccines, including inactivated and subunit influenza vaccines for seasonal or 
pandemic flu, with or without adjuvant) may be administered up to 8 days prior to 
each dose and/or at least 14 days after any dose of study vaccine; 
• 
History of allergic disease or reactions likely to be exacerbated by any component of 
the vaccine. Additionally, consider allergic reactions to other material or equipment 
related to study participation (such as materials that may possibly contain latex -
gloves, syringes, etc.). Please note, the vaccine and vials in this study do not contain 
latex; 
• 
Pregnant or lactating female; 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions (if of childbearing potential); 
• 
Previous episode/history of HZ. 
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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. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines. 
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 informed consent and subject informed assent, as appropriate. 
• 
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, as appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 
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6.1.1. 
Subject identification and randomisation of treatment 
The original subject identification numbers used in the primary studies ZOSTER-006/022 
(containing up to 5 digits) will be used in the ZOSTER-049 study and they will be 
preceded by an additional sixth digit: a number 6 for the subjects initially enrolled in 
ZOSTER-006 and a number 2 for the subjects initially enrolled in ZOSTER-022. E.g., if 
two subjects, one from ZOSTER-006 and the other from ZOSTER-022 both with subject 
identification number 111 are to be enrolled in ZOSTER-049, they will be attributed the 
following identification numbers: 
− 
600111 for the subject initially enrolled in ZOSTER-006; 
− 
200111 for the subject initially enrolled in ZOSTER-022. 
Subject numbers will be pre-loaded into a centralised randomisation system on the 
internet (SBIR) that will be used for subject number assignment. Refer to the SPM for 
further details on the assignment of subject identification numbers. 
6.1.1.1. 
Randomisation of supplies 
For the 1-Additional Dose, Revaccination and Control groups: 
The randomisation 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 of supplies will be shipped 
to the study centres /warehouse(s). 
For countries/centres that will enrol subjects in the 1-Additional Dose, Revaccination and 
Control groups an over-randomisation of supplies will be prepared in order to take 
advantage of greater rates of recruitment in one or more centres and thus reduce the 
overall recruitment period in these groups. 
6.1.1.2. 
Randomisation of treatment 
6.1.1.2.1. Treatment allocation to the subject for the 1-Additional Dose, 
Revaccination and Control groups 
The target will be to enrol approximately 240 eligible subjects who will be randomly 
assigned to the 3 study groups in a (1:1:2) ratio (approximately 60 subjects in each group 
1-Additional Dose and Revaccination and 120 subjects in group Control). Allocation of a 
subject to a study group at the investigator site will be performed using SBIR. 
The treatment numbers will be allocated by dose. The randomisation algorithm will use a 
minimisation procedure accounting for age at primary vaccination (50-59, 60-69 and 
≥ 70 YOA) at the time of first vaccination in the ZOSTER-006/022 studies and country. 
All factors will have equal weight in the minimisation algorithm. 
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the study staff in charge of the vaccine administration will 
access SBIR. The randomisation system will determine the study group and will provide 
the treatment number to be used for the first dose. Note that the treatment number issued 
for the Control group will not be used for administration. 
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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. 
6.1.1.2.2. 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. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
6.1.2. 
Allocation of subjects to assay subsets 
Subjects who were part of the immunogenicity subset in the ZOSTER-006/022 studies 
will be allocated to the HI subset of the LTFU group in the ZOSTER-049 study. From 
this HI subset, subjects will be allocated to the CMI subset of the LTFU group if they 
were part of the CMI subset in the ZOSTER-006 study. 
Subjects who developed HZ episode(s) during the ZOSTER-006/022 studies (confirmed 
HZ) and/or during the interval between the end of the ZOSTER-006/022 studies and 
beginning of ZOSTER-049 study and/or during the ZOSTER-049 study (suspected HZ) 
will be included in the HZ subset. 
Subjects who were part of the immunogenicity subset in the ZOSTER-006/022 studies 
will be excluded from allocation to the three groups 1-Additional Dose, Revaccination 
and Control. Subjects can be allocated to the three groups 1-Additional Dose, 
Revaccination and Control if they: 
• 
received 2 doses of HZ/su vaccine in the ZOSTER-006/022 studies; 
• 
were NOT part of the immunogenicity and CMI subsets in the ZOSTER-006/022 
studies; 
• 
were part of the ATP cohort for analyses of efficacy in the ZOSTER-006/022 
studies; 
• 
did NOT develop HZ (confirmed or suspected HZ) prior to enrolment in this 
ZOSTER-049 study. 
• 
and comply with inclusion and exclusion criteria (see Sections 5.2 and 5.3, 
respectively) for the 1-Additional Dose, Revaccination and Control groups. 
As there is a requirement to collect CMI samples for subjects enrolled in the 1-Additional 
Dose, Revaccination and Control groups, these subjects will be enrolled in selected 
countries and sites that have access to a facility for CMI sample processing. 
Refer to Table 4 for a description of subsets and to Table 19 for a schedule of 
immunological sampling and read-outs. 
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6.2. 
Method of blinding 
This is an open-label study with two treatment groups (1-Additional Dose and 
Revaccination). 
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. 
6.3. 
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. 
6.3.1. 
Data collection 
6.3.1.1. 
Monthly contacts 
After Visit Month 0, monthly contacts between the subjects/ subject’s caregiver and the 
investigator and/or his delegate will take place to collect information on any event of 
interest that may have occurred [see Section 6.5.7 for details]. The contacts will not take 
place at months that coincide with the subject’s scheduled study visits. Also, subjects 
with suspected HZ will be contacted periodically as outlined in Table 7. The contacts will 
take place using the most convenient method suited for the sites (e.g., telephone calls by 
site staff or 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 caregiver will respond to a standard set of questions in 
a language that is understandable to them. The investigator and/or his delegate will 
transcribe the relevant information on any event of interest in the appropriate of the 
subject’s eCRF, in English. In case of ongoing HZ, subjects / subjects’ caregiver will also 
be reminded to complete Zoster Brief Pain Inventory (ZBPI) questionnaires as described 
in Section 4.5.2.3. 
6.3.1.2. 
Diary cards and questionnaires 
The diary cards and/or questionnaires to be completed by the subject/ subject’s caregiver 
will be distributed and explained by the investigator or his/her 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, an aide (such 
as a family member or caregiver who is not involved in the study) may provide assistance 
with reading the questions (verbatim) and/or transcribing the subject’s responses on the 
questionnaires and/or diary cards. 
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For subjects in the two groups (1-Additional Dose and Revaccination, only), 7-day and 
30-day diary cards will be dispensed on the day of vaccination to be completed by the 
subjects/ subjects’ caregiver. The 7-day diary cards will be completed for solicited AEs 
(from Day 0 to Day 6 after each vaccination) and the 30-day diary cards will be 
completed by for unsolicited AEs (from Day 0 to Day 29 after each vaccination) and any 
concomitant medication and vaccination taken from Day 0 to Day 29 after each 
vaccination (see Table 6 and Table 26). 
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. In case questionnaires are completed at the study site, study staff 
can assist in reading the questions (verbatim). 
6.4. 
Outline of study procedures 
Table 5 presents the list study of procedures for the LTFU group. 
Table 6 presents the list study of procedures for the three groups 1-Additional Dose, 
Revaccination and Control. 
Table 7 presents follow-up procedures to be performed for each suspected HZ case. 
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Table 5 
List of study procedures (for the LTFU group) 
Epoch 
LONG-TERM FOLLOW-UP 
Type of contact 
Visit MONTH 0 Monthly 
contacts 1 
Visit/ Contact 
YEAR 1, 2, 3, 4, 5 2 
Study conclusion 
Visit/ Contact 3  
Year 6 2 
Timepoints 
Day 0/ 
Month 0 
 
Month  
12, 24, 36, 48, 60 
Month  
72 
Sampling timepoints 
Post-Primary 
 
Post-Primary 
Post-Primary 
Informed consent 
● 
 
 
 
Check inclusion criteria 
● 
 
 
 
Check exclusion criteria 
● 
 
 
 
Medical history including HZ history (see Section 
6.5.3) 
● 
 
 
 
Physical examination (see Section 6.5.4) 
O 
 
 
 
Training on self-reporting by subjects 4 
O 
 
O 
 
Blood sampling (approximately 5 mL) for all LTFU 
non-subset subjects (Table 4 and Section 6.5.8.1) 
● 
 
 
 
Blood sampling (approximately 5 mL) for HI Ab 
determination (Table 4 and Section 6.5.8.1) 
● 
 
● 
● 
Blood sampling (approximately 20 mL) for CMI 
responses (Table 4 and Section 6.5.8.1) 
● 
 
● 
● 
Blood sampling (approximately 5 mL) for Ab 
determination for the HZ subset (Table 4 and 
Section 6.5.8.1 
● 
 
● 
● 
Dispensing of HZ-specific diary cards to all 
subjects  
O 
 
 
 
Recording of IMCs (Section 7.7) 
● 
● 
● 
● 
Reporting of SAEs related to investigational 
vaccine (Table 25) 
● 
● 
● 
● 
Recording of SAEs related to study participation or 
to concurrent GSK medication/vaccine (Table 25) 
● 
● 
● 
● 
Follow-up of HZ (Section 4) 
● 
● 
● 
● 
Recording of concomitant medication/vaccination 
by study staff/investigator (Section 7.6.2) 
● 
● 
● 
● 
E-signature at year 2 and year 4 (for the year 2 and 
year 4 analyses) 
 
 
● 5 
 
Study conclusion (e signature) 
 
 
 
● 
● 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. 
Post-Primary = Post-primary vaccination with HZ/su in studies ZOSTER-006/022; Ab = Antibody; HI = Humoral 
Immunogenicity; CMI = Cell-Mediated Immunity; mL = Millilitre; HZ = Herpes Zoster; IMC = Intercurrent Medical 
Conditions; SAE = Serious Adverse Event; GSK = GlaxoSmithKline. 
1 After Visit Month 0, monthly phone contacts between the subjects and the investigator and/or his delegate will be 
scheduled to collect information on safety, on the occurrence of HZ, and to follow-up ongoing HZ cases (see 
Section 6.3.1.1). Monthly contacts will occur after Visit Month 0 until the subject’s last visit, except at months that 
coincide with the subject’s scheduled visits. 
2 The study procedures applicable for the Visit Year 1 to Visit Year 6 are identical (except Visit Year 6 is the Study 
Conclusion). 
3 Refer to Section 6.5.11. 
4 Subjects/ subject’s caregiver will be instructed to contact their study site immediately if he/she develops any 
symptoms suggestive of HZ and/or, if he/she manifests any symptoms he/she perceives as serious. 
5 E-sign off at year 2 and year 4 for the year 2 and year 4 analyses. 
 
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Table 6 
List of study procedures (for the 1-Additional Dose, Revaccination and Control groups) 
Epoch 
LONG-TERM FOLLOW-UP 
Type of contact 
Visit MONTH 0 Visit Month 
1 
Visit Month 
2† 
Visit Month 
3‡ 
Monthly 
contacts a 
Visit  
YEAR 1, 2, 3, 4, 5 b 
Study conclusion 
Visit c 
Year 6 b 
Timepoints  
Day 0/ 
Month 0 
Month 1 
Month 2 † 
Month 3 ‡ 
 
Month  
12, 24, 36, 48, 60 
Month  
72 
Sampling timepoints 
Pre-Vacc 
Post-Vacc 1 
 
Post-Vacc 2 
 
Post-Vacc 2 
Post-Vacc 2 
Informed consent 
● 
 
 
 
 
 
 
Check inclusion criteria 
● 
 
 
 
 
 
 
Check exclusion criteria 
● 
 
 
 
 
 
 
Medical history including HZ history (see Section 6.5.3) 
● 
 
 
 
 
 
 
Physical examination (see Section 6.5.4) 
O 
 
 
 
 
 
 
Pregnancy test if applicable d (see Section 6.5.5) 
● 
 
● 
 
 
 
 
Check contraindications (see Section 6.5.6) 
O 
 
O 
 
 
 
 
Training on self-reporting by subjects e 
O 
O 
O 
O 
 
O 
 
Randomisation 
O 
 
 
 
 
 
 
Pre-vaccination body temperature f 
● 
 
● 
 
 
 
 
Blood sampling (approximately 5 mL) for HI Ab determination 
(Table 4 and Section 6.5.8.1) 
● 
● 
 
● 
 
● 
● 
Blood sampling (approximately 20 mL) for CMI responses (Table 4 
and Section 6.5.8.1) 
● 
● 
 
● 
 
● 
● 
Recording of treatment number 
● 
 
● 
 
 
 
 
Vaccination f 
● 
 
● 
 
 
 
 
Dispensing of HZ-specific diary cards to all subjects 
O 
 
 
 
 
 
 
Reporting of medically attended visits until 6 months after Visit 
Month 0 or last HZ/su vaccination (see Section 9.1.5 and Table 26) 
g 
● 
● 
● 
● 
● 
 
 
Reporting of pIMDs according to guidelines in Section 9.1.6.1 (see 
Table 26) h 
● 
● 
● 
● 
● 
● 
 
Reporting of pIMD related to investigational vaccine 
● 
● 
● 
● 
● 
● 
● 
Reporting of pregnancy f (see Table 26) 
● 
● 
● 
● 
● 
● 
● 
Recording of IMCs (see Section 7.7) 
● 
● 
● 
● 
● 
● 
● 
Reporting of all SAEs (Table 26) h 
● 
● 
● 
● 
● 
● 
 
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Epoch 
LONG-TERM FOLLOW-UP 
Type of contact 
Visit MONTH 0 Visit Month 
1 
Visit Month 
2† 
Visit Month 
3‡ 
Monthly 
contacts a 
Visit  
YEAR 1, 2, 3, 4, 5 b 
Study conclusion 
Visit c 
Year 6 b 
Timepoints  
Day 0/ 
Month 0 
Month 1 
Month 2 † 
Month 3 ‡ 
 
Month  
12, 24, 36, 48, 60 
Month  
72 
Sampling timepoints 
Pre-Vacc 
Post-Vacc 1 
 
Post-Vacc 2 
 
Post-Vacc 2 
Post-Vacc 2 
Reporting of SAEs related to investigational vaccine (Table 26) 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to study participation or to concurrent 
GSK medication/vaccine (Table 26) 
● 
● 
● 
● 
● 
● 
● 
Follow-up of HZ (see Section 4 and Table 26) 
● 
● 
● 
● 
● 
● 
● 
Recording of concomitant medication/vaccination by study 
staff/investigator (Section 7.6.2) 
● 
● 
● 
● 
● 
● 
● 
Dispensing of 7-day diary cards for solicited AEs to the 7-day diary 
card and 30-day diary cards for unsolicited AEs and concomitant 
medication/vaccination to all vaccinated subjects f  
O 
 
O 
 
 
 
 
Daily post-vaccination recording by subjects of solicited symptoms 
(Days 0 - 6 after each vaccination) on the 7-day diary card by all 
vaccinated subjects f (see Table 26) 
O 
 
O 
 
 
 
 
Daily post-vaccination recording of unsolicited symptoms (Days 0 - 
29 after each vaccination), and concomitant medication/ 
vaccination (Days 0 - 29 after each vaccination) on the 30-day 
diary card by all vaccinated subjects f (see Table 26) 
O 
 
O 
 
 
 
 
Returning by subjects of 7-day diary cards for solicited symptoms 
and 30-day diary cards for unsolicited AEs and concomitant 
medication and vaccination f 
 
O 
 
O 
 
 
 
Transcription of 7-day diary cards for solicited symptoms and 30-
day diary cards for unsolicited AEs and concomitant medication 
and vaccination by study staff/investigator f 
 
● 
 
● 
 
 
 
E-signature at Month 3 (for the Month 3 analysis) 
 
 
 
● 
 
 
 
E-signature at year 2 and year 4 (for the year 2 and year 4 
analyses for the Control group, only) 
 
 
 
 
 
● i 
 
Study conclusion (e signature) 
 
 
 
 
 
 
● 
● 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. 
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Pre-Vacc = Pre Vaccination; Post Vacc 1 = Post Vaccination 1; Post Vacc 2 = Post Vaccination 2; Ab = Antibody; HI = Humoral Immunogenicity; CMI = Cell-Mediated Immunity; mL = 
Millilitre; pIMDs = potential Immune-Mediated Diseases; IMC = Intercurrent Medical Conditions; SAE = Serious Adverse Event; GSK = GlaxoSmithKline; HZ = Herpes Zoster. 
† Visit Month 2 for Vacc 2 is only for the Revaccination group.  
‡ Visit Month 3 for blood sample is only for the Revaccination and Control groups. 
a After Visit Month 3 (After Visit Month 1 for the 1-Additional Dose group), monthly phone contacts between the subjects and the investigator and/or his delegate will be scheduled for 
the subject to respond to a standard set of questions, in a language that is understandable to the subject, to collect information on safety, on the occurrence of HZ, and to follow-
up ongoing HZ cases (see Section 6.3.1.1). The Control group will also have a phone contact at Visit Month 2. Monthly contacts will occur after Visit Month 3 until the subject’s last 
visit, except at months that coincide with the subject’s scheduled visits. 
b The study procedures applicable for the Visit Year 1 to Visit Year 6 are identical (except Visit Year 6 is the Study Conclusion). 
c Refer to Section 6.5.11. 
d Only applicable for females of childbearing potential. 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 (see Section 6.5.5). 
e Subjects/ subject’s caregiver will be instructed to contact their study site immediately if he/she develops any symptoms suggestive of HZ and/or, if he/she manifests any symptoms 
he/she perceives as serious. 
f A study procedure only for the two groups vaccinated with 1 or 2 additional doses of HZ/su vaccine (1-Additional Dose and Revaccination).  
g The reporting of medically attended visits will be from Visit Month 0 until 6 months (for the Control and 1-Additional Dose groups) and from Visit Month 0 until 6 months after last 
HZ/su vaccination (for the Revaccination group) (see Section 9.1.5 and Table 26). 
h The reporting of all SAEs and pIMDs will be from Visit Month 0 until 12 months (for Control and 1-Additional Dose groups) and from Visit Month 0 until 12 months after last HZ/su 
vaccination (for the Revaccination group) (see Table 26). 
i E-sign off at year 2 and year 4 for the year 2 and year 4 analyses (for the Control group, only). 
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Table 7 
Study procedures to be performed during the follow-up period for each suspected HZ case 
 
VISITS/CONTACTS IN CASE OF HZ 
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-0 
Day HZ-7 
Day HZ-14 
Day HZ-21 
Day HZ-28 
Day HZ-56 
Day HZ-91† 
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 4.5.3 * 
● 
 
 
 
 
 
 
Record relevant information regarding HZ in eCRF by 
study staff/investigator 
● 
● 
● 
● 
● 
● 
● 
Record concomitant medication/vaccination according to 
guidelines in Section 7.6 
● 
● 
● 
● 
● 
● 
● 
Record IMCs according to guidelines in Section 7.7 
● 
● 
● 
● 
● 
● 
● 
Record any medical attention received for HZ or any HZ-
related complication 
● 
● 
● 
● 
● 
● 
● 
Dispense ZBPI questionnaires to subjects ‡ 
O 
 
 
 
 
 
 
Completion of ZBPI questionnaires by the subjects until 
pain ceases or LSLV/C (ZBPI pain data will be collected 
until at least Day HZ-91) † 
O 
O 
O 
O 
O 
O 
O 
Return completed ZBPI questionnaires to study 
staff/investigator according to instructions provided by the 
investigator/study staff to subjects 
 
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; LSLV/C = 
Last Subject Last Visit/Contact. 
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Note: If HZ-associated pain ceases (defined as a 28-day [or 4-week] pain free period) and the HZ rash resolves, subsequent HZ follow-up visits or contacts will be cancelled. 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-0 defined as the first visit of the assigned episode, prior to the pain free period. 
 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 at Visit HZ-1 (i.e., <3 lesions present or only papules present), the 
investigator has the option of collecting three additional samples prior to or at Visit HZ-2 (preferably within 7 days). When the subject returns to repeat sample collection, if 
possible, 3 samples from separate lesions should be collected. 
‡ The study staff/investigator will dispense additional questionnaires and provide instructions for the subject to return the completed questionnaires to the study site. The subjects will 
be given a new supply of questionnaires as necessary. 
† Subjects with suspected HZ will be asked to complete the ZBPI questionnaire at Day HZ-0 (Visit HZ-1) to rate HZ-associated pain within the last 24 hours (If the time between the HZ 
onset and clinical evaluation at Visit HZ-1 is greater than 24 hours, the subject will be asked to complete a second ZBPI also for the elapsed time between the HZ onset and 24 
hours before Visit HZ-1); daily from Day HZ- 1 to Day HZ-28, and weekly from Day HZ-29 onwards until a 4-week pain-free period is documented. 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 ZBPI questionnaires will resume 
based upon the weekly schedule established at the start of the assigned episode. For all subjects with ongoing HZ-associated pain at the time of the end of study, ZBPI data will 
be collected until a 4-week pain-free period is documented OR until at least Day HZ-91 (See Section 4.5.2.3). 
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Time intervals between the yearly study visits/contacts related to study procedures 
performed on subjects are presented in Table 8 for the LTFU group, in Table 9 for the 1-
Additional Dose and Control groups and in Table 10 for the Revaccination group. In 
addition; between Visit Month 0 and the last yearly visit, monthly contacts between the 
subjects and the investigator and/or his delegate will be scheduled. These monthly 
contacts will not take place if coinciding with the yearly study visits. Intervals of 25 – 45 
days are recommended between the monthly contacts. 
Table 8 
Intervals between study visits for the LTFU group 
Interval between Visits/ Contacts 
Optimal length of interval  
(in months) 1 
Allowed interval  
(range in days) 2 
Visit Month 0 → Visit/ Contact Year 1 
12 months 
335 – 395 
Visit Month 0 → Visit/ Contact Year 2 
24 months 
700 – 760 
Visit Month 0 → Visit/ Contact Year 3 
36 months 
1065 – 1125 
Visit Month 0 → Visit/ Contact Year 4 
48 months 
1430 – 1490 
Visit Month 0 → Visit/ Contact Year 5 
60 months 
1795 – 1855 
Visit Month 0 → Visit/ Contact Year 6 3 
72 months 
2160 – 2220 
1 Whenever possible the investigator should arrange study visits/contacts within this interval. 
2 Subjects will not be eliminated from the ATP cohort for analysis if they make the study visit outside this interval. 
3 For subjects in HZ follow-up at the time of their last yearly visit, their study conclusion will coincide with their last Day 
HZ-91 visit (see Table 11). 
Table 9 
Intervals between study visits for the 1-Additional Dose and Control 
groups 
Interval between Visits 
Optimal length of interval  
(in months) 1 
Allowed interval  
(range in days) 
Visit Month 0 → Visit Month 1 
1 month 
28 – 48 2 
Visit Month 0 → Visit Month 3 * 
3 months 
75 – 105 3 
Visit Month 0 → Visit Year 1 
12 months 
335 – 395 3 
Visit Month 0 → Visit Year 2 
24 months 
700 – 760 3 
Visit Month 0 → Visit Year 3 
36 months 
1065 – 1125 3 
Visit Month 0 → Visit Year 4 
48 months 
1430 – 1490 3 
Visit Month 0 → Visit Year 5 
60 months 
1795 – 1855 3 
Visit Month 0 → Visit Year 6 4 
72 months 
2160 – 2220 3 
* Interval ONLY for the Control group. 
1 Whenever possible the investigator should arrange study visits within this interval. 
2 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. 
3 Subjects may not be eliminated from the ATP cohort for analysis if they make the study visit outside this interval. 
4 For subjects in HZ follow-up at the time of their last yearly visit, their Study conclusion will coincide with their last Day 
HZ-91 visit (see Table 11). 
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Table 10 
Intervals between study visits for the Revaccination group 
Interval between Visits 
Optimal length of interval  
(in months) 1 
Allowed interval  
(range in days) 
Visit Month 0 → Visit Month 1 
1 month 
28 – 48 3 
Visit Month 0 → Visit Month 2 
2 months 
49 – 83 2 
Visit Month 2 → Visit Month 3 
1 month 
28 – 48 2 
Visit Month 2 → Visit Year 1 
12 months 
335 – 395 3 
Visit Month 2 → Visit Year 2 
24 months 
700 – 760 3 
Visit Month 2 → Visit Year 3 
36 months 
1065 – 1125 3 
Visit Month 2 → Visit Year 4 
48 months 
1430 – 1490 3 
Visit Month 2 → Visit Year 5 
60 months 
1795 – 1855 3 
Visit Month 2 → Visit Year 6 4 
72 months 
2160 – 2220 3 
1 Whenever possible the investigator should arrange study visits within this interval. 
2 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. 
3 Subjects may not be eliminated from the ATP cohort for analysis if they make the study visit outside this interval. 
4 For subjects in HZ follow-up at the time of their last yearly visit, their Study conclusion will coincide with their last Day 
HZ-91 visit (see Table 11). 
Time intervals between study visits/contacts to be performed for follow-up of HZ are 
presented in Table 11. 
Table 11 
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-0) → Visit HZ-2 (Day HZ-7) 
7 days 
Day HZ-7 (+/- 3 days)* 
Visit HZ-2 (Day HZ-7) → Contact HZ-3 (Day HZ-14) 
7 days 
Day HZ-14 (+/- 3 days)* 
Contact HZ-3 (Day HZ-14) → Contact HZ-4 (Day HZ-21) 
7 days 
Day HZ-21 (+/- 3 days)* 
Contact HZ-4 (Day HZ-21) → Visit HZ-5 (Day HZ-28)  
7 days 
Day HZ-28 (+/- 3 days)* 
Visit HZ-5 (Day HZ-28) → Contact HZ-6 (Day HZ-56) 
28 days 
Day HZ-56 (+/- 7 days)* 
Visit HZ-1 (Day HZ-0) → Visit HZ-7 (Day HZ-91) 
91 days 
Day HZ-91 (+ 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 (i.e., 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). Follow-up of HZ-associated pain 
persisting beyond Visit HZ-7 (Day HZ-91) or other complications will be done at monthly contacts between the 
subject and the investigator and/or investigator’s delegate.  
* If contacted early in the window, then remaining days in the interval will need to be captured with the next contact. 
Refer to Section 6.6 for study procedures to be considered during special circumstances 
(Amended 11 May 2020). 
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6.5. 
Detailed description of study procedures 
6.5.1. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 6.1 for the requirements on how to obtain 
informed consent and assent, as appropriate. 
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. 
For subjects with suspected HZ at Visit HZ-1 (i.e., either ongoing cases or subjects 
developing a new case), an informed consent addendum or update may be required to 
inform these subjects of the change in the follow-up period for pain assessment 
questionnaire. 
6.5.2. 
Check inclusion and exclusion criteria 
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment. 
6.5.3. 
Medical history 
Obtain the subject’s clinically relevant 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 visit 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 [CVA]), any pIMDs (see Table 24). 
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 
treated with surgery). A predefined list of categories and diseases will be available in the 
eCRF. 
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In addition, history of prior HZ episode must be recorded. 
Any available information for the diagnosis of HZ episode (clinical diagnosis, PCR, 
laboratory methods, etc.) during the interval between the end of the ZOSTER-006/022 
studies and beginning of the ZOSTER-049 study is to be collected. 
6.5.4. 
Physical examination 
A history-directed physical examination according to local practice should be performed 
to ensure the subject is in good physical condition. 
6.5.5. 
Pregnancy test 
Female subjects of childbearing potential are to have a urine or serum pregnancy test 
before randomisation (in the 1-Additional Dose, Revaccination and Control groups) and 
prior to study vaccine second dose administration (in the Revaccination group, only). The 
study vaccines may only be administered if the pregnancy test is negative. Note: The 
urine 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. 
6.5.6. 
Check contraindications, warnings and precautions to 
vaccination 
Contraindications to vaccination must be checked before randomisation (in the 1-
Additional Dose, Revaccination and Control groups, only) and prior to study vaccine 
second dose administration (in the Revaccination group, only). Refer to Section 7.5 for 
more details. 
6.5.7. 
Training on self-reporting by subjects 
Subjects/ subject’s caregiver will be instructed at Visit Month 0 (and will be reminded at 
yearly visit or phone contact) 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 in the 
groups 1-Additional Dose and Revaccination, only). 
• 
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. 
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6.5.7.1. 
Reminder for monthly follow-up contacts/yearly follow-up visits 
The subject/ subject’s caregiver will be reminded that, after Visit Month 0, monthly 
contacts between the subjects and the investigator and/or his delegate will take place 
(except at months that coincide with the subject’s scheduled visits [see Section 6.3.1.1]) 
in order to collect all relevant information on occurrence or follow up of a suspected 
episode of HZ (Section 4.5), SAEs (Section 9.3), IMCs (Section 7.7) or the use of 
concomitant medications and/or vaccinations (Section 7.6)], and that information will be 
recorded in the appropriate section of the subject’s eCRF. 
6.5.8. 
Sampling 
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. 
6.5.8.1. 
Blood sampling for immune response assessments 
As specified in (Table 4, Table 5, Table 15 and Table 19), blood samples will be taken 
during study visits from subsets of subjects as follows: 
• 
All subjects (N ≤ 14,448) entering the study will have a HI blood sample 
(approximately 5 mL) at Visit Month 0. 
For subjects in the LTFU group, who do not belong to any subset, these samples will 
be stored and tested for HI only if the subject develops HZ during the ZOSTER-049 
study or if there are other reasons requiring the HI testing of these samples. 
• 
LTFU Group (HI subset): Subjects (N ≤ 1,729) who were in the immunogenicity 
subset during studies ZOSTER-006/022 and continue participation in this study. 
Blood samples (approximately 5 mL) will be collected and tested from Visit Month 0 
to Visit Year 6, on a yearly basis, to assess HI responses. 
• 
LTFU Group (CMI subset): Subjects (N ≤ 234) who were in the CMI subset 
during study ZOSTER-006 and continue participation in this study. Blood samples 
(approximately 20 mL) will be collected and tested from Visit Month 0 to Visit 
Year 6 on a yearly basis to assess CMI responses. 
• 
HZ subset: Subjects (N to be determined) who developed confirmed HZ during 
ZOSTER-006 or ZOSTER-022, or who develop HZ during the interval between the 
end of the ZOSTER-006/022 and the beginning of ZOSTER-049, or who develop 
suspected HZ during ZOSTER-049 will be part of the HZ subset. Blood sampling for 
subjects in the HZ subset is described below. 
Subjects who develop HZ at any time after enrolment in ZOSTER-006 or ZOSTER-
022 and who are already part of the HI subset in ZOSTER-006 or ZOSTER-022 will 
provide blood samples to assess HI responses (approximately 5 mL) from Visit 
Month 0 to Visit Year 6 irrespective of when the HZ episode occurs. If these subjects 
are part of the ZOSTER-006 CMI subset, then they will also continue to provide 
blood to assess CMI responses (approximately 20 mL). 
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Subjects who develop HZ at any time after enrolment in ZOSTER-006 or ZOSTER-
022 and who were NOT part of the HI or CMI subsets in these studies, will provide 
blood samples to assess HI responses (approximately 5 mL) beginning at the annual 
visit in the ZOSTER-049 study subsequent to the occurrence of the HZ episode. The 
blood sample taken upon enrolment at Visit Month 0 will be tested and included in 
the analyses for these subjects. 
• 
1-Additional Dose Group: Subjects (N = 60) to be administered HZ/su vaccine on a 
1-dose schedule at Visit Month 0. Blood samples (approximately 5 and 20 mL) will 
be collected at Visit Month 0, Visit Month 1, and from Visit Year 1 to Visit Year 6 
on a yearly basis to assess HI and CMI responses. 
• 
Revaccination Group: Subjects (N = 60) to be administered HZ/su vaccine on a 2-
dose schedule at Visit Month 0 and Visit Month 2. Blood samples (approximately 5 
and 20 mL) will be collected at Visit Month 0, Visit Month 1, Visit Month 3 and 
from Visit Year 1 to Visit Year 6 on a yearly basis to assess HI and CMI responses. 
• 
Control Group: Subjects (N = 120) in the non-vaccinated control group. Blood 
samples (approximately 5 and 20 mL) will be collected at Visit Month 0, Visit 
Month 1, Visit Month 3 and from Visit Year 1 to Visit Year 6 on a yearly basis to 
assess HI and CMI responses. 
After centrifugation, serum samples for HI assessment should be kept at –20°C/ –4°F or  
–70/80°C until shipment. 
The blood samples for CMI assessment should be stored at the investigator’s site at room 
temperature and they must not be centrifuged. Samples will be shipped at room 
temperature (20 to 25°C/68 to 77°F) to the designated laboratory for cell separation to be 
performed within 24 hours. 
Refer to the Module on Biospecimen Management in the SPM for general handling of 
blood samples. 
6.5.8.2. 
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 4.5.2.4.1, 4.5.3 and 6.7.4.2). Samples for HZ 
cases assessment should be kept at –20°C/ –4°F or –70/80°C until shipment. 
Refer to the SPM for more details on sample storage conditions. 
6.5.9. 
Check and record concomitant medication/vaccination and IMCs 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.6. 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 7.7. 
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6.5.10. 
Recording of AEs and SAEs 
• 
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 subject/ subject’s caregiver will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
• 
For the two groups (1-Additional Dose and Revaccination, only), at each vaccination 
visit, diary cards will be provided to the subject/ subject’s caregiver (see Section 
6.3.1.2). The subjects/ subject’s caregiver will be trained on how to complete the 
diary cards. The subject/ subject’s caregiver will record any solicited AEs (from Day 
0 to Day 6 after each vaccination) on the 7-day diary cards and will record any 
unsolicited AEs (from Day 0 to Day 29 after each vaccination) and any concomitant 
medication and vaccination taken from Day 0 to Day 29 after each vaccination on 
the 30-day diary cards (see Table 6 and Table 26). 
• 
The subject/ subject’s caregiver will be instructed to return the completed diary cards 
to the investigator at the next study visit. The study staff/investigator will collect and 
verify completed diary cards during discussion with the subject/ subject’s caregiver 
on Visit Month 1 (1-Additional Dose and Revaccination groups) and Visit Month 3 
(Revaccination group, only). 
• 
Any unreturned diary cards will be sought from the subject/ subject’s caregiver 
through telephone call(s) or any other convenient procedure. The investigator will 
transcribe the collected information into the eCRF in English. 
6.5.11. 
Study conclusion 
Study conclusion takes place at the last yearly visit/ contact (i.e., the study visit/ contact 
following completion of approximately 6 years follow-up from Visit Month 0) for 
subjects not in HZ follow-up at the time of the last yearly visit. The study conclusion 
visit/ contact for subjects in HZ follow-up at the time of the last yearly visit will occur 
after until a 4-week pain-free period is documented OR after 90 days of HZ follow-up 
has been completed and will be combined with the visit/ contact at Day HZ-91. The Day 
HZ-91 visit/ contact will preferably be a visit, but a contact is an option. 
At the study conclusion visit/contact, the investigator will: 
• 
review data collected to ensure accuracy and completeness, 
• 
complete the Study Conclusion screen in the eCRF. 
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6.6. 
Study procedures during special circumstances (Amended 
11 May 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 special circumstances to the study conduct will be documented in the 
clinical study report.  
• 
Yearly site visits/contact may be made by other means of virtual contact or home 
visit, if appropriate. 
• 
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 3, 28 April 2020) or other relevant authority guidance 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 8 to Table 10), then the allowed 
interval may be extended by 30 days as outlined from Table 12 to Table 14. 
− 
The visit can be replaced by a phone contact or other means of virtual contact 
and will be performed in the interval predefined in the protocol. The blood 
sampling can be performed according to the interval allowed during special 
circumstances as shown from Table 12 to Table 14. 
Table 12 
Intervals for blood sampling for the LTFU group during special 
circumstances (Amended 11 May 2020) 
Interval for blood sampling 
Optimal length of 
interval  
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval 
during special 
circumstances 
(range in days) 
Visit Month 0 → Blood sampling Year 1 
12 months 
335 – 395 
335 – 425 
Visit Month 0 → Blood sampling Year 2 
24 months 
700 – 760 
700 – 790 
Visit Month 0 → Blood sampling Year 3 
36 months 
1065 – 1125 
1065 – 1155 
Visit Month 0 → Blood sampling Year 4 
48 months 
1430 – 1490 
1430 – 1520 
Visit Month 0 → Blood sampling Year 5 
60 months 
1795 – 1855 
1795 – 1885 
Visit Month 0 → Blood sampling Year 6 
72 months 
2160 – 2220 
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling as close to the optimal window as possible.  
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Table 13 
Intervals for blood sampling for the 1-Additional Dose and Control 
groups during special circumstances (Amended 11 May 2020) 
Interval for blood sampling 
Optimal length 
of interval  
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval during 
special circumstances 
(range in days) 
Visit Month 0 → Blood sampling Year 1 
12 months 
335 – 395 
335 – 425  
Visit Month 0 → Blood sampling Year 2 
24 months 
700 – 760 
700 – 790  
Visit Month 0 → Blood sampling Year 3 
36 months 
1065 – 1125 
1065 – 1155 
Visit Month 0 → Blood sampling Year 4 
48 months 
1430 – 1490 
1430 – 1520 
Visit Month 0 → Blood sampling Year 5 
60 months 
1795 – 1855 
1795 – 1885 
Visit Month 0 → Blood sampling Year 6 
72 months 
2160 – 2220 
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling as close to the optimal window as possible. 
Table 14 
Intervals for blood sampling for the Revaccination group during 
special circumstances (Amended 11 May 2020) 
Interval for blood sampling 
Optimal length 
of interval  
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval during 
special circumstances 
(range in days) 
Visit Month 2 → Blood sampling Year 1 
12 months 
335 – 395  
335 – 425  
Visit Month 2 → Blood sampling Year 2 
24 months 
700 – 760  
700 – 790  
Visit Month 2 → Blood sampling Year 3 
36 months 
1065 – 1125  
1065 – 1155  
Visit Month 2 → Blood sampling Year 4 
48 months 
1430 – 1490  
1430 – 1520 
Visit Month 2 → Blood sampling Year 5 
60 months 
1795 – 1855  
1795 – 1885 
Visit Month 2 → Blood sampling Year 6 
72 months 
2160 – 2220  
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling 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 7 and Table 11. 
− 
If the subject is not able to immediately 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, HZ related treatments 
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 suspected HZ lesions 
themselves. The photographs will be transferred to the investigator via email 
or other modes of virtual contact when possible. 
− 
If feasible, the subject may be asked to collect rash lesion sample at home. 
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− 
HZ-specific diary cards may be transmitted from and to the site by electronic 
means and/or conventional mail.  
− 
ZBPI questionnaire may be transmitted from and to the site by electronic 
means and/or conventional mail. If this is not feasible, the study 
staff/investigator can conduct ZBPI questionnaire by telephone contact. Study 
staff/investigator will read the questions (verbatim) and transcribe the 
subject’s responses on the questionnaires. 
Impact on the modified TVC for efficacy and ATP for efficacy and immunogenicity 
(humoral and CMI) will be determined on a case by case basis. 
6.7. 
Biological sample handling and analysis 
Please refer to the SPM 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. 
Any sample testing will be done in line with the consent of the individual subject. 
Refer also to the a 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). 
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. 
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6.7.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.5 for the definition of 
cohorts to be analysed). 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. 
6.7.2. 
Biological samples 
Table 15 
Biological samples 
Sample type 
Quantity 
(approximate volume) 
Unit Timepoint(s) 1 
Subset Name 2 
Blood  
(Humoral immunology) 
5 
mL Visit Month 0 
All Subjects 
Blood  
(Humoral immunology) 
5 
mL 
Visit Month 0,  
Visit Years  
1, 2, 3, 4, 5 and 6 
LTFU Group HI subset 
Blood  
(Humoral immunology) 
5 
mL 
Visit Month 0,  
Visit Years  
1, 2, 3, 4, 5 and 6 
HZ subset 
Blood  
(Humoral immunology) 
5 
mL 
Visit Month 0,  
Visit Month 1,  
Visit Month 3 3  
and Visit Years  
1, 2, 3, 4, 5 and 6 
1-Additional Dose Group, 
Revaccination Group; 
Control Group 
Blood  
(Cell-mediated 
immunology) 
20 
mL 
Visit Month 0,  
and Visit Years  
1, 2, 3, 4, 5 and 6 
LTFU Group CMI subset 
Blood  
(Cell-mediated 
immunology) 
20 
mL 
Visit Month 0,  
Visit Month 1,  
Visit Month 3 3  
and Visit Years  
1, 2, 3, 4, 5 and 6 
1-Additional Dose Group  
Revaccination Group  
Control Group 
Specimens of HZ 
lesions 
3 replicate samples, taken on 
the same day, of the highest 
priority lesion type available (1) 
vesicle fluid; 2) crust; 3) crust 
swab; 4) papule swab) 4 
NA 
Scheduled in case 
of suspected HZ for 
diagnosis 
Subjects clinically diagnosed as 
having a suspected case of HZ 
mL = Millilitre, LTFU = Long-Term Follow-Up; HI = Humoral Immunogenicity; HZ = Herpes Zoster; CMI = Cell-Mediated 
Immunity; NA = Not Applicable. 
1 Refer to Section 6.5.8.1 for the blood sampling timepoints. 
2 Refer to Table 4 and Table 19 for description of the subsets and Section 6.1.2 for the allocation of subjects to 
subsets. 
3 Only the Revaccination and Control groups. 
4 If during clinical evaluation at Visit HZ-1, the investigator determines that adequate rash samples are not present at 
Visit HZ-1 (i.e., <3 lesions present or only papules present), the investigator has the option of collecting three 
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additional samples prior to or at Visit HZ-2 (preferably within 7 days). See Table 7 and the SPM for further details 
on sample collection. 
6.7.3. 
Laboratory assays 
Please refer to 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. 
Laboratory assays, which will be used in this study, are summarised in Table 16 
(Humoral Immunity), Table 17 (Cell-Mediated Immunity) and Table 18 (Molecular 
Biology), respectively. 
Table 16 
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; IgG = Immunoglobulin class G; ELISA = Enzyme-linked Immunosorbent Assay; NA = Not applicable; 
mIU = milli-international unit. 
* see Table 31 in Appendix B. 
Table 17 
Cell-Mediated Immunity (CMI)  
System 
Component 
Challenge 
Method 
Unit 
Cut-off 
Laboratory 
PBMC 
CD4.polypositives  
CD40L+IL-2+TNFα+IFNγ* 
gE 
ICS 
Events 
N/A 
CEVAC + 
PBMC 
GSK 
Biologicals* 
PBMC = Peripheral Blood Mononuclear Cells; IL-2 = Interleukin-2; TNF = Tumor Necrosis Factor; IFN = Interferon; gE 
= Glycoprotein E; ICS = Intracellular cytokine staining; 
 N/A = Not 
Applicable. 
* CD4.polypositives CD40L+IL-2+TNF-α + IFN-γ = CD4+ T-cells expressing at least 2 activation markers (from among 
IFN-γ, IL-2, TNF-α and CD40L). 
+ CEVAC refers to the Centre for Vaccinology, (see Table 32 in Appendix B). 
* see Table 31 in Appendix B. 
Table 18 
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* 
HZ = Herpes Zoster; DNA = Deoxyribonucleic acid; PCR = Polymerase Chain Reaction. 
* see Table 31 in Appendix B. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
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6.7.4. 
Biological samples evaluation 
6.7.4.1. 
Immunological read-outs 
The plan for immunogenicity testing on samples obtained is shown in Table 19. 
Table 19 
Immunological read-outs 
Blood sampling timepoint 1 
Subset Name 2 
Approximate  
No. of Subjects Component 
Visit No.3 
Month Timing 
Visit Month 0 
0 
Post-Primary All Subjects 
≤ 14448 4 
Ab gE ELISA 
LTFU Group CMI subset 
≤ 234 
ICS gE 
Pre-Vacc 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS & 
 
Visit Month 1 
1 
Post-Vacc 1 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS & 
 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Visit Month 3 
3 
Post–Vacc 2 
Revaccination and Control Groups 
180 
gE ICS & 
 
Revaccination and Control Groups 
180 
Ab gE ELISA 
Visit Year 1, 
Visit Year 2, 
Visit Year 3, 
Visit Year 4, 
Visit Year 5, 
Visit Year 6 
12, 
24, 
36, 
48, 
60, 
72 
Post-Primary 
LTFU Group CMI subset 
≤ 234 
gE ICS g 
LTFU Group HI subset 
≤ 1729 5 
Ab gE ELISA 
HZ subset 
TBD 
Ab gE ELISA 
Post-Vacc 1/2 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS & 
 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Post-Primary = Post-primary vaccination during ZOSTER-006/022; Pre-Vacc = Pre Vaccination; Post-Vacc 1 = Post 
Vaccination 1 (post dose 1); Post-Vacc 2 = Post-Vaccination 2 (post dose 2); LTFU = Long-Term Follow-Up; CMI 
= Cell-Mediated Immunity; HI = Humoral Immunogenicity; HZ = Herpes Zoster; TBD = To Be Determined; ICS = 
Intracellular cytokine staining; gE = Glycoprotein E; Ab = Antibody; ELISA = Enzyme-linked Immunosorbent 
Assay; 
 
1 Refer to Section 6.5.8.1 for the blood sampling timepoints. 
2 Refer to Table 4 and Table 15 for description of the subsets. 
3 Refer to Table 8, Table 9 and Table 10 for the intervals between study visits for the LTFU group, the 1-Additional 
Dose and Control groups and for the Revaccination group, respectively. 
4 All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 0. For 
subjects in the LTFU group, who do not belong to any subset, these samples will be stored and tested for HI only 
if the subject develops HZ during the ZOSTER-049 study or if there are other reasons requiring the HI testing of 
these samples (see Section 6.5.8.1). 
5 Subjects to be included in the LTFU Group HI subset are from the immunogenicity subset in studies ZOSTER-
006/022 [N = 1269 (ZOSTER-006) + 460 (ZOSTER-022) = 1729 subjects at a maximum]. 
6 
experiments will be performed on available PBMC following gE ICS analysis. 
Additional blood samples given at the pre-vaccination (Month 0) and 1 month post-dose 
2 (Month 3) timepoints in the ZOSTER-006/022 primary studies will be tested for the 
analysis of the humoral immune response from subjects in the 1-Additional Dose, 
Revaccination and Control groups and from subjects belonging to the HZ subset, if they 
were not tested previously. 
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Additional testing (e.g., VZV specific CMI measurements on available blood samples) 
may be performed if deemed appropriate by GSK Biologicals should any findings in the 
present study, or in other studies, indicate that further investigation of the 
immunogenicity of the vaccine is warranted. 
6.7.4.2. 
Test for laboratory diagnosis of HZ 
In case of a suspected HZ case diagnosis in any of the subjects, clinical specimens from 
HZ lesions will be collected to confirm the diagnosis of HZ by PCR (Table 18). Please 
refer to Appendix A for or a detailed description of the PCR. 
6.7.5. 
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. 
7. 
STUDY VACCINE AND ADMINISTRATION 
7.1. 
Description of study vaccine 
The study vaccine/product to be used has been developed and manufactured by GSK 
Biologicals. 
The Quality Control Standards and Requirements for the study vaccine are described in 
separate Quality Assurance documents (e.g., release protocols, certificate of analysis) and 
the required approvals have been obtained. 
The vaccine is labelled and packed according to applicable regulatory requirements. 
Table 20 
Study vaccine 
Treatment 
name 
Vaccine 
name 
Formulation 
Presentation 
Volume to be 
administered* 
Group 
Number 
of doses 
HZ/su 
VZV gE 
gE=50µg 
Lyophilized 
pellet in a 
monodose vial 
0.5 mL 
1-Additional Dose 
1 
AS01B 
MPL=50µg; 
QS21=50µg; 
Liposomes 
Liquid in a 
monodose vial 
Revaccination 
2 
*Refer to the SPM for the volume after reconstitution. 
HZ/su = Herpes Zoster subunit vaccine; VZV = Varicella Zoster Virus, gE = recombinant purified Glycoprotein E; μg = 
Microgram; mL = Millilitre; AS01B = Adjuvant System AS01B; MPL = 3-O-desacyl-4’-monophosphoryl lipid A; 
QS21 = Quillaja saponaria Molina, fraction 21 (purified saponin extract from the South American tree). 
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7.2. 
Storage and handling of study vaccine 
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 authorised study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature 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).
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 vaccine. 
7.3. 
Dosage and administration of study vaccine 
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 (between 2°C/36°F and 30°C/86°F). 
Vaccine will be administered as indicated in Table 21. 
The reconstituted vaccine (0.5 mL) should be administered by IM injection into the 
deltoid muscle of the non-dominant arm using a standard aseptic technique. 
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Table 21 
Dosage and administration 
Type of contact 
(and timepoint) 
Study group 
Volume to be 
administered 
Treatment 
name 
Route 1 
Site 
Side 2 
Visit Month 0 
(Month 0) 
1-Additional Dose 
0.5 mL 
HZ/su 
IM 
Deltoid 
Non-dominant 
Revaccination 
Visit Month 2 
(Month 2) 
Revaccination 
1 Intramuscular (IM) 
2 In rare situations when there is no other alternative, the injection may be given in the dominant arm. 
7.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5 % additional vaccine doses will be 
supplied to replace those that are unusable. 
Additional doses of the study vaccine will be supplied if necessary. 
7.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
HZ/su. 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 Dose 1. 
• 
Pregnancy (see Section 9.2.1). 
• 
An SAE judged to be vaccine-related by the investigator. 
• 
An episode of HZ between Visit Month 0, (Vaccination 1) and Visit Month 2 
(Vaccination 2). 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
resulting from disease (e.g., malignancy, HIV infection) or 
immunosuppressive/cytotoxic therapy (e.g., medications used during cancer 
chemotherapy, organ transplantation or to treat autoimmune disorders). However 
subjects who have received less than 15 consecutive days of immunosuppressants or 
other immune modifying drugs should not be contraindicated from receiving 
subsequent vaccinations. Also, for corticosteroids, prednisone < 20 mg/day, or 
equivalent, is allowed. Inhaled, topical and intra-articular corticosteroids are allowed. 
• 
Other events that constitute contraindications to administration of HZ/su vaccine. 
− 
Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, exposes the subject to unacceptable risk from 
subsequent vaccination. In such cases, the investigator should use his/her 
clinical judgement prior to administering the next dose of the vaccine. Refer to 
Section 9.1.6.1 for the definition of pIMDs. 
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The following events constitute contraindications to administration of HZ/su 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 6.4), or the subject may be withdrawn 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  37.5°C/99.5°F for oral, axillary or tympanic 
route, or  38.0°C/100.4°F for rectal route. The preferred route for recording 
temperature in this study will be oral. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
7.6. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit/ contact, the investigator should question the subject/ subject’s 
caregiver about any medications/products taken and vaccinations received by the subject. 
7.6.1. 
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 period starting 30 days (Days 0-29) following each dose/the 
dose of study vaccine. This also applies to concomitant medication administered 
prophylactically in anticipation of reaction to the vaccination and any medication 
intended to treat an AE (For the 1-Additional Dose and Revaccination groups 
ONLY). 
E.g., an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature  37.5°C/99.5°F for oral, axillary or tympanic route, or 
 38.0°C/100.4°F for rectal route]. 
• 
Any concomitant medications/products/vaccines listed in Section 7.6.2, respecting 
the detailed time window. 
• 
Any concomitant medications relevant to a SAE/pIMD to be reported as per protocol 
or administered 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. 
• 
Any concomitant medication/product administered for the treatment of HZ or any 
HZ-related complications (including pain) during the study period must be recorded 
in the eCRF and coded as ‘Treatment for HZ’. 
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7.6.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 11.5 for cohorts to be analysed. 
•
Use of any investigational or non-registered product (pharmaceutical product or
device) during the study period;
•
Administration of long-acting immune-modifying drugs (e.g., infliximab, rituximab)
at any time during the study period;
•
Chronic administration (defined as > 14 consecutive days in total) of
immunosuppressants or other immune-modifying drugs at any time during the study
period. For corticosteroids, this will mean prednisone ≥ 20 mg/day or equivalent. A
prednisone dose of < 20 mg/day is allowed. Inhaled, topical and intra-articular
corticosteroids are allowed;
•
Administration of immunoglobulins and/or any blood products during the study
period;
•
Administration of cytotoxic chemotherapy at any time during the study period
•
Prolonged use (> 14 consecutive days) of oral and/or parenteral antiviral agents that
are active against VZV (acyclovir, valacyclovir, famciclovir, etc.) during the study
period for an indication other than to treat suspected or confirmed HZ or an HZ-
related complication (topical use of these antiviral agents is allowed);
•
Receipt of a vaccine against VZV or HZ (including an investigational or non- 
registered vaccine other than the HZ/su vaccine administered in this study to groups
1-Additional Dose and Revaccination) during the entire study period;
•
Administration of a vaccine not foreseen by the study protocol within 30 days prior
to dose 2 of vaccine and/or within 30 days after any dose. However, licensed
nonreplicating 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 to 8 days prior to dose 2 and/or at least 14 days after any
dose of study vaccine (for the 1-Additional Dose and Revaccination groups, only);
In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a
pandemic) is organised by the public health authorities, outside the routine
immunisation program, the time period described above can be reduced if necessary
for that vaccine provided it is licensed and used according to its Summary of Product
Characteristics (SmPC) or Prescribing Information and according to the local
governmental recommendations and provided a written approval of the Sponsor is
obtained.
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7.7. 
Intercurrent medical conditions (IMCs) that may lead to 
elimination of a subject from ATP analyses 
At each study visit subsequent to study enrolment until the study end, 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 (see Table 25). 
An IMC is defined as a condition that has the capability of confounding the immune 
response to the study vaccine or its interpretation. Subjects may be eliminated from 
certain ATP cohorts for immunogenicity if, during the study, they incur an IMC. 
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. 
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 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 (i.e., lack of efficacy), abuse or misuse. 
Examples of an AE include: 
•
Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after investigational vaccine administration
even though they may have been present prior to the start of the study.
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• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with vaccine(s)/product(s) administration. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of subject’s previous therapeutic regimen). 
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 clinically relevant conditions or signs and/or symptoms present in a 
subject prior to the study entry. 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 any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
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d. Results in disability/incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
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 22): 
Table 22 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
9.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited (Table 23): 
Table 23 
Solicited general adverse events 
Fatigue 
Fever 
Gastrointestinal symptoms † 
Headache 
Myalgia 
Shivering 
†Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain. 
Note: Temperature (oral route preferred) will be recorded in the evening. Should 
additional temperature measurements be performed at other times of day, the highest 
temperature will be recorded in the eCRF. 
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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 his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
9.1.5. 
Medically attended visits 
The subjects in the 1-Additional Dose, Revaccination and Control groups only will be 
asked if they received medical attention defined as hospitalization, an emergency room 
visit or a visit to or from medical personnel (medical doctor) for any reason, other than 
routine health care visits. This information on medically attended visits will be collected 
from Visit Month 0 until 6 months (for the Control and 1-Additional Dose groups) and 
from Visit Month 0 until 6 months after last HZ/su vaccination (for the Revaccination 
group) and will be recorded in the eCRF (see Table 6 and Table 26). 
9.1.6. 
Adverse events of specific interest 
9.1.6.1. 
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 24. 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e., pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD. 
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Table 24 
List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including paralyses/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  
• 
Immune-mediated peripheral 
neuropathies and 
plexopathies, (including 
chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy 
and polyneuropathies 
associated with monoclonal 
gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), including 
diffuse systemic form and 
CREST syndrome 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and 
Still’s disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) 
and undifferentiated 
spondyloarthritis  
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localised Scleroderma 
(Morphoea) 
Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis.  
• 
Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, 
Kawasaki's disease, 
microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenia 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic anaemia 
• 
Autoimmune neutropenia  
• 
Autoimmune pancytopenia 
• 
Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune diseases 
(including autoimmune 
uveitis and autoimmune 
retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathy
Sarcoidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
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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 
(including 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. 
The period for reporting pIMDs for the 1-Additional Dose, Revaccination and Control 
groups only will be from Visit Month 0 until 12 months (for Control and 1-Additional 
Dose groups) and from Visit Month 0 until 12 months after last HZ/su vaccination (for 
the Revaccination group) (see Table 6 and Table 26). 
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 at the time of vaccination must 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), 
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− 
ectopic and molar pregnancy, 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
European Medicines Agency (EMA) Guideline on pregnancy exposure [EMA, 
2006]. It is recognised that national regulations might be different. 
• 
Any early neonatal death (i.e., death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect (as per [Centers for Disease Control 
Metropolitan Atlanta Congenital Defects Program (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 investigational 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. 
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 
The time period for collecting and recording SAEs will begin at the first study visit 
Month 0 and will end at the last study visit/ contact at the end of the study for each 
subject. See Section 9.4 for instructions on reporting of SAEs. 
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the first receipt of study vaccine until the subject 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 Month 0 up to the last study visit/ contact at the end of the 
study*. 
* If the AEs/SAEs leading to withdrawal from the study are not related to 
investigational vaccine, study participation or to GSK concomitant 
medication/vaccine, or if not due to HZ complications, only the name 
(diagnosis/description) of the event will be recorded in the eCRF. No other details 
about these type of AEs/SAEs will be recorded during the entire study (for the LTFU 
group), after 12 months from visit Month 0 (for the Control and 1-Additional Dose 
groups) and after 12 months from last HZ/su vaccination (for the Revaccination 
group). 
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In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e., 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
An overview of the protocol-required reporting periods for AEs/SAEs, IMCs and HZ 
complications for the LTFU group is given in Table 25. An overview of the protocol-
required reporting periods for AEs/SAEs, IMCs and HZ complications as well as 
medically attended events and pIMDs for the 1-Additional Dose, Revaccination and 
Control groups, and pregnancies for the 1-Additional Dose and Revaccination groups as 
applicable, is given in Table 26. 
Table 25 
Reporting periods for collecting safety information (for the LTFU 
group) 
Event a 
Visit 
Month 0 
Visit 
Year 1 - 5 
Study conclusion 
visit/ contact  
Year 6 
Timing of reporting 
Month 0 
Month 12 - 
60
Month 72 
Reporting of SAEs related to investigational vaccine, related to 
study participation or to GSK concomitant medication/vaccine 
 
 
 
 
 
 
 
 
 
IMCs (see Section 7.7) 
 
 
 
 
 
 
 
 
 
HZ complications (see Section 4.4) (including SAE information) b 
 
 
 
 
 
 
 
 
 
Related AEs/SAEs leading to withdrawal from the study (see 
Section 9.3.1) c 
 
 
 
 
 
 
 
 
 
AE = Adverse Event; SAE = Serious Adverse Event; GSK = GlaxoSmithKline; IMC = Intercurrent Medical Condition; 
HZ = Herpes Zoster. 
a The reporting period of all events starts from the time the subject consents to participate in the study. 
b A HZ complication related to a HZ episode which was initiated during the primary study or during the interval between 
the end of ZOSTER-006/022 and beginning of the ZOSTER-049 study is to be recorded in general medical history 
at the first Month 0 Visit of study ZOSTER-049. 
c If the AEs/SAEs are not related to investigational vaccine, study participation or to GSK concomitant 
medication/vaccine, or if not due to HZ complications, only  the name diagnosis/description) of the event will be 
recorded in the eCRF. No other details about AEs/SAEs will be recorded. 
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Table 26 
Reporting periods for collecting safety information (for the 1-Additional Dose, Revaccination and Control groups) 
Event 
Visit 
Month 0 
Dose 1 
 
 
 
Visit  
Month 2‡ 
Dose 2 
 
 
 
 
 
Visit/ contact 
Year 1 - 5 
Study 
conclusion visit/ 
contact  
Year 6 
Timing of reporting 
Month 0 
Day 6 post  
Dose 1 
Day 29 post 
Dose 1 
 
Month 2‡ Day 6 post 
 Dose 2‡ 
Day 29 post 
Dose 2‡ 
 
Month 6  
Month 12 - 60 Month 72 
Reporting of solicited AEs ¥ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of unsolicited AEs ¥ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of medically attended visits until 6 
months after last HZ/su vaccination  
(see Section 9.1.5) a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of pIMDs until 12 months after last 
HZ/su vaccination (see Section 9.1.6.1) b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of pregnancies ¥ (see Section 9.2.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of IMCs (see Section 7.7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of all SAEs until 12 months after last 
HZ/su vaccination b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporting of SAEs related to investigational 
vaccine, related to study participation or 
concurrent GSK medication/vaccine c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Event 
Visit 
Month 0 
Dose 1 
 
 
 
Visit  
Month 2‡ 
Dose 2 
 
 
 
 
 
Visit/ contact 
Year 1 - 5 
Study 
conclusion visit/ 
contact  
Year 6 
Timing of reporting 
Month 0 
Day 6 post  
Dose 1 
Day 29 post 
Dose 1 
 
Month 2‡ Day 6 post 
 Dose 2‡ 
Day 29 post 
Dose 2‡ 
 
Month 6  
Month 12 - 60 Month 72 
HZ complications (see Section 4.4) (including 
SAE information) d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to withdrawal from the study 
(see Section 9.3.1) e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = Adverse Event; pIMDs = potential immune-mediated Diseases; IMC = Intercurrent Medical Condition; SAE = Serious Adverse Event; GSK = GlaxoSmithKline; HZ = Herpes 
Zoster. 
‡ Visit Month 2 Dose 2 is only for the Revaccination group. 
¥ Only for the 1-Additional Dose and Revaccination groups, as applicable. 
a The reporting of medically attended visits will be from Visit Month 0 until 6 months (for the Control and 1-Additional Dose groups) and from Visit Month 0 until 6 months after last HZ/su 
vaccination (for the Revaccination group) (see Table 6). 
b The reporting of pIMDs and all SAEs will be from Visit Month 0 until 12 months (for the Control and 1-Additional Dose groups) and from Visit Month 0 until 12 months after last HZ/su 
vaccination (for the Revaccination group) (see Table 6). 
c The reporting period of these events starts from the time the subject consents to participate in the study. 
d A HZ complication related to a HZ episode which was initiated during the primary study or during the interval between the end of ZOSTER-006/022 and beginning of the ZOSTER-049 
study is to be recorded in general medical history at the first Month 0 Visit of study ZOSTER-049. HZ will be recorded in HZ-specific screens. 
e Twelve months after visit Month 0 (for the Control and 1-Additional Dose groups) and after 12 months after last HZ/su vaccination (for the Revaccination group), if AEs/SAEs are not 
related to investigational vaccine, study participation or to GSK concomitant medication/vaccine, or if not due to HZ complications, only the name (diagnosis/description) of the 
event will be recorded in the eCRF. No other details about AEs/SAEs will be recorded. 
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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 25 and Table 26. 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 investigational 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 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/ delegate 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 in Table 27. 
Table 27 
Intensity scales for solicited symptoms 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 
Fever* 
 
Record temperature in °C/°F 
Temperature will be analyzed in 0.5°C increments from 
≥ 37.5°C 
Headache 
0 
Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal symptoms 
0 
Normal 
(nausea, vomiting, diarrhea and/or 
abdominal pain) 
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 
Normal 
 
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 
* Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal 
route. The preferred route for recording temperature in this study will be oral. 
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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 
The preferred route for recording temperature in this study is oral.  
Grade 3 fever will be defined as temperature > 39.0C for oral, axillary or tympanic route 
and > 39.5C for rectal route. 
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. 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2. 
9.3.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. 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 investigational vaccine will be considered and 
investigated. The investigator will also consult the IB 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 
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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. 
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual 
vaccine/product administered. The investigator should, therefore, assess whether the AE 
could be causally related to vaccination rather than to the individual vaccines. 
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 investigational 
vaccine? 
YES 
: 
There is a reasonable possibility that the 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. 
• 
Other cause (specify). 
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). 
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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 28, 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 28, 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 28, once the investigator determines that 
the event meets the protocol definition of a pIMD. 
Table 28 
Timeframes for submitting serious adverse events, pregnancy and 
other event 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, pregnancies and pIMDs 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs, pregnancies and pIMDs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
US sites only: 
Fax: 1-610-787-7053  
Canadian sites only: 
Fax: 1-866-903-4718 
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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. 
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. 
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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. 
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 28. 
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 investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
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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 for SAEs; refer to Table 28). 
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 end of the study. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
Cases of new onset of autoimmune diseases and other immune-mediated inflammatory 
disorders documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until study 
conclusion. 
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, stabilised, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up. 
• 
with other non-serious AEs, cases of new onset of autoimmune diseases, until study 
conclusion 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 recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
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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 an AE should 
be recorded in the subject’s eCRF (refer to Section 7.6.1). 
9.7. 
Subject card 
Study subjects/ subject’s 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 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’ caregiver must be instructed to keep subject cards in their possession 
at all times. 
10. 
SUBJECT COMPLETION AND WITHDRAWAL 
10.1. 
Subject completion 
A subject who returns for the concluding visit/ contact foreseen in the protocol is 
considered to have completed the study. 
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 did 
not come back for the concluding visit/ contact foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
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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, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
HZ episode. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because the subject has withdrawn 
consent, the investigator will document the reason for withdrawal of consent, if specified 
by the subject 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). 
10.2.2. 
Subject withdrawal from investigational vaccine 
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e., when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational 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. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
Information relative to premature discontinuation of the investigational vaccine will 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 or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
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• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Other (specify). 
11. 
STATISTICAL METHODS 
11.1. 
Primary endpoint 
• 
Confirmed HZ cases (LTFU and Control groups); 
− 
Confirmed HZ cases during the ZOSTER-049 study.  
11.2. 
Secondary endpoints 
• 
Confirmed HZ cases; 
− 
Confirmed HZ cases since one month post dose 2 in the previous ZOSTER-
006/022 studies; 
• 
PHN cases; 
− 
PHN cases during the ZOSTER-049 study and since one month post dose 2 in 
the previous ZOSTER-006/022 studies;  
• 
HZ related complications (other than PHN); 
− 
HZ related complications (other than PHN) during the ZOSTER-049 study and 
since one month post dose 2 in the previous ZOSTER-006/022 studies;  
• 
Antigen-gE humoral immunogenicity at Months 0, 12, 24, 36, 48, 60 and 72 (LTFU 
HI subset, 1-Additional Dose, Revaccination and Control groups), at Month 1 (1-
Additional Dose, Revaccination and Control groups), and at Month 3 (Revaccination 
and Control groups); 
− 
Anti-gE Ab concentrations as determined by ELISA; 
• 
CMI in terms of frequencies of antigen-specific CD4+ T cells at Months 0, 12, 24, 
36, 48, 60 and 72 (LTFU CMI subset, 1-Additional Dose, Revaccination and Control 
groups), at Month 1 (1-Additional Dose, Revaccination and Control groups), and at 
Month 3 (Revaccination and Control groups); 
− 
Frequencies of CD4+ T cells with antigen-specific Interferon gamma (IFN-γ) 
and/or Interleukin-2 (IL-2) and/or Tumour Necrosis Factor alpha (TNF-α) 
and/or CD40 Ligand (CD40L) secretion/expression to gE as determined by ICS; 
• 
Solicited local and general symptoms in subjects administered with 1 or 2 additional 
doses of HZ/su vaccine (1-Additional Dose and Revaccination groups); 
− 
Occurrence, intensity and duration of each solicited local symptom within 7 
days (Days 0 − 6) after each vaccination; 
− 
Occurrence, intensity, duration and relationship to vaccination of each solicited 
general symptom within 7 days (Days 0 − 6) after each vaccination; 
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• 
Unsolicited AEs in subjects administered with 1 or 2 additional doses of HZ/su 
vaccine (1-Additional Dose and Revaccination groups); 
− 
Occurrence, intensity and relationship to vaccination of unsolicited AEs during 
30 days (Days 0 − 29) after each vaccination, according to the Medical 
Dictionary for Regulatory Activities (MedDRA) classification; 
• 
Serious AEs; 
− 
Occurrence and relationship to vaccination of all SAEs; 
− 
from Visit Month 0 until 12 months: for Control and 1-Additional Dose groups; 
− 
from Visit Month 0 until 12 months after last HZ/su vaccination: for the 
Revaccination group; 
− 
Occurrence of SAEs related to investigational vaccine, related to study 
participation or to GSK concomitant medication/vaccine during the entire study 
period in all subjects; 
• 
Occurrence of AEs of specific interest: Potential immune-mediated diseases (pIMDs) 
(1-Additional Dose, Revaccination and Control groups); 
− 
Occurrence and relationship to vaccination of all pIMDs; 
− 
from Visit Month 0 until 12 months: for Control and 1-Additional Dose groups; 
− 
from Visit Month 0 until 12 months after last HZ/su vaccination: for the 
Revaccination group. 
11.3. 
Tertiary endpoints  
11.4. 
Determination of sample size 
In ZOSTER-006, 7344 subjects have been included in the modified Total Vaccinated 
cohort (mTVc) for the analysis in that study and will be eligible to be included in this 
LTFU efficacy analysis. Considering that about 50% of the subjects may not come back 
for the ZOSTER-049 study, we could expect that 3672 subjects will be willing and 
eligible to participate. 
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In ZOSTER-022, 13,500 subjects have been vaccinated with at least one dose of HZ/su 
vaccine or one dose of placebo. Considering that 90% will be evaluable for the mTVC, 
we could expect that 6075 subjects from the vaccinated group will be eligible to be 
included in the LTFU efficacy analysis. Considering that 55% of the subjects may not 
come back for the ZOSTER-049 study, we could expect that 2734 subjects will be 
willing and eligible to participate. 
Thus in total, 6406 evaluable subjects can be expected in this LTFU efficacy analysis. 
11.4.1. 
VE assessment 
Considering that 240 subjects will be randomised within the groups 1-Additional Dose, 
Revaccination and Control, approximately 6000 subjects would be expected to be 
evaluable for the efficacy assessment in the mTVc. 
The sample size will allow us to get a Lower Limit (LL) of 95% CI (95%LL) of the VE 
above 30% overall over the study with a probability of at least 99%. 
Because no placebo group is enrolled in this study, an approximate power computation 
has been derived considering the incidence rate in the vaccine group as compared to the 
incidence rate of the historical control from the ZOSTER-006/022 studies. 
For each year of VE exploratory assessment 
 
 
 
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11.5. 
Cohorts for Analyses 
11.5.1. 
Total vaccinated cohort 
The Total Vaccinated cohort (TVc) will include all subjects from the ZOSTER-006/022 
studies who are enrolled in the ZOSTER-049. 
The TVc for the groups 1-Additional Dose and Revaccination will include all vaccinated 
subjects from the ZOSTER-006/022 studies that received at least one additional dose of 
HZ/su vaccine in the ZOSTER-049 study. 
The TVc for analysis of efficacy and immunogenicity will include subjects for whom 
data related to efficacy and immunogenicity endpoints are available. 
The TVc for analysis of safety will include all subjects with at least one vaccine dose 
administered. 
11.5.2. 
Modified Total Vaccinated cohort (LTFU and Control group) 
The mTVc will be the primary population for efficacy analysis, which excludes subjects 
in the TVc for efficacy analysis who were not administered with the second vaccination 
during the ZOSTER-006/022 study, or who developed a confirmed case of HZ prior to 1 
month after the second vaccination in the ZOSTER-006/022 primary study. 
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11.5.3. 
According To Protocol cohort for analysis of efficacy (LTFU and 
Control groups) 
The According To Protocol (ATP) cohort for analysis of efficacy will include all 
evaluable subjects: 
• 
Who meet all eligibility criteria; 
• 
Who have received 2 doses of the HZ/su study vaccine according to their random 
assignment in the primary ZOSTER-006/022 studies; 
• 
For whom administration site of study vaccine is known and correct from ZOSTER-
006/022; 
• 
Who have not received a vaccine not specified or forbidden in the protocol; 
• 
Complying with the procedures defined in the protocol; 
• 
Who did not receive a medication/ product leading to elimination from the ATP 
analysis; 
• 
Who did not present with an IMC leading to exclusion from an ATP analysis; 
• 
Who complied with the vaccination schedule, i.e., 49-83 days between the first and 
the second dose in ZOSTER-006/022; 
• 
Who did not develop a confirmed case of HZ prior to 1 month (30 days) after the 
second vaccination, during the ZOSTER-006/022 studies. 
11.5.4. 
According To Protocol cohort for analysis of immunogenicity (1-
Additional Dose, Revaccination and Control groups) 
The ATP cohort for analysis will include all subjects from the TVc: 
• 
Who meet all eligibility criteria; 
• 
Who have received 1 dose (1-Additional Dose group) or 2 doses (Revaccination 
group) of study vaccine(s) according to their random assignment; 
• 
For whom administration site of study vaccine is known and correct; 
• 
Who have not received a vaccine not specified or forbidden in the protocol; 
• 
Who complied with the procedures defined in the protocol; 
• 
Who did not receive a medication/ product leading to exclusion from an ATP 
analysis; 
• 
Who did not present with an IMC leading to exclusion from an ATP analysis; 
• 
Who complied with the vaccination schedule, i.e., 49-83 days between the first and 
the second dose for the Revaccination group; 
• 
Who complied with the Month 1 blood sample schedule, i.e., 28-48 days from 
Month 0 to Month 1 for the 1-Additional Dose group and Control group; 
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• 
Who complied with the post-Dose 2 blood sample schedule, i.e., 28-48 days post-
Dose 2 for the Revaccination group; 
• 
Who had immunogenicity results available post-dose 1 for the 1-Additional Dose 
group, ,post dose 2 for the Revaccination group and at Month 1 and Month 3 for the 
Control group; 
• 
Who had no episode of HZ prior to study start; 
• 
Who received 2 doses of HZ/su vaccine in the primary ZOSTER-006/022 studies. 
11.5.5. 
According To Protocol cohort for analysis of persistence of 
immunogenicity (LTFU group) 
The ATP cohort for analysis of persistence of immunogenicity (humoral/CMI) will 
include all evaluable subjects i.e., those who were included in the ATP cohort for 
immunogenicity (humoral/CMI) in the primary ZOSTER-006/022 studies, or were 
excluded from this cohort solely because they had no blood samples taken, or because of 
incompliance with blood sample schedule, and: 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity up to the timepoint considered (see Section 
7.6.2); 
• 
Who did not present with an IMC leading to elimination from the ATP analysis for 
immunogenicity (including HZ infection) up to the timepoint considered (see Section 
7.7); 
• 
For whom persistence immunogenicity results are available for the considered time 
point. 
11.5.6. 
According To Protocol cohort for analysis of persistence of 
immunogenicity (1-Additional Dose, Revaccination and Control 
groups) 
The ATP cohort for analysis of persistence of immunogenicity will include all evaluable 
subjects i.e., those who were included in the ATP cohort for analysis of immunogenicity 
in the ZOSTER-049 study, or were excluded from this cohort solely because they had no 
blood samples taken or because of incompliance with blood sample schedule, and: 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity up to the timepoint considered (see Section 
7.6.2); 
• 
Who did not present with an IMC leading to elimination from the ATP analysis for 
immunogenicity (including HZ infection) up to the timepoint considered (see Section 
7.7); 
• 
For whom persistence immunogenicity results are available for the timepoint 
considered. 
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11.6. 
Derived and transformed data 
11.6.1. 
Handling of missing data 
For a given subject and a given measurement, missing or non-evaluable measurements 
will not be imputed. The missing endpoint and censoring are supposed to occur 
independently, and the pattern of the missing value(s) being either Missing Completely 
At Random (MCAR) or Missing At Random (MAR) only. 
For the analysis of solicited symptoms, missing or non-evaluable measurements will not 
be replaced. Therefore, the analysis of the solicited symptoms based on the TVc will 
include only subjects/doses with documented safety data (i.e., symptom screen/sheet 
completed). 
For the analysis of unsolicited symptoms/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 the analysis of immunogenicity, missing or non-evaluable measurements will not be 
replaced. Therefore, a subject will be excluded from an analysis if all measurements are 
missing or non-evaluable. 
11.6.2. 
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-dose 2 anti-gE Ab concentration as compared to the 
prevaccination anti-gE Ab concentration, for subjects who are seropositive at 
baseline, or, 
• 
a 4-fold increase in the post-dose 2 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 
concentration transformations. 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. 
The Mean Geometric Increase (MGI) is defined as the geometric mean of the within 
subject ratios of two different timepoints. 
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11.6.3. 
CMI response 
• 
For the descriptive analyses, the frequency of CD4[2+] T-cells upon in vitro 
stimulation with the gE-antigen (induction condition) is calculated by dividing the 
number of activated CD4[2+] T-cells (numerator) over the total number of CD4 T-
cells involved (denominator). The same calculation will be performed for the 
frequency computation for any kinds of cells and for each individual activation 
marker as appropriate. 
 
• 
The frequency of gE-specific CD4 T-cells for each individual subject is calculated as 
the difference between the frequency of CD4[2+] T-cells, upon in vitro stimulation 
with the gE antigen (induction condition) minus the frequency of CD4[2+] T-cells 
upon in vitro stimulation in medium only (background condition). The differences 
less or equal to one are imputed to one gE-specific CD4[2+] T-cell per 106 CD4+ T-
cells. The same calculation will be performed for the frequency computation for any 
kind of cells and for each individual activation marker as appropriate. 
 
• 
The GM frequency calculations are performed by taking the anti-log of the mean of 
the log frequency transformations. 
• 
The CMI vaccine response to gE will be based on the gE-specific data. The VRR is 
defined as the percentage of subjects who have at least: 
− 
a 2-fold increase as compared to the threshold 320 polypositive CD4+ 
T cells/106 CD4+ T cells, for subjects with pre-vaccination T-cell frequencies 
below the threshold 320 polypositive CD4+ T cells/106  CD4+ T cells; 
− 
a 2-fold increase as compared to pre-vaccination T-cell frequencies, for subjects 
with pre-vaccination above the threshold 320 polypositive CD4+ T cells/106 
CD4+ T cells. 
• 
 
 
 
 

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CD
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CD
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N
n
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background
 
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N
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N
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if
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n
N
n
Freq
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11.7. 
Statistical analyses 
11.7.1. 
Analysis of demographics (for each of the four groups of the 
study) 
Demographic characteristics (age at first vaccination in the ZOSTER-006/022 studies, 
gender, geographic ancestry, and ethnicity), cohort description and withdrawal status will 
be summarised by group. 
The mean age at first vaccination in the ZOSTER-006/022 studies (plus range and 
standard deviation) of the enrolled subjects, as a whole, and stratified by age group will 
be calculated. 
In addition, for the 1-Additional Dose, Revaccination and Control groups, the mean age 
at Month 0 in the ZOSTER-049 (plus range and standard deviation) of the enrolled 
subjects, as a whole, and by age group (50-59, 60-69 and  70 YOA) will be calculated. 
The distribution of subjects enrolled among the study sites will be tabulated. 
Frequency tables will be generated for categorical variables such as gender. 
Mean, median and standard error will be provided for continuous data such as age. 
11.7.2. 
Analysis of efficacy (LTFU and Control groups) 
The primary analysis of efficacy will be performed on the mTVc, the analysis will be also 
performed on the TVc and the ATP for efficacy to complement the mTVc analysis. 
The analysis on mTVc and ATP cohort for efficacy will be performed over the follow-up 
time from one month post Dose 2 to the confirmed HZ case for a subject with a 
confirmed HZ case, and to the date of last contact for subjects without a confirmed HZ 
case. 
The analysis on the TVc will be performed over the complete follow-up period and will 
include confirmed HZ cases from Dose 1 for vaccine efficacy evaluation. The end of the 
follow-up period will be calculated according to the same principle as will be done for 
the mTVc and ATP analyses for efficacy, i.e., up to the confirmed HZ case for a subject 
with a confirmed HZ case, or up to the date of last contact for subjects without a 
confirmed HZ case. 
All analyses will be performed overall and by age strata. The age strata for reporting 
purposes are 50-59, 60-69, and,  70 YOA at primary vaccination. When overall VE is 
presented, the age factor will include the 3 main age strata 50-59, 60-69, and  70 YOA. 
When VE by age is presented, the same model will be run using only the data pertaining 
to the strata under consideration. 
In addition, the analysis will be performed on subjects  60 YOA at inclusion in the 
ZOSTER-006/022 studies. 
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The primary analysis will be to assess the VE during this study and will use the historical 
control estimates adjusted for age at randomisation during the ZOSTER-006/022 studies. 
The method using the historical control estimates will be further explained in the 
Statistical Analysis Plan (SAP). Vaccine effects will be estimated by calculating the VE 
and estimating 95% CIs based on the variance of the observed population in this study 
and treating the historical control as constant. 
The secondary analysis will be to assess the VE over each year of follow-up. Results 
from the ZOSTER-006/022 studies will be pooled for each year after vaccination with 
methods used in these studies. For overlapping years between ZOSTER-006/022 studies 
and this study, all the data will be pooled. For the non-overlapping years only the data 
from this ZOSTER-049 study will be used. 
The assessment of the VE over the overall period including period from vaccination 
during the ZOSTER-006/022 studies up to the end of this long-term study will be done 
with a method that will be described in the SAP. 
Any available information for the diagnosis of HZ episodes (clinical diagnosis, PCR, 
laboratory methods, etc.) during the interval between the end of the ZOSTER-006/022 
studies and beginning of the ZOSTER-049 study is to be collected. Confirmation of all of 
these cases in the exact way as what will be done for cases collected during the clinical 
study follow-up periods of the ZOSTER-006, ZOSTER-022 and ZOSTER-049 will not 
be possible. Therefore, these cases will not be part of all efficacy analyses. A sensitivity 
analysis to assess the impact of these cases on the VE will be performed (this will be 
described in the SAP). 
The purpose of these analyses will be descriptive and therefore the CIs will not be 
adjusted for multiple testing. 
The analyses will be performed for confirmed HZ cases, for PHN and for complications 
(other than PHN).  
Any exploratory or sensitivity analysis may be performed in addition to the analyses 
described above on an ad-hoc basis. However, the significance level of those analyses 
may not be fully controlled. 
11.7.3. 
Analysis of immunogenicity 
The primary analysis will be based on the ATP cohort. If, in any vaccine group the 
percentage of vaccinated subjects with serological results excluded from the ATP cohort 
for analysis of immunogenicity is 5% or more, a second analysis based on the TVc will 
be performed to complement the ATP analysis. 
All analyses will be presented overall and by age strata. The main age strata for reporting 
purposes are 50-59, 60-69 and  70 YOA. Additional analysis will be presented in 
 60 YOA. 
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11.7.3.1. 
Assessment for 1-Additional Dose, Revaccination and Control groups 
11.7.3.1.1. Humoral immune response 
Descriptive analysis – within group: 
The following parameters will be tabulated by vaccine group at each time point when a 
blood sample result is available: 
• 
Seropositivity rate with exact 95% CI; 
• 
GMC with 95% CI;  
• 
The MGI Post Month 1 and Post Month 3 current study over pre-vaccination in the 
primary studies with 95% CI; 
• 
The MGI Post Month 3 primary vaccination over the Post Month 1 and Post Month 3 
current study with 95% CI; 
• 
The MGI Post Month 1 and Post Month 3 current study over Visit Month 0, in the 
current study with 95% CI; 
• 
VRR [post additional dose groups over pre-vaccination in the primary studies] with 
exact 95% CI; 
• 
The distribution of Ab titres will be tabulated and also presented using reverse 
cumulative curves. 
Persistence analysis 
Persistence data will be analysed from the Visit Year 1 to the Visit Year 6 timepoint after 
vaccination. 
For each year X (X varying from year 1 to year 6): The analysis of Ab persistence will 
be based on the ATP cohort for persistence at year X –adapted for each timepoint. If the 
percentage of subjects, excluded from the ATP cohort for the Year X follow-up 
serological results, is higher than 5% for any group, a second analysis based on the TVc 
at Year X will be performed to complement the ATP analysis. 
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The following parameters will be tabulated by group at each timepoint when a blood 
sample result is available: 
• 
Seropositivity rate with exact 95% CI; 
• 
GMC with 95% CI; 
• 
The MGI Post Month 3 primary vaccination over the Post year x for the 1-Additional 
Dose or Revaccination group with 95% CI; 
• 
The MGI Post year x for the 1-Additional Dose or Revaccination group over Visit 
Month 0, in the current study with 95% CI; 
• 
The MGI Post year x over pre-vaccination in the primary ZOSTER-006/022 studies 
with 95% CI; 
• 
VRR [post year x (1-Additional Dose or Revaccination group) over pre-vaccination 
in the primary ZOSTER-006/022 studies] with exact 95% CI; 
• 
The distribution of Ab titres will be tabulated and also presented using reverse 
cumulative curves. 
11.7.3.1.2. Cell-mediated immune response 
Descriptive statistics (N, mean, SD, min, Q1, median, Q3, max) of the following 
parameters will be tabulated by group at all timepoints: 
• 
Descriptive statistics of the frequency of CD4+ T-cells expressing at least two 
activation markers (among IFN-, IL-2, TNF-, CD40L) for gE-specific stimulation.  
• 
 
.  
11.7.3.2. 
Analysis on subjects with HZ cases 
The following analysis will be also performed at each time point when a blood sample 
result is available on subjects who had a HZ case: 
• 
Seropositivity rate with exact 95% CI; 
• 
GMC with 95% CI. 
11.7.3.3. 
Analysis of persistence (immune subset of LTFU group) 
Since the interval between the end of ZOSTER-006/022 studies and the start of this study 
will vary per subject and is dependent on receipt of approval or implementing the study 
in the different participating countries, some results from the first blood sample may 
correspond to year 5, year 6 or year 7 post vaccination. To be able to complement the 
modelling prediction by descriptive data analysis, yearly timeframes will be defined 
around the anniversary date post vaccination. The details of the set up for these intervals 
will be described in the SAP. 
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11.7.3.3.1. Humoral immune response 
For the yearly prediction of the GMCs (year 5 to year 10 and beyond): the analysis of Ab 
persistence will be based on the ATP cohort for persistence adapted for each year. 
In order to assess the persistence at Year 5, 6, 7, 8, 9 and 10 and beyond after the primary 
vaccination in the ZOSTER-006/022 studies, a longitudinal analysis will be performed 
and will include all results from ZOSTER-006/022 studies and all results from this 
ZOSTER-049 study. 
The following parameters will be tabulated by vaccine group for all timeframes (Refer to 
the SAP): 
• 
Seropositivity rate with exact 95% CI; 
• 
GMC with 95% CI; 
• 
Vaccine response rate with exact 95% CI; 
• 
MGI from baseline with 95% CI for anti-gE; 
• 
The distribution of Ab titres will be tabulated and also presented using reverse 
cumulative curves. 
Note that the baseline that will be used for the computation of MGI and VRR will be the 
concentration obtained at pre-vaccination in the primary studies. 
11.7.3.3.2. Cell-mediated immune response 
For the yearly prediction of the CMI (year 5 to year 10 and beyond): the analysis of CMI 
persistence will be based on the ATP cohort for persistence adapted for each year.  
In order to assess the persistence at Year 5, 6, 7, 8, 9 and 10 and beyond after the primary 
vaccination in the ZOSTER-006/022, a longitudinal analysis will be performed and will 
include all results from ZOSTER-006/022 studies and all results from this ZOSTER-049 
study. 
Descriptive statistics (N, mean, SD, min, Q1, median, Q3, max) of the following 
parameters will be tabulated by group for all timeframes (Refer to the SAP): 
• 
Descriptive statistics of the frequency of CD4+ T-cells secreting at least two 
activation markers (from among IFN-, IL-2, TNF-, CD40L) for gE-specific 
stimulation. 
The following parameters will be tabulated by vaccine group for all timeframes when a 
blood sample result is available: 
• 
Vaccine response rate with exact 95% CI. 
• 
Note that the baseline that will be used for the computation of VRR will be the 
concentration obtained at pre-vaccination in the primary studies. 
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11.7.4. 
Analysis of safety 
The analysis will be performed on the TVC. 
The results for the analysis of safety will be tabulated as: 
• 
The percentage of subjects with at least one local solicited AE, with at least one 
general solicited AE and with any solicited AEs during the solicited 7-day follow-up 
period will be tabulated with exact 95% CI after each vaccine dose and overall (1-
Additional Dose and Revaccination groups). The same tabulation will be performed 
for grade 3; 
• 
The percentage 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 (1-
Additional Dose and Revaccination groups). For all solicited symptoms, the same 
tabulation will be performed for grade 3 solicited AEs and for solicited general AEs 
with relationship to vaccination (1-Additional Dose and Revaccination groups); 
• 
The percentage 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 
(1-Additional Dose and Revaccination groups); 
• 
The proportion of subjects with at least one report of unsolicited AE classified by the 
MedDRA Preferred Terms and reported up to 30 days after each vaccination will be 
tabulated with exact 95% CI (1-Additional Dose and Revaccination groups); 
• 
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 (1-Additional Dose and 
Revaccination groups); 
• 
Total number/percentages of doses (per dose and overall) followed by AEs will be 
tabulated (1-Additional Dose and Revaccination groups); 
• 
Number of subjects with pIMDs will be tabulated (1-Additional Dose, Revaccination 
and Control groups); 
• 
SAEs related to investigational vaccine (all groups); 
• 
SAEs related to study participation or to GSK concomitant medication/vaccine (all 
groups); 
• 
Adverse events (AEs)/SAEs leading to withdrawal from the study (all groups); 
• 
IMCs (all groups); 
• 
HZ complications (all groups). 
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11.8. 
Interpretation of analyses 
Long term efficacy part: 
All the analyses will be descriptive with the aim to characterise the long-term efficacy. 
Additional dose and revaccination part: 
All the analyses will be descriptive with the aim to characterise the effect of 1 and 2 
additional doses of HZ/su vaccine. 
11.9. 
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. 
11.9.1. 
Sequence of analyses 
The analysis will be performed in the following steps: 
1. A final analysis on: 
− 
immunogenicity and safety (SAEs and pIMDs) data in (1-Additional dose, 
Revaccination and Control groups), and; 
− 
reactogenicity data (1-Additional Dose and Revaccination groups), 
will be performed when all those data up to Visit Month 3 are available and as clean 
as possible. Because the analysis is purely descriptive, no adjustment on type I error 
is foreseen. No clinical study report is planned to be written at this time and at this 
point no individual data listings will be provided. At this point, the GSK central 
clinical team will have access to the lab data and the treatment assignment from 
SBIR. 
2. Two intermediate analyses to assess the VE at year 2 and year 4 (LTFU and Control 
groups): 
− 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 2 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 2 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. Please refer 
to the SAP.  
− 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 4 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 4 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. Please refer 
to the SAP.  
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3. End of study analysis: 
− 
The end of study analysis will be performed at the end of study. This end of 
study analysis will combine both of the previous analyses, as well as analyses up 
to the study end. Individual data listings will be generated at this stage. An 
integrated end-of-study report will be written. 
11.9.2. 
Statistical considerations for interim analyses 
Because the analysis is purely descriptive, no adjustment on type I error is foreseen. 
12. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality 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 of omissions or inconsistencies with documentation and 
approval 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 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. 
12.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, 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. 
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The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and 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. 
For eCRF, the monitor freezes completed and approved screens at each visit. 
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. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. 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. 
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. 
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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. 
12.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed. 
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before the 
initiation of the analysis/study. 
Results are publicly registered within 8 months of the completion of the analysis. GSK 
also aims to publish the results of these studies in the searchable, peer reviewed scientific 
literature. Manuscripts are submitted within 18 months of the completion of the analysis. 
At the time of publication, this protocol will be fully disclosed. 
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. 
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13. 
COUNTRY SPECIFIC REQUIREMENTS 
All countries will comply with AE and SAE reporting as described in Section 9.4 of the 
protocol. Additionally, countries and sites will follow all applicable local regulations and 
guidelines for AE and SAE reporting as required by their respective healthcare authorities 
and ethics committees. 
13.1. 
Requirements for France 
This section includes all the requirements of the French law (n° 2004-806 of 09 August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol. 
Concerning the « STUDY POPULATION » 
• 
In line with the local regulatory requirements, the following text about «PAYMENT 
TO SUBJECTS » is added:  
Subjects will be paid for the inconvenience of participating in the study. The amount 
of payment is stated in the ICF. Subjects not completing the study for whatever 
reason could be paid at the discretion of the Investigator, generally on a pro rata 
basis. 
• 
In line with the local regulatory requirements, the following text about 
« NATIONAL FILE » is added: 
All subjects who will be paid, will be recorded into the “national File” by the 
investigator. They could be identified and monitored under the « Fichier national ». 
The following details will be described: 
• 
Reference of the study, 
• 
Surname and first name, 
• 
Date and place of birth, 
• 
Sex, 
• 
Dates of beginning and termination of the study, 
• 
Exclusion period, 
• 
The total amount of allowance. 
• 
In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS » is added: 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category. 
It is the investigator’s responsibility to ensure and to document (in source document - 
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category. 
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Concerning the “DATA ANALYSIS AND STATISTICAL CONSIDERATIONS” 
and specially in the “SAMPLE SIZE ASSUMPTION” 
• 
The expected number of patients to be recruited in France is declared to the French 
regulatory authority. 
Concerning the “STUDY CONDUCT CONSIDERATIONS” 
• 
In section “Regulatory and Ethical Considerations, Including the Informed Consent 
Process” 
Concerning the process for informing the patient or his/her legally authorised 
representative, the following text is added: 
• 
French Patient ICF is a document which summarises the main features of the study 
and allows collection of the patient's written consent in triplicate. It also contains a 
reference to the authorisation of ANSM and the approval from the French Ethic 
committee and the maintenance of confidentiality of the returned consent form by 
GSK France. 
Concerning the process for obtaining subject informed consent: 
• 
When biomedical research is carried out on an adult in the care of a “tutelle” 
guardian, consent is given by their legal representative and, if the committee 
mentioned in article L. 1123-1 considers that the research in question, because of the 
gravity of the restraints or the specificity of the medical acts involved, entails a 
serious risk of affecting their private life or the integrity of their body, by the family 
council if it has been instated, or by the judge of “tutelle” guardians. 
• 
When biomedical research is carried out on an adult in the care of a "curatelle" 
guardian, consent is given by the subject assisted by his guardian. 
However, if the adult in the care of a "curatelle" guardian is invited to participate in 
research which the committee mentioned in article L. 1123-1 considers, because of 
the gravity of the restraints or the specificity of the medical acts involved, to entail a 
serious risk of affecting their private life or the integrity of their body, the matter is 
submitted to the judge of guardians who decides whether the adult is capable of 
giving his consent. In the case of incapacity, the judge will decide whether or not to 
authorise the biomedical research. 
• 
When biomedical research, which complies with the conditions laid down in article 
L. 1121-8, is considered for an adult incapable of expressing his consent and not 
under a legal protection order, consent is given by a person of confidence as defined 
in article L. 1111-6 and, failing this, by a person who maintains close and stable 
links with the subject. However, if the committee mentioned in article L. 1123-1 
considers that the research in question, because of the gravity of the restraints or the 
specificity of the medical acts involved, entails a serious risk of affecting their 
private life or the integrity of their body, consent is given by the judge of guardians. 
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Concerning the management of the Patient ICFs, the following text is added: 
• 
The first copy of the Patient ICF is kept by the investigator. The second copy is kept 
by the Director of the Medical Direction of GSK France and the last copy is given to 
the patient or his/her legally authorised representative. 
• 
The second copy of all the consent forms will be collected by the investigator at the 
end of the trial under the Clinical Research Assistant’s (CRA's) control, and placed 
in a sealed envelope bearing only: 
− 
the study number, 
− 
the identification of the Centre : name of the principal investigator and number 
of centre), 
− 
the number of informed consents, 
− 
the date,  
− 
and the principal investigator’s signing. 
Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director. 
In section concerning the “ NOTIFICATION TO THE HOSPITAL DIRECTOR ” 
the following text is added (if applicable) 
• 
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63). 
In section concerning the “ INFORMATION TO THE HOSPITAL 
PHARMACIST ” the following text is added (if applicable) 
• 
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g., included in the CIB), the name of the investigator(s), 
the number of sites involved in his establishment and the estimated time schedule of 
the trial. 
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In section “ DATA MANAGEMENT ” the following text is added 
• 
" Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerised in GSK data bases by GSK 
Laboratory or on its behalf, for reasons of follow up, clinical trial management and 
using the results of said clinical trial. According to the Act n° 78-17 of 6th January 
1978 further modified, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GSK Laboratory (Clinical 
Operations Department)." 
Concerning Monitoring visits 
• 
The Health Institution and the Investigator agree to receive on a regular basis a CRA 
of GSK or of a service provider designated by GSK. The Health Institution and the 
Investigator agree to be available for any phone call and to systematically answer to 
all correspondence regarding the Study from GSK or from a service provider 
designated by GSK. In addition, the Health Institution and the Investigator agree that 
the CRA or the service provider designated by GSK have direct access to all the data 
concerning the Study (test results, medical record, etc …). This consultation of the 
information by GSK is required to validate the data registered in the eCRF, in 
particular by comparing them directly to the source data. In accordance with the 
legal and regulatory requirements, the strictest confidentiality will be respected. 
Concerning Data entry into the eCRF (Amended 11 May 2020) 
The Health Institution and the Investigator agree to meet deadlines, terms and conditions 
of the Study’s eCRF use here below : 
The Health Institution and the Investigator undertake: 
1. That the Investigator and the staff of the investigator centre make themselves 
available to attend the training concerning the computer system dedicated to the 
eCRF of the Study provided by GSK or by a company designated by GSK. 
2. That the Investigator and the staff of the investigator centre use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended and 
for which they have been entrusted to them, namely for the Study achievement, to 
the exclusion of any other use. 
3. That the Investigator and the staff of the investigator centre use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations which 
will have been provided by GSK. 
4. To keep the IT Equipment and/or access codes in a safe and secure place and to only 
authorise the use of this IT Equipment by investigator centre staff designated by the 
principal investigator to enter the data of the Study. 
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5. That the Investigator and the staff of the investigator centre enter the data of the 
eCRF related to a patient visit in the 10 days following the date of the patient visit or, 
for the patient test results, in the 10 days following the reception of the results of 
such tests. For a subject last visit, the recommended time frame for data entry is 5 
working days. 
6. That the Investigator resolves and returns to GSK the data queries issued by GSK or 
a service provider designated by GSK within 10 days after the reception of the 
request of clarification or in a period of 5 days during the final stage of clarification 
of the data base or in such other period as provided by GSK and/or a company 
designated by GSK. 
7. To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes. 
8. To return at the end of the Study the IT Equipment and/or access codes to GSK or to 
any company designated by GSK and any training material and documentation. The 
IT Equipment cannot under any circumstances be kept by the Health Institution or 
the Investigator for any reason whatsoever. 
Concerning CTR publication 
• 
It is expressly specified that GSK and/or the Sponsor can make available to the 
public the results of the Study by the posting of the said results on a website of the 
GSK Group named Clinical Trial Register (CTR) including the registration of all the 
clinical trials conduct by the GSK Group and this before or after the publication of 
such results by any other process.  
Concerning Data Protection French Law of 6 January 1978 (CNIL) 
• 
In accordance with the Data Protection French Law of 6 January 1978 as modified, 
computer files used by GSK to monitor and follow the implementation and the 
progress of the Study are declared with the CNIL by GSK. The Investigator has 
regarding the processing data related to him a right of access, of rectification and of 
opposition with GSK in accordance with the legal provisions. This information can 
be transferred or be accessed to other entities of GSK Group in France, Britain or 
United States, what the Investigator agrees by the signature of the present Protocol. 
13.2. 
Requirements for Germany 
EXPLANATORY STATEMENT CONCERNING GENDER DISTRIBUTION 
(ARTICLE 7, PARAGRAPH 2 (12) OF THE GERMAN GCP ORDER) 
• 
There is no intention to conduct specific analyses investigating the relationship 
between the gender of the subjects and the safety of the GSK Biologicals’ HZ/su 
vaccine. The ratio of male to female subjects recruited into the study ZOSTER-049 
is expected to be in line with the demographics of the population aged  50 YOA in 
the Member State. 
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13.3. 
Requirements for Japan 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare [MHW]/ Ministry of Health, Labour and Welfare Notification No.28 dated 
27th March, 1997)” GCP and, Article 14-3 and 80-2 of the Pharmaceutical Affairs Law 
and Evaluation and Licensing Division, Pharmaceutical Safety Bureau of MHW, 
Notification No. 1061, 1998. 
Clinical Trial Notification to Regulatory Authority 
GSK Japan will submit the CTN to the regulatory authorities in accordance with Article 
80-2 of the Pharmaceutical Affairs Law before conclusion of any contract for the conduct 
of the study with study sites. 
Informed Consent of Subjects 
Informed consent will be obtained before the subject can participate in the study. The 
contents and process of obtaining informed consent will be in accordance with all 
applicable regulatory requirements. 
Informed Consent 
Prior to the start of the study, the investigator (or subinvestigator) should fully inform the 
potential subject of the study including the written information given approval by the 
IRB. The investigator (or subinvestigator) should provide the subject ample time and 
opportunity to inquire about details of the study and to decide whether or not to 
participate in the study. After giving informed consent based on his/her free will, the 
subject should sign and personally date the consent form. If the subject wishes to 
consider the content of the written information at home, he/she may sign the consent 
form at home. The person who conducted the informed consent discussion should sign 
and personally date the consent form. If the subject is unable to read, an impartial witness 
should be present during the entire informed consent discussion, and the witness should 
sign and personally date the consent form. The investigator (or subinvestigator) should 
retain this signed and dated form (and other written information) together with the source 
medical records, such as clinical charts (in accordance with the rules for records 
retention, if any, at each medical institution) and give a copy to the subject. 
If information becomes available that may be relevant to the subject's willingness to 
continue participation in the study (revision of informed consent form and other 
written information) 
If information becomes available that may be relevant to the subject's willingness to 
continue participation in the study, the investigator (or subinvestigator) should 
immediately inform the subject of it to confirm the willingness to continue participation 
in the study, and document the communication of this information (in medical records). If 
necessary, the investigator should revise the written information to be provided to 
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subjects, promptly report it to the sponsor, and obtain approval from the IRB. The 
investigator should not enrol any new subject in the study before the IRB’s approval. 
After the IRB approves the revision of the written information to be provided to subjects, 
the investigator (or subinvestigator) should inform each subject participating in the study 
of the revised written information, and obtain written informed consent. 
Study Monitoring 
By monitoring the parties involved in the study including medical institutions, 
investigators, subinvestigators, study collaborators, and storage managers, monitors will: 
1. Oversee the process of obtaining written informed consent, the control of 
investigational products and the progress of the study (including withdrawals and 
adverse events, and ensure that the conduct of the study is in compliance with GCP, 
Revised GCP, this protocol, and any other written agreement between the sponsor 
and the investigator/institution. 
2. Collect and provide information that is necessary to conduct the study properly 
(information on investigational products’ safety, efficacy and quality). 
3. Verify that the investigator/institution has adequate qualifications and resources and 
remain adequate throughout the study period, and that facilities, including 
laboratories, equipment, and staff, are adequate to safely and properly conduct the 
study and remain adequate throughout the study period. 
4. Verify that source documents and other study records are accurate, complete, kept 
up-to-date and maintained. 
5. Determine whether the person responsible for retaining records is maintaining the 
essential documents at each medical institution. 
6. Check the accuracy and completeness of the CRF entries, source documents and 
other study-related records against each other. 
The investigator and institution should agree to allow the monitor direct access to 
essential documents and other relevant documents. 
Direct access to essential documents by monitors and the scope of those documents will 
be specified separately in the written procedures for monitoring prepared for this study. 
Source Data Recorded Directly on CRF 
The following data may be recorded directly on the CRFs and considered to be source 
data. 
1. Assessment of causality between adverse events and the investigational product. 
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Deviations from and Changes of Protocol 
Deviations from Protocol 
The investigator (or sub-investigator) may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to subjects without agreement by the 
sponsor or prior IRB approval. As soon as possible, the implemented deviation or change 
and the reasons for it should be submitted to the head of the medical institution and the 
IRB for approval, and via the head of the medical institution to the sponsor for 
agreement. 
The investigator (or subinvestigator) should document all deviations from the approved 
protocol. The investigator should document the reason only for the deviation from, or the 
change of, the protocol to eliminate an immediate hazard(s) to subjects, and submit it to 
the sponsor and the head of the medical institution, and retain its copy. 
Changes of Protocol 
1. If it becomes necessary to make any changes significantly affecting the conduct of 
the study, and/or increasing the risk to subjects, the sponsor should promptly 
document the changes and reasons for them and amend the protocol after discussion 
with the (coordinating [investigator, committee members] and) investigators, and 
notify the heads of the medical institutions and investigators of the changes of the 
protocol (sample ICF and other written information, if necessary). The investigator 
should not implement any significant changes without approval from the IRB. 
2. For changes other than the above 1), the sponsor should document the changes and 
reasons for them and inform the heads of the medical institutions and investigators of 
the changes of the protocol. Such changes require prior approval from the IRB, 
except where necessary to eliminate an immediate hazard(s), or when the change(s) 
involves only logistical or administrative aspects of the study. The investigator 
should promptly report the changes implemented without prior approval to the IRB 
for approval. 
Study Period 
The exact study period has not been confirmed at the time of this protocol. When needed 
and available, the study period can be communicated at local level, outside of this 
protocol. 
Shingrix was approved in Japan on 23 March 2018, after study start. Therefore, this study 
is being conducted as a post-marketing study from the approval date in Japan.  
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14. 
REFERENCES 
Araújo LQ, MacIntyre CR, Vujacich C. Epidemiology and burden of herpes zoster and 
post-herpetic neuralgia in Australia, Asia and South America. Herpes 2007; 14(Suppl 2): 
40A–44A. 
Carter WP, Germann CA, Baumann MR. Ophthalmic diagnoses in the ED: herpes zoster 
ophthamicus. Am. J. Ophthalmol. 2008; 612-7. 
CDC. Prevention of herpes zoster. Recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. 2008; 57: 1-30. 
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 2007. 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf. Website 
accessed 19 October 2015. 
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 
EMEA. Zostavax Summary of Product Characteristics. 2011. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Summary_for_the_public/human/000674/WC500053457.pdf. Website accessed 19 
October 2015. 
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. 
Garcia Cenoz M, Castilla J, Montes Y, et al. Varicella and herpes zoster incidence prior 
to the introduction of systematic child vaccination in Navarre, 2005-2006. An Sist Sanit 
Navar. 2008; 31: 71-80. 
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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): 731-40. 
Kang CI, Choi CM, Park TS, et al. Incidence of herpes zoster and seroprevalence of 
varicella-zoster virus in young adults of South Korea. Int J Inf Dis. 2008; 12(3): 245-7. 
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. 
Morrison VA, Johnson GR, Schmader KE, et al. Long-Term Persistence of Zoster 
Vaccine Efficacy. Clin Infect Dis. 2015; 60(6): 900-9. 
Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine 
to prevent herpes zoster and postherpetic 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. 
Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the Efficacy of Zoster 
Vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy. Clin 
Infect Dis. 2012; 55: 1320-28. 
Scott F, Johnson R, Leedham-Green M, et al. The burden of herpes zoster: A prospective 
population based study. Vaccine. 2006; 24: 1308-1314. 
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. 
TGA eBS Australian Register of Therapeutic Goods Medicines. Public summary 
ZOSTAVAX FROZEN zoster virus vaccine live min 19400 PFU/0.65mL powder for 
injection vial. 2015. 
https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs%2FPublicHTML%2FpdfStore.n
sf&docid=DCED7AF72A4FC616CA257EDE003CB146&agid=(PrintDetailsPublic)&act
ionid=1. Website accessed 19 October 2015. 
Toyama N, Shiraki K, and Members of the Society of the Miyazaki Prefecture 
Dermatologists. Epidemiology of herpes zoster and its relationship to varicella in Japan: 
A 10-year survey of 48,388 herpes zoster cases in Miyazaki prefecture. J Med Virol. 
2009; 81(12): 2053-58. 
Zostavax (Zoster Vaccine Live) Prescribing information. June 2011. 
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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 microtitre 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 microtitre 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. 
Intracellular cytokine staining (ICS): 
CMI responses will be performed by GSK Biologicals (or designated laboratory) on 
thawed Peripheral Blood Mononuclear Cells (PBMCs) by ICS. The assay will be 
performed on samples collected during the course of the study. This assay provides 
information on the frequency of CD4 T cells responding to culture medium or antigens 
(gE peptide pool) by expressing molecules involved in immunity such as IFN-, IL-2, 
TNF-, and CD40L (here considered as activation markers). 
Briefly, PBMC collected from the subjects are stimulated for two hours using culture 
medium (for evaluation of the non-specific response), a pool of overlapping peptides 
covering the entire sequence of the vaccine antigen gE. Then, an intracellular block 
(brefeldin A) is added to inhibit cytokine secretion for a subsequent overnight incubation. 
Cells are then harvested, stained for surface markers (CD3, CD4 and CD8) and fixed. 
The fixed cells are then permeabilised and stained with Abs specific to the activation 
markers assessed, washed and analyzed by cytofluorometry.  
The results of ICS assays are expressed as the frequency of specific CD4 T cells per 
million total CD4 T cells. 
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PCR assay for confirmation of suspected case of HZ: 
HZ cases will be confirmed by a Polymerase Chain Reaction (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. 
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 (i.e., 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 (i.e., 
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 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, 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. 
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• 
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”. 
• 
If PCR results for a particular subject do not confirm or exclude a “suspected HZ 
case” (i.e., 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 3): 
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: 
a. 
If the VZV PCR signal is ≥ the cut-off level, i.e., the technical limit of detection 
(LOD) of the assay (10 VZV DNA copies), the sample will be considered as 
“VZV positive”. 
b. 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. 
c. 
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. 
a. 
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. 
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b. 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; i.e., lowest concentration that can be 
detected by PCR in at least 95% of the tests). 
Figure 3 
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 samples 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; i.e., lowest concentration that can be detected by PCR in at least 95% of the tests) 
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APPENDIX B 
CLINICAL LABORATORIES 
Table 31 
GSK Biologicals’ laboratories 
Laboratory 
Address 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
GSK = GlaxoSmithKline 
Table 32 
Outsourced laboratories 
Laboratory 
Address 
CEVAC - University of Ghent 
De Pintelaan, 185 - B-9000 Ghent - Belgium 
CEVAC = Centre for Vaccinology 
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APPENDIX C 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 1 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Amendment number: 
Amendment 1 
Amendment date: 
19 February 2016 
Co-ordinating author: 
, Scientific writer, XPE Pharma & 
Science, Contractor for GSK Biologicals 
Rationale/background for changes: 
• 
This amendment was done for countries that will recruit subjects in the 1-
Additional Dose, Revaccination and Control groups. Administrative changes were 
done for Germany and Japan. 
• 
The additional inclusion and exclusion criteria for the 1-Additional Dose and 
Revaccination groups will also be made applicable to the Control group to allow 
non-biased randomisation of subjects into the 3 groups (Sections 5.2, 5.3, 6.1.2, 
6.5.5, 6.5.6 and Table 6) and an additional exclusion criterion has been added for 
1-Additional Dose, Revaccination and Control groups (Section 5.3). 
• 
The reference to “GSK Japan” has been changed to “Japan Vaccine Co., Ltd.” 
(Investigator Agreement page for Japan and in the requirements for Japan Section 
13.3). 
• 
The study period indicated was also corrected as per local request in the 
requirements for Japan (Section 13.3). 
• 
Typographical errors were corrected in addition to the term “ZOSTER-056” that 
was corrected to “ZOSTER-049” in the requirements for Germany (Section 13.2). 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Investigator Agreement page 
GSK Japan study 
representative / Joint 
Vaccine Co Japan Vaccine 
Co., Ltd. representative 
name, function and title 
 
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Synopsis and Section 1.2.2 Rationale for the study design 
1-Additional Dose Group: 
Section 5.2 
Inclusion criteria for enrolment 
Additional inclusion criteria for the 1-Additional Dose, and Revaccination and 
Control groups, ONLY: 
Section 5.3 
Exclusion criteria for enrolment 
Additional exclusion criteria for the 1-Additional Dose, and Revaccination and 
Control groups, ONLY: 
• 
Use of any investigational or non-registered product (pharmaceutical product or 
device) within 30 days preceding the first dose of study vaccine or planned use 
during the study period; 
Additional exclusion criterion for the 1-Additional Dose, Revaccination and Control 
groups, ONLY: 
Section 6.1.2 Allocation of subjects to assay subsets 
• 
and did NOT develop HZ (confirmed or suspected HZ) prior to enrolment in this 
ZOSTER-049 study. 
• 
and comply with inclusion and exclusion criteria (see Sections 5.2 and 5.3, 
respectively) to be part of the randomised groups). 
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Table 6 
List of study procedures (for the 1-Additional Dose, Revaccination and Control groups) 
Epoch 
LONG-TERM FOLLOW-UP 
Type of contact 
Visit MONTH 0 Visit Month 1  Visit Month 2† Visit Month 3‡ Monthly 
contacts a 
Visit  
YEAR 1, 2, 3, 4, 5 b 
Study conclusion 
Visit c 
Year 6 b 
Timepoints  
Day 0/ 
Month 0  
Month 1 
Month 2 † 
Month 3 ‡ 
 
Month  
12, 24, 36, 48, 60 
Month  
72 
Sampling timepoints 
Pre-Vacc 
Post-Vacc 1  
Post-Vacc 2 
 
Post-Vacc 2 
Post-Vacc 2 
Pregnancy test if applicable d, e (see Section 6.5.5) 
● 
 
● 
 
 
 
Check contraindications e (see Section 6.5.6) 
O 
 
O 
 
 
 
Training on self-reporting by subjects  f e 
O 
O 
O 
O 
 
O 
 
Pre-vaccination body temperature e f 
● 
 
● 
 
 
 
Vaccination e f 
● 
 
● 
 
 
 
Reporting of pregnancy e f (see Table 23) 
● 
● 
● 
● 
● 
● 
● 
Dispensing of 7-day diary cards for solicited AEs to the 7-day diary 
card and 30-day diary cards for unsolicited AEs and concomitant 
medication/vaccination to all vaccinated subjects e f 
O 
 
O 
 
 
 
Daily post-vaccination recording by subjects of solicited symptoms 
(Days 0 - 6 after each vaccination) on the 7-day diary card by all 
vaccinated subjects e f (see Table 23) 
O 
 
O 
 
 
 
Daily post-vaccination recording of unsolicited symptoms (Days 0 - 
29 after each vaccination), and concomitant medication/ 
vaccination (Days 0 - 29 after each vaccination) on the 30-day 
diary card by all vaccinated subjects e f (see Table 23) 
O 
 
O 
 
 
 
Returning by subjects of 7-day diary cards for solicited symptoms 
and 30-day diary cards for unsolicited AEs and concomitant 
medication and vaccination e f 
O 
 
O 
 
 
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Epoch 
LONG-TERM FOLLOW-UP 
Type of contact 
Visit MONTH 0 Visit Month 1  Visit Month 2† Visit Month 3‡ Monthly 
contacts a 
Visit  
YEAR 1, 2, 3, 4, 5 b 
Study conclusion 
Visit c 
Year 6 b 
Timepoints  
Day 0/ 
Month 0  
Month 1 
Month 2 † 
Month 3 ‡ 
 
Month  
12, 24, 36, 48, 60 
Month  
72 
Sampling timepoints 
Pre-Vacc 
Post-Vacc 1  
Post-Vacc 2 
 
Post-Vacc 2 
Post-Vacc 2 
Transcription of 7-day diary cards for solicited symptoms and 30-
day diary cards for unsolicited AEs and concomitant medication 
and vaccination by study staff/investigator e f 
● 
 
● 
 
 
e A study procedure only for the two groups vaccinated with 1 or 2 additional doses of HZ/su vaccine (1-Additional Dose and Revaccination). Subjects/ subject’s caregiver will be 
instructed to contact their study site immediately if he/she develops any symptoms suggestive of HZ and/or, if he/she manifests any symptoms he/she perceives as 
serious. 
f Subjects/ subject’s caregiver will be instructed to contact their study site immediately if he/she develops any symptoms suggestive of HZ and/or, if he/she manifests any symptoms 
he/she perceives as serious. A study procedure only for the two groups vaccinated with 1 or 2 additional doses of HZ/su vaccine (1-Additional Dose and 
Revaccination). 
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Section 6.5.5 Pregnancy test 
Female subjects of childbearing potential are to have a urine or serum pregnancy test  
before randomisation ( in the 1-Additional Dose, Revaccination and Control groups) 
and prior to any study vaccine second dose administration (in groups 1-Additional Dose 
and the Revaccination group, only).The study vaccines may only be administered if the 
pregnancy test is negative. Note: The urine pregnancy test must be performed even if the 
subject is menstruating at the time of the study visit. 
Section 6.5.6 Check contraindications, warnings and precautions to vaccination 
Contraindications to vaccination must be checked at the beginning of each vaccination 
visitbefore randomisation (in groups the 1-Additional Dose, and Revaccination and 
Control groups, only) and prior to study vaccine second dose administration (in the 
Revaccination group, only). Refer to Sections 7.5 for more details. 
Section 13.2 Requirements for Germany 
•
There is no intention to conduct specific analyses investigating the relationship
between the gender of the subjects and the safety of the GSK Biologicals’ HZ/su
vaccine. The ratio of male to female subjects recruited into the study ZOSTER-
05649 is expected to be in line with the demographics of the population aged
 50 YOA in the Member State.
Section 13.3 Requirements for Japan 
Clinical Trial Notification to Regulatory Authority 
GSKJapan Vaccine Co., Ltd. will submit the CTN to the regulatory authorities in 
accordance with Article 80-2 of the Pharmaceutical Affairs Law before conclusion of any 
contract for the conduct of the study with study sites. 
Study Period 
January, 2016 – February, 2018 (current estimation)The exact study period has not been 
confirmed at the time of this protocol. When needed and available, the study period can 
be communicated at local level, outside of this protocol. 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 2 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Amendment number: 
Amendment 2 
Amendment date: 
19 January 2017 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes: 
• 
This protocol is being amended after study start, because this being a long-term 
follow-up study and considering the age of the study population and the study 
duration (6 years), the current safety data collection requirement of the protocol 
will lead to collection of safety data that is not relevant for assessing the safety 
profile of the vaccine. This amendment was done to qualify that for the recording 
of AEs/SAEs leading to withdrawal which are not related to: 
− 
investigational vaccine, 
− 
study participation, 
− 
GSK concomitant medication/vaccine, 
− 
HZ complications. 
Only the name (diagnosis/description) of the event will be recorded in the eCRF. 
No other details about these types of AEs/SAEs will be recorded during the entire 
study (for the LTFU group), after 12 months from Visit Month 0 (for the Control 
and 1-Additional Dose groups) and after 12 months from last HZ/su vaccination 
(for the Revaccination group) as indicated in Sections 9.3.1 and Tables 22 and 23. 
• 
The footnote was added to Synopsis Table 1 and Tables 1 and 16 for clarity that 
all subjects entering the study will have a humoral immunogenicity (HI) blood 
sample at Visit Month 0 and for subjects in the LTFU group, who do not belong to 
any subset, these samples will be stored and tested for HI only if the subject 
develops HZ during the ZOSTER-049 study or if there are other reasons requiring 
the HI testing of these samples. 
• 
Although no confirmed signals related to hypersensitivity reactions (including 
anaphylaxis) have been identified during the HZ/su clinical program, a mitigation 
strategy for the potential risk has been added to the Risk Assessment Section 1.3.1. 
• 
The CMI Vaccine Response Rate (VRR) for gE was defined to align with the 
Statistical Analysis Plan (SAP) in Section 11.5.3. 
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• 
In addition to the Vaccine Efficacy (VE), it is now specified that assessments of 
immunogenicity will be performed when the last subjects have completed their 
year 2 and year 4 visit/contact, in the sequence of analyses Section 11.8.1. 
• 
The statement was added “If during the conduct of the study the HZ/su vaccine 
(GSK 1437173A) is approved in Japan, the study will then be locally amended to 
be conducted as a post-marketing study.” in Section 13.3. 
• 
The PCR algorithm text and Figure 3 were updated in APPENDIX A. 
• 
Typographic errors were corrected and other minor modifications were made 
throughout for clarification. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Title page 
Co-ordinating author 
, XPE Pharma and Science, Contractor 
for GSK BiologicalsScientific Writer 
Contributing authors 
• 
, Clinical Research and 
Development Lead 
• 
, Lead Study Delivery Lead 
• 
, Lead Study Delivery Lead 
• 
, Lead Study Delivery Lead 
• 
 and 
, Study 
Delivery Leads 
• 
, Study Delivery Lead, 
SynteractHCR Benelux, Contractor for GSK 
Biologicals 
• 
, and 
, and 
 
, SynteractHCR Benelux, Contractors for 
GSK Biologicals/ 
• 
, Global Vaccine Clinical 
LaboratoriesClinical Laboratory Sciences 
Clinical readout Team Leader 
• 
, Global Vaccine Clinical 
LaboratoriesClinical Laboratory Sciences Study 
Manager 
• 
, Vaccine Supply Coordinator 
• 
 
, Safety representative 
• 
, Oversight Data Manager 
• 
 and 
 (USA), Global 
Regulatory Affairs 
• 
, Zoster Portfolio level Clinical 
Research and Development and Epidemiology 
Project Lead for Zoster, GlaxoSmithKline 
Biologicals, Belgian RDC 
Copyright 2015-20167 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
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Sponsor signatory 
Lidia Oostvogels, Zoster Portfolio level Clinical 
Research and Development and Epidemiology 
Project Lead for Zoster, GlaxoSmithKline 
Biologicals, Belgian RDC 
Synopsis 
Rationale for the 
study and study 
design 
Two large pivotal phase III trials ZOE-50 and ZOE-70 that 
enrolled subjects  50 and  70 years of age (YOA) 
respectively, are evaluateding the vaccine efficacy (VE), 
immunogenicity and safety of GSK Biologicals’ HZ/su 
vaccine. 
The results for the ZOSTER-022 study are not yet available 
demonstrated that the HZ/su vaccine reduced the risks of 
HZ and PHN among adults  70 YOA. 
Since the mean follow-up period for VE at the time of the 
final analysis in the ZOSTER-006/022 studies will only be 
aroundwas about four years, further follow-up for long term 
efficacy assessment is needed, in order to establish that the 
HZ/su vaccine provides not only strong, but also persistent 
protection. 
Due to the high VE observed in the ZOSTER-006/022 
studyies, it was considered that subjects having received 
placebo during both of the ZOSTER-006/022 studies should 
be offered cross-vaccination with HZ/su vaccine as soon as 
possible. 
Objectives 
Secondary 
•
To assess the VE in the prevention of HZ over each year
of follow-up from one month post dose 2 in the
ZOSTER-006/022 studies as measured by the reduction
in HZ risk in subjects  50 YOA and within each of the
specified age ranges* at the time of first vaccination in
the ZOSTER-006/022 studies;
Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Epochs 
From ZOSTER-006 
primary study 
From ZOSTER-022 
primary study 
Total 
Epoch 001 
LTFU 
≤ 14208 ** 
x 
** All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 
0. For subjects in the LTFU group, who do not belong to any subset, these samples will be stored and tested
for HI only if the subject develops HZ during the ZOSTER-049 study or if there are other reasons requiring the
HI testing of these samples.
LIST OF ABBREVIATIONS 
ORF: 
Open Reading Frame 
VR: 
Vaccine Response 
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TRADEMARKS 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
 
Varivax® (Merck & Co., Inc.) 
 
 
Section 1.1 
Background 
The potential of vaccination to protect against HZ was evaluated in a large efficacy study 
in which Zostavax (a live attenuated HZ vaccine that is a high titre preparation of the 
varicella vaccine, Varivax [both manufactured by Merck & Co., Inc.]) partially protected 
immunocompetent older adults against HZ [Oxman, 2005]. 
Two large pivotal phase III trials ZOE-50 and ZOE-70 that enrolled subjects  50 and 
 70 years of age (YOA) respectively, are evaluateding the vaccine efficacy (VE), 
immunogenicity and safety of GSK Biologicals’ HZ/su vaccine. 
The results for the ZOSTER-022 study are not yet available demonstrated that the HZ/su 
vaccine reduced the risks of HZ and PHN among adults  70 YOA [Cunningham, 
2016]. 
Section 1.2.1 Rationale for the study 
Since the mean follow-up period for VE at the time of the final analysis in the ZOSTER-
006/022 studies will only be aroundwas about four years, further follow-up for long term 
efficacy assessment is needed, in order to establish that the HZ/su vaccine provides not 
only strong, but also persistent protection. 
Due to the high VE observed in the ZOSTER-006/022 studyies, it was considered that 
subjects having received placebo during both of the ZOSTER-006/022 studies should be 
offered cross-vaccination with HZ/su vaccine as soon as possible. 
Section 1.3.1 Risk Assessment 
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational HZ/su vaccine 
Hypersensitivity reactions 
(including anaphylaxis) 
No confirmed signals related 
to this potential risk have 
been identified during the 
clinical program. Available 
clinical data do not highlight 
any concern. 
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. 
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Section 2.2 
Secondary objectives 
• 
To assess the VE in the prevention of HZ over each year of follow-up from one 
month post dose 2 in the ZOSTER-006/022 studies as measured by the reduction in 
HZ risk in subjects  50 YOA and within each of the specified age ranges* at the 
time of first vaccination in the ZOSTER-006/022 studies; 
Section 3 
STUDY DESIGN OVERVIEW 
Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Epochs 
From ZOSTER-006 
primary study 
From ZOSTER-022 
primary study 
Total 
Epoch 001 
LTFU 
 
 
≤ 14208 ** 
x 
** All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 
0. For subjects in the LTFU group, who do not belong to any subset, these samples will be stored and tested 
for HI only if the subject develops HZ during the ZOSTER-049 study or if there are other reasons requiring the 
HI testing of these samples (see Section 6.5.8.1). 
Section 5.3 
Exclusion criteria for enrolment 
• 
Chronic administration (defined as ≥ > 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to Visit Month 0 of study ZOSTER-049 or expected administration at 
any time during the study period. 
Section 6.3.1.1 
Monthly contacts 
After Visit Month 0, monthly contacts between the subjects/ subject’s caregiver and the 
investigator and/or his delegate will take place to collect information on any event of 
interest that may have occurred [see Section 6.5.7 for details]. 
Section 6.3.1.2 
Diary cards and questionnaires 
For subjects in the two groups (1-Additional Dose and Revaccination, only), 7-day and 
30-day diary cards will be dispensed on the day of vaccination to be completed by the 
subjects/ subjects’ caregiver. 
Section 6.5.5 Pregnancy test 
Female subjects of childbearing potential are to have a urine or serum pregnancy test 
before randomisation (in the 1-Additional Dose, Revaccination and Control groups) and 
prior to study vaccine second dose administration (in the Revaccination group, only). The 
study vaccines may only be administered if the pregnancy test is negative. Note: The 
urine pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit. 
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Section 6.6.4.1. 
Immunological read-outs 
Table 16 
Immunological read-outs 
Blood sampling timepoint 1 
Subset Name 2 
Approximate  
No. of Subjects Component 
Visit No.3 
Month Timing 
Visit Month 0 
0 
Post-Primary All Subjects 
≤ 14448 4 
Ab gE ELISA 
LTFU Group CMI subset 
≤ 234 
ICS gE 
Pre-Vacc 
1-Additional Dose, Revaccination and Control 
Groups 
240 
ICS gE 
Visit Month 1 
1 
Post-Vacc 1 
1-Additional Dose, Revaccination and Control 
Groups 
240 
ICS gE 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Visit Month 3 
3 
Post–Vacc 2 
Revaccination and Control Groups 
180 
ICS gE 
Revaccination and Control Groups 
180 
Ab gE ELISA 
Visit Year 1, 
Visit Year 2, 
Visit Year 3, 
Visit Year 4, 
Visit Year 5, 
Visit Year 6 
12, 
24, 
36, 
48, 
60, 
72 
Post-Primary 
LTFU Group CMI subset 
≤ 234 
ICS gE 
LTFU Group HI subset 
≤ 1729 45 
Ab gE ELISA 
HZ subset 
TBD 
Ab gE ELISA 
Post-Vacc 1/2 
1-Additional Dose, Revaccination and Control 
Groups 
240 
ICS gE 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Post-Primary = Post-primary vaccination during ZOSTER-006/022; Pre-Vacc = Pre Vaccination; Post-Vacc 1 = Post 
Vaccination 1 (post dose 1); Post-Vacc 2 = Post-Vaccination 2 (post dose 2); LTFU = Long-Term Follow-Up; CMI 
= Cell-Mediated Immunity; HI = Humoral Immunogenicity; HZ = Herpes Zoster; TBD = To Be Determined; ICS = 
Intracellular cytokine staining; gE = Glycoprotein E; Ab = Antibody; ELISA = Enzyme-linked Immunosorbent 
Assay. 
1 Refer to Section 6.5.8.1 for the blood sampling timepoints. 
2 Refer to Table 4 and Table 12 for description of the subsets. 
3 Refer to Table 8, Table 9 and Table 10 for the intervals between study visits for the LTFU group, the 1-Additional 
Dose and Control groups and for the Revaccination group, respectively. 
4 All subjects (N ≤ 14,448) entering the study will have a HI blood sample (approximately 5 mL) at Visit Month 
0. For subjects in the LTFU group, who do not belong to any subset, these samples will be stored and 
tested for HI only if the subject develops HZ during the ZOSTER-049 study or if there are other reasons 
requiring the HI testing of these samples (see Section 6.5.8.1).  
45 Subjects to be included in the LTFU Group HI subset are from the immunogenicity subset in studies ZOSTER-
006/022 [N = 1269 (ZOSTER-006) + 460 (ZOSTER-022) = 1729 subjects at a maximum]. 
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Section 7.5 
Contraindications to subsequent vaccination 
Also, for corticosteroids, prednisone < 20 mg/day, or equivalent, is allowed. Inhaled, and 
topical and intra-articular corticosteroids are allowed. 
Section 7.6.1 Recording of concomitant medications/products and concomitant 
vaccinations 
Any concomitant medications relevant to a SAE/pIMD to be reported as per protocol or 
administered 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 
eExpedited Adverse Event report. 
Section 7.6.2 Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
• 
Chronic administration (defined as > 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs at any time during the study 
period. For corticosteroids, this will mean prednisone ≥ 20 mg/day or equivalent. 
Section 9.3.1 Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first study visit Month 0 up to the last study visit/ contact at the end of the 
study*. 
* If the AEs/SAEs are not related to investigational vaccine, study participation or 
to GSK concomitant medication/vaccine, or if not due to HZ complications, only 
the name (diagnosis/description) of the event will be recorded in the eCRF. No 
other details about AEs/SAEs will be recorded during the entire study (for the 
LTFU group), from Visit Month 0 until 12 months (for the Control and 1-
Additional Dose groups) and from Visit Month 0 until 12 months after last HZ/su 
vaccination (for the Revaccination group). 
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Table 22 
Reporting periods for collecting safety information (for the LTFU 
group) 
Event a 
Visit 
Month 0 
Visit 
Year 1 - 5 
Study 
conclusion 
visit/ contact 
Year 6 
Timing of reporting 
Month 0 
Month 12 - 60 
Month 72 
Reporting of SAEs related to investigational vaccine, related to 
study participation or to GSK concomitant medication/vaccine 
AEs/SAEs leading to withdrawal from the study 
IMCs (see Section 7.7) 
HZ complications (see Section 4.4) (including SAE information) b 
AEs/SAEs leading to withdrawal from the study (see Section 
9.3.1) c 
AE = Adverse Event; SAE = Serious Adverse Event; GSK = GlaxoSmithKline; IMC = Intercurrent Medical Condition; 
HZ = Herpes Zoster. 
a The reporting period of all events starts from the time the subject consents to participate in the study. 
b A HZ complication related to a HZ episode which was initiated during the primary study or during the interval between 
the end of ZOSTER-006/022 and beginning of the ZOSTER-049 study is to be recorded in general medical history 
at the first Month 0 Visit of study ZOSTER-049. 
c If the AEs/SAEs are not related to investigational vaccine, study participation or to GSK concomitant 
medication/vaccine, or if not due to HZ complications, only  the name diagnosis/description) of the event 
will be recorded in the eCRF. No other details about AEs/SAEs will be recorded. 
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Table 23 
Reporting periods for collecting safety information (for the 1-Additional Dose, Revaccination and Control groups) 
Event 
Visit 
Month 0 
Dose 1 
 
 
 
Visit  
Month 2‡ 
Dose 2 
 
 
 
 
 Visit/ contact 
Year 1 - 5 
Study conclusion 
visit/ contact  
Year 6 
Timing of reporting 
Month 0 
Day 6 post  
Dose 1 
Day 29 post 
Dose 1 
 
Month 2‡ Day 6 post 
 Dose 2‡ 
Day 29 post 
Dose 2‡ 
 Month 6  Month 12 - 60 
Month 72 
AEs/SAEs leading to withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HZ complications (see Section 4.4) (including 
SAE information) d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to withdrawal from the study 
(see Section 9.3.1) e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e Twelve months after last HZ/su vaccination, if the AEs/SAEs are not related to investigational vaccine, study participation or to GSK concomitant medication/vaccine, or 
if not due to HZ complications, only the name (diagnosis/description) of the event will be recorded in the eCRF. No other details about AEs/SAEs will be recorded.  
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Section 9.5.1.2 
Follow-up after the subject is discharged from the study 
• 
with other non-serious AEs, cases of new onset of autoimmune diseases, until study 
conclusion or they are lost to follow-up. 
Section 11.5.3 CMI response 
• 
The CMI vaccine response to gE will be based on the gE-specific data as computed 
above. The lower limit of linearity (LLL) for the assay will be used as threshold for 
vaccine response assessment and the estimated value will be detailed in the 
Statistical Analysis Plan (SAP). The Vaccine Response (VRR) is defined as the 
percentage of subjects who have at least: 
− 
at least a 2-fold increase as compared to the LLL, for subjects with pre-
vaccination T-cell frequencies below the LLLthreshold 320 polypositive CD4+ 
T cells/10E6 CD4+ T cells, for subjects with pre-vaccination T-cell 
frequencies below the threshold 320 polypositive CD4+ T cells/10E6 CD4+ 
T cells; 
− 
at least a 2-fold increase as compared to pre-vaccination T-cell frequencies, for 
subjects with pre-vaccination above the LLLthreshold 320 polypositive CD4+ T 
cells/10E6 CD4+ T cells. 
Section 11.6.3.3 
Analysis of persistence (immune subset of LTFU group) 
Since the interval between the end of ZOSTER-006/022 studies and the start of this study 
will vary per subject and is dependent on receipt of approval or implementing the study 
in the different participating countries, some results from the first blood sample may 
correspond to year 5, year 6 or year 7 post vaccination. 
Section 11.8.1. 
Sequence of analyses 
At this point, the GSK central clinical team will have access to the lab data and the 
treatment assignment from SBIR. 
2. Two intermediate analyses to assess the VE at year 2 and year 4 (LTFU and Control 
groups): 
• 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 2 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 2 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. 
• 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 4 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 4 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. 
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Section 13.3 Requirements for Japan 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare [MHW]/ Ministry of Health, Labour and Welfare Notification No.28 dated 
27th March, 1997)” GCP and, Article 14-3 and 80-2 of the Pharmaceutical Affairs Law 
and Evaluation and Licensing Division, Pharmaceutical Safety Bureau of MHW, 
Notification No. 1061, 1998. 
Study Period 
The exact study period has not been confirmed at the time of this protocol. When needed 
and available, the study period can be communicated at local level, outside of this 
protocol. 
If during the conduct of the study the HZ/su vaccine (GSK 1437173A) is approved in 
Japan, the study will then be locally amended to be conducted as a post-marketing 
study. 
REFERENCES 
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. 
APPENDIX A 
LABORATORY ASSAYS 
PCR assay for confirmation of suspected case of HZ: 
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. 
•
Ascertainment of HZ cases including the PCR testing algorithm to classify HZ
suspected cases
Blood samples collected at Visit Month 0 will be tested to assess VZV serological status 
of subjects born in 1980 or later or before 1980 in a tropical region, and with no 
serological evidence of prior VZV infection available at the time of Visit Month 0, in the 
following cases: 
•
The subject presents with suspected HZ according to criterion (1) with rash
disseminated from onset and PCR confirmation of the presence of VZV DNA (see
Figure 3): If the subject is found to have been seronegative at Visit Month 0
(baseline), the case will not be considered a confirmed HZ case for the efficacy
analysis.
•
The subject presents with suspected HZ with rash disseminated from onset and PCR
results are inconclusive (see Figure 3): If the subject is found to have been
seronegative at Visit Month 0 (baseline), the case will not be considered a confirmed
HZ case for the efficacy analysis.
•
The subject presents with suspected HZ according to criterion (1) with rash
disseminated from onset but no rash lesion samples are available for PCR testing: If
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the subject is found to have been seronegative at Visit Month 0 (baseline), the case 
will not be considered a confirmed HZ case for the efficacy analysis. 
• 
The subject presents with suspected HZ and was diagnosed with VZV-related 
disease according criterion (2): if the subject is found to have been seronegative at 
Visit Month 0 (baseline), the case will not be considered a confirmed HZ case for the 
efficacy analysis. 
Figure 3 
Algorithm for HZ case definition by PCR 
Former Figure 3 
 
 
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New Figure 3 
 
VZV: Varicella Zoster Virus; PCR: real-time Polymerase Chain Reaction; DNA: Deoxyribonucleic Acid; ORF: Open 
Reading Frame; HZAC: Herpes Zoster Ascertainment Committee. 
Note: The cut-off level of the VZV PCR assay is defined as the technical limit of detection of the assay (LOD of 10 VZV 
DNA copies; i.e., lowest concentration that can be detected by PCR in at least 95% of the tests) 
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; i.e., lowest concentration that can be detected by PCR in at least 95% of the tests) 
** Blood samples collected at Visit Month 0 prior to vaccination will be used for testing of VZV serological-status if all of 
the following three conditions apply: 
− 
Subject was diagnosed with suspected HZ, presented with disseminated rash from onset, and had VZV-positive 
PCR results, or VZV inconclusive PCR results, according the algorithm above; Subject was born in 1980 or later, 
OR was born before 1980 in a tropical region; 
− 
No serological evidence of prior VZV infection was available at Visit Month 0. 
In these subjects, a suspected HZ case with VZV positive PCR results according to the algorithm above is not 
considered a confirmed case of HZ if the subject was diagnosed with suspected HZ (see Section 4.5.2) and 
presented with a disseminated rash from onset, and the subject was VZV seronegative at baseline. 
In these subjects, a suspected HZ case with VZV inconclusive PCR results according to the algorithm above is not 
considered a confirmed case of HZ if the subject was diagnosed with suspected HZ according criterion (1) (see 
Section 4.5.2) and presented with a disseminated rash from onset, and the subject was VZV seronegative at 
baseline. 
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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Administrative Change 1 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
Administrative change 
number: 
Administrative change 1 
Administrative change date: 
05 May 2017 
Co-ordinating author: 
, Scientific writer 
Rationale/background for changes: 
•
The back-up study contact telephone number for reporting SAEs, pregnancies and
pIMDs in the US was deleted in Section 9.4.2, since that telephone number, which
was originally provided to the sites as a courtesy, has been inactivated.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Section 9.4.2 Contact information for reporting serious adverse events, pregnancies 
and pIMDs 
Study Contact for Reporting SAEs, pregnancies and pIMDs 
Back-up Study Contact for Reporting SAEs, pregnancies and pIMDs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
US sites only: 
Fax:  Tel: 31-610-787-3185 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 3 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Amendment number: 
Amendment 3 
Amendment date: 
16 March 2018 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes: 
• 
This protocol is being amended following a request by the European Medicines 
Agency (EMA). Vaccine efficacy (VE) in prevention of Herpes Zoster (HZ) 
related complications (other than Postherpetic Neuralgia [PHN]) in the overall 
study population and VE in the prevention of PHN over each year of follow-up 
from one month post dose 2 in the ZOSTER-006/022 studies until the end of the 
ZOSTER-049 study will be assessed. The corresponding objectives and endpoints 
were added. In addition, as per EMA’s request, a sensitivity analysis will be 
performed to assess the impact on VE of HZ episodes occurring during the interval 
between the end of the ZOSTER-006/022 studies and beginning of the ZOSTER-
049. 
• 
 
 
 
• 
Since the HZ/su vaccine was first approved in Canada and the United States in 
October 2017, the Trademarks were updated to include the trade name Shingrix. 
(Amended 23 October 2018) 
• 
Typographic errors were corrected and other minor modifications were made 
throughout for clarification. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Title page 
Contributing authors 
• 
, Clinical Research and 
Development Lead, XPE Pharma and Science, 
Consultant for GSK Vaccines 
• 
 
, Project 
Statistician 
• 
, Lead Study Delivery Lead 
• 
, Lead Study Delivery Lead 
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• 
, Lead Study Delivery Lead  
• 
 and 
 
 
 Study Delivery Leads 
• 
, 
 and 
 
 SynteractHCR Benelux, Contractors for 
GSK Biologicals/  
, Study Delivery 
Managers 
• 
 
, Vaccine Supply 
Coordinator 
• 
, Vaccine Supply Coordinator 
• 
, Clinical Safety 
representative 
• 
, Clinical Safety representative 
• 
 
, 
Safety representative 
• 
, Oversight Data Manager 
• 
 
 and 
 
 (USA), Global Regulatory Affairs 
• 
 and 
 (USA), Global 
Regulatory Affairs 
• 
 
, Global Patent 
• 
, Project level Clinical Research and 
Development Lead, GlaxoSmithKline Biologicals, 
Belgian RDC 
• 
 
, Clinical and 
Epidemiology Project Lead for Zoster, 
GlaxoSmithKline Biologicals, Belgian US RDC 
GSK Biologicals’ Protocol DS v14.1.1 
Copyright 2015-2018 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. ©2015-2018 GSK group of companies or its 
licensor 
Protocol Amendment 3 Sponsor Signatory Approval 
Sponsor signatory 
Lidia Oostvogels Anne Schuind, Clinical and 
Epidemiology Project Lead for Zoster, 
GlaxoSmithKline Biologicals, Belgian US RDC 
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Synopsis 
Rationale for the 
study and study 
design 
• 
Rationale for the study 
GlaxoSmithKline (GSK) Biologicals’ candidate study vaccine 
for the prevention of HZ, is a recombinant subunit (su) 
vaccine consisting of Varicella Zoster Virus (VZV) 
glycoprotein E (gE) as antigen and an adjuvant system 
(AS01), has been and is being evaluated in several studies in 
older adults and immunocompromised adults. In these studies 
it was shown to elicit strong cellular and humoral immune 
responses. Furthermore, the safety and reactogenicity profile 
of the candidate study vaccine was clinically acceptable. 
Objectives 
Primary 
• 
To assess the VE in the prevention of HZ over the total 
duration of the ZOSTER-049 study overall as measured 
by the reduction in HZ risk in subjects ≥ 50 YOA overall 
at the time of first vaccination in the ZOSTER-006/022 
studies. 
 
Secondary 
• 
To assess the VE in the prevention of HZ from one month 
post dose 2 in the ZOSTER-006/022 studies until the end 
of the ZOSTER-049 study as measured by the reduction 
in HZ risk in subjects  50 YOA overall and within each 
of the specified age ranges* at the time of first 
vaccination in the ZOSTER-006/022 studies; 
• 
To assess the VE in the prevention of HZ over each year 
of follow-up from one month post dose 2 in the 
ZOSTER-006/022 studies as measured by the reduction 
in HZ risk in subjects  50 YOA overall and within each 
of the specified age ranges* at the time of first 
vaccination in the ZOSTER-006/022 studies; 
• 
To assess the VE over the total duration of the ZOSTER-
049 study overall in prevention of PHN in subjects 
 50 YOA overall and within each of the specified age 
ranges* at the time of first vaccination in the ZOSTER-
006/022 studies; 
• 
To assess the VE in the prevention of PHN from one 
month post dose 2 in the ZOSTER-006/022 studies until 
the end of the ZOSTER-049 study in subjects  50 YOA 
overall and within each of the specified age ranges* at 
the time of first vaccination in the ZOSTER-006/022 
studies; 
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•
To assess the VE over the total duration of the
ZOSTER-049 study in prevention of HZ related
complications (other than PHN) in subjects ≥ 50 YOA
overall and within each of the specified age ranges* at
the time of first vaccination in the ZOSTER-006/022
studies;
•
To assess the VE in the prevention of HZ related
complications (other than PHN) from one month post
dose 2 in the ZOSTER-006/022 studies until the end of
the ZOSTER-049 study in subjects ≥ 50 YOA overall
and within each of the specified age ranges* at the time
of first vaccination in the ZOSTER-006/022 studies;
•
To assess persistence of humoral immune responses at
Year 5, 6, 7, 8, 9 and 10 and beyond after the primary
vaccination in the ZOSTER-006/022 studies in the HI
subset in subjects  50 YOA overall and within each of
the specified age ranges* at the time of first vaccination,
in the ZOSTER-006/022 studies;
•
To assess persistence of vaccine induced cell-mediated
immune responses at Year 5, 6, 7, 8, 9 and 10 and beyond
after the primary vaccination in the ZOSTER-006/022
studies in the CMI subset in subjects  50 YOA overall
and within each of the specified age ranges* at the time
of first vaccination, in the ZOSTER-006 study;
Tertiary 
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Endpoints 
Primary 
• 
Confirmed HZ cases (LTFU and Control groups); 
− 
Confirmed HZ cases during the ZOSTER-049 study. 
 
Secondary 
• 
PHN cases; 
− 
PHN cases during the ZOSTER-049 study and since 
one month post dose 2 in the previous ZOSTER-
006/022 studies; 
• 
HZ related complications (other than PHN); 
− 
HZ related complications (other than PHN) during 
the ZOSTER-049 study and since one month post 
dose 2 in the previous ZOSTER-006/022 studies; 
Tertiary 
LIST OF APPENDICES 
PAGE 
APPENDIX A 
LABORATORY ASSAYS 
 
 
 
 
141 
APPENDIX B 
CLINICAL LABORATORIES 
 
 
 
145 
APPENDIX C 
AMENDMENTS AND ADMINISTRATIVE  
            CHANGES TO THE PROTOCOL  
 
 
146 
LIST OF ABBREVIATIONS 
EMA: 
 
European Medicines Agency 
 
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TRADEMARKS 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
Generic description 
Varivax® (Merck & Co., Inc.) 
 
Varicella vaccine consisting of live 
attenuated varicella-zoster virus (Oka strain) 
Zostavax® (Merck & Co., Inc.) 
 
Herpes zoster vaccine consisting of high-
titre live attenuated Varicella-zoster virus 
(Oka strain) 
QS-21: Quillaja saponaria Molina, fraction 
21 (Licensed by GSK from Antigenics Inc, a 
wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation) 
 
Triterpene glycoside immune enhancer 
 
Trademarks of the GSK group of 
companies 
 
Generic description 
Shingrix 
 
Herpes zoster vaccine non-live 
recombinant, AS01B adjuvanted 
Section 1.1 Background 
GlaxoSmithKline (GSK) Biologicals’ candidate study vaccine (Shingrix) for the 
prevention of HZ, is a recombinant subunit (su) vaccine consisting of Varicella Zoster 
Virus (VZV) glycoprotein E (gE) as antigen and an adjuvant system (AS01), has been 
and is being evaluated in several studies in older adults and immunocompromised adults. 
In these studies it was shown to elicit strong cellular and humoral immune responses. 
Furthermore, the safety and reactogenicity profile of the candidate study vaccine was 
clinically acceptable. 
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name 
Shingrix) was first approved in the United States and Canada in October 2017. 
Section 2.1 Primary Objective 
• 
To assess the VE in the prevention of HZ over the total duration of the ZOSTER-049 
study overall as measured by the reduction in HZ risk in subjects ≥ 50 YOA overall 
at the time of first vaccination in the ZOSTER-006/022 studies. 
Section 2.2 Secondary Objective 
• 
To assess the VE in the prevention of HZ from one month post dose 2 in the 
ZOSTER-006/022 studies until the end of the ZOSTER-049 study as measured by 
the reduction in HZ risk in subjects  50 YOA overall and within each of the 
specified age ranges* at the time of first vaccination in the ZOSTER-006/022 
studies; 
• 
To assess the VE in the prevention of HZ over each year of follow-up from one 
month post dose 2 in the ZOSTER-006/022 studies as measured by the reduction in 
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HZ risk in subjects  50 YOA overall and within each of the specified age ranges* at 
the time of first vaccination in the ZOSTER-006/022 studies; 
•
To assess the VE over the total duration of the ZOSTER-049 study overall in
prevention of PHN in subjects  50 YOA overall and within each of the specified
age ranges* at the time of first vaccination in the ZOSTER-006/022 studies;
•
To assess the VE in the prevention of PHN from one month post dose 2 in the
ZOSTER-006/022 studies until the end of the ZOSTER-049 study in subjects
 50 YOA overall and within each of the specified age ranges* at the time of first
vaccination in the ZOSTER-006/022 studies;
•
To assess the VE over the total duration of the ZOSTER-049 study in prevention of
HZ related complications (other than PHN) in subjects ≥ 50 YOA overall and
within each of the specified age ranges* at the time of first vaccination in the
ZOSTER-006/022 studies;
•
To assess the VE in the prevention of HZ related complications (other than PHN)
from one month post dose 2 in the ZOSTER-006/022 studies until the end of the
ZOSTER-049 study in subjects ≥ 50 YOA overall and within each of the specified
age ranges* at the time of first vaccination in the ZOSTER-006/022 studies;
•
To assess persistence of humoral immune responses at Year 5, 6, 7, 8, 9 and 10 and
beyond after the primary vaccination in the ZOSTER-006/022 studies in the HI
subset in subjects  50 YOA overall and within each of the specified age ranges* at
the time of first vaccination, in the ZOSTER-006/022 studies;
•
To assess persistence of vaccine induced cell-mediated immune responses at Year 5,
6, 7, 8, 9 and 10 and beyond after the primary vaccination in the ZOSTER-006/022
studies in the CMI subset in subjects  50 YOA overall and within each of the
specified age ranges* at the time of first vaccination, in the ZOSTER-006 study;
Section 2.3 Tertiary Objective 
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Table 14 
Cell-Mediated Immunity (CMI) 
System 
Component 
Challenge 
Method 
Unit 
Cut-off 
Laboratory 
PBMC 
GSK 
Biologicals* 
PBMC = Peripheral Blood Mononuclear Cells; IL-2 = Interleukin-2; TNF = Tumor Necrosis Factor; IFN = Interferon; gE 
= Glycoprotein E; ICS = Intracellular cytokine staining; 
; N/A = Not 
Applicable. 
* see Table 28 in Appendix B. 
Table 16 
Immunological read-outs 
Blood sampling timepoint 1 
Subset Name 2 
Approximate  
No. of Subjects Component 
Visit No.3 
Month Timing 
Visit Month 0 
0 
Post-Primary 
All Subjects 
≤ 14448 4 
Ab gE ELISA 
LTFU Group CMI subset 
≤ 234 
ICS gE 
Pre-Vacc 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS gE& 
 
Visit Month 1 
1 
Post-Vacc 1 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS gE& 
 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Visit Month 3 
3 
Post–Vacc 2 
Revaccination and Control Groups 
180 
gE ICS gE& 
 
Revaccination and Control Groups 
180 
Ab gE ELISA 
Visit Year 1, 
Visit Year 2, 
Visit Year 3, 
Visit Year 4, 
Visit Year 5, 
Visit Year 6 
12, 
24, 
36, 
48, 
60, 
72 
Post-Primary 
LTFU Group CMI subset 
≤ 234 
gE ICS gEg 
LTFU Group HI subset 
≤ 1729 5 
Ab gE ELISA 
HZ subset 
TBD 
Ab gE ELISA 
Post-Vacc 1/2 
1-Additional Dose, Revaccination and Control 
Groups 
240 
gE ICS gE& 
 
1-Additional Dose, Revaccination and Control 
Groups 
240 
Ab gE ELISA 
Post-Primary = Post-primary vaccination during ZOSTER-006/022; Pre-Vacc = Pre Vaccination; Post-Vacc 1 = Post 
Vaccination 1 (post dose 1); Post-Vacc 2 = Post-Vaccination 2 (post dose 2); LTFU = Long-Term Follow-Up; CMI 
= Cell-Mediated Immunity; HI = Humoral Immunogenicity; HZ = Herpes Zoster; TBD = To Be Determined; ICS = 
Intracellular cytokine staining; gE = Glycoprotein E; Ab = Antibody; ELISA = Enzyme-linked Immunosorbent 
Assay; 
 .. 
6 
on available PBMC following gE ICS analysis. 
Section 6.6.5 
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 candidate study vaccine. 
Section 7.1 Description of study vaccine 
The candidate study vaccine/product to be used has been developed and manufactured by 
GSK Biologicals. 
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Section 9.2.1 
Pregnancy 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the EMA 
European Medicines Agency (EMA) Guideline on pregnancy exposure [EMA, 2006]. It 
is recognised that national regulations might be different. 
Section 11.1 
Primary endpoint 
• 
Confirmed HZ cases (LTFU and Control groups); 
− 
Confirmed HZ cases during the ZOSTER-049 study. 
Section 11.2 
Secondary endpoint 
• 
PHN cases; 
− 
PHN cases during the ZOSTER-049 study and since one month post dose 2 in 
the previous ZOSTER-006/022 studies; 
• 
HZ related complications (other than PHN); 
− 
HZ related complications (other than PHN) during the ZOSTER-049 study 
and since one month post dose 2 in the previous ZOSTER-006/022 studies; 
Section 11.3 
Tertiary endpoint 
Section 11.6.2 
Humoral immune response 
Section 11.7.2. 
Analysis of efficacy (LTFU and Control groups) 
The primary analysis will be to assess the VE during this study and will use the historical 
control estimates adjusted for age at randomisation during the ZOSTER-006/022 studies. 
The method using the historical control estimates will be further explained in the 
Statistical Analysis Plan (SAP). 
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Any available information for the diagnosis of HZ episodes (clinical diagnosis, PCR, 
laboratory methods, etc.) during the interval between the end of the ZOSTER-006/022 
studies and beginning of the ZOSTER-049 study is to be collected. Confirmation of all 
of these cases in the exact way as what will be done for cases collected during the 
clinical study follow-up periods of the ZOSTER-006, ZOSTER-022 and ZOSTER-049 
will not be possible. Therefore, these cases will not be part of all efficacy analyses. A 
sensitivity analysis to assess the impact of these cases on the VE will be performed (this 
will be described in the SAP). 
will be described in the SAP). 
The purpose of these analyses will be descriptive and therefore the CIs will not be 
adjusted for multiple testing. 
The analyses will be performed for confirmed HZ case and for PHN cases, for PHN and 
for complications (other than PHN). 
Section 11.7.3.1.2.  
Cell-mediated immune response 
• 
Descriptive statistics of the frequency of CD4+ T-cells expressing at least two 
activation markers (from among IFN-, IL-2, TNF-, CD40L) for gE-specific 
stimulation. 
Section 11.7.3.3.2  
Cell-mediated immune response 
For the yearly prediction of the GMCs CMI (year 5 to year 10 and beyond): the analysis 
of CMI persistence will be based on the ATP cohort for persistence adapted for each 
year. 
Section 11.9.1 
Sequence of analyses 
2. Two intermediate analyses to assess the VE at year 2 and year 4 (LTFU and Control 
groups): 
− 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 2 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 2 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. Please refer 
to the SAP 
− 
An assessment of the VE and immunogenicity will be performed when the last 
subjects have completed their year 4 visit/contact and when efficacy data (on 
confirmed HZ cases), immunogenicity data as well as related SAEs up to year 4 
are available and as clean as possible. Because the analysis is purely descriptive, 
no adjustment on type I error is foreseen. A clinical study report is planned to be 
written at this time but no individual data listings will be provided. Please refer 
to the SAP 
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Section 13.1 
Requirements for France 
It is expressly specified that GSK and/or the Sponsor can make available to the public the 
results of the Study by the posting of the said results on a website of the GSK Group 
named Clinical Trial Registredr (CTR) including the registration of all the clinical trials 
conduct by the GSK Group and this before or after the publication of such results by any 
other process. 
APPENDIX A 
LABORATORY ASSAYS 
Intracellular cytokine staining (ICS): 
CMI responses will be performed by GSK Biologicals (or designated laboratory) on 
thawed Peripheral Blood Mononuclear Cells (PBMCs) by ICS. The assay will be 
performed on samples collected during the course of the study. This assay provides 
information on the frequency of CD4 T cells responding to culture medium or antigens 
(gE peptide pool) by secreting cytokine expressing molecules involved in immunity such 
as IFN-, IL-2, TNF-, and CD40L (here considered as activation markers). 
Briefly, PBMC collected from the subjects are stimulated for two hours using culture 
medium (for evaluation of the non-specific response), a pool of overlapping peptides 
covering the entire sequence of the vaccine antigen gE. Then, an intracellular block 
(brefeldin A) is added to inhibit cytokine secretion for a subsequent overnight incubation. 
Cells are then harvested, stained for surface markers (CD3, CD4 and CD8) and fixed. 
The fixed cells are then permeabilised and stained with anti-cytokine Abs specific to the 
activation markers assessed, washed and analyzed by cytofluorometry. 
The results of ICS assays are expressed as the frequency of specific CD4 T cells per 
million total CD4 T cells. 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 4 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Amendment number: 
Amendment 4 
Amendment date: 
23 October 2018  
Co-ordinating author: 
, Scientific Writer, XPE Belgium, 
Contractor for GSK 
Rationale/background for changes: 
(from page 4) 
• 
This amendment relates to the time frame of completing the Zoster Brief Pain 
Inventory (ZBPI) questionnaire. This change will ensure thorough reporting of 
postherpetic neuralgia cases. Subjects with suspected herpes zoster (HZ) are 
required to complete the questionnaire until a 4-week pain-free period is 
documented and beyond Day HZ-91, if applicable. This amendment removes the 
stipulation “or until Day HZ-91” and therefore, if pain develops after Day HZ-91 
to capture of cases of postherpetic neuralgia according to the protocol definition.  
• 
Reporting of cytotoxic chemotherapy as a concomitant medication was clarified. 
• 
 Other minor changes include correcting and updating text regarding country 
approvals of Shingrix, and correcting minor typographical errors. 
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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Section 4.5.1 Definitions 
For all subjects in case of a suspected or confirmed case of HZ: 
Zoster Brief Pain Inventory (ZBPI) questionnaire: To be completed by subjects 
with suspected HZ (or subject’s caregiver) on Day HZ-0 (Visit HZ-1) and daily from 
Day HZ-1 (day after the Visit HZ-1) up to Day HZ-28, and weekly from Day HZ-29 
onwards until a 4-week pain-free period is documented or until Day HZ-91.  
Section 4.5.2 Evaluation of suspected case of HZ 
Changed this sentence to a subheader: 4.5.2.1: For clinically diagnosed suspected HZ 
cases, the following will take place at Visit HZ-1: 
Deleted or until Day HZ-91 in 3 places: 
− 
28 days after HZ-associated pain ceases or until Day HZ-91.  
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-91  
If HZ-associated pain ceases (defined as a 28-day [or 4-week] pain free period) or until 
Day HZ-91, the study staff/investigator will inform the subject/ subject’s caregiver to 
stop completing the ZBPI questionnaires and will provide instructions for the subject 
to return the completed questionnaires to the study site. 
Text was edited as follows: 
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 
cCollection 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-0 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-91) 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-91, and rash has resolved, collection of information 
on pain will end for study purposes and the subject will be followed as per the 
investigators discretion. Once a pain free period of 4 weeks has been documented or 
information on pain till Day HZ-91 has been collected, subjects with ongoing 
symptoms related to suspected HZ episode including ongoing pain will be followed as 
per the investigator discretion. 
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Changed this sentence to a subheader: 4.5.2.2: The following will take place at each 
visit or contact that occurs for each episode: 
Other subheading numbers in this section changed when new subheadings were added:  
4.5.2.1 4.5.2.3 Evaluation of severity of HZ-associated pain using the Zoster Brief Pain 
Inventory 
4.5.2.2 4.5.2.4 Confirmation of a suspected case of HZ 
4.5.2.2.1 4.5.2.4.1 Confirmation of suspected HZ by PCR 
4.5.2.2.2 4.5.2.4.2 Confirmation of suspected HZ by the HZAC 
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 Month 0 until 
the study conclusion Visit. 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) will be collected daily until Day- HZ-28, and 
weekly from Day HZ-29 until the subject has no HZ-associated pain for 4 consecutive 
weeks, or until Day HZ-91. 
Visits/contacts will also restart according to the schedule in Table 7 with Day HZ-0 
defined as the first visit of the assigned episode, prior to the pain free period. Follow-
up will end at Day HZ-91 as is described in Section 4.5.2. 
Notes to Table 7 Study Procedure 
† Subjects with suspected HZ will be asked to complete the ZBPI questionnaire at Day 
HZ-0 (Visit HZ-1) to rate HZ-associated pain within the last 24 hours (If the time 
between the HZ onset and clinical evaluation at Visit HZ-1 is greater than 24 hours, the 
subject will be asked to complete a second ZBPI also for the elapsed time between the 
HZ onset and 24 hours before Visit HZ-1); daily from Day HZ- 1 to Day HZ-28, and 
weekly from Day HZ-29 onwards until a 4-week pain-free period is documented or 
until Day HZ-91. 
 Added † to the column heading for  
Visit HZ-7 
Day HZ-91† 
Note to Table 11 Intervals between visits/… 
Note: If HZ-associated pain ceases (i.e., 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). Follow-up of HZ-associated 
pain persisting beyond Visit HZ-7 (Day HZ-91) or other complications will be done at monthly contacts 
between the subject and the investigator and/or investigator’s delegate.  will end for study purposes and 
the subject will be followed as per the investigators discretion.  
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Section 6.5.1 Informed Consent 
For subjects with suspected HZ at Visit HZ-1 (i.e., either ongoing cases or subjects 
developing a new case), an informed consent addendum or update may be required 
to inform these subjects of the change in the follow-up period for pain assessment 
questionnaire. 
Section 7.6.2 Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
Added: Administration of cytotoxic chemotherapy at any time during the study 
period 
Section 13.3 Requirements for Japan 
Study Period 
Shingrix was approved in Japan on 23 March 2018, after study start. Therefore, this 
study is being conducted as a post-marketing study from the approval date in Japan.  
Minor changes include: 
Title page: 
Co-ordinating Author: added GSK Scientific Writer to 
 and added  
, Scientific Writer XPE Belgium, Contractor for GSK  
Contributing Authors:  
Added 
, Clinical Research and Development Lead and deleted 
 
• 
Added and 
, Study Delivery Leads and deleted: 
 
 Study Delivery Lead, Synteract, HCR Benelux, Contractor for GSK 
Biologicals 
• 
added 
, Clinical Laboratory Sciences Study Manager and 
deleted 
,  
Changed: 
• 
, Clinical Safety representative 
• 
, Clinical Safety representative 
To: 
• 
 and 
, Clinical Safety representatives 
• 
Changed: 
, Clinical Safety Representative Physician 
• 
Added 
 and deleted 
 (USA), Global Regulatory Affairs 
• 
Added 
 and, Lead Statisticians 
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Section 1.1. Background  
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name 
Shingrix) was first approved in Canada and the United States and Canada in October 
2017.  
Section 13.3 Requirements for Japan 
If during the conduct of the study the HZ/su vaccine (GSK 1437173A) is approved in 
Japan, the study will then be locally amended to be conducted as a post-marketing 
study.  
Shingrix was approved in Japan on 23 March 2018, after study start. Therefore, this 
study is being conducted as a post-marketing study from the approval date in Japan. 
Changes to APPENDIX C: Amendments And Administrative Changes To The 
Protocol 
Protocol Administrative Change 1 date  
Date of Administrative Change 19 February 2016 05 May 2017 
• 
Amendment 3 rationale in appendix section 
Since the HZ/su vaccine was first approved in Canada and the United States and 
Canada in October 2017, the Trademarks were updated to include the trade name 
Shingrix. 
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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Administrative Change 2 
eTrack study number and 
Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
Administrative change 
number: 
Administrative change 2 
Administrative change date: 
11 February 2019 
Co-ordinating author: 
, Scientific writer  
Rationale/background for changes: 
The Japan Vaccine Company will no longer be in operation as of 01 April 2019. 
Therefore, the reference to “Japan Vaccine Co., Ltd.” has been changed to “GSK 
Japan”. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Signature page (page 7): Japan Vaccine Company, Ltd GSK Japan representative 
name, function and title 
• 
Authors: deleted Study Delivery Lead, and 
,  
Section 13.3 Requirements for Japan 
Clinical Trial Notification to Regulatory Authority 
Japan Vaccine Company, Ltd GSK Japan will submit the CTN to the regulatory 
authorities in accordance with Article 80-2 of the Pharmaceutical Affairs Law before 
conclusion of any contract for the conduct of the study with study sites. 
Other changes: Footer on page 2: ©2015-20189 GSK group of companies or its licensor 
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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 5 
eTrack study number 
and Abbreviated Title 
201190 (ZOSTER-049 EXT:006-022) 
IND number 
BB-IND 13857 
EudraCT number 
2015-001778-17 
Amendment number: 
Amendment 5 
Amendment date: 
11 May 2020 
Co-ordinating author: 
, Scientific Writer 
Rationale/background for changes: 
This protocol amendment 5 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 6.6 outlines the measures which include allowing flexibility in schedule and 
procedures to optimize site staff safety, patient safety and to preserve study integrity. 
Other changes include, 
•
The classification of HZ cases by HZAC has been clarified with the addition of
“not able to decide” to be classified as “not HZ” to Section 4.5.2.4.2 for
confirmation of suspected HZ by the HZAC.
•
The timelines concerning data entry into the eCRF for France in Section 13.1 have
been updated to align with the timelines presented in the data management plan.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
List of abbreviations 
COVID-19: 
Coronavirus Disease 2019 
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Synopsis and Section 3. Study design overview 
Refer to Section 6.6 for study procedures to be considered during special 
circumstances. 
Section 4.5.2.4.2. 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”. 
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. 
Section 6.4. Outline of study procedures 
Refer to Section 6.6 for study procedures to be considered during special 
circumstances. 
Section 6.6. 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 special circumstances to the study conduct will be documented in the 
clinical study report.  
•
Yearly site visits/contact may be made by other means of virtual contact or home
visit, if appropriate.
•
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 3, 28 April 2020) or other relevant authority guidance for more
details.
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•
If despite best efforts it is not possible to collect the biological samples within the
interval predefined in the protocol (see Table 8 to Table 10), then the allowed
interval may be extended by 30 days as outlined from Table 12 to Table 14.
−
The visit can be replaced by a phone contact or other means of virtual contact
and will be performed in the interval predefined in the protocol and the blood
sampling can be performed according to the interval allowed during special
circumstances as shown from Table 12 to Table 14.
Table 12 
Intervals for blood sampling for the LTFU group during special 
circumstances 
Interval for blood sampling 
Optimal length of 
interval  
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval 
during special 
circumstances 
(range in days) 
Visit Month 0 → Blood sampling Year 1 
12 months 
335 – 395 
335 – 425 
Visit Month 0 → Blood sampling Year 2 
24 months 
700 – 760 
700 – 790 
Visit Month 0 → Blood sampling Year 3 
36 months 
1065 – 1125 
1065 – 1155 
Visit Month 0 → Blood sampling Year 4 
48 months 
1430 – 1490 
1430 – 1520 
Visit Month 0 → Blood sampling Year 5 
60 months 
1795 – 1855 
1795 – 1885 
Visit Month 0 → Blood sampling Year 6 
72 months 
2160 – 2220 
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling as close to the optimal window as possible. 
Table 13 
Intervals for blood sampling for the 1-Additional Dose and Control 
groups during special circumstances 
Interval for blood sampling 
Optimal length 
of interval 
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval during 
special circumstances 
(range in days) 
Visit Month 0 → Blood sampling Year 1 
12 months 
335 – 395 
335 – 425 
Visit Month 0 → Blood sampling Year 2 
24 months 
700 – 760 
700 – 790 
Visit Month 0 → Blood sampling Year 3 
36 months 
1065 – 1125 
1065 – 1155 
Visit Month 0 → Blood sampling Year 4 
48 months 
1430 – 1490 
1430 – 1520 
Visit Month 0 → Blood sampling Year 5 
60 months 
1795 – 1855 
1795 – 1885 
Visit Month 0 → Blood sampling Year 6 
72 months 
2160 – 2220 
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling as close to the optimal window as possible. 
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Table 14 
Intervals for blood sampling for the Revaccination group during special 
circumstances 
Interval for blood sampling 
Optimal length 
of interval 
(in months) 
Allowed interval 
during normal 
circumstances 
(range in days) 
Allowed interval 
during special 
circumstances 
(range in days) 
Visit Month 2 → Blood sampling Year 1 
12 months 
335 – 395 
335 – 425 
Visit Month 2 → Blood sampling Year 2 
24 months 
700 – 760 
700 – 790 
Visit Month 2 → Blood sampling Year 3 
36 months 
1065 – 1125 
1065 – 1155 
Visit Month 2 → Blood sampling Year 4 
48 months 
1430 – 1490 
1430 – 1520 
Visit Month 2 → Blood sampling Year 5 
60 months 
1795 – 1855 
1795 – 1885 
Visit Month 2 → Blood sampling Year 6 
72 months 
2160 – 2220 
2160 – 2250 
Note: Investigator should prioritize performing the blood sampling 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 7 and Table 11.
−
If the subject is not able to immediately 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, HZ related treatments
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 suspected HZ lesions
themselves. The photographs will be transferred to the investigator via email
or other modes of virtual contact when possible.
−
HZ specific diary cards may be transmitted from and to the site by electronic
means and/or conventional mail.
−
ZBPI questionnaire may be transmitted from and to the site by electronic
means and/or conventional mail. If this is not feasible, the study
staff/investigator can conduct ZBPI questionnaire by telephone contact. Study
staff/investigator will read the questions (verbatim) and transcribe the
subject’s responses on the questionnaires.
Impact on the modified TVC for efficacy and ATP for efficacy and immunogenicity 
(humoral and CMI) will be determined on a case by case basis. 
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Section 13.1. Requirements for France 
Concerning Data entry into the eCRF 
9.
That the Investigator and the staff of the investigator centre enter the data of the
eCRF related to a patient visit in the 3 10 days following the date of the patient visit
or, for the patient test results, in the 3 10 days following the reception of the results
of such tests. For a subject last visit, the recommended time frame for data entry is
5 working days.
10. That the Investigator resolves and returns to GSK the data queries issued by GSK or
a service provider designated by GSK within 7 10 days after the reception of the
request of clarification or in a period of one (1)5 days during the final stage of
clarification of the data base or in such other period as provided by GSK and/or a
company designated by GSK.
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