A Phase II, Observer-blind, Randomized, Controlled Study to Evaluate the Immunogenicity and Safety of a Varicella Vaccine at Various Potencies Compared With Varivax, as a First Dose, Administered in Healthy Children in Their Second Year of Life
Phase: PHASE2
Conditions: Chickenpox
Sponsor: GlaxoSmithKline

TITLE PAGE 
Protocol Title: A phase II, observer-blind, randomized, controlled study to evaluate the 
immunogenicity and safety of a varicella vaccine at various potencies compared with Varivax, as 
a first dose, administered in healthy children in their second year of life 
Protocol Number: 217212 (VNS 20-006) 
Amendment Number: 3.0 
Product: Investigational varicella vaccine 
Short Title: A study on the immune response and safety of various potencies of an 
investigational chickenpox vaccine compared with a marketed chickenpox vaccine, given to 
healthy children 12 to 15 months of age 
Study Phase: II 
Sponsor Name: GlaxoSmithKline Biologicals SA (GSK) 
Legal Registered Address: Rue de l’Institut 89, Rixensart, 1330 Belgium 
ClinicalTrials.gov Identifier: NCT05084508 
EudraCT Number: 2022-001910-21 
Date of Original Protocol: Final Version 2: 12 July 2021 
Date of Protocol Amendment 1.0: 08 October 2021 
Date of Protocol Amendment 2.0: 15 November 2021 
Date of Protocol Amendment 3.0: 18 May 2022 
 
 
 
1

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
 
 
Md Ahsan Habib, MBBS, MIPH 
Clinical and Epidemiology Project Lead 
GlaxoSmithKline Biologicals SA 
 
 
Date 
 
 
 
 
 
 
 
 
Refer to the Study Reference Manual for Medical Monitor’s name and contact 
information. 
 
 
2
PPD

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 3.0 
18-May-2022
Yes 
Global 
Amendment 2.0 
15-Nov-2021
Yes 
Global 
Amendment 1.0 
08-Oct-2021
Yes 
Global 
Original Protocol (Final Version 2) 
12-Jul-2021
- 
- 
Amendment 3.0 (18-May-2022) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The protocol was amended primarily to reflect the expansion of the study to the countries other 
than the United States of America (US). Outside of the US, participants will have the same 
vaccination schedule but will be co-administered Prevnar 13 only if the pneumococcal conjugate 
vaccine is recommended at 12-15 months as per national immunization schedule. Also, the 
storage conditions for Varivax were updated with the country-specific details, and corrections 
were made to the temperature excursions for study vaccines. Additionally, this amendment 
conditionally allowed administration of a second dose of Varivax and/or Havrix in non-US 
countries (not part of the study procedures). 
Table 2 
Description of the Most Important Changes in Amendment 3.0 
Section # and Name Description of Change 
Brief Rationale 
1.1. Synopsis 
1.3. Schedule of 
Activities 
2.1. Study Rationale 
5.1. Inclusion Criteria 
Updated the text to reflect the following (in bold; in the exact or 
similar wording): 
In this study, all participants recruited in the US will be 
co-administered with a measles, mumps and rubella vaccine (M-M-R 
II, also called M-M-RVaxPro in countries outside the US, and 
hereafter designated as MMR), a hepatitis A vaccine (Havrix) and a 
13-valent pneumococcal conjugate vaccine (Prevnar 13).
Participants recruited outside of the US will be co-administered
with MMR, Havrix, and in some countries, with Prevnar 13.
Outside the US, Prevnar 13 will only be administered in countries
where pneumococcal conjugate vaccine is recommended at 12-15
months as per national immunization schedule.
To reflect addition 
of non-US sites to 
the study and clarify 
the inclusion criteria 
applicable to the 
participants at 
non-US sites. 
To note that in some 
countries, there can 
be a different name 
for the MMR 
vaccine. 
1.2. Synopsis 
1.3. Schedule of 
At the end of the study or shortly after the study, depending on 
the vaccines’ availability, GSK will provide a second dose of 
To allow 
administration of the 
3

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Section # and Name Description of Change 
Brief Rationale 
Activities 
2.1. Study Rationale 
 
Varivax and/or Havrix to participants enrolled in non-US 
countries if local health departments do not routinely provide 
varicella and/or hepatitis A vaccine. Study participants who do 
not achieve the pre-specified seroresponse threshold criteria will 
be re-vaccinated with a dose of Varivax. 
second dose of the 
varicella or 
hepatitis A vaccine 
(not part of study 
procedures). 
6.2. Preparation/Handl
ing/Storage/Accounta
bility 
Added the text (in bold): 
Varivax will be stored at −15°C to −30°C (+5°F to −22°F) in the 
US and other countries with frozen formulation and at +2°C to 
+8°C (+36°F to +46°F) in the rest of the world. (Note: refrigerated 
Varivax vaccine will be used at non-US sites, while frozen Varivax 
vaccine will be used at sites in the US and other countries with 
frozen formulation.) 
To specify the 
storage conditions 
for the study vaccine 
at the US and 
non-US sites. 
Throughout the 
protocol where 
applicable 
Removed the statements implying the study will be conducted in the 
US only; made updates regarding other countries to the scientific 
rationale for study design; mentioned Independent Ethics 
Committee(s) as entities overseeing the ethics conduct of the study 
besides Institutional Review Boards; mentioned the non-US-specific 
regulatory requirements the study will be performed in accordance 
with. 
To reflect addition 
of non-US sites to 
the study and note 
applicable 
administrative 
changes to the 
conduct of the study. 
The detailed description of changes (i.e., added/removed text) and minor updates is provided in 
Appendix 5. 
4

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3
TABLE OF CONTENTS ........................................................................................................5
TABLE OF TABLES ...............................................................................................................8
TABLE OF FIGURES ...........................................................................................................09
1.0 
PROTOCOL SUMMARY ........................................................................................10
1.1
Synopsis ...........................................................................................................10
1.2
Schema ............................................................................................................11
1.3
Schedule of Activities .....................................................................................12
2.0 
INTRODUCTION......................................................................................................16
2.1
Study Rationale ..............................................................................................16
2.2
Background ....................................................................................................16
2.3
Benefit/Risk Assessment ................................................................................17
2.3.1
Risk Assessment ................................................................................17
2.3.2
Risk Mitigation Strategies .................................................................18
2.3.3
Benefit Assessment ...........................................................................19
2.3.4
Overall Benefit/Risk Conclusion .......................................................19
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................20
4.0 
STUDY DESIGN ........................................................................................................21
4.1 
Overall Design ................................................................................................21
4.2 
Scientific Rationale for Study Design ...........................................................24
4.2.1
Rationale for Clinical Study Population ............................................24
4.2.2
Choice of Comparator and Co-administered Vaccines .....................24
4.2.3
Rationale for Blinding .......................................................................24
4.2.4
Justification for Dose of Varicella Vaccine .......................................25
4.3 
End of Study Definition .................................................................................25
5.0 
STUDY POPULATION ............................................................................................26
5.1 
Inclusion Criteria ...........................................................................................26
5.2 
Exclusion Criteria ..........................................................................................26
5.2.1
Medical Conditions ...........................................................................26
5.2.2
Prior and Concomitant Therapy ........................................................27
5.2.3
Prior/Concurrent Clinical Study Experience .....................................27
5.2.4
Other Exclusions ...............................................................................28
5.3 
Lifestyle Considerations, Activity, and Dietary Restrictions .....................28
5

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
5.4
Screen Failures ...............................................................................................28
5.5
Criteria for Temporary Delay for Enrollment and/or Intervention 
Administration ...............................................................................................28
6.0 
STUDY INTERVENTION ........................................................................................29
6.1
Study Interventions Administered ...............................................................29
6.2
Preparation/Handling/Storage/Accountability ...........................................33
6.2.1
Minimizing Environmental Contamination with Genetically 
Modified Organisms ..........................................................................34
6.3
Measures to Minimize Bias: Randomization and Blinding........................34
6.3.1
Participant Identification ...................................................................34
6.3.2
Randomization to Study Intervention ................................................34
6.3.3
Intervention Allocation to Participants ..............................................34
6.3.4
Blinding and Unblinding ...................................................................35
6.4
Study Intervention Compliance ....................................................................36
6.5
Dose Modification ..........................................................................................36
6.6
Continuing Access to Study Intervention after the End of the 
Study................................................................................................................36
6.7
Treatment of Overdose ..................................................................................36
6.8
Concomitant Therapy ....................................................................................37
7.0 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................38
7.1
Discontinuation of Study Intervention .........................................................38
7.2
Contraindications to Subsequent Study Interventions 
Administration ...............................................................................................38
7.3
Participant Discontinuation/Withdrawal from the Study .........................38
7.4
Lost to Follow-up ...........................................................................................39
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................40
8.1
Immunogenicity Assessments .......................................................................40
8.1.1
Biological Samples ............................................................................40
8.1.2
Laboratory Assays .............................................................................41
8.1.3
Immunological Correlates of Protection ...........................................41
8.2 
Safety Assessments .........................................................................................41
8.2.1
Pre-intervention Administration Procedures .....................................41
8.2.2
Clinical Safety Laboratory Tests .......................................................42
8.2.3
Safety Monitoring and Study Holding Rules ....................................42
8.3 
Adverse Events ...............................................................................................44
8.3.1
Time Period and Frequency for Collecting AE and SAEs and 
Other Safety Information ...................................................................44
8.3.2
Method of Detecting AEs and SAEs .................................................45
8.3.3
Regulatory Reporting Requirements for SAEs .................................45
8.3.4
Treatment of AEs ..............................................................................46
8.3.5
Participant Card .................................................................................46
8.3.6
Medical Device Deficiencies .............................................................46
6

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
8.4
Pharmacokinetics and Pharmacodynamics .................................................47
8.5
Study Procedures During Special Circumstances ......................................47
9.0 
STATISTICAL CONSIDERATIONS .....................................................................49
9.1
Statistical Hypotheses ....................................................................................49
9.2
Sample Size Determination ...........................................................................49
9.3
Populations for Analyses ...............................................................................49
9.4
Statistical Analyses.........................................................................................50
9.4.1
Statistical Analysis Plan ....................................................................50
9.4.2
Primary Endpoint Analyses ...............................................................50
9.4.3
Secondary Endpoints Analyses .........................................................51
9.5 
Interim Analysis .............................................................................................51
9.5.1
Sequence of Analyses ........................................................................51
9.5.2
Statistical Considerations for Interim Analysis .................................51
10.0 
REFERENCES ...........................................................................................................52
11.0 
APPENDICES ............................................................................................................53
Appendix 1
Abbreviations and the Glossary of Terms .....................................54
Appendix 2
Regulatory, Ethical, and Study Oversight Considerations ..........60
Regulatory and Ethical Considerations ............................................................60
Financial Disclosure.........................................................................................60
Informed Consent Process ...............................................................................61
Data Protection.................................................................................................61
Administrative Structure ..................................................................................62
Medical Monitor ..............................................................................................62
Dissemination of Clinical Study Data..............................................................62
Publication Policy ............................................................................................62
Data Quality Assurance ...................................................................................63
Source Documents ...........................................................................................64
Study and Study Center Start and Closure .......................................................64
Appendix 3 
Clinical Laboratory Tests ...............................................................65
Appendix 4 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................66
Adverse Events ................................................................................................66
Serious Adverse Events ...................................................................................67
Solicited Events ...............................................................................................67
Unsolicited Events ...........................................................................................68
COVID-19 Cases .............................................................................................68
Assessment of Intensity and Toxicity ..............................................................68
Assessment of Causality ..................................................................................70
Medically Attended Visits ...............................................................................71
Assessment of Outcomes .................................................................................71
Reporting, Follow-up, and Assessment of AEs ...............................................72
Appendix 5 
Protocol Amendment History .........................................................76
Appendix 6 
Signature of Investigator ..............................................................100
7

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
TABLE OF TABLES 
Table 1
Document History ..............................................................................................3
Table 2
Description of the Most Important Changes in Amendment 3.0 .......................3
Table 3
Schedule of Activities ......................................................................................12
Table 4
Intervals Between Study Visits ........................................................................15
Table 5
Study Objectives and Endpoints ......................................................................20
Table 6
Study Groups ...................................................................................................23
Table 7
Study Intervention Administered .....................................................................30
Table 8
Laboratory Assay .............................................................................................41
Table 9
Study Holding Rules ........................................................................................43
Table 10
Exact 95% Confidence Interval for the Percentage of Participants with 
Adverse Event Based on the Exposed Set and for the Percentage of 
Participants with Seroresponse Based on the Per Protocol Set........................49
Table 11
Analysis Sets ....................................................................................................50
Table 12
Study Administrative Structure........................................................................62
Table 13
Intensity Scales for Solicited Symptoms in Toddlers (12 to 15 Months 
of Age) .............................................................................................................69
8

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
TABLE OF FIGURES 
Figure 1
Study Design Overview ...................................................................................22
Figure 2
Communication Flow: Identification of Holding Rules by the 
Investigator ......................................................................................................44
9

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A phase II, observer-blind, randomized, controlled study to evaluate the 
immunogenicity and safety of a varicella vaccine at various potencies compared with Varivax, as 
a first dose, administered in healthy children in their second year of life. 
Short Title: A study on the immune response and safety of various potencies of an 
investigational chickenpox vaccine compared with a marketed chickenpox vaccine, given to 
healthy children 12 to 15 months of age. 
Rationale: Varicella (chickenpox) is an acute, highly contagious infectious disease caused by 
the varicella zoster virus. Safe and effective varicella vaccines have shown to have significant 
global and national public health impact when implanted in national immunization plans, e.g., as 
in the United States of America (US). GlaxoSmithKline Biologicals SA (GSK) is developing a 
candidate varicella vaccine (VNS vaccine). The main purpose of this study is to demonstrate the 
immunogenicity of the investigational VNS vaccine in 3 potencies compared with commercially 
available Merck’s varicella vaccine, Varivax (hereafter designated as VV vaccine), when given 
as a first dose to children 12 to 15 months of age. In this study, all participants recruited in the 
US will be co-administered with a measles, mumps and rubella vaccine (M-M-R II, also called 
M-M-RVaxPro in countries outside the US, and hereafter designated as MMR), a hepatitis A 
vaccine (Havrix) and a 13-valent pneumococcal conjugate vaccine (Prevnar 13). Participants 
recruited outside of the US will be co-administered with MMR, Havrix, and in some countries, 
with Prevnar 13. Outside the US, Prevnar 13 will only be administered in countries where 
pneumococcal conjugate vaccine is recommended at 12-15 months as per national immunization 
schedule. At the end of the study or shortly after the study, depending on the 
vaccines’availability, GSK will provide a second dose of Varivax and/or Havrix to participants 
enrolled in non-US countries if local health departments do not routinely provide varicella and/or 
hepatitis A vaccine. Study participants who do not achieve the pre-specified seroresponse 
threshold criteria will be re-vaccinated with a dose of Varivax. 
Objectives, Endpoints, and Estimands: The study will evaluate the immune response of the 
investigational VNS vaccine (formulated at 3 different potencies) and the VV vaccine in terms of 
geometric mean concentration (GMC) and in terms of seroresponse rate (percentage of 
participants for whom the post-dose anti-glycoprotein E [gE] antibody concentration is 
≥300 mIU/mL) to gE. The study will also evaluate the safety and the reactogenicity (incidence of 
solicited adverse events [AEs], unsolicited AEs, and serious adverse events [SAEs]) following 
the administration of the VNS and VV vaccines. 
Overall Design: This will be a phase II, observer-blind, randomized, multicenter controlled 
study with 5 parallel intervention groups of healthy children aged 12 to 15 months at the time of 
intervention. Participants will be randomized to receive a single dose of an investigational 
varicella vaccine (3 groups each receiving one of the 3 different vaccine potencies [a low, 
medium, and high potency of the VNS vaccine, respectively]) or a single dose of a comparator 
licensed varicella vaccine (2 groups each receiving one of the 2 different lots of the VV vaccine, 
which will be pooled for all analyses). All participants in the US will be co-administered with 
MMR, Havrix, and Prevnar 13 vaccines. Participants recruited outside of the US will be 
co-administered with MMR, Havrix, and in some countries, with Prevnar 13. Outside the US, 
10

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Prevnar 13 will only be administered in countries where pneumococcal conjugate vaccine is 
recommended at 12-15 months as per national immunization schedule. If Prevnar 13 is to be 
administered, participants are required to have previously received the primary series of 
pneumococcal conjugate vaccine in their first year of life with last dose at least 60 days prior to 
study entry. 
Randomization to one of the 5 groups will be performed in a 2:2:2:1:1 ratio prior to intervention. 
There will be 3 study visits, at Day 1 (intervention), Day 15 (virtual or in-person), and Day 43, as 
well as 1 safety call and 1 safety follow-up contact, at Day 2-3 and Day 181, respectively. 
Number of Participants: Approximately 800 participants will be randomly assigned to the 
5 study groups to provide approximately 200 enrolled participants per each VNS group and 
100 enrolled participants per each VV group. Approximately 90% of the enrolled participants are 
expected to be included in the Per Protocol Set (PPS) and evaluated for immunogenicity. 
Intervention Groups and Duration: 
VNS_Low: VNS low potency vaccine, MMR*, Havrix, and Prevnar 13** 
VNS_Med: VNS medium potency vaccine, MMR*, Havrix, and Prevnar 13** 
VNS_High: VNS high potency vaccine, MMR*, Havrix, and Prevnar 13** 
VV_Lot1: VV vaccine Lot 1, MMR*, Havrix, and Prevnar 13** 
VV_Lot2: VV vaccine Lot 2, MMR*, Havrix, and Prevnar 13** 
*M-M-R II or M-M-RVaxPro, depending on the country. 
**Prevnar 13 will only be administered to participants enrolled in the US and in countries where 
pneumococcal conjugate vaccine is recommended at 12-15 months as per national immunization 
schedule. 
Statistical Methods: Three analyses sets will be used in this study, the Enrolled Set, the 
Exposed Set (ES), and the PPS. The intercurrent medical conditions that may lead to elimination 
from the PPS will be confirmed immunodeficiency conditions, or development of varicella or 
herpes zoster in the interval between study intervention administration and the collection of the 
blood specimen for immunogenicity at Visit 3. The immunogenicity analyses will be based on 
the PPS. The statistical analyses in this study will be descriptive. The study includes 
2 immunogenicity objectives (one primary and one secondary) and one safety objective. The 
GMCs will be summarized by group with their 95% confidence interval (CI) derived considering 
log-transformed anti-gE antibody concentrations are normally distributed with unknown 
variance. The seroresponse rates to gE will be summarized by group with their 95% CIs. The 
safety analyses will be based on the ES. 
Data Monitoring Committee: An Independent Data Monitoring Committee comprising of 
clinical experts and an independent biostatistician will perform periodic safety reviews of the 
unblinded study data. 
1.2 
Schema 
See Figure 1 in Section 4.1.
11

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
1.3 
Schedule of Activities 
Table 3 
Schedule of Activities 
Age 
12-15 months of age at the time of study intervention
administration
Notes 
Type of contact 
Visit 1 
Safety call 
Visit 2* 
Visit 3 
Safety 
follow-up 
contact 
Time points
Day 1
Day 2-3
Day 15
Day 43
Day 181
Informed consent 
● 
See Appendix 2 for details 
Check inclusion/exclusion criteria 
● 
See Section 5.1 and Section 5.2 for 
details 
Collect demographic data 
● 
See Section 8.2.1.1 for details 
Medical history 
● 
See Section 8.2.1.1 for details 
Vaccination history 
(protocol-specific vaccines including pneumococcal 
conjugate vaccine **) 
● 
See Section 8.2.1.1 for details 
See Section 5.1 for details 
Physical examination 
● 
See Section 8.2.1.1 for details 
Randomization 
○ 
See Section 6.3.2 for details 
Study interventions
See Appendix 1 for the definition 
Check contraindications, warnings and precautions 
to study intervention administration 
○ 
See Section 8.2.1.2 for details 
Check criteria for temporary delay for enrollment 
and study intervention administration 
● 
See Section 5.5 for details 
Study group and treatment number allocation 
○ 
See Section 6.3.3 for details 
Body temperature before study intervention 
administration 
● 
The preferred location for measuring 
temperature will be the axilla. Fever is 
defined as body temperature 
≥ 38.0°C/100.4°F 
Study intervention (VNS vaccine/VV vaccine, 
MMR, Havrix, and Prevnar 13**) administration 
● 
Study participants who do not achieve 
the pre-specified seroresponse 
threshold criteria will be re-vaccinated 
with a dose of Varivax 
Recording of administered study treatment number 
●
12

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
Age 
12-15 months of age at the time of study intervention
administration
Notes 
Type of contact 
Visit 1 
Safety call 
Visit 2* 
Visit 3 
Safety 
follow-up 
contact 
Time points
Day 1
Day 2-3
Day 15
Day 43
Day 181
Distribute eDiaries/download the app 
○ 
An eDiary/personal electronic device 
application (app) will be used to 
capture solicited administration site or 
systemic events. The participant’s 
parent(s)/LAR(s) should be trained on 
the use of the eDiary/app. See 
Appendix 4 for details 
Second dose of Varivax and/or Havrix 
x 
At the end of the study or shortly after 
the study, depending on the vaccines’ 
availability, GSK will provide a 
second dose of Havrix and/or Varivax 
in countries where they are not 
routinely provided. The administration 
of the second dose of Havrix and 
Varivax is not part of the study 
procedures, however, the 
administration of the second dose (or 
the date of the planned visit for 
administration) should be recorded in 
the eCRF. 
Laboratory assessment
Blood sampling for antibody determination (~3 mL) 
● 
See Section 8.1.1 for details 
Safety assessments
Record any concomitant medications/vaccinations 
● 
● 
● 
● 
See Section 6.8 for details 
Record any intercurrent medical conditions 
● 
See Section 9.3 for more information 
Phone contact for safety follow-up 
● 
● 
Or any other convenient procedure 
Recording of solicited administration site events 
from Day 1-4 post study intervention administration 
○ 
○ 
Only events following the 
administered dose of VNS vaccine or 
VV vaccine will be solicited 
Safety follow-up with clinical staff to review 
post-vaccination safety data 
● 
Recording of solicited systemic events (drowsiness, 
loss of appetite and irritability) from Day 1-15 post 
study intervention administration 
○ 
○ 
○ 
See Section 8.3 and Appendix 4 
13

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
Age 
12-15 months of age at the time of study intervention
administration
Notes 
Type of contact 
Visit 1 
Safety call 
Visit 2* 
Visit 3 
Safety 
follow-up 
contact 
Time points
Day 1
Day 2-3
Day 15
Day 43
Day 181
Recording of solicited systemic events (fever, 
varicella-like rash [including injection site 
varicella-like rash] and general rash [not varicella-
like]) from Day 1-43 post study intervention 
administration 
○ 
○ 
○ 
○ 
See Section 8.3 and Appendix 4 
Recording of non-serious AEs from Day 1-43 post 
study intervention administration 
● 
● 
● 
● 
See Section 8.3 and Appendix 4 
eDiary/app completion reminder 
● 
Review of eDiaries/app data 
○ 
● 
● 
Return of eDiaries/uninstall or disable the app 
○ 
See Section 8.5 for details 
Recording of SAEs 
● 
● 
● 
● 
● 
See Section 8.3 for details and 
Appendix 4 for the definition 
Recording of SAEs related to study participation, or 
to a concurrent GSK medication/vaccine 
● 
● 
● 
● 
● 
The collection and reporting periods 
start once the participant’s 
parent(s)/LAR(s)’s informed consent 
is obtained 
Study conclusion 
● 
See Section 4.3 for the definition. 
AE = adverse event; App = application; eDiary = Electronic Diary; gE = glycoprotein E; LAR = legally acceptable representative; MMR = M-M-R II or M-M-
RVaxPro; SAE = serious adverse event; 
VNS vaccine = investigational vaccine; VV vaccine = comparator vaccine (Varivax); MMR, Havrix, and Prevnar 13 = co-administered vaccines. 
Notes: 
* Visit 2 (Day 15) may be conducted in-person or virtually.
** Prevnar 13 will only be administered to participants in the United States and in the countries where pneumococcal conjugate vaccine is recommended at 12-15
months as per national immunization schedule. 
●is used to indicate a study procedure that requires documentation in the individual electronic case report form (eCRF).
○is used to indicate a study procedure that does not require documentation in the individual eCRF.
x  is used to indicate a procedure (that is not part of the study) that requires documentation in the individual eCRF
Refer to Table 4 for allowed intervals between study visits. 
Refer to the Study Reference Manual /pharmacy manual for the volume of the vaccine after reconstitution. 
14

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
Table 4 
Intervals Between Study Visits 
Interval 
Planned visit interval* 
Allowed interval range 
Visit 1→ Safety call 
1 to 2 days 
1 to 3 days 
Visit 1→Visit 2 
14 days 
14 to 19 days 
Visit 1→Visit 3 
42 days 
35 to 56 days 
Visit 1→ Safety follow-up contact 
180 days 
180 to 201 days 
*Number of days between the visits.
Note: Whenever possible, the investigator should arrange study visits following the planned visit interval. Deviation from allowed interval between Visit 1 and
Visit 3 will lead to elimination from the Per Protocol Set.
15

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
2.0 INTRODUCTION 
2.1 
Study Rationale 
Varicella (i.e., chickenpox) is an acute, highly contagious infectious disease caused by the 
varicella zoster virus, which typically affects children under 10 years of age. Safe and effective 
varicella vaccines to prevent varicella have shown to have significant global and national public 
health impact when implanted in national immunization plans, e.g., as in the United States of 
America (US) and many other countries worldwide. 
GlaxoSmithKline Biologicals SA (hereafter designated as GSK) is developing a candidate 
varicella vaccine (VNS vaccine). The main purpose of this study is to demonstrate the 
immunogenicity of the investigational VNS vaccine in 3 potencies (designated as VNS_Low 
vaccine, VNS_Med vaccine, and VNS_High vaccine), when compared with the commercially 
available Merck’s varicella vaccine, Varivax (designated as VV vaccine), when given as a first 
dose to children 12 to 15 months of age. In order to obtain more representative data on the 
comparator, participants enrolled in the VV group will be randomized to 2 different lots 
(designated as VV_Lot1 and VV_Lot2). Throughout the study, the VV lots will be analyzed as 
pooled lots. 
In addition to assessing the immunogenicity of both varicella vaccines, this study intends to also 
generate safety data in the participants. 
All participants recruited in the US will be co-administered with a measles, mumps, rubella 
vaccine (M-M-R II, hereafter designated as MMR), a hepatitis A vaccine (Havrix) and a 
13-valent pneumococcal conjugate vaccine  (Prevnar 13). Participants recruited outside of the 
US will be co-administered with an MMR vaccine (M-M-R II or M-M-RVaxPro depending on 
the country), Havrix, and in some countries, with Prevnar 13. Outside the US, Prevnar 13 will 
only be administered in countries where pneumococcal conjugate vaccine is recommended at 
12-15 months as per national immunization schedule. 
At the end of the study or shortly after the study, depending on the vaccines’ availability, GSK 
will provide a second dose of Varivax and/or Havrix to participants enrolled in non-US countries 
if local health departments do not routinely provide varicella and/or hepatitis A vaccine. 
Study participants who do not achieve the pre-specified seroresponse threshold criteria will be 
re-vaccinated with a dose of Varivax. 
2.2 
Background 
Varicella is characterized by fever and a generalized, itchy, vesicular rash. It is commonly 
regarded as a mild childhood illness. However, serious complications such as secondary bacterial 
16

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
infection and pneumonia from varicella infections can occur, leading to hospitalizations and in 
rare cases even to death [CDC, 2015]. 
Universal mass vaccination against varicella is implemented in several countries [WHO, 2014; 
CDC, 2015]. It has led to a decrease in varicella morbidity (cases and hospitalizations) and 
mortality (deaths) [Wagenpfeil, 2004; Siedler, 2010; CDC, 2018]. 
GSK’s candidate VNS vaccine strain has been derived from an Oka varicella strain. Of the 
varicella strains investigated in preclinical studies, only the Oka strain was considered suitable 
for vaccine production by the World Health Organization (WHO). The vaccines containing this 
strain were developed and evaluated in healthy and immunocompromised adults, adolescents and 
children by several pharmaceutical companies. The VNS vaccine is intended for active 
immunization for the prevention of varicella in healthy individuals of 12 months of age and 
older. The VNS vaccine has never been administered to humans. 
Whereas there are no safety and effectiveness data available for the candidate VNS vaccine, this 
vaccine is expected to have a similar safety and efficacy profile as the 2 most widely used 
varicella vaccines containing an Oka varicella strain (Merck’s Varivax and GSK’s Varilrix 
vaccines). The summaries of the currently available clinical data on these vaccines are provided 
in the current Investigator’s Brochure (IB). 
2.3 
Benefit/Risk Assessment 
2.3.1 
Risk Assessment 
The investigational VNS vaccine is expected to have a benefit-risk profile similar to Merck’s 
Varivax and GSK’s Varilrix vaccines. Detailed information about the expected risks and 
reasonably expected adverse events (AEs) of these 2 licensed varicella vaccines are summarized 
in the current IB. No significant safety concerns have been identified in clinical trials and during 
post-marketing use of these vaccines. 
The most common currently known AEs following administration of varicella vaccines are local 
reactions, such as pain, soreness, erythema, and swelling. Based on the information from the 
manufacturers’ clinical trials of varicella vaccines, local reactions are reported by 19% of 
children. These local adverse reactions are generally mild and self-limited. A varicella-like rash 
at the injection site is reported by 3% of children. A median of 2 lesions have been present. 
These lesions generally occur within 2 weeks and may be maculopapular rather than vesicular. A 
generalized varicella-like rash is reported by 4% to 6% of recipients of the varicella vaccine, 
with an average of 5 lesions. Most of these generalized rashes occur within 3 weeks and may be 
mainly maculopapular. Systemic reactions are not common. Fever within 42 days of vaccination 
is reported by 15% of children. The majority of these episodes of fever have been attributed to 
concurrent illness rather than to the vaccine. Varicella vaccine is a live virus vaccine and may 
17

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
result in a latent infection, similar to that caused by wild varicella virus. Consequently, zoster 
caused by the vaccine virus has been reported [CDC, 2015] but rarely so. 
Additional risks may be associated with the co-administered vaccines, MMR, Havrix, and 
Prevnar 13. These vaccines are widely used in the US and some other countries per routine 
pediatric immunization schedule and may cause expected and reasonable AEs. Refer to the 
package inserts or prescribing information for information regarding the summary of adverse 
reactions of MMR, Havrix, and Prevnar 13. 
During this study of the candidate VNS vaccine, there may also be risks related to the blood 
sampling (e.g., bruising and pain at the blood draw site). 
2.3.2 
Risk Mitigation Strategies 
For the safety of the participants, the protocol has incorporated various risk mitigation measures, 
including appropriate inclusion and exclusion criteria (see Section 5.1 and Section 5.2), checking 
contraindications to vaccinations (see Section 8.2.1.2) and close monitoring of participants after 
vaccinations. 
All study activities at the study center will be performed by trained clinical staff authorized by 
the study investigator. The attendance of the study participants to in-person study visits is 
expected to pose risks that do not extend the risks associated with clinic visits for routine 
immunization of children 12 to 15 months of age. 
After the vaccination, participants will be observed for at least 30 minutes, with medical 
attention available in case of anaphylaxis. 
The burden of the study for the participant will be minimized as much as possible. For taking 
blood samples, 3 attempts at most should be performed. If the investigator/designee is not 
successful after the third attempt, the investigator/designee will make no further attempts. A 
local numbing cream or patch will also be offered at the discretion of the investigator prior to 
blood sampling, to minimize pain when blood samples are drawn. 
The blinded monitoring of study data will be performed by the GSK’s designee/Contract 
Research Organization (IQVIA) (see study administrative structure in Appendix 2 [Table 12]). 
Additional unblinded safety monitoring will be performed by an Independent Data Monitoring 
Committee (IDMC). Monthly Safety Review Team (SRT) review by GSK will occur up to the 
completion of enrollment and vaccination of the first 200 participants, to monitor cumulative, 
blinded safety data (including serious and non-serious AEs) (see Section 8.2.3). In addition, for 
the first 200 study participants through their Day 43 follow-up, the following criteria would be 
applied, that would result in a pause in study activities, including dosing and enrollment: 
a. Any death considered at least possibly related to vaccination (refer to Section 8.3.3 for 
expedited reporting) 
18

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
b. ≥1 participant with SAE(s) considered at least possibly related to vaccination (refer to 
Section 8.3.3 for expedited reporting) 
c. ≥2 participants with the same or similar Grade 3 unsolicited adverse events (AE) 
considered to be at least possibly related to vaccination, (refer to Section 8.3.1 for 
diligent reporting of Grade 3 unsolicited AEs at each contact/visit) 
Note: “similarity” of the events will be based on medical judgment. 
An enrollment pause is also foreseen for the first IDMC review after 200 participants 
(approximately 50 participants in each group, considering pooled VV groups) are enrolled and 
vaccinated. The analysis will take place once all 200 participants have returned for their Day 43 
visit (Visit 3) or have withdrawn from the study, within the allowed interval for the visit. A 
positive outcome of the IDMC review will be a pre-requisite for the continuation of the study. 
GSK/IQVIA will immediately notify the investigators if any additional safety or toxicology 
information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), European Union (EU) CTR, and applicable 
regulatory requirements. Aspects of the study concerned with the investigational medicinal 
products will meet the requirements of EU – Good Manufacturing Practice, as applicable. 
2.3.3 
Benefit Assessment 
By receiving the investigational VNS vaccine or the comparator vaccine Varivax, the 
participants are expected to be protected against varicella. 
By receiving the co-administered vaccines MMR, Havrix, and Prevnar 13 [if applicable] 
vaccines), the participants are expected to be protected against measles, mumps and rubella 
(MMR), hepatitis A (Havrix) and pneumococcal infections (Prevnar 13, if applicable). 
All participants will undergo a physical examination at the first study visit; these evaluations, 
made by skilled and trained clinical staff, may potentially provide participants’ parent(s)/legally 
acceptable representatives (LAR[s]; see the definition in Appendix 1) with valuable knowledge 
about the participant’s health. In case the study staff discovers any medical condition, the 
participant may be referred to the local healthcare system. 
2.3.4 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize possible risks to the participants in this 
study, the potential risks associated with the study intervention(s) and study assessments are 
balanced by the potential benefits that may be provided to the participants. 
19

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
3.0 OBJECTIVES AND ENDPOINTS 
Table 5 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the immune response of VNS vaccine 
(formulated with different potencies) and VV 
vaccine in terms of geometric mean concentration 
at Day 43 
• 
Anti-gE antibody concentration at Day 43 
Secondary 
• 
To evaluate the immune response of VNS vaccine 
(formulated with different potencies) and VV 
vaccine in terms of seroresponse rate* at Day 43 
• 
Seroresponse to gE at Day 43 
• 
To evaluate safety and reactogenicity following 
administration of VNS and VV vaccines 
Solicited events 
• 
Percentage of participants reporting each solicited 
administration site event in terms of injection site 
redness, pain and swelling within 4 days (Day 1 to 
Day 4) post-dose of VNS vaccine or VV vaccine 
• 
Percentage of participants reporting each solicited 
systemic event in terms of fever, varicella-like 
rash†, and general rash (not varicella-like) within 
43 days (Day 1 to Day 43) post-dose of study 
interventions** 
• 
Percentage of participants reporting each solicited 
systemic event in terms of drowsiness, loss of 
appetite, and irritability within 15 days (Day 1 to 
Day 15) post-dose of study interventions** 
Unsolicited adverse events (AEs)*** 
• 
Percentage of participants reporting unsolicited AEs 
within 43 days (Day 1 to Day 43) post-dose of 
study interventions** 
Serious adverse events (SAEs) 
• 
Percentage of participants reporting SAEs 
post-dose of study interventions** up to the end of 
study 
AE = adverse event; gE = glycoprotein E; SAE = serious adverse event; VNS vaccine = investigational vaccine, VV 
vaccine = comparator vaccine (Varivax). 
*Seroresponse rate is defined as the percentage of participants for whom post-dose of the study interventions 
(Day 43), the anti-gE antibody concentration is ≥300 mIU/mL. 
**Study interventions = VNS vaccine (investigational vaccine); VV vaccine (Varivax, comparator vaccine); MMR 
(M-M-R II or M-M-RVaxPro), Havrix and Prevnar 13 (if applicable) vaccines (co-administered vaccines). 
Note: Prevnar 13 will only be administered to participants enrolled in the United States and in countries where 
pneumococcal conjugate vaccine is recommended at 12-15 months as per national immunization schedule 
*** Unsolicited AEs include non-serious and serious AEs. 
† Includes injection site varicella-like rash. 
20

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
4.0 STUDY DESIGN 
4.1 
Overall Design 
This will be a phase II, observer-blind (see the definition in Appendix 1), randomized, 
multicenter controlled study with 5 parallel intervention groups of healthy children aged 12 to 
15 months at the time of intervention. Participants will be randomized to receive a single dose of 
an investigational varicella vaccine (3 groups of 200 participants each receiving one of the 3 
different vaccine potencies [a low, a medium, and a high potency of the VNS vaccine, 
respectively]) or a single dose of a comparator licensed varicella vaccine (2 groups of 
100 participants each receiving one of the 2 different lots of the VV vaccine, which will be 
pooled for all analyses).  
All participants will be co-administered with an MMR vaccine, a hepatitis A vaccine (Havrix) 
and, if applicable, a 13-valent pneumococcal conjugate vaccine (Prevnar 13). Prevnar 13 will 
only be administered to participants enrolled in the US and in countries where pneumococcal 
conjugate vaccine is recommended at 12-15 months as per national immunization schedule.  
At the end of the study or shortly after the study, depending on the vaccines’ availability, GSK 
will provide a second dose of Varivax and/or Havrix to participants enrolled in non-US countries 
if local health departments do not routinely provide varicella and/or hepatitis A vaccine. Study 
participants who do not achieve the pre-specified seroresponse threshold criteria will be 
re-vaccinated with a dose of Varivax.  
The study design diagram is provided in Figure 1. 
21

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Figure 1 
Study Design Overview 
 
VNS_Low, VNS_Med, and VNS_High vaccine = VNS vaccine in low, medium, and high potency; VV_Lot 1 and 
VV_Lot 2 = VV vaccine in 2 lots 
a VV_Lot 1 and VV_Lot 2 groups will be analyzed as pooled groups 
b Contact (by telephone call or any other convenient procedure) for the safety follow-up will take place 6 months 
post-dose of study interventions 
c Study interventions: VNS vaccine (investigational vaccine) or VV vaccine (Varivax, comparator vaccine); MMR 
(M-M-R II or M-M-RVaxPro), Havrix, and Prevnar 13 if applicable (co-administered vaccines). Note: Prevnar 13 
will only be administered to participants enrolled in the US and in countries where pneumococcal conjugate vaccine 
is recommended at 12-15 months as per national immunization schedule 
d Recording in the electronic Case Report Form 
e Blood sampling for anti-glycoprotein E enzyme-linked immunosorbent assay 
f Independent Data Monitoring Committee review details are provided in Section 8.2.3. 
g Visit 2 for review of post-vaccination safety data may be a virtual visit 
h Safety call to remind completion of the electronic Diary/smartphone application and address any potential early 
post-vaccination safety concerns 
*Drowsiness, loss of appetite, irritability 
**Fever, varicella-like rash (including injection site varicella-like rash) and general rash (not varicella-like) 
Healthy children aged 12 to 15 months will be enrolled in this study according to the inclusion 
and exclusion criteria (see Section 5.0). The randomization to one of the 5 groups will be 
performed in a 2:2:2:1:1 ratio prior to intervention. 
The study groups are shown in Table 6. 
22

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Table 6 
Study Groups 
Study 
groups 
Number of 
participants 
Age 
(Min-Max) 
Study interventions 
Blinding 
Visit 1 → Safety follow-up 
contact (observer-blind) 
VNS_Low 
200 
12 – 15 months 
VNS_Low vaccine, MMR, 
Havrix, and Prevnar 13* 
× 
VNS_Med 
200 
12 – 15 months 
VNS_Med vaccine, MMR, 
Havrix, and Prevnar 13* 
× 
VNS_High 
200 
12 – 15 months 
VNS_High vaccine, MMR, 
Havrix, and Prevnar 13* 
× 
VV_Lot 1 
100 
12 – 15 months 
VV vaccine (Varivax Lot 1), 
MMR, Havrix, and 
Prevnar 13* 
× 
VV_Lot 2 
100 
12 – 15 months 
VV vaccine (Varivax Lot 2), 
MMR, Havrix, and 
Prevnar 13* 
× 
VNS_Low, VNS_Med, and VNS_High vaccine = VNS vaccine in low, medium, and high potency; VV_Lot 1 and 
VV_Lot 2 vaccines = VV vaccine in 2 lots; MMR = M-M-R II or M-M-RVaxPro; MMR, Havrix, and Prevnar 13 = 
co-administered vaccines 
*Prevnar 13 will only be administered to participants enrolled in the United States and in the countries where 
pneumococcal conjugate vaccine is recommended at 12 to 15 months as per national immunization schedule 
There will be 3 in-person study visits: on Day 1, when the participants receive study 
intervention, on Day 15 (either in-person or virtually, for review of post-vaccination safety data), 
and on Day 43, when blood sampling for vaccine antibody testing will be performed. There will 
also be 1 safety call on Day 2-3 and 1 safety follow-up contact, on Day 181; these may be 
performed over the phone or by any other convenient means of communication. Refer to the 
Study Reference Manual which will contain a guide telephone script to be used for the Day 2-3 
safety call, Day 15 (if the visit is conducted virtually) and for the Day 181 safety follow-up call. 
The visits should occur within a pre-defined visit window (see Table 4). 
The study will be performed in the observer-blind manner (see the definition in Appendix 1 and 
additional details in Section 4.2.3). An IDMC will perform periodic safety reviews of the study 
data. An enrollment pause is foreseen for the first IDMC review after 200 participants 
(approximately 50 participants in each group, considering pooled VV groups) are enrolled and 
vaccinated (See Section 8.2.3 for additional details). 
The safety data will be collected through an Electronic Diary (eDiary)/personal electronic device 
application (app) for solicited events and at study visits/contacts for unsolicited events. The 
humoral immunogenicity testing of blood samples will be performed by enzyme-linked 
immunosorbent assay (ELISA) method at GSK’s laboratory or in a laboratory designated by 
GSK. 
23

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
4.2 
Scientific Rationale for Study Design 
4.2.1 
Rationale for Clinical Study Population 
Varicella (chickenpox) is common in children under 10 years of age. In many countries 
worldwide, vaccination against varicella in early years of life is recommended to prevent 
development of chickenpox in older age. According to the WHO, the countries which decide to 
introduce routine childhood varicella immunization, should administer the first dose at 12 to 
18 months of age [WHO, 2014]. In the US, the incidence of varicella has decreased significantly 
since implementation of the national varicella vaccination program in 1996 [CDC, 2015]. In the 
US, as per the recommendation of the Advisory Committee on Immunization Practices (ACIP) 
children are routinely administered the first dose of the varicella vaccine at 12 to 15 months of 
age and the second dose at 4 to 6 years of age. However, the second dose may be administered at 
an earlier age provided that the interval between the first and second dose is at least 3 months 
[ACIP, 2007]. 
4.2.2 
Choice of Comparator and Co-administered Vaccines 
This will be an active-controlled study. The co-administered interventions will be included to 
maintain the standard of care. 
4.2.2.1 
Comparator 
The varicella vaccine manufactured by Merck & Co, Varivax, similarly to the investigational 
VNS vaccine, contains an Oka varicella strain and is intended for the vaccination against 
varicella in healthy individuals from 12 months of age. Varivax has proven effectiveness. It is 
approved in more than 70 countries. It is the only varicella vaccine licensed in the US, where it is 
considered the standard of care. 
4.2.2.2 
Co-administered Vaccines 
MMR, Havrix, and Prevnar 13 vaccines are part of the routine pediatric vaccination schedules in 
the US [ACIP, 2007] and some other countries. 
4.2.3 
Rationale for Blinding 
Because of the difference in the presentation of the investigational VNS vaccine and the 
commercial VV vaccine, i.e., the difference in the labeling of the vaccine vials and the difference 
in the appearance of the diluent presentation (a prefilled syringe for VNS vaccine versus a vial 
for the VV vaccine), double blinding is not possible. The study will be conducted in an 
observer-blind manner. See the definitions of double-blinding and observer-blind in Appendix 1 
and refer to Section 6.3.4 for details. 
24

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
4.2.4 
Justification for Dose of Varicella Vaccine 
In general, varicella dosing recommendations include 1 or 2 doses. In the US, it is recommended 
that the pediatric population receives 2 doses of varicella vaccine. In EU, vaccination with 
2 doses of varicella vaccine is recommended in different countries according to local and 
regional public health guidelines. 
The participants in this study will receive a single dose of investigational or comparator varicella 
vaccine. The second dose of varicella vaccine will not be offered in this study, as the study 
participants will not yet reach an appropriate age within the study time frame as per the ACIP 
recommended schedule [ACIP, 2007]. 
4.3 
End of Study Definition 
A participant is considered to have completed the study if he/she returns for the last visit/contact 
or is available for the last scheduled procedure/contact as described in the protocol. 
The end of the study (EoS) is defined as the date of the Last Participant Last Visit (LPLV) or 
date of last testing results released whichever comes last. In the latter, EoS must be achieved no 
later than 8 months after the LPLV. 
25

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
5.0 STUDY POPULATION 
Participants shall be enrolled into the study according to inclusion criteria and if they meet none 
of the exclusion criteria. Prospective approval of protocol deviations to enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
• 
Healthy participants as established by medical history and clinical examination before 
entering into the study. 
• 
A male or female between, and including, 12 and 15 months of age (i.e., from his/her 1-year 
birthday until the day before age of 16 months) at the time of the administration of the study 
interventions. 
• 
Written informed consent obtained from the parent(s)/LAR(s) of the participant prior to 
performance of any study-specific procedure. 
• 
Participants’ parent(s)/LAR(s), who, in the opinion of the investigator, can and will comply, 
with the requirements of the protocol (e.g., completion of eDiaries, return for follow-up 
visits). 
• 
Only for US participants and participants in countries where pneumococcal conjugate 
vaccine is recommended at 12-15 months of life as per national immunization schedule: 
Participants who previously received the primary series of pneumococcal conjugate vaccine 
in their first year of life with the last dose at least 60 days prior to study entry. 
5.2 
Exclusion Criteria 
5.2.1 
Medical Conditions 
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the 
study interventions including hypersensitivity to neomycin or gelatin. 
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on 
medical history and physical examination (no laboratory testing required). 
• Hypersensitivity to latex. 
• Major congenital defects, as assessed by the investigator. 
• History of varicella. 
• Recurrent history of or uncontrolled neurological disorders or seizures. 
• Participant with history of SARS-CoV-2 infection who is still symptomatic. 
• Any other clinical condition that, in the opinion of the investigator, might pose additional risk 
to the participant due to participation in the study. 
 
26

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Refer to Section 5.5 for criteria for temporary delay or enrollment and/or intervention. 
5.2.2 
Prior and Concomitant Therapy 
• Use of any investigational or non-registered product (drug, vaccine or medical device) other 
than the study interventions during the period beginning 30 days before the dose of study 
interventions (Day -29 to Day 1), or planned use during the study period. 
• Chronic administration (defined as more than 14 days in total) of immunosuppressants, or 
other immune-modifying drugs during the period starting 90 days prior to the study 
interventions administration. For corticosteroids, this will mean prednisone equivalent 
≥ 0.5 mg/kg/day or 20 mg/day whichever is the maximum dose for pediatric participants, or 
equivalent. Inhaled and topical steroids are allowed. 
• Administration of immunoglobulins and/or any blood products or plasma derivatives during 
the period starting 180 days before the dose of study interventions or planned administration 
during the study period. 
• Administration of long-acting immune-modifying drugs at any time during the study period 
(e.g., infliximab). 
• Previous vaccination against measles, mumps, rubella, hepatitis A, and/or varicella virus. 
• Previous administration of a booster dose of any pneumococcal conjugate vaccine. 
• Planned administration/administration of a vaccine not foreseen by the study protocol in the 
period starting 30 days before the dose and ending at 43 days after the dose of study 
interventions administration* (Visit 3) with the exception of inactivated influenza (flu) 
vaccine which may be given at any time during the study and administered at a different 
location than the study interventions. 
Any other age-appropriate vaccine may be given starting at Visit 3 and anytime thereafter. 
*In case of emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is recommended and/or organized by public health authorities outside the routine 
immunization program, the time period described above can be reduced if necessary for that 
vaccine, provided it is used according to the local governmental recommendations and that 
the Sponsor/designee is notified accordingly. 
5.2.3 
Prior/Concurrent Clinical Study Experience 
• Concurrently participating in another clinical study, at any time during the study period, in 
which the participant has been or will be exposed to an investigational or a 
non-investigational intervention (drug/invasive medical device [see the definition in 
Appendix 1]). 
27

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
5.2.4 
Other Exclusions 
• Child in care (see the definition in Appendix 1). 
• Any study personnel’s immediate dependents, family, or household members. 
• Participants with the following high-risk individuals in their household: 
o Immunocompromised individuals. 
o Pregnant women without documented history of varicella. 
o Newborn infants of mothers without documented history of varicella. 
o Newborn infants born < 28 weeks of gestation. 
5.3 
Lifestyle Considerations, Activity, and Dietary Restrictions 
No restrictions for this study. 
5.4 
Screen Failures 
Not applicable as there is no screening phase of the potential participants as part of this study. 
5.5 
Criteria for Temporary Delay for Enrollment and/or Intervention 
Administration 
Enrollment and/or study intervention administration may be postponed within the permitted time 
interval until transient circumstances cited below are resolved and the participant stays eligible: 
• Acute disease and/or fever at the time of enrollment and/or study intervention administration. 
Fever is defined as temperature ≥ 38.0°C (100.4°F) by any route. The preferred location for 
measuring temperature will be the axilla. 
• Participants with a minor illness (such as mild diarrhea, mild upper respiratory infection) 
without fever may be enrolled and/or dosed at the discretion of the investigator. 
• Use of antipyretics and/or analgesics and/or antibiotics within 3 days prior to study 
intervention administration. 
28

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
6.0 STUDY INTERVENTION 
For the definition of study intervention, refer to Appendix 1. 
6.1 
Study Interventions Administered 
The study interventions that will be administered in the study are provided in Table 7. 
 
29

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
Table 7 
Study Intervention Administered 
Study 
intervention 
VNS_Low vaccine 
VNS_Med vaccine 
VNS_High vaccine 
Varivax 
Study 
intervention 
formulation: 
Live 
attenuated 
varicella 
virus (OKA 
strain) 
(≥ 1×103.0
pfu/dose) 
Water for 
injections 
Live attenuated 
varicella virus 
(Oka strain) 
(≥ 1×103.0 
pfu/dose) 
Water for 
injections 
Live attenuated 
varicella virus 
(Oka strain) 
(≥ 1×103.0 
pfu/dose) 
Water for 
injections 
Varicella virus 
Oka/Merck 
strain (live, 
attenuated) 
(≥ 1350 
pfu/dose) 
Water for 
injections q.s. 
0.5 mL 
Presentation: 
Powder for 
suspension 
for injection 
(vial) 
Solution for 
suspension 
for injection 
(syringe) 
Powder for 
suspension for 
injection (vial) 
Solution for 
suspension 
for injection 
(syringe) 
Powder for 
suspension for 
injection (vial) 
Solution for 
suspension for 
injection 
(syringe) 
Powder for 
suspension for 
injection (vial) 
Solution for 
suspension for 
injection 
Type: 
Biologic/Combination 
Product 
Biologic/Combination Product 
Biologic/Combination Product 
Biologic/Combination Product 
Route of 
administration: 
Subcutaneous injection 
Subcutaneous injection 
Subcutaneous injection 
Subcutaneous injection 
Administration site: 
Location 
Arm 
Arm 
Arm 
Arm 
Directionality 
Upper 
Upper 
Upper 
Upper 
Laterality 
Left 
Left 
Left 
Left 
Number of 
doses to be 
administered: 
1 
1 
1 
2*** 
Volume to be 
administered*: 
At least 0.28 mL 
At least 0.5 mL 
At least 0.5 mL 
0.5 mL 
Packaging and 
labeling  
Refer to SRM for more details 
Refer to SRM for more details 
Refer to SRM for more details 
Refer to SRM for more details 
Manufacturer: 
GSK 
GSK 
GSK 
Merck & Co. 
30

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
Study intervention 
(co-administered) 
MMR 
Havrix 
Prevnar 13** 
Study intervention 
formulation: 
Live attenuated 
measles virus 
Enders' 
Edmonston strain 
(≥ 3.0 log10 
TCID50); Live 
attenuated mumps 
virus Jeryl Lynn™ 
[Level B] strain 
(≥ 4.1 log10 
TCID50); Live 
attenuated rubella 
virus Wistar RA 
27/3 strain (≥ 3.0 
log10 TCID50) 
Water 
for 
injection
s q.s. 0.5 
mL 
Hepatitis A virus antigen 
(HM175 strain) (720 ELISA 
Units) adsorbed on aluminum 
hydroxide; Aluminum 
hydroxide (0.25 mg Al3+); 
Water for injections q.s. 0.5 mL 
PS1(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS3(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS4(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS5(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS6A(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS6B(4.4 µg)-CRM197 adsorbed on aluminum phosphate; 
PS7F(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS9V(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS14(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS18C(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS19A(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS19F(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
PS23F(2.2 µg)-CRM197 adsorbed on aluminum phosphate; 
Aluminum phosphate (0.125 mg Al3+); 
Water for injections q.s. 0.5 mL 
Presentation: 
Powder for 
suspension for 
injection (vial) 
Solution 
for 
suspensi
on for 
injection 
Suspension for injection 
(syringe) 
Suspension for injection (syringe) 
Type: 
Biologic/Combination Product 
Biologic/Combination Product 
Biologic/Combination Product 
Route of 
administration: 
Subcutaneous injection 
Intramuscular injection 
Intramuscular injection 
Administration site: 
Location 
Arm 
Thigh 
Thigh 
Directionality 
Upper 
Anterolateral 
Anterolateral 
Laterality 
Right 
Right 
Left 
Number of doses to be 
administered: 
1 
2*** 
1 
Volume to be 
administered*: 
0.5 mL 
0.5 mL 
0.5 mL 
Packaging and labeling 
Refer to SRM for more details 
Refer to SRM for more details 
Refer to SRM for more details 
Manufacturer: 
Merck & Co 
GSK 
Pfizer 
TCID50 = tissue cell culture infectious doses 50%; PS = polysaccharide; CRM197 = non-toxic cross-reacting mutant of diphtheria toxin; ELISA = enzyme-linked immunosorbent 
assay; GSK = GlaxoSmithKline Biologicals SA; pfu = plaque-forming units; SRM = Study Reference Manual; VNS_Low, VNS_Med, and VNS_High = VNS vaccine in low, 
medium, and high potency; MMR = measles, mumps, rubella vaccine (M-M-R II or M-M-RVaxPro) 
* Refer to the Study Reference Manual/pharmacy manual for the volume after reconstitution
31

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
 
**Prevnar 13 will only be administered to participants enrolled in the United States and in countries where pneumococcal conjugate vaccine is recommended at 12 to 15 months as 
per national immunization schedule 
*** For non-US participants only. At the end of the study or shortly after the study, depending on the vaccines’ availability, GSK will provide a second dose of 
Havrix and/or Varivax in countries where they are not routinely provided. The administration of the second dose of Havrix and Varivax is not part of the study 
procedures.
32

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
6.2 
Preparation/Handling/Storage/Accountability 
The study intervention(s) must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be continuously 
monitored with calibrated (if not validated) temperature monitoring device(s) and recorded. 
Refer to the Study Reference Manual (SRM)/pharmacy manual for more details on storage of the 
study intervention(s). 
Varivax will be stored at −15°C to −30°C (+5°F to −22°F) in the US and other countries with 
frozen formulation and at +2°C to +8°C (+36°F to +46°F) in the rest of the world. (Note: 
refrigerated Varivax vaccine will be used at non-US sites, while frozen Varivax vaccine will be 
used at sites in the US and other countries with frozen formulation.) 
Temperature excursions must be reported in degree Celsius, as described below: 
• For VNS Diluent 
Any temperature excursion outside the range of +1.5°C to +8.4°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. The impacted IMPs may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the SRM/pharmacy 
manual for more details on actions to take. 
• For VNS Antigen 
Any temperature excursion above −15.0°C (for −20°C/−4°F label storage condition) impacting 
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 above −20.0°C up to −15.0°C impacting IMPs, there is no need to report 
in (e)TDF, but adequate actions must be taken to restore the −20°C/−4°F or below label storage 
temperature. The impacted IMPs may still be used, but the site should avoid re-occurrence of 
such temperature excursion. Refer to the SRM/pharmacy manual for more details on actions to 
take. 
• For Varivax Diluent, Varivax antigen with refrigerated formulation and all other 
products (Prevnar 13, Havrix, MMR) 
Any temperature excursion outside the range of 2.0°C to +8.0°C (for +2°C to +8°C/+36°F to 
+46°F label storage condition) impacting study interventions must be reported in the appropriate 
33

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
(e)TDF. The impacted study interventions must not be used and must be stored in quarantine at 
label temperature conditions until usage approval has been obtained from the sponsor. 
• For Varivax Antigen in the US and other countries with frozen formulation 
Any temperature excursion above −15.0°C impacting study interventions must be reported in the 
appropriate (e)TDF. The impacted study interventions must not be used and must be stored in 
quarantine at label temperature conditions until usage approval has been obtained from the 
sponsor. 
All study interventions that are impacted by a temperature excursion may not be used and must 
be quarantined at label storage conditions until usage approval has been obtained from/via the 
local study contact (e.g., Site Monitor). Refer to the SRM/pharmacy manual for details and 
instructions on the temperature excursion reporting and usage decision process, packaging, and 
accountability of the study interventions. 
6.2.1 
Minimizing Environmental Contamination with Genetically Modified 
Organisms 
Not applicable. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Participant Identification 
The participant identification numbers (IDs) will be assigned sequentially to the participants 
whose parent(s)/LAR(s) have consented to participate in the study, according to the range of 
participant IDs allocated to each study center. 
6.3.2 
Randomization to Study Intervention 
The country and center will be used as minimization factors for randomization. Randomization 
of vaccines will be performed using Interactive Voice Response System (IVRS)/Interactive Web 
Response System (IWRS). The participants will receive a unique treatment number (refer to 
Appendix 1 for the definition). Once a treatment number has been assigned, it cannot be 
re-assigned. 
6.3.3 
Intervention Allocation to Participants 
Allocation of the participant to an intervention group at the study center will be performed using 
IVRS/IWRS randomization through Interactive Response Tool (IRT; refer to Appendix 1 for the 
definition) operated at the study level, before the first vaccination and after assessment of 
eligibility (i.e., after screening conclusion). The country and center will be used as minimization 
factors. 
34

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
The actual randomization assignment the participant received (to one of the groups) will be 
identifiable via IRT in case of unblinding. 
After obtaining the signed and dated Informed Consent Form (ICF) from the participant’s 
parent(s)/LAR(s) and having checked the eligibility of the participant, the delegated clinical 
study staff will access IVRS/IWRS. Upon entering the participant ID, the randomization system 
will determine the intervention group and provide the treatment number. 
Refer to the IVRS/IWRS user guide or the SRM for specific instructions related to instances 
when IVRS/IWRS is not available. 
Refer to the SRM for additional information related to the treatment number allocation. 
6.3.4 
Blinding and Unblinding 
Data will be collected in an observer-blind manner. To do so, study interventions will be 
prepared and administered by qualified study personnel who will not participate in data 
collection, evaluation, review, or the entry of any study endpoint. 
The laboratory in charge of sample testing will be blinded to the study intervention assignment. 
Codes will be used to link the participant and study to each sample. There will be no link 
between the study intervention groups and the identity of the participant. 
6.3.4.1 
Emergency Unblinding 
Unblinding a participant’s individual treatment number should occur ONLY in case of a medical 
emergency when knowledge of the intervention is essential for the clinical management or 
welfare of the participant. 
In case of emergency, the investigator will have unrestricted, immediate, and direct access to the 
participant’s individual study intervention through IVRS/IWRS. At activation, the study centers 
will be provided instructions and/or other applicable information for emergency unblinding. The 
IRT used by the IVRS/IWRS provider will be programmed with blind-breaking instructions. In 
case of an emergency, the investigator has the sole responsibility for determining if unblinding of 
a participant’s intervention is warranted. The participant safety must always be the first 
consideration in making such a determination. 
If a participant’s intervention assignment is unblinded, the Medical Monitor (see the definition in 
Appendix 1) must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation (see the definition in 
Appendix 1) and electronic Case Report Form (eCRF), as applicable. The participant may 
continue in the study. 
In the event of a Quality Assurance audit, the auditor(s) may be allowed access to unblinded 
study treatment information records to verify that vaccine dispensing has been done accurately. 
35

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
A physician other than the investigator (e.g., an emergency room physician) or participant’s 
parent(s)/LAR(s)/caregiver (see the definition in Appendix 1)/family member may also request 
emergency unblinding. Instructions for this will be provided to the participants’ parent(s)/LAR(s) 
at enrollment. 
6.3.4.2 
Emergency Unblinding Prior to Regulatory Reporting of Serious Adverse Events 
GSK policy (which incorporates ICH E2A guideline, EU Clinical Study Directive, and US 
Federal Regulations) is to unblind the report of any unexpected SAE that is 
attributable/suspected to be attributable to the investigational vaccine prior to regulatory 
reporting. 
IQVIA will follow these policies along with IQVIA’s standard procedures and will be 
responsible for unblinding the intervention assignment in accordance with the specified 
timeframes for expedited reporting of SAEs (refer to Appendix 4 for details). 
In addition, IQVIA may unblind the intervention assignment for any participant with a suspected 
unexpected serious adverse reaction (SUSAR) or an SAE that is fatal or life-threatening. If the 
SAE requires an expedited regulatory report be sent to 1 or more regulatory agencies, a copy of 
the report, identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or the sponsor’s policy. 
6.4 
Study Intervention Compliance 
When the study intervention is administered at the study center, participants will receive it from 
the authorized study center staff. The date of administration of each study intervention dose in 
the clinic will be recorded in the source documents and in the eCRF. 
6.5 
Dose Modification 
Not applicable. 
6.6 
Continuing Access to Study Intervention after the End of the Study 
At the end of the study or shortly after the study, depending on the vaccines’ availability, GSK 
will provide a second dose of Varivax and/or Havrix to participants enrolled in non-US countries 
if local health departments do not routinely provide varicella and/or hepatitis A vaccine.  
6.7 
Treatment of Overdose 
Any dose of any study vaccine greater than the recommended dose per protocol is considered an 
overdose. All cases of vaccine overdose should be reported as AEs (or SAEs, if SAE criteria are 
met) and followed accordingly. Sponsor does not recommend specific treatment for an overdose. 
36

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
6.8 
Concomitant Therapy 
At each study visit/contact, the investigator or designee should question the participant’s 
parent(s)/LAR(s) about any medications/products/supplements taken and vaccinations received 
by the participant, whether prescribed or over the counter. 
The following concomitant therapies must be recorded in the eCRF: 
• All concomitant medication associated with AE, including vaccines/products, except 
vitamins and dietary supplements, administered after the first dose of study intervention 
(Day 1 to Day 43). 
• All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines. 
• All concomitant medication which may explain/cause/be used to treat an SAE including 
vaccines/products. These must also be recorded in the Expedited Adverse Event report. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The record of a concomitant medication should include at a minimum the reason for use, dates of 
administration including start and end dates, dosage information including dose and frequency. 
37

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
7.0 DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Not applicable as this is a single dose study. 
7.2 
Contraindications to Subsequent Study Interventions Administration 
Not applicable as this is a single dose study. 
7.3 
Participant Discontinuation/Withdrawal from the Study 
The participant’s parent(s)/LAR(s) may withdraw the participant from the study at any time or 
the investigator may decide to withdraw a participant for safety, compliance, administrative, or 
other reasons. 
A participant is considered a “withdrawal” from the study when no study procedure has 
occurred, no follow-up has been performed, and no further information has been collected for 
this participant from the date of withdrawal/last contact. 
From an analysis perspective, a study “withdrawal” refers to any participant who was not 
available for the concluding contact planned in the protocol. 
All data and samples collected up to and including the date of withdrawal of/last contact with the 
participant parent(s)/LAR(s) will be included in the study analyses. 
The primary reason for study withdrawal shall be documented in the eCRF. Examples of the 
reasons may include: 
• Adverse event requiring expedited reporting to IQVIA (see Appendix 4 for the details 
regarding such events) 
• Unsolicited non-serious AE 
• Solicited AE 
• Withdrawal by the participant’s parent(s)/LAR(s) but not due to AE* 
• Migrated/moved from the study area 
• Lost to follow-up 
• Study termination 
• Other (specify) 
38

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
*If a participant is withdrawn from the study because the participant’s parent(s)/LAR(s) have 
withdrawn consent and the reason for withdrawal was provided, the investigator must document 
this reason in the eCRF. 
Participants who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from participants who are withdrawn for other reasons. The investigators should 
follow-up with parent(s)/LAR(s) of participants who are withdrawn from the study as a result of 
an SAE/AE until the event is resolved (see Appendix 4 for details regarding follow-up for AEs). 
7.4 
Lost to Follow-up 
A participant will be considered “lost to follow-up” if he/she fails to return for the scheduled 
visit and cannot be contacted by the study center. 
Refer to the SRM for a description of actions to be taken before considering the participant lost 
to follow-up. 
39

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
8.0 STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are only permitted when necessary for the management of 
immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or when 
the study team becomes aware of them. The purpose of this communication is to determine if the 
participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the Schedule of Activities (SoA; 
Section 1.3). 
All screening evaluations must be completed and the results reviewed before confirming that 
potential participants meet all eligibility criteria. 
The investigator will maintain a log of all participants screened. All relevant information, such as 
confirmation of eligibility and reasons for screening failure will be mentioned in this screening 
log. 
The SRM provides the investigator and study center personnel with detailed administrative and 
technical information that does not impact the participant safety. 
8.1 
Immunogenicity Assessments 
8.1.1 
Biological Samples 
Biological samples will be used for research planned in the protocol and for purposes related to 
the improvement, development and quality assurance of the laboratory tests described in this 
protocol. 
Findings in this or future studies may make it desirable to use samples acquired in this study for 
research not planned in this protocol. In this case, all participants will be asked to give consent to 
allow GSK or a contracted partner, to use the samples for further research. The further research 
will be subject to prior Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
approval, if required by local legislation. 
Information on further research and its rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the participant’s 
parent(s)/LAR(s). 
By default, collected samples will be stored for a maximum of 20 years. This storage period 
begins when the last participant performs the last study visit. This timeline can be adapted based 
on local laws, regulations or guidelines requiring different timeframes or procedures. In all cases, 
the storage period should be aligned with participant’s consent. These additional requirements 
must be formally communicated to, discussed and agreed with GSK. 
40

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
8.1.2 
Laboratory Assays 
All laboratory testing will be performed as indicated in Table 8 at GSK laboratory or in a 
laboratory designated by GSK. 
Table 8 
Laboratory Assay 
Assay type 
System 
Component 
Method 
Humoral Immunity 
(Antibody determination) 
Serum 
Anti-gE antibodies 
ELISA 
gE = glycoprotein E; ELISA = enzyme-linked immunosorbent assay 
8.1.3 
Immunological Correlates of Protection 
There is no established correlate of protection (see the definition in Appendix 1) with the assay 
to be used in this study for the varicella vaccines administered in the frame of this study. 
The investigator, even though remaining blinded with respect to each child’s group attribution, 
will be provided with the list of children who fail to serorespond to varicella virus (i.e., achieve a 
post-vaccination anti-gE antibody concentration ≥300 mIU/mL) in a timely manner (no later than 
12 months after the last sampling date of the last child enrolled). 
Upon receiving the result, the investigator will assess if any step needs to be taken regarding the 
individual child. Study participants who do not achieve the pre-specified seroresponse threshold 
criteria will be re-vaccinated with a dose of Varivax. 
8.2 
Safety Assessments 
8.2.1 
Pre-intervention Administration Procedures 
8.2.1.1 
Collection of Demographic Data, Medical/vaccination history, Physical 
Examination 
Demographic data such as age in months, sex, race, and ethnicity will be collected from each 
participant. Medical history should be collected and it should be verified that none of exclusion 
criteria related to medical and vaccination history (Section 5.2) are met. Prior vaccination history 
with respect to pneumococcal conjugate vaccine should be obtained and recorded in the eCRF. 
Physical examination will be performed for each participant. If the investigator determines that 
the participant’s health on the day of the study intervention administration temporarily precludes 
dosing, the visit will be rescheduled. Refer to Section 5.5 for the list of criteria for the temporary 
delay of study intervention administration. 
8.2.1.2 
Checking Contraindications, Warnings, and Precautions to Intervention 
Administration 
The body temperature of each participant will be measured prior to the study intervention 
administration. GSK will provide the study center with the temperature measuring device which 
41

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
are standard devices validated by GSK’s Quality Assurance Team to ensure consistency in the 
data across study centers. If the participant has a fever (defined as temperature ≥ 38.0° C 
[100.4° F] regardless of the location of measurement) on the day of the intervention 
administration, or other health conditions that can be considered temporary, Visit 1 can be 
rescheduled (see Section 5.5) as long as the eligibility criteria are still met (See Section 5.1 and 
Section 5.2). 
8.2.2 
Clinical Safety Laboratory Tests 
No clinical safety laboratory tests are planned per protocol. Clinical safety laboratory tests may 
be performed at the investigator’s discretion if deemed necessary in case of safety concerns. 
8.2.3 
Safety Monitoring and Study Holding Rules 
Besides safety monitoring by blinded Study/Center Monitors (see the definition in Appendix 1), 
an IDMC comprising of clinical experts and an independent biostatistician will provide safety 
oversight during the active vaccination period, through unblinded review of the cumulative 
safety data. 
Up to the completion of enrollment and vaccination of the first 200 participants through their 
Day 43 follow-up, enrollment will be paused for an ad hoc IDMC review of the cumulative 
safety data if any of the holding rules are met (See Section 8.2.3.1). 
An enrollment pause is foreseen for the first IDMC review after 200 participants (50 in each 
group, considering pooled VV groups) are enrolled and vaccinated. The analysis will take place 
once all 200 participants have returned for their Day 43 visit (Visit 3) or have withdrawn from 
the study, within the allowed interval for the visit. A positive outcome of the IDMC review will 
be a pre-requisite for the continuation of the study. 
Monthly SRT review will occur up to the enrollment and vaccination of the first 200 participants 
through their Day 43 follow-up, to monitor cumulative, blinded, safety data (including serious 
and non-serious AEs). The blinded safety data review by the SRT may trigger an emergency 
ad hoc IDMC review before 200 participants are enrolled and vaccinated. During the study, as 
per the IDMC charter, ad hoc IDMC meetings may be convened when a safety concern has been 
observed. In this case, enrollment shall be paused. 
A subsequent IDMC review meeting is planned during the study, after Day 43 safety follow-up 
of 400 participants is completed, no enrollment pause is foreseen for this review. The details of 
the review will be described in an IDMC charter. The analysis will take place once all 
400 participants have returned for their Day 43 visit (Visit 3) or have withdrawn from the study, 
within the allowed interval for the visit. 
42

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
8.2.3.1 
Study Holding Rules 
The safety holding rules defined in Table 9 only apply to the first 200 study participants enrolled. 
Holding rules 1-3 will be assessed by the investigator on a continuous basis. Holding rules 1-3 
will be assessed by the IDMC during the safety evaluations on unblinded data. 
Table 9 
Study Holding Rules 
Holding 
Rule 
Event 
Number of participants to 
pause vaccination in all 
groups, pending further 
evaluation by IDMC  
1 
Any death considered at least possibly related to study vaccination 
≥ 1 
2 
Any SAE(s) considered at least possibly related to vaccination 
≥ 1 
3 
Same or similar* Grade 3 unsolicited AE considered to be at least possibly 
related to vaccination 
≥ 2 
AE = adverse event; IDMC = Independent Data Monitoring Committee; SAE = serious adverse event 
*based on medical judgment 
If the investigator becomes aware of a holding rule being met, he/she must suspend 
administration of the study intervention, pause enrollment, and inform IQVIA immediately (e.g., 
holding rules 1-3). Refer to Appendix 4 for contact information. 
GSK via IQVIA will inform all study investigators to suspend the study intervention and 
enrollment if any of the holding rules are met. 
The following communication sequence for the identification of holding rules by the investigator 
must be followed (Figure 2). 
 
43

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Figure 2 
Communication Flow: Identification of Holding Rules by the Investigator 
 
CRDL = Clinical Research and Development Lead; GSB = Global Safety Board; IDMC = Independent Data 
Monitoring Committee; IVRS = Interactive Voice Response System; SRT = Safety Review Team 
*Investigators are responsible to inform the Institutional Review Board/Independent Ethics Committee if a holding 
rule has been met. 
8.2.3.2 
Outcome of Safety Evaluation 
If a safety signal is observed during the safety evaluations, or if any of the holding rules is met 
for the first 200 participants, the IDMC Chair (or his/her representative) is responsible for the 
urgent communication to GSK, including the rationale for the decision to put the study 
intervention administration on hold or not. 
If no safety signal is observed in the first 200 participants, the favorable outcome of the safety 
evaluations will be documented and provided in writing, authorizing the investigator to start 
enrollment and dosing of the remaining participants in the study. 
GSK via IQVIA will be accountable for notifying all investigators of the decision whether to 
suspend, modify or continue the conduct of the study on all groups or on selected groups. 
Refer to Section 8.2.3.1 for a flow chart for escalation of safety signal. 
8.3 
Adverse Events 
8.3.1 
Time Period and Frequency for Collecting AE and SAEs and Other Safety 
Information 
The definitions of an AE or SAE are provided in Appendix 4. 
44

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Collection of AEs starts on the day of the study intervention (Day 1) up to Day 43 unless the AE 
leads to study discontinuation. Collection of SAEs starts the day of the study intervention 
(Day 1) and up to Day 181 unless the SAE leads to study discontinuation. The frequency for 
collection of AEs and SAEs is shown in the SoA (Section 1.3). 
Provided that GSK marketed study interventions registered in the US are combination products 
(see Table 7, and the definition of a combination product in Appendix 1), associated AEs 
meeting pre-specified definitions will be classified as medical device AEs and SAEs, as well as 
adverse device effects (ADEs), serious adverse device effects (SADEs), and unanticipated 
serious adverse device effects (USADEs). Definitions of these events are provided in 
Appendix 4. Details on recording, follow-up and reporting of medical device deficiencies are 
provided in Section 8.3.6. 
8.3.2 
Method of Detecting AEs and SAEs 
The methods for detecting and recording AEs and SAEs, and the assessment of AE/SAE 
intensity, causality and outcome are provided in Appendix 4. 
The study center staff should instruct participants’ parent(s)/LAR(s) on how to report signs and 
symptoms (e.g., crying and pain) in the individual participant. They will be instructed to report 
both specific and non-specific symptoms. 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
non-leading verbal questioning of the participants’ parent(s)/LAR(s) is the preferred method to 
inquire about AE occurrences. Examples of the open-ended questions include “Did you have any 
significant medical problem since the last study visit?” The study center staff should refrain from 
detailed questions, e.g., “Since the last visit, have you experienced any of the following 
(checklist)?” 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up. Further information on follow-up 
procedures is provided in Appendix 4. 
8.3.3 
Regulatory Reporting Requirements for SAEs 
Once the investigator or designee becomes aware that a study participant has experienced an 
SAE, they or designated study staff must report it to IQVIA within 24 hours using an electronic 
Expedited AE Report in the eCRF. 
The investigator will provide an assessment of causality at the time of the initial report, as 
defined in the Appendix 4. New or updated information will be recorded on the originally 
completed form with all changes signed and dated by the investigator and reported to IQVIA 
45

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
within 24 hours. This is essential for meeting GSK legal obligations and ethical responsibilities 
for the participant’s safety and the safety of a study intervention under clinical investigation. 
For coronavirus disease 2019 (COVID-19)-related SAEs, reports should be submitted following 
routine procedures for SAEs. 
Local regulatory requirements and GSK’s policy for the preparation of an investigator safety 
report for suspected SUSARs must be followed. These reports will be forwarded to investigators 
as necessary. 
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation. GSK and IQVIA 
will comply with country-specific requirements related to safety reporting to the regulatory 
authority, IRB/IEC, and investigators. 
8.3.4 
Treatment of AEs 
Any medication administered for the treatment of an SAE should be recorded in the Expedited 
AE Report. 
8.3.5 
Participant Card 
The investigator or investigator’s designee must provide the participant’s parent(s)/LAR(s) with 
a “participant card” containing information about the clinical study. The participant’s 
parent(s)/LAR(s) will be instructed to keep the participant card in their possession at all times 
throughout the study. In an emergency, this card serves to inform the responsible attending 
physician/caregiver/family member/participant’s parent(s)/LAR(s) that the participant is in a 
clinical study and that relevant information may be obtained by contacting the investigator or 
his/her backup. 
8.3.6 
Medical Device Deficiencies 
This clinical study will collect information of any device deficiencies associated with the study 
interventions that are combination products (GSK marketed combination products registered in 
the US). Refer to Appendix 1 for the definition of a combination product and a medical device 
deficiency. 
8.3.6.1 
Detection, Follow-up, and Reporting of Medical Device Deficiencies 
The investigator is responsible for the detection, documentation and prompt reporting of any 
medical device deficiency occurring during the study to IQVIA. Device deficiencies should be 
reported within 24 hours after the investigator determines that the event meets the protocol 
definition of a device deficiency. New or updated information will be recorded on the originally 
completed form with all changes signed and dated by the investigator and reported to IQVIA 
within 24 hours. 
46

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Refer to Appendix 4 for details on recording and reporting of medical device deficiencies. 
The investigator will ensure to follow the participants with reported device deficiencies and 
perform any additional investigations to determine the nature and/or causality of the deficiency. 
8.3.6.2 
Regulatory Reporting of Medical Device Deficiency When Used as Combination 
Product 
The investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for GSK to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. Refer to Appendix 4 for details of reporting. 
The investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB/IEC. 
8.4 
Pharmacokinetics and Pharmacodynamics 
Pharmacokinetic and pharmacodynamic parameters are not evaluated in this study. 
8.5 
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 followed. For the duration of such special circumstances, the following measures may be 
implemented for enrolled participants: 
• Safety follow-up may be made by a phone call or other means of virtual contact. 
• If the eDiary device was provided to the participant’s parent(s)/LAR(s), it may be 
returned to the study center by conventional mail after the end of the relevant data 
collection period (refer to the SRM for details). If the app was provided to the 
participants’ parent(s)/LAR(s) for use on their personal device, the app can be disabled 
remotely. 
• Visits for suspected AEs may take place in a different location* other than the study 
center or at participant’s home. If this is not feasible, then the medical evaluation of AEs 
may take place remotely with documentation of symptoms by other means of 
communication (e.g., phone call or videoconference), if possible. 
• Biological samples may be collected at a different location* other than the study center 
or at participant’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use. 
47

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
*Note: 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 may need to be covered by 
proper insurance for the conduct of study on participants by investigator and study center staff 
other than the designated study center. 
The impact on the PPS for immunogenicity will be determined on a case-by-case basis. Any 
impact of the above-mentioned measures on the study results will be described in the Clinical 
Study Report (CSR). 
48

CONFIDENTIAL 
217212 (VNS 20-006) 
Protocol Amendment 3.0 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
There are no statistical hypotheses in this study. All analyses are descriptive. 
9.2 
Sample Size Determination 
The target enrollment will be of 800 participants randomly assigned to 5 study groups 
(VNS_Low, VNS_Med, VNS_High, VV_Lot1, and VV_Lot2 groups) in a 2:2:2:1:1 ratio. 
Table 10 demonstrates the accuracy which can be achieved in terms of percentage of participants 
with AE based on the ES (200 participants per group considering pooled VV_Lot1 and VV_Lot2 
groups), and in terms of percentage of participants with seroresponse based on the PPS 
(10% unevaluable participants out of the 200 enrolled participants is considered leading to about 
180 participants in the PPS per group). 
Table 10 
Exact 95% Confidence Interval for the Percentage of Participants with 
Adverse Event Based on the Exposed Set and for the Percentage of 
Participants with Seroresponse Based on the Per Protocol Set 
Endpoint 
n 
N 
% 
Exact 95% CI 
% of participants with an AE 
0 
200 
0.0 
[0.00%; 1.83%] 
10 
200 
5.0 
[2.42%; 9.00%] 
20 
200 
10.0 
[6.22%; 15.02%] 
40 
200 
20.0 
[14.69%; 26.22%] 
Seroresponse rate 
144 
180 
80.0 
[73.40%; 85.58%] 
153 
180 
85.0 
[78.93%; 89.885%] 
162 
180 
90.0 
[84.66%; 93.96%] 
171 
180 
95.0 
[90.72%; 97.69%] 
AE = adverse event; CI = confidence interval; n/N = number of participants with an observation/total number of 
participants 
See the analysis sets definitions in Section 9.3. Refer to Appendix 1 for the definitions of 
eligible, enrolled, and evaluable participants. 
9.3 
Populations for Analyses 
For purposes of analysis, the analysis sets are defined in Table 11. 
49

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Table 11 
Analysis Sets 
Analysis set 
Description 
Enrolled Set 
Participants who received a study intervention or were randomized. Note that as per GCP 
enrolled participants’ parent(s)/LAR(s) should have completed the informed consent 
process and participants should be eligible before initiating any study procedure. 
Exposed Set (ES) 
All participants who received a study intervention. Analysis per group is based on the 
varicella intervention administered. 
Per Protocol Set 
(PPS) 
All eligible participants who received all study interventions as per protocol, were not 
unblinded, had immunogenicity results post-dose, complied with blood draw intervals 
(refer to Table 3), without intercurrent medical conditions that may interfere with 
immunogenicity and without prohibited concomitant medication/vaccination (see the 
footnote). 
GCP = good clinical practice; LAR = legally acceptable representative 
Note: Intercurrent medical conditions that may lead to elimination from the PPS are defined as confirmed 
immunodeficiency condition, or development of varicella or herpes zoster in the interval between study intervention 
administration and the collection of the blood specimen for immunogenicity at Visit 3. 
9.4 
Statistical Analyses 
9.4.1 
Statistical Analysis Plan 
The statistical analysis plan (SAP) will be developed and finalized before the First Participant 
First Visit (FPFV). This section is a summary of the planned statistical analyses of the primary 
and secondary immunogenicity endpoints. 
Descriptive analyses of safety and demography summaries will be described in the SAP. 
There is no intention to conduct specific analyses investigating the relationship between the 
gender of the participants and the immunogenicity and safety of the study vaccine. The ratio of 
male to female participants recruited into this study is expected to be in line with the 
demographics of the population aged 12 to 15 months of age. 
9.4.2 
Primary Endpoint Analyses 
The primary analysis of immunogenicity endpoints will be based on the PPS. 
The geometric mean concentrations (GMCs) will be summarized by group with their 95% CI 
derived considering log-transformed anti-gE antibody concentrations are normally distributed 
with unknown variance. The concentration below the assay cut-off will be assigned half the 
cut-off for the purpose of GMC computation. 
The group GMC ratio with nominal 95% CI will also be provided. This will be obtained using an 
analysis of variance (ANOVA) model on log-transformed concentrations. The model based on 
the data from all groups will include group and country as a fixed effect. 
50

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
9.4.3 
Secondary Endpoints Analyses 
The analysis of secondary immunogenicity endpoints will be primarily based on the PPS. 
Seroresponse rate is defined as the percentage of participants for whom the post-dose anti-gE 
antibody concentration (Day 43) is ≥ 300 mIU/mL. 
The seroresponse rates will be summarized by group with their 95% exact CI based on 
Clopper-Pearson method [Clopper and Pearson, 1934]. 
The 2-sided 95% CI on group difference in seroresponse rate (pooled VV group minus each 
VNS group [Low, Med, High]) will be computed based on the method of Miettinen and 
Nurminen [Miettinen and Nurminen, 1985]. 
9.5 
Interim Analysis 
9.5.1 
Sequence of Analyses 
Apart from the analyses to be performed in support to the IDMC, a statistical analysis and a 
report including safety and final immunogenicity data for all participants up to Day 43 time point 
are planned. Following unblinding for the analysis up to Day 43, accessibility to group 
attribution will be limited so that the study center blinding is maintained until the 6-month safety 
follow-up is completed for all participants. 
One integrated CSR containing all data including the safety follow-up beyond Day 43 will then 
be generated upon study completion. This report will be made available to the investigators. If 
there is a delay in availability of the immunogenicity data, leading to a window between the 
2 analyses shorter than what is planned at the time of protocol writing, only 1 statistical analysis 
including all immunogenicity and safety data will be performed. 
9.5.2 
Statistical Considerations for Interim Analysis 
All analyses are descriptive and therefore no statistical adjustment for interim analyses is 
required. 
51

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
10.0 REFERENCES 
Advisory Committee on Immunization Practices (ACIP). Prevention of varicella: 
recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for 
Disease Control, Atlanta, GA. MMWR. 2007;56(No. RR-4). 
Centers for Disease Control and Prevention (CDC). CDC 24/7: Saving Lives, Protecting People. 
Last reviewed: 31 December 2018. https://www.cdc.gov/chickenpox/hcp/index.html. Accessed: 
22 March 2021. 
Centers for Disease Control and Prevention (CDC) The Pink Book: Course Textbook; 13th 
Edition April 2015, Updated December 2020; Chapter 22 Varicella. 
http://www.cdc.gov/vaccines/pubs/pinkbook/varicella.html. Accessed: 22 March 2021. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
binomial. Biometrika. 1934; 26:404-413. 
Miettinen O., Nurminen M. Comparative analysis of 2 rates. Statistics in Medicine 1985; 
4(2):213-26. 
Siedler A, Arndt U. Impact of the routine varicella vaccination programme on varicella 
epidemiology in Germany. Euro Surveill. 2010;15(13). 
Wagenpfeil S, Neiss A, Banz K, et al. Empirical data on the varicella situation in Germany for 
vaccination decisions. Clin Microbiol Infect. 2004;10(5):425-30. 
World Health Organization (WHO). Varicella Vaccines - WHO Position Paper. WHO, Geneva, 
Switzerland. Weekly Epidemiological Record. 2014;25:265-288. 
52

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
11.0 APPENDICES 
53

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 1 
Abbreviations and the Glossary of Terms 
ACIP 
Advisory Committee on Immunization Practices 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
App 
Application 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019  
CRM197 
Non-toxic Cross-Reacting Mutant of Diphtheria Toxin 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture Tool 
eDiary 
Electronic Diary 
ELISA 
Enzyme-linked immunosorbent assay 
EoS 
End of Study 
ES 
Exposed Set 
EU 
European Union 
FPFV 
First Participant First Visit 
GCP 
Good Clinical Practice 
gE 
Glycoprotein E 
GMC 
Geometric Mean Concentration 
HRP 
Horseradish Peroxidase 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Tool 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LAR 
Legally Acceptable Representative 
LPLV 
Last Participant Last Visit 
MMR 
Measles, mumps, and rubella vaccine 
PPS 
Per Protocol Set 
PS 
Polysaccharide 
SADE 
Serious Adverse Device Effect 
54

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
(e)TDF 
(electronic) Temperature Excursion Decision Form 
US 
United States of America 
USADE 
Unanticipated Serious Adverse Device Effect 
VNS 
Varicella vaccine (investigational vaccine) 
VV 
Varicella vaccine (comparator vaccine) 
WHO 
World Health Organization 
Glossary of Terms 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the use of a 
medicinal product, whether or not considered related to the 
medicinal product. 
An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the use of a 
medicinal product. For marketed medicinal products, this also 
includes failure to produce expected benefits (i.e., lack of efficacy), 
abuse or misuse. 
Blinding: 
A procedure in which 1 or more parties to the study are kept 
unaware of the intervention assignment in order to reduce the risk of 
biased study outcomes. The level of blinding is maintained 
throughout the conduct of the study, and only when the data are 
cleaned to an acceptable level of quality will appropriate personnel 
be unblinded or when required in case of a serious adverse event. In 
an observer-blind study, the participant’s parent(s)/LAR(s), the 
study center and sponsor personnel involved in the clinical 
evaluation of the participants are blinded while other study 
personnel may be aware of the treatment assignment. 
In a double-blind study, the participant’s parent(s)/LAR(s), the 
investigator and sponsor staff who are involved in the treatment or 
clinical evaluation of the participants and the review or analysis of 
data are all unaware of the intervention assignment. 
55

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Caregiver: 
A caregiver is someone who 
• lives in the close surroundings of a participant and has a 
continuous caring role or 
• has substantial periods of contact with a participant and is 
engaged in his/her daily health care (e.g., a relative of the 
participant). 
Certified copy: 
A copy (irrespective of the type of media used) of the original record 
that has been verified (i.e., by a dated signature or by generation 
through a validated process) to have the same information, including 
data that describe the context, content, and structure, as the original. 
Child in care: 
A child who has been placed under the control or protection of an 
agency, organization, institution or entity by the courts, the 
government or a government body, acting in accordance with 
powers conferred on them by law or regulation. The definition of a 
child in care can include a child cared for by foster parents or living 
in a care home or institution, provided that the arrangement falls 
within the definition above. The definition of a child in care does not 
include a child who is adopted or has an appointed legal 
guardian/LAR(s). 
Combination 
product: 
Combination product comprises any combination of 
• drug 
• device 
• biological product 
Each drug, device, and biological product included in a combination 
product is a constituent part. 
Eligible: 
Qualified for enrollment into the study based upon strict adherence 
to inclusion/exclusion criteria. 
Enrollment: 
The process of registering a participant into a clinical study by 
assigning participant identification number after signing the ICF. 
Enrolled participant: 
“Enrolled” means a participant’s parent’s/LAR’s agreement to 
participate in a clinical study following completion of the informed 
consent process. Potential participants who are screened for 
determining eligibility for the study, but do not participate in the 
study, are not considered enrolled. 
Essential documents: Documents which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced. 
56

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the per protocol 
analysis. 
Immunological 
correlate of 
protection: 
A correlate of risk that has been validated to predict a certain level 
of protection from the targeted endpoint. 
Intervention: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo 
intended to be administered to a participant. 
Invasive medical 
device: 
A device which, in whole or in part, penetrates inside the body, 
either through a body orifice or through the surface of the body 
Investigational 
vaccine/product: 
A pharmaceutical form of an active ingredient being tested in a 
clinical study, including a product with a marketing authorization 
when used in a way different from the approved form, or when used 
for an unapproved indication, or when used to gain further 
information about an approved use. 
Investigator: 
A person responsible for the conduct of the clinical study at a study 
center. If a study is conducted by a team of individuals at a study 
center, the investigator is the responsible leader of the team and may 
be called the principal investigator. 
The investigator can delegate study-related duties and functions 
conducted at the study center to qualified individual or party to 
perform those study-related duties and functions. 
Interactive 
Voice/Web 
Response System: 
The software that enables the randomizing of participants into 
clinical trials and allocation of the study product to them in a blinded 
fashion. This technology allows study centers to interact with a 
database by pressing keypad buttons on a phone and following voice 
or online prompts in order to enter in information. 
Legally acceptable 
representative: 
An individual or juridical or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the 
participant's participation in the clinical trial. The terms legal 
representative and legally authorized representative are used in some 
settings. 
Medical device 
deficiency: 
A device deficiency is an inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safety, or 
performance. Device deficiencies include malfunctions, use errors 
and information supplied by the manufacturer. 
57

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Medical Monitor
 
 
IQVIA’s delegate providing significant scientific contribution to the 
conduct of the study. The terms Medical Officer, Medical Advisor 
are also used in some settings. 
Medically attended 
AEs: 
Symptoms or illnesses requiring hospitalization, or emergency room 
visit, or visit to/by a health care provider. 
Participant: 
An individual whose parent(s)/LAR(s) has been contacted to 
participate or participates in the clinical trial, either as a recipient of 
the vaccine(s)/product or as a control. 
Participant ID: 
A unique identification number assigned to each participant who 
consents to participate in the study. 
Protocol 
amendment: 
The ICH defines a protocol amendment as “A written description of 
a change(s) to or formal clarification of a protocol.” GSK further 
details this to include a change to an approved protocol that affects 
the safety of participants, scope of the investigation, study design, or 
scientific integrity of the study. 
Randomization: 
Process of random attribution of intervention to participants to 
reduce selection bias. 
Safety Review 
Team: 
This team lead by safety comprises of core representatives from 
GSK global safety, clinical, epidemiology, regulatory, and statistics 
departments, who are also part of the study team. For this study, the 
team is responsible for reviewing observed safety concerns based on 
blinded safety data. 
Solicited events: 
Events to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively solicited 
from the participant or an observer during a specified follow-up 
period following study intervention administration. 
Source data: 
All information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the 
study. Source data are contained in source documents (original 
records or certified copies). 
Source documents: 
Original legible documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, participants' 
diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, 
58

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
participant files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical study). 
Study/Center 
Monitor: 
An individual assigned by GSK/IQVIA (see the study administrative 
structure in Appendix 2 [Table 12]) and responsible for assuring 
proper conduct of clinical studies at 1 or more study centers. The 
terms Clinical Research Monitor and Clinical Research Associate 
are used in some settings. 
Study intervention: 
Any investigational or marketed product(s) or placebo intended to be 
administered to a participant during the study. 
Treatment number: 
A number identifying intervention given to a participant, according 
to intervention allocation. 
Unsolicited events: 
Any AE reported in addition to those solicited during the clinical 
study. Also, any “solicited” symptom with onset outside of the 
specified period of follow-up for solicited symptoms will be 
reported as an unsolicited AE. 
59

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− Applicable ICH GCP Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments (see the definition in Appendix 1), ICF, IB, and 
other relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator for review and approval. These documents will be signed and dated by the 
investigator before the study is initiated. 
• Any protocol amendments will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. Furthermore, any substantial amendments to the 
protocol may require regulatory authority approval before implementation per local 
legislation. 
• IQVIA will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAE(s) or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
• After reading the protocol, all principal investigators will sign the protocol signature 
page and send a copy of the signed page to IQVIA (Appendix 6). 
Financial Disclosure 
Investigators and sub-investigators will provide IQVIA with sufficient, accurate financial 
information as requested to allow GSK/IQVIA to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing financial interest information prior initiation of the study center and at 
60

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
the end of the study. Investigators are responsible for providing a financial disclosure update if 
their financial interests change at any point during their participation in a study and for 1 year 
after completion of the study. 
Informed Consent Process 
• The investigator or his/her representative must fully explain the nature of the study to the 
participant’s parent(s)/LAR(s) and answer all questions regarding the study. 
• Participants’ parent(s)/LAR(s) must be informed that their participation is voluntary. 
• Freely given and written/witnessed/thumb printed informed consent must be obtained 
from each participant’s parent(s)/LAR(s)/witness, as appropriate, prior to participation in 
the study. 
• The content of the ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written or witnessed/thumb printed 
informed consent was obtained before the participant was enrolled in the study and the 
date the consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• Participants’ parent(s)/LAR(s) must be re-consented to the most current version of the 
ICF(s) or an ICF addendum during their participation in the study. 
• A copy of the ICF(s) must be provided to the participants’ parent(s)/LAR(s). 
Data Protection 
• Any participant records or datasets that are transferred to IQVIA/GSK will contain the 
participant ID only; participant names or any information which would make the 
participant identifiable will not be transferred. 
• The participants’ parents/LARs must be informed that: 
− Their child’s study-related data will be used by GSK in accordance with local data 
protection law. 
− Their child’s medical records may be examined by Clinical Quality Assurance 
auditors or other authorized personnel appointed by GSK/IQVIA, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
− GSK will ensure protection of the personal data of the investigator and study center 
staff which is collected within the framework of and for the purpose of the study, in 
accordance with the Data Privacy Notice that will be sent to the site staff. 
The participants’ parent(s)/LAR(s) must be notified about their rights regarding the use of their 
personal data in accordance with the data privacy section of the ICF. 
61

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Administrative Structure 
Table 12 
Study Administrative Structure 
Function 
Responsible organization 
Clinical Supply Management, Quality Assurance Auditing 
GSK 
Laboratory Assessments 
GSK 
Randomization, Blinding, Unblinding 
Cenduit 
Study Operations Management, Medical Monitoring, Study Master File 
IQVIA 
Biostatistics, Medical Writing 
IQVIA 
Medical Monitor 
Refer to the SRM. 
Dissemination of Clinical Study Data 
The key design elements of this protocol and results summaries will be posted on 
ClinicalTrials.gov, EudraCT, and/or GSK Clinical Study Register in compliance with applicable 
regulations/GSK policy. GSK will aim to register protocols summaries prior to study start and 
target results summaries submission within 12 months of primary/study completion date. Where 
external regulations require earlier disclosure, GSK will follow those timelines. 
Where required by regulation, summaries will also be posted on applicable national or regional 
clinical study registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to statistical 
tables, figures, and relevant reports. GSK will also provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results with 
the study participants’ parent(s)/LAR(s), as appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science or improve patient care. This helps to ensure the data provided by study participants are 
used to maximum effect in the creation of knowledge and understanding. 
Publication Policy 
GSK aims to submit for publication the results of the study in searchable, peer reviewed 
scientific literature within 18 months from LPLV and follow authorship and other guidance from 
the International Committee of Medical Journal Editors. 
62

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Data Quality Assurance 
• The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Appendix 1 for definitions of essential and 
source documents). The document storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search, and retrieval. 
• Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, eCRF), the copy should fulfill the 
requirements for certified copies (see Appendix 1 for the definition of a certified copy). 
• All participant data related to the study will be recorded on printed or eCRF unless transmitted 
to GSK/IQVIA electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants (see Appendix 1 for 
the definition of source documents) that supports information entered in the eCRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents or certified copies for such 
review and inspection. 
• IQVIA is responsible for the data management of this study including quality checking of the 
source data (see Appendix 1 for the definition of source data). 
• Study monitors will perform ongoing source data verification to confirm that data entered in 
the eCRF by authorized site personnel are attributable, legible, contemporaneous, original, 
accurate, and complete. Changes to source data must be traceable, not obscure the original 
entry, and be fully explained if necessary (e.g., via an audit trail). The safety and rights of 
participants must be protected, and the study conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• Quality tolerance limits will be pre-defined to identify systematic issues that can impact 
participant safety and/or the reliability of study results. 
• Study records and source documents pertaining to the conduct of this study, including signed 
ICFs, must be retained by the investigator for 25 years from issuance of the final 
CSR/equivalent summary unless local/country-specific regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period 
63

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
without the written approval of GSK. No records may be transferred to another location or 
party without written notification to GSK. 
Source Documents 
• Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of the 
location(s) of their source documents. 
• Data transcribed into the eCRF from source documents must be consistent with those source 
documents; any discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
• Definitions of what constitutes source data and documents can be found in Appendix 1. 
Study and Study Center Start and Closure 
The first act of recruitment is the date of the first participant enrollment and is considered the 
study start date. 
GSK/IQVIA reserves the right to close the study center or terminate the study at any time for any 
reason. Study centers will be closed upon study completion. A study center is considered closed 
when all required documents and study supplies have been collected and a study center closure 
visit has been performed. 
The investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center may include but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, GSK’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, GSK/IQVIA shall promptly inform the 
investigators, the IRBs/IECs, and the regulatory authorities of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participants and should assure appropriate participant therapy and/or 
follow-up. 
64

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 3 
Clinical Laboratory Tests 
Enzyme-linked immunosorbent assay 
Anti-gE ELISA is a two-step ELISA based on the antibody and antigen interaction, which allows 
the detection and the quantification of specific immunoglobulin G (IgG) antibodies directed 
against gE in tested serum samples. 
Briefly, diluted serum samples are added onto a 96-polystyrene-well microplate pre-coated with 
gE. Then goat antibodies directed against human IgG antibodies and conjugated to horseradish 
peroxidase (a-IgG-HRP) are added and will bind to anti-gE IgG if present. After a washing step, 
the addition of a chromogen-substrate solution specific for HRP will provide means of detecting 
the anti-gE specific for the pre-coated antigen. The HRP catalyzes an enzymatic reaction which 
is stopped by the addition of sulphuric acid, resulting in a color change from blue to yellow. 
The optical density recorded is proportional to the concentration of the anti-gE antibodies present 
in the serum sample. Antibody titre is expressed in mIU/mL. 
65

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Adverse Events 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant that is temporally 
associated with the use of study intervention, whether or not considered related to the study intervention. 
An AE can, therefore, be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• 
Significant or unexpected worsening or exacerbation of the condition/indication under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though they may have 
been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention. 
• 
Signs or symptoms temporally associated with study intervention administration. 
• 
Signs, symptoms that require medical attention (e.g., hospital stays, physician visits, and emergency 
department visits). 
• 
Pre- or post-intervention events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures). 
• 
Clinically significant abnormal laboratory findings following the start of the study. 
 
Events NOT Meeting the AE Definition 
• 
Situations where an untoward medical occurrence did not occur (e.g., social and/or convenience admission to 
a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not worsen. 
• 
Pre-existing conditions or signs and/or symptoms present in a participant prior to the first/the study 
vaccination. These events will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or diagnosed prior to informed 
consent signature) that did not worsen from baseline. 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments, unless judged by the 
investigator as more severe than expected for the participant’s condition, or that are present or detected at the 
start of the study and do not worsen. 
• 
However, if 1 or both of the following conditions apply, then the event should be reported promptly to 
IQVIA as an SAE: 
− 
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than expected for 
the individual participant, or 
− 
The investigator considers that there is a reasonable possibility that the event was related to the 
administration of the study intervention. 
66

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event that hypothetically might have caused death had it been 
more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s office or in an out-patient 
setting. Complications that occur during hospitalization are also considered as AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event will also be considered serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
d) Results in disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza-like illness, and accidental trauma (e.g., sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial disruption. 
e) Other situations 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These should also be considered serious. Examples 
of such events are invasive or malignant cancers, intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization. 
Solicited Events 
Solicited Events will include the following: 
a) Solicited administration site events 
The following administration site events will be solicited for toddlers 12 to 15 months of age at the time of the 
study intervention: 
• 
Pain 
• 
Redness 
• 
Swelling 
b) Solicited systemic events 
The following systemic events will be solicited for toddlers 12 to 15 months of age at the time of the study 
intervention: 
67

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Solicited Events will include the following: 
• 
Fever 
• 
Varicella-like rash (including injection site varicella-like rash) 
• 
General rash (not varicella-like) 
• 
Drowsiness 
• 
Loss of appetite 
• 
Irritability 
Note: participants’ parent(s)/LAR(s) will be instructed to measure and record body temperature in the evening 
using the temperature measuring device provided by GSK. The recommended route of temperature measurement 
will be the axilla. Should additional temperature measurements be performed at other times of day, participants’ 
parent(s)/LAR(s) will be instructed to record the highest temperature in the eDiary/personal electronic device 
app. 
Unsolicited Events 
Definition of an Unsolicited Adverse Event: 
An unsolicited AE is an AE that was not included in a list of solicited events using an eDiary/personal electronic 
device app. Unsolicited events must have been spontaneously communicated by a participant’s parent(s)/LAR(s) 
who have signed the informed consent. Unsolicited AEs include both serious and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a hospitalization, or an 
emergency room visit, or visit to/by a health care provider). The participant’s parent(s)/LAR(s) will be instructed 
to contact the site as soon as possible to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant/parental/LAR(s)’ concern. Detailed information about reported unsolicited 
AEs will be collected by qualified study center personnel and documented in the participant’s records. 
Unsolicited AEs that are not medically attended or perceived as a concern by the participant’s parent(s)/LAR(s) 
will be collected during an interview with the participant’s parent(s)/LAR(s) and by review of available medical 
records at the next visit. 
COVID-19 Cases 
Diagnosis of COVID-19 should be made in accordance with the WHO case definition. Cases 
should be categorized as AEs (unsolicited or AEs leading to withdrawal) or SAEs, and routine 
procedures for recording, evaluation, follow-up, and reporting of AEs and SAEs should be 
followed in accordance with the time period set out in the protocol. 
Assessment of Intensity and Toxicity 
The intensity of the following solicited AEs will be assessed as described in Table 13. 
68

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Table 13 
Intensity Scales for Solicited Symptoms in Toddlers (12 to 15 Months of Age) 
Toddler (12 to 15 months of age) 
Adverse Event 
Intensity Grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Minor reaction to touch 
2 
Moderate: Cries/protests on touch 
3 
Severe: Cries when limb is moved/spontaneously painful 
Redness at injection site 
Greatest surface diameter in mm 
Swelling at injection site 
Greatest surface diameter in mm 
Fever* 
Temperature in °C/°F 
Varicella-like rash** 
Number of lesions 
General rash (not 
varicella-like)  
0 
None 
1 
Mild: Rash which is easily tolerated by the child, causing minimal 
discomfort and not interfering with everyday activities 
2 
Moderate: Rash which is sufficiently discomforting to interfere with 
normal everyday activities 
3 
Severe: Rash which prevents normal, everyday activities (in a young 
child, such an AE would, for example, prevent attendance at 
school/day care and would cause the parent(s)/LAR(s) to seek 
medical advice) 
Drowsiness 
 
0 
Behavior as usual 
1 
Mild: Drowsiness easily tolerated 
2 
Moderate: Drowsiness that interferes with normal activity 
3 
Severe: Drowsiness that prevents normal activity 
Loss of appetite 
 
0 
Appetite as usual 
1 
Mild: Eating less than usual/no effect on normal activity 
2 
Moderate: Eating less than usual/interferes with normal activity 
3 
Severe: Not eating at all 
Irritability 
 
0 
Behavior as usual 
1 
Mild: Crying more than usual/no effect on normal activity 
2 
Moderate: Crying more than usual/interferes with normal activity 
3 
Severe: Crying that cannot be comforted/prevents normal activity 
*Fever is defined as temperature ≥ 38.0°C (100.4°F) by any route. The preferred location for measuring temperature 
will be the axilla. 
**A typical varicella-like rash manifests as a rash/lesions that may appear within 2 weeks (or sometimes later) after 
the varicella vaccination. Lesions may contain spots, bumps, blisters, or crusts. Refer to the Study Reference Manual 
for detailed varicella-like rash guidelines. 
The maximum intensity of administration site redness/swelling/fever/varicella-like rash will be 
scored as follows: 
 
Redness/swelling 
Varicella-like rash* 
Fever† 
0 
None 
None 
< 38.0°C (100.4°F) 
1 
> 0 - ≤ 5 mm 
1-25 lesions 
≥ 38.0°C (100.4°F) - ≤ 39.0°C (102.2°F) 
2 
> 5 - ≤ 20 mm 
26-50 lesions 
> 39.0°C (102.2°F) - ≤ 39.5°C (103.1°F) 
3 
> 20 mm 
≥ 51 lesions 
> 39.5°C (103.1°F) 
*Including injection site varicella-like rash 
†Temperature will be analyzed in 0.5°C increments from ≥ 38.0°C (≥ 100.4°F). 
69

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
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 judgment. 
The intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities. 
3 (severe) 
= 
An AE that prevents normal everyday activities. Such an AE 
would, for example, prevent attendance at a childcare facility and 
would cause the parent(s)/LAR(s) to seek medical advice. 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. 
Grade 3 is a category used for rating the intensity of an event; and both AEs and SAEs 
can be assessed as Grade 3. An event is defined as “serious” when it meets one of the 
pre-defined outcomes as described above. 
Assessment of Causality 
All solicited administration site and systemic events will be considered causally related to 
administration of the study intervention. The complete list of these events is provided in 
Table 13. 
Alternative possible causes, such as the natural history of underlying disease, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study intervention 
will be considered and investigated. The investigator will also consult the IB and/or the 
Summary of Product Characteristics and/or Prescribing Information for marketed products to 
assist in making his/her assessment. Causality should be assessed by the investigator using the 
following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the study 
intervention? 
YES 
: 
There is a reasonable possibility that the study intervention 
contributed to the AE. 
NO 
: 
There is no reasonable possibility that the AE is causally related to 
the administration of the study intervention. There are other, more 
likely causes and administration of the study intervention is not 
suspected to have contributed to the AE. 
70

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
If an event meets the criteria to be determined as “serious”, additional examinations/tests will be 
performed by the investigator to determine ALL possible contributing factors for each SAE. 
Possible contributing factors include: 
• Medical history. 
• Other medication. 
• Protocol required procedure. 
• Other procedure not required by the protocol. 
• Lack of efficacy of the study intervention, if applicable. 
• An error in study intervention administration. 
Other cause (specify). There may be situations when an SAE has occurred, and the investigator 
has minimal information to include in the initial report to IQVIA. However, it is very important 
to record an assessment of causality for every event before submitting the Expedited AE Report 
to IQVIA. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality after receiving additional 
information and update the SAE information accordingly. 
Medically Attended Visits 
For each solicited and unsolicited AE the participant experiences, the participant’s 
parent(s)/LAR(s) will be asked if the participant received medical attention (defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, 
including emergency room visits). This information will be recorded in the CRF/paper Expedited 
Adverse Events Report as applicable/in the eCRF. 
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. 
71

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Reporting, Follow-up, and Assessment of AEs 
Recording AEs and SAEs 
All AEs and SAEs should be recorded into the appropriate section of the eCRF, irrespective of intensity or 
whether or not they are considered intervention-related. 
AE and SAE Recording 
• 
The participants’ parent(s)/LAR(s) will be instructed to contact the investigator immediately should the 
participants manifest any signs or symptoms they perceive as serious. 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., 
hospital progress notes, laboratory and diagnostics reports) relative to the event. The investigator will then 
record all relevant information regarding an AE/SAE in the eCRF. The investigator is not allowed to send 
photocopies of the participant’s medical records to either the sponsor or IQVIA instead of appropriately 
completing the eCRF. However, there may be instances when copies of medical records for certain cases are 
requested by the sponsor or IQVIA. In this instance, all participant identifiers will be blinded on the copies of 
the medical records prior to submission to the sponsor or IQVIA. 
• 
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. 
 
The Use of eDiary/personal electronic device app 
An eDiary will be used in this study to capture solicited administration site or systemic events. The participants’ 
parent(s)/LAR(s) should be trained on how and when to complete the eDiary/enter information into the app. 
Anyone who measures administration site or systemic events and who will record the event in the eDiary/app 
should be trained on using the eDiary/app. This training must be documented in the participant’s source 
documents. If any individual other than the participant’s parent(s)/LAR(s) is making entries in the eDiary/app, 
their identity must be documented in the eDiary/app/participant’s source documents. 
 
Time Period for Collecting and Recording of AEs and SAEs 
All solicited administration site events that occur during 4 days (Day 1 to Day 4), and solicited systemic events 
that occur during 15 days (Day 1 to Day 15) or 43 days (Day 1 to Day 43), following administration of the study 
intervention, must be recorded into the eDiary/personal electronic device app, irrespective of intensity. 
Unsolicited events occurring from Day 1 to Day 43 and SAEs occurring up the end of the study should be 
recorded into the appropriate section of the eCRF, irrespective of intensity or whether or not they are considered 
vaccination-related. 
 
72

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Follow-up of AEs and SAEs 
After the initial AE/SAE or any other event of interest for the study, the investigator is required to proactively 
follow each participant at subsequent visits/contacts. All SAEs will be followed until the event is resolved, 
stabilized, or otherwise explained or the participant is lost to follow-up. 
Other non-serious AEs must be followed until the last contact or until the participant is lost to follow-up. 
Follow-up During the Study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or recovering/resolving 
will be reviewed at subsequent visits/contacts until the last visit/contact of the participant. 
If the participant dies during participation in the study or during a recognized follow-up period, IQVIA will be 
provided with any available post-mortem findings, including histopathology. 
Follow-up After the Participant is Discharged from the Study 
The investigator will provide any new or updated relevant information on previously reported SAE to IQVIA 
using electronic Expedited AE Report as applicable. The investigator is obliged to perform or arrange for the 
conduct of supplemental clinical examinations/tests and/or evaluations to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. 
Updating of SAE Information After Removal of Write Access to the Participant’s eCRF 
When additional SAE information is received after removal of write access to the participant’s eCRF, new or 
updated information should be recorded on the appropriate paper report, with all changes signed and dated by the 
investigator. The updated report should be faxed to IQVIA as described within the timeframes specified in 
Section 8.3.1. 
 
Events Requiring Expedited Reporting to IQVIA: 
SAE(s) throughout the study 
• 
Once the investigator or designee become aware that study participant(s) have experienced an SAE, the 
investigator or designated study staff must complete information in the electronic Expedited AE Report in 
the eCRF WITHIN 24 HOURS. The report will always be completed as thoroughly as possible with all 
available details of the event. 
• 
Even if the investigator does not have all information regarding an SAE, the report should still be completed 
within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 
HOURS. The investigator will always provide an assessment of causality at the time of the initial report. 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of SAEs. 
Grade 3 unsolicited AE(s) at least possibly related to vaccination for the first 200 study participants 
through their Day 43 follow-up: 
• 
Once the investigator or designee become aware that study participant(s) have experienced a Grade 3 
unsolicited AE considered to be at least possibly related to vaccination, the investigator or designated study 
staff must complete information in the AE form in the eCRF WITHIN 24 HOURS. The AE form 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 Grade 3 unsolicited AE considered to be at 
least possibly related to vaccination, the AE form should still be completed within 24 hours. Once additional 
relevant information is received, the AE form should be updated WITHIN 24 HOURS. The investigator will 
always provide an assessment of causality at the time of the initial completion of the AE form. 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of AE(s). 
 
SAE Reporting to IQVIA via an Electronic Data Capture Tool 
• 
The primary mechanism for reporting an SAE to IQVIA will be the electronic Data Capture (EDC) Tool. 
73

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
• 
If the EDC is unavailable for more than 24 hours, then the study center will use the paper Expedited AE 
Report. 
• 
The study center staff will enter the SAE data into the EDC as soon as it become available. 
• 
After the study is completed at a given site, the EDC will be taken offline to prevent the entry of new data or 
changes to existing data. 
• 
If a study center receives a report of a new SAE from a participant or receives updated data on a previously 
reported SAE after the EDC has been taken offline, then the study center can report this information on a 
paper Expedited AE Report (see the next section) or to the Medical Monitor by phone. 
• 
Contacts of the Medical Monitor for SAE reporting can be found in the SRM. 
 
Backup SAE Reporting to IQVIA via Paper (in Case of EDC Failure) 
• 
Fax transmission of the SAE paper Expedited AE Report is the preferred method to transmit this information 
to the Medical Monitor. 
• 
In rare circumstances and in the absence of Fax equipment, notification by phone is acceptable with a copy 
of the Expedited AE Report sent by overnight mail or courier service. 
• 
Initial notification via phone does not replace the need for the investigator to complete and sign the 
Expedited AE Report within the designated reporting timeframes. 
• 
Contacts of the Medical Monitor for SAE reporting can be found in the SRM. 
Definitions of Medical Device Adverse Events and Adverse Device Effects 
A Medical Device AE is: 
Any untoward medical occurrence, in a clinical study participant, users, or other persons, temporally associated 
with the use of study intervention whether or not considered related to a medical device. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medical device. This definition includes events related to the 
medical device or comparator and events related to the procedures involved. 
An Adverse Device Effect (ADE) is: 
Any AE related to the use of a medical device. This definition includes any AE resulting from: 
• insufficient or inadequate instructions for use (i.e., user error), or 
• any malfunction of a medical device, or 
• intentional misuse of the medical device. 
74

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Definitions of a Medical Device SAE, Serious Adverse Device Effect, and Unexpected 
Serious Adverse Device Effect 
A Medical Device SAE is Any SAE that: 
a. 
Led to death 
b. 
Led to serious deterioration in the health of the participant, that either resulted in: 
• 
A life-threatening illness or injury. The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
A permanent impairment of a body structure or a body function. 
• 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing condition, or a 
procedure required by the protocol, without serious deterioration in health, is not considered an SAE. 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to 
a body structure or a body function. 
c. 
Is a suspected transmission of any infectious agent via a medicinal product 
A Serious Adverse Device Effect (SADE) is: 
• 
A SADE is defined as an ADE that has resulted in any of the consequences characteristic of a serious adverse 
event. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not been taken, intervention 
had not occurred, or circumstances had been less fortunate. 
An Unanticipated SADE (USADE) is: 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a SADE that by its nature, 
incidence, severity or outcome has not been identified in the current version of the IB. 
 
Recording and Reporting of Device Deficiencies 
• 
Device deficiencies must be reported to IQVIA within 24 hours after the investigator determines that the 
event meets the definition of a device deficiency. 
• 
Fax transmission of the paper “Medical device or combination product with device deficiency/incident report 
form” is the preferred method to transmit this information to IQVIA. 
• 
In rare circumstances and in the absence of Fax equipment, notification by phone is acceptable with a copy 
of “Medical device or combination product with device deficiency/incident report form” sent by overnight 
mail or courier service. 
• 
IQVIA will review all device deficiencies and determine and document in writing whether they could have 
led to an SAE. These device deficiencies will be reported to the regulatory authorities and IRBs/IECs as 
required by national regulations. 
 
 
75

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 5 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment 
(Amendment 3) is located directly before the Table of Contents (TOC). 
Detailed description of the changes in Protocol Amendment 3: 
(additional text in bold and italic; deletions in strikethrough) 
 
General Changes: 
• Throughout the protocol, the reference that the study will be conducted in the US, was 
removed. Rationale: the study will be expanded to the countries outside the US. 
• A note, “if applicable” is added to Prevnar 13 vaccination where necessary. 
• M-M-RVaxPro was mentioned as a name for the MMR vaccine in some countries. 
• Added “approximately” to “50 participants in each group”, whenever mentioned. 
• Through the protocol, it is noted that the IEC, besides IRB, will also be an entity 
overseeing the ethical conduct of the study. The text regarding EU-specific regulations 
was also added as applicable. 
• “Study as a whole” was replaced with “country” as a minimization factor for analysis. 
• Added the note/footnote, Participants recruited outside of the US will be 
co-administered with MMR, Havrix, and in some countries, with Prevnar 13. 
Prevnar 13 will only be administered to participants enrolled in the United States and 
in countries where pneumococcal conjugate vaccine is recommended at 12-15 months 
as per national immunization schedule, when applicable (throughout the protocol and in 
the Schedule of Activities). 
• Added the note, At the end of the study or shortly after the study, depending on the 
vaccines’ availability, GSK will provide a second dose of Varivax and/or Havrix to 
participants enrolled in non-US countries if local health departments do not routinely 
provide varicella and/or hepatitis A vaccine. Study participants who do not achieve the 
pre-specified seroresponse threshold criteria will be re-vaccinated with a dose of 
Varivax (throughout the protocol and in the Schedule of Activities). 
• Title Page, Sponsor’s Signature Page, Header: updated the number of the protocol 
amendment from 2.0 to 3.0. Added the date of the amendment as applicable.  
• Title Page: added the clinical trial registry numbers. 
Note: In various sections, the repeated changes with the same or similar wording are not detailed 
if they have been made clear earlier. 
Note: The minor changes such as for grammar/readability/correction of typos are not listed. 
1.0, Protocol Summary 
Rationale: Participants recruited outside of the US will be co-administered with MMR, 
Havrix, and in some countries, with Prevnar 13. Outside the US, Prevnar 13 will only be 
76

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
administered in countries where pneumococcal conjugate vaccine is recommended at 
12-15 months as per national immunization schedule. At the end of the study or shortly after 
the study, depending on the vaccines’ availability, GSK will provide a second dose of Varivax 
and/or Havrix to participants enrolled in non-US countries if local health departments do not 
routinely provide varicella and/or hepatitis A vaccine. Study participants who do not achieve 
the pre-specified seroresponse threshold criteria will be re-vaccinated with a dose of Varivax. 
Overall Design: Participants recruited outside of the US will be co administered with MMR, 
Havrix, and in some countries, with Prevnar 13. Outside the US, Prevnar 13 will only be 
administered in countries where pneumococcal conjugate vaccine is recommended at 12-15 
months as per national immunization schedule. If Prevnar 13 is to be administered, 
participants are required to have previously received the primary series of pneumococcal 
conjugate vaccine in their first year of life with last dose at least 60 days prior to study entry. 
1.3, Schedule of Activities 
Added the information about Prevnar 13 administration at non-US sites. 
Added the row with about the conditional administration of the second dose of Varivax and/or 
Havrix. Noted that, The administration of the second dose of Havrix and Varivax is not part of 
the study procedures, however, the administration of the second dose (or the date of the 
planned visit for administration) should be recorded in the eCRF. 
2.1, Study Rationale 
Same changes as in Protocol Summary. 
2.3.2, Risk Mitigation Strategies 
The burden of the study for the participant will be minimized as much as possible. For taking 
blood samples, 3 attempts at most should be performed. If the investigator/designee is not 
successful after the third attempt, the investigator/designee will make no further attempts. A 
local numbing cream or patch will also be offered at the discretion of the investigator prior to 
blood sampling, to minimize pain when blood samples are drawn. 
GSK/IQVIA will immediately notify the investigators if any additional safety or toxicology 
information becomes available during the study. 
This study will be performed in compliance with the protocol, ICH GCP, EU CTR, and 
applicable regulatory requirements. Aspects of the study concerned with the investigational 
medicinal products will meet the requirements of European Union – Good Manufacturing 
Practice, as applicable. 
4.1, Overall Design 
Same changes as in Protocol Summary and Study Rationale. 
4.2.1, Rationale for Clinical Study Population 
77

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
In many countries worldwide, vaccination against varicella in early years of life is 
recommended to prevent development of chickenpox in older age. 
The incidence of varicella has decreased significantly since implementation of the national 
varicella vaccination program in 1996 in the US [CDC, 2015]. 
In the US, the incidence of varicella has decreased significantly since implementation of the 
national varicella vaccination program in 1996 [CDC, 2015]. 
Adolescents (≥13 years) and adults should receive 2 doses of the single-antigen varicella vaccine 
4 to 8 weeks apart. 
4.2.2.1, Comparator 
Varivax has proven effectiveness. It is approved in more than 70 countries. 
4.2.2.2, Co-administered vaccines 
MMR, Havrix, and Prevnar 13 vaccines are part of the routine pediatric vaccination schedules in 
the US and some other countries. 
4.2.4, Justification for Dose of Varicella Vaccine 
In general, varicella dosing recommendations include 1 or 2 doses. In the US, it is recommended 
that the pediatric population receives 2 doses of varicella vaccine, with the first dose 
administered at 12 to 15 months of age and the second dose administered between 4 and 6 years 
of age. In EU, vaccination with 2 doses of varicella vaccine is recommended in different 
countries according to local and regional public health guidelines. 
5.1, Inclusion Criteria 
• 
Only for US participants and participants in countries where pneumococcal conjugate 
vaccine is recommended at 12-15 months of life as per national immunization schedule: 
Participants who previously received the primary series of pneumococcal conjugate vaccine 
in their first year of life with the last dose at least 60 days prior to study entry. 
6.1, Study Interventions Administered 
Table 7, Study Intervention Administered 
Changed the number of doses for Varivax and Havrix from 1 to 2. 
Added the footnotes: 
**Prevnar 13 will only be administered to participants enrolled in the United States and in 
countries where pneumococcal conjugate vaccine is recommended at 12 to 15 months as per 
national immunization schedule 
*** For non-US participants only. At the end of the study or shortly after the study, depending 
on the vaccines’ availability, GSK will provide a second dose of Havrix and/or Varivax in 
78

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
countries where they are not routinely provided. The administration of the second dose of 
Havrix and Varivax is not part of the study procedures. 
6.2, Preparation/Handling/Storage/Accountability 
Varivax will be stored at −15°C to −30°C (+5°F to −22°F) in the US and at +2°C to +8°C 
(+36°F to +46°F) in the rest of the world. (Note: Refrigerated Varivax vaccine will be used at 
non-US sites, while frozen Varivax vaccine will be used at sites in the US and other countries 
with frozen formulation). 
Temperature excursions, For VNS Diluent: 
Any temperature excursion outside the range of 0+1.5°C to +8.0+8.4°C (for +2 to +8°C/+36 to 
+46°F label storage condition). 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMPs, 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 
• For Varivax Diluent, Varivax antigen with refrigerated formulation and all other products 
(Prevnar 13, Havrix, MMR) 
• For Varivax antigen in the US and other countries with frozen formulation 
Any temperature excursion above −2015.0°C (for −20°C/−4°F label storage condition) 
impacting study interventions must be reported in the appropriate (e)TDF. 
6.3.2, Randomization to Study Intervention, 6.3.3, Intervention Allocation to Participants 
The study as a whole country and center will be used as minimization factors for randomization. 
6.6, Continuing Access to Study Intervention after the End of the Study 
There will be no continuing access to study intervention after the end of the study. At the end of 
the study or shortly after the study, depending on the vaccines’ availability, GSK will provide a 
second dose of Varivax and/or Havrix to participants enrolled in non-US countries if local 
health departments do not routinely provide varicella and/or hepatitis A vaccine. 
8.1.3, Immunological Correlates of Protection 
..while all children are expected to receive a second dose of the varicella vaccine as per ACIP 
recommended schedule at 4 to 6 years of age [ACIP, 2007]. 
9.4.1, Statistical Analysis Plan 
There is no intention to conduct specific analyses investigating the relationship between the 
gender of the participants and the immunogenicity and safety of the study vaccine. The ratio 
79

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
of male to female participants recruited into this study is expected to be in line with the 
demographics of the population aged 12 to 15 months of age. 
Appendix 1 
Abbreviations and the Glossary of Terms 
IEC 
Independent Ethics Committee 
MMR Measles, mumps, and rubella vaccine 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
• The investigator will be responsible for the following: 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
Amendment 2.0 (15-November-2021) 
Overall Rationale for the Amendment: 
This protocol was amended at the request of CBER to add drowsiness, loss of appetite, 
irritability, and general rash (not varicella-like) to the list of solicited systemic events. In 
addition, the reporting instructions for the Grade 3 unsolicited events (at least possibly related to 
vaccination for the first 200 study participants through their Day 43 follow-up) were updated. 
Description of the Most Important Changes in Amendment 2 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities Added the recording of solicited systemic events of 
drowsiness, loss of appetite and irritability from Day 1 to Day 
15 post study intervention. 
These adverse reactions 
are commonly 
described in the setting 
of vaccine trials in 
children over 
12 months of age. 
Added the additional solicited systemic event to be collected 
from Day 1 to Day 43 post study intervention: general rash 
(not varicella-like). 
3.0 Objectives and 
Endpoints 
Included general rash (not varicella-like) in the endpoint 
related to solicited systemic event collected from Day 1 to Day 
43. 
Added the endpoint of the percentage of participants reporting 
each solicited systemic event in terms of drowsiness, loss of 
appetite, and irritability from Day 1 to Day 15. 
4.0 Overall Design 
Added the collection of solicited systemic events of 
drowsiness, loss of appetite, and irritability from Day 1 to Day 
15 and clarified that fever, varicella-like rash (including 
injection site varicella-like rash) and general rash (not 
varicella-like) will be collected from Day 1 to Day 43. 
80

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Section # and Name 
Description of Change 
Brief Rationale 
6.2 Preparation/Handling/
Storage/Accountability 
Removed the mention of Varivax antigen from the products to 
be stored between 2.0°C to +8.0°C. 
The Varivax antigen 
used in the study is a 
frozen one and not a 
refrigerated one. 
Appendix 4 Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, 
and Reporting 
Added general rash (not varicella-like), drowsiness, loss of 
appetite, irritability to the list of solicited systemic events. 
These adverse reactions 
are commonly 
described in the setting 
of vaccine trials in 
children over 
12 months of age. 
Added intensity scales grades for drowsiness, loss of appetite, 
irritability and general rash (not varicella-like). 
To provide the 
instructions for 
assessment of intensity 
of the newly added 
events. 
Removed the requirement for the investigator to confirm the 
review of an SAE/Grade 3 unsolicited AE at least possibly 
related to vaccination for the first 200 study participants 
through their Day 43 follow-up by ticking the “reviewed” box 
in the electronic report. 
For the alignment with 
the electronic case 
report form. 
Updated the reporting of Grade 3 unsolicited adverse events at 
least possibly related to vaccination for the first 200 study 
participants through their Day 43 follow-up.  
Detailed description of the changes in Protocol Amendment 2: 
(additional text in bold+italic; deletions in strikethrough) 
1.3, Schedule of Activities 
Table 3 Schedule of Activities 
The added cells and text: 
Recording of solicited systemic 
events (drowsiness, loss of appetite 
and irritability) from Day 1-15 post 
study intervention administration 
○ 
○ 
○ 
 
 
See Section 8.3 and 
Appendix 4 
Recording of solicited systemic 
events (fever, varicella-like rash 
[including injection site 
varicella-like rash] and general rash 
[not varicella-like]) from Day 1-43 
post study intervention administration 
○ 
○ 
○ 
○ 
 
See Section 8.3 for details 
and Appendix 4 for 
definitions 
Recording of non-serious AEs from 
Day 1-43 post study intervention 
administration 
● 
● 
● 
● 
 
See Section 8.3 for details 
and Appendix 4 for 
definitions 
 
3.0, Objectives and Endpoints 
81

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Table 5, Study Objectives and Endpoints 
The following change was made: 
• 
To evaluate safety and reactogenicity following 
administration of VNS and VV vaccines 
Solicited events 
• 
Percentage of participants reporting each solicited 
administration site event in terms of injection site 
redness, pain and swelling within 4 days (Day 1 to 
Day 4) post-dose of VNS vaccine or VV vaccine 
• 
Percentage of participants reporting each solicited 
systemic event in terms of fever, and varicella-like 
rash†, and general rash (not varicella-like) within 
43 days (Day 1 to Day 43) post-dose of study 
interventions 
• 
Percentage of participants reporting each solicited 
systemic event in terms of drowsiness, loss of 
appetite, and irritability within 15 days (Day 1 to 
Day 15) post-dose of study interventions** 
Unsolicited adverse events (AEs)*** 
• 
Percentage of participants reporting unsolicited AEs 
within 43 days (Day 1 to Day 43) post-dose of 
study interventions** 
Serious adverse events (SAEs) 
• 
Percentage of participants reporting SAEs 
post-dose of study interventions** up to the end of 
study 
4.1, Overall Design 
Figure 1, Study Design Overview 
The obsolete figure was replaced with the new one. The footnote was updated. 
The obsolete figure: 
82

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
 
The new figure: 
 
VNS_Low, VNS_Med, and VNS_High vaccine = VNS vaccine in low, medium, and high potency; VV_Lot 1 and 
VV_Lot 2 = VV vaccine in 2 lots 
a VV_Lot 1 and VV_Lot 2 groups will be analyzed as pooled groups 
83

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
b Contact (by telephone call or any other convenient procedure) for the safety follow-up will take place 6 months 
post-dose of study interventions 
c Study interventions: VNS vaccine (investigational vaccine) or VV vaccine (Varivax, comparator vaccine); 
M-M-R II, Havrix, and Prevnar 13 (co-administered vaccines) 
d Recording in the electronic Case Report Form 
e Blood sampling for anti-glycoprotein E enzyme-linked immunosorbent assay 
f Independent Data Monitoring Committee review details are provided in Section 8.2.3. 
g Visit 2 for review of post-vaccination safety data may be a virtual visit 
h Safety call to remind completion of the eDiary/app and address any potential early post-vaccination safety concerns 
*Drowsiness, loss of appetite, irritability 
**Fever, varicella-like rash (including injection site varicella-like rash) and general rash (not varicella-like) 
6.2, Preparation/Handling/Storage/Accountability 
• For Varivax Antigen Diluent and All Other Products (Prevnar 13, Havrix, M-M-R II) 
8.2.3.1, Study Holding Rules 
Figure 2 
Communication Flow: Identification of Holding Rules by the Investigator 
Obsolete figure: 
 
New figure: 
84

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
 
CRDL = Clinical Research and Development Lead; GSB = Global Safety Board; IDMC = Independent Data 
Monitoring Committee; IVRS = Interactive Voice Response System; SRT = Safety Review Team 
*Investigators are responsible to inform the Institutional Review Board if a holding rule is met. 
9.5.1, Sequence of Analyses 
Apart from the analyses to be performed in support to the IDMC, a statistical analysis and a 
report including safety and final immunogenicity data for all participants up to Day 43 time 
point is planned. Following unblinding for the analysis up to Day 43, accessibility to group 
attribution will be limited so that the study center blinding is maintained until the 6-month safety 
follow-up is completed for all participants. 
Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Solicited Events will include the following: 
c) Solicited administration site events 
The following administration site events will be solicited for toddlers 12 to 15 months of age at the time of the 
study intervention: 
• 
Pain 
• 
Redness 
• 
Swelling 
d) Solicited systemic events 
The following systemic events will be solicited for toddlers 12 to 15 months of age at the time of the study 
intervention: 
85

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
• 
Fever 
• 
Varicella-like rash (including injection site varicella-like rash) 
• 
General rash (not varicella-like) 
• 
Drowsiness 
• 
Loss of appetite 
• 
Irritability 
Note: participants’ parent(s)/LAR(s) will be instructed to measure and record body temperature in the evening 
using the temperature measuring device provided by GSK. The recommended route of temperature measurement 
will be the axilla. Should additional temperature measurements be performed at other times of day, participants’ 
parent(s)/LAR(s) will be instructed to record the highest temperature in the eDiary/personal electronic device 
app. 
b) Solicited systemic events 
The following systemic events will be solicited for childrentoddlers 12 to 15 months of age at the time of the 
study intervention: 
• 
Fever 
• 
Varicella-like rash (including injection site varicella-like rash) 
• 
General rash (not varicella-like) 
• 
Drowsiness 
• 
Loss of appetite 
• 
Irritability  
86

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Table 15 Intensity Scales for Solicited Symptoms in Toddlers (12 to 15 Months of Age) 
Toddler (12 to 15 months of age) 
Adverse Event 
Intensity Grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Minor reaction to touch 
2 
Moderate: Cries/protests on touch 
3 
Severe: Cries when limb is moved/spontaneously painful 
Redness at injection site 
Greatest surface diameter in mm 
Swelling at injection site 
Greatest surface diameter in mm 
Fever* 
Temperature in °C/°F 
Varicella-like rash** 
Number of lesions 
General rash (not 
varicella-like)  
0 
None 
1 
Mild: Rash which is easily tolerated by the child, causing minimal 
discomfort and not interfering with everyday activities 
2 
Moderate: Rash which is sufficiently discomforting to interfere with 
normal everyday activities 
3 
Severe: Rash which prevents normal, everyday activities (in a 
young child, such an AE would, for example, prevent attendance at 
school/day care and would cause the parent(s)/LAR(s) to seek 
medical advice) 
Drowsiness 
 
0 
Behavior as usual 
1 
Mild: Drowsiness easily tolerated 
2 
Moderate: Drowsiness that interferes with normal activity 
3 
Severe: Drowsiness that prevents normal activity 
Loss of appetite 
 
0 
Appetite as usual 
1 
Mild: Eating less than usual/no effect on normal activity 
2 
Moderate: Eating less than usual/interferes with normal activity 
3 
Severe: Not eating at all 
Irritability 
 
0 
Behavior as usual 
1 
Mild: Crying more than usual/no effect on normal activity 
2 
Moderate: Crying more than usual/interferes with normal activity 
3 
Severe: Crying that cannot be comforted/prevents normal activity 
*Fever is defined as temperature ≥ 38.0°C (100.4°F) by any route. The preferred location for measuring temperature 
will be the axilla. 
**A typical varicella-like rash manifests as a rash/lesions that may appear within 2 weeks (or sometimes later) after 
the varicella vaccination. Lesions may contain spots, bumps, blisters, or crusts. Refer to the Study Reference 
Manual for detailed varicella-like rash guidelines. 
Time Period for Collecting and Recording of AEs and SAEs 
All solicited administration site and solicited systemic events that occur during 4 days (Day 1 to Day 4), and 
solicited systemic events that occur during 145 days (Day 1 to Day 15) andor 43 days (Day 1 to Day 43), 
respectively, following administration of the study intervention must be recorded into the eDiary/personal 
electronic device app, irrespective of intensity or whether or not they are considered intervention-related. 
Unsolicited events occurring from Day 1 to Day 43 and SAEs occurring up the end of the study should be 
recorded into the appropriate section of the eCRF, irrespective of intensity or whether or not they are considered 
vaccination-related. 
 
Events Requiring Expedited Reporting to IQVIA: 
SAE(s) throughout the study 
87

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
• 
Once the investigator or designee become aware that study participant(s) have experienced an SAE, the 
investigator or designated study staff must complete information in the electronic Expedited AE Report in 
the eCRF WITHIN 24 HOURS. The report will always be completed as thoroughly as possible with all 
available details of the event. 
• 
Even if the investigator does not have all information regarding an SAE, the report should still be completed 
within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 
HOURS. The investigator will always provide an assessment of causality at the time of the initial report. 
• 
The investigator will be required to confirm the review of the SAE causality by ticking the “reviewed” box in 
the electronic Expedited AE Report within 72 hours of submission of the SAE. 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of SAEs. 
Grade 3 unsolicited AE(s) at least possibly related to vaccination for the first 200 study participants through 
their Day 43 follow-up: 
• 
Once the investigator or designee become aware that study participant(s) have experienced a Grade 3 
unsolicited AE considered to be at least possibly related to vaccination, the investigator or designated study 
staff must complete information in the electronic Expedited AE Report AE form in the eCRF WITHIN 
24 HOURS. The report AE form 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 Grade 3 unsolicited AE considered to be at 
least possibly related to vaccination, the reportAE form should still be completed within 24 hours. Once 
additional relevant information is received, the reportAE form should be updated WITHIN 24 HOURS. The 
investigator will always provide an assessment of causality at the time of the initial reportcompletion of the 
AE form. 
• 
The investigator will be required to confirm the review of the Grade 3 unsolicited AE(s) causality by ticking 
the “reviewed” box in the electronic Expedited AE Report within 72 hours of submission of the Grade 3 
unsolicited AE(s). 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of AE(s). 
Amendment 1.0 (08-October-2021) 
Overall Rationale for the Amendment: 
This protocol was amended at the request of CBER to add early safety time point checks, to 
exclude participants with a history of SARS-CoV-2 (severe acute respiratory syndrome 
coronavirus 2) infection who remain symptomatic, to exclude susceptible high-risk individual 
members of the potential participant’s household, to clarify that varicella-like-rash includes 
injection site varicella-like rash, to include holding rules for the first 200 study participants 
enrolled and to revise the grading to assess the severity of the varicella-like rash. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added 1 safety call and 1 new study 
visit  
To address any potential safety concerns that 
may have arisen during the early post-
vaccination time period and review post-
vaccination safety data, respectively. 
1.3 Schedule of 
Activities 
Added 1 safety call and 1 new study 
visit  
To address any potential safety concerns that 
may have arisen during the early post-
vaccination time period and review post-
vaccination safety data, respectively. 
88

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Table 4 Intervals 
Between Study 
Visits 
Added 1 safety call and 1 new study 
visit with accompanying intervals 
To address any potential safety concerns that 
may have arisen during the early post-
vaccination time period and review post-
vaccination safety data, respectively. 
2.3.2 Risk 
Mitigation 
Strategies 
Inserted holding rules 
To ensure participant safety 
3 Objectives and 
endpoints 
Added clarification that injection site 
varicella-like rash is included as 
solicited systemic event 
To clarify AE information 
4.1 Overall Design, 
Figure 1 Study 
Design Overview 
Added 1 safety call and 1 new study 
visit to study Schema 
To address any potential safety concerns that 
may have arisen during the early 
post-vaccination time period and review 
post-vaccination safety data, respectively. 
4.1 Overall Design 
Added 1 safety call and 1 new study 
visit in the footnote 
To address any potential safety concerns that 
may have arisen during the early 
post-vaccination time period and review 
post-vaccination safety data, respectively. 
5.2 Exclusion 
Criteria 
Inserted new criterion  
To exclude participants with susceptible 
high-risk individuals in their household, in case 
of varicella transmission  
5.2 Exclusion 
Criteria 
Inserted new criterion  
To exclude participants with a history of 
SARS-CoV-2 infection who remain 
symptomatic 
8.1.3 
Immunological 
Correlates of 
Protection 
Added sentence “Study participants 
who do not achieve the pre-specified 
seroresponse threshold criteria will be 
re-vaccinated with a dose of Varivax.” 
To specify when re-vaccination should take 
place.  
8.2.3 Study 
Holding Rules and 
Safety Monitoring 
Adapted text to reflect the inclusion of 
holding rules  
To further clarify procedures for safety 
monitoring by the IDMC and the SRT 
8.2.3 Study 
Holding Rules and 
Safety Monitoring  
Added Section 8.2.3.1 and Table 9, 
both titled Study Holding Rules 
To include holding rules as this is considered as 
a first time in human study 
8.2.3 Study 
Holding Rules and 
Safety Monitoring 
Added Section 8.2.3.2, Outcome of 
Safety Evaluation 
To explain what will happen following the 
outcome of the review by the IDMC of the 
safety data of the first 200 participants  
Appendix 4 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting 
Updated reporting requirements to 
include events listed in Holding Rules, 
clarification that injection site 
varicella-like rash is included as 
solicited systemic event, update of 
grading for varicella-like rash and fever 
 
To include holding rules as this is considered a 
first time in human study, clarify AE 
information 
Appendix 5 
Protocol 
Inserted new appendix 
To track protocol amendment history 
89

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Amendment 
History 
Non-substantial changes such as editorial changes and administrative changes are not included in 
this list. 
Detailed description of the changes in Protocol Amendment 1: 
(additional text in bold and italic; deletions in strikethrough) 
 
1.1, Synopsis (Overall Design): 
Randomization to one of the 5 groups will be performed in a 2:2:2:1:1 ratio prior to intervention. 
There will be 23 study visits, at Day 1 (intervention), Day 15 (virtual or in-person), and Day 43, 
as well as a 1 safety call and 1 safety follow-up contact, at Day 2-3 and Day 181, respectively. 
1.2, Schema: Third visit and safety call added to schema. 
Added the following to Schema footnotes: 
g Visit 2 for review of post-vaccination safety data may be a virtual visit. 
h Safety call to remind completion of the eDiary/app and check on potential early post-vaccination safety events 
1.3, Schedule of Activities: Third visit and safety call added. 
Age 
12-15 months of age at the time of study intervention 
administration 
Notes 
 
 
 
Type of contact 
Visit 1 Safety call 
Visit 2† Visit 23 
Safety 
follow-up 
contact 
 
Time points 
Day 1 Day 2-3 
Day 15 Day 43 
Day 181  
Informed consent 
● 
 
 
 
 
See Appendix 2 for 
details 
Check 
inclusion/exclusion 
criteria 
● 
 
 
 
 
See Section 5.1 and 
Section 5.2 for 
details 
Collect demographic 
data 
● 
 
 
 
 
See Section 8.2.1.1 
for details 
Medical history 
● 
 
 
 
 
See Section 8.2.1.1 
for details 
Vaccination history 
(protocol-specific 
vaccines including PCV) 
● 
 
 
 
 
See Section 8.2.1.1 
for details 
See Section 5.1 for 
details 
Physical examination 
● 
 
 
 
 
See Section 8.2.1.1 
for details 
Randomization 
○ 
 
 
 
 
See Section 6.3.2 for 
details 
Study interventions 
 
See Appendix 1 for 
the definition 
90

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Age 
12-15 months of age at the time of study intervention 
administration 
Notes 
 
 
 
Type of contact 
Visit 1 Safety call 
Visit 2† Visit 23 
Safety 
follow-up 
contact 
 
Time points 
Day 1 Day 2-3 
Day 15 Day 43 
Day 181  
Check contraindications, 
warnings and 
precautions to study 
intervention 
administration 
○ 
 
 
 
 
See Section 8.2.1.2 
for details 
Check criteria for 
temporary delay for 
enrollment and study 
intervention 
administration 
● 
 
 
 
 
See Section 5.5 for 
details 
Study group and 
treatment number 
allocation  
○ 
 
 
 
 
See Section 6.3.3 for 
details 
Body temperature before 
study intervention 
administration 
● 
 
 
 
 
The preferred 
location for 
measuring 
temperature will be 
the axilla. Fever is 
defined as body 
temperature ≥ 
38.0°C/100.4°F 
Study intervention (VNS 
vaccine/VV vaccine, and 
M-M-R II, Havrix, and 
Prevnar 13) 
administration 
● 
 
 
 
 
Study participants 
who do not achieve 
the pre-specified 
seroresponse 
threshold criteria 
will be re-vaccinated 
with a dose of 
Varivax The 
investigator will 
assess if re-
vaccination with 
Varivax is needed 
for the children who 
fail to serorespond to 
varicella virus (i.e., 
post-vaccination 
anti-gE antibody 
concentration is 
<300 mIU/mL at 
Day 43) after the 
Day 43 
immunogenicity 
results are available. 
Recording of 
administered study 
treatment number 
● 
 
 
 
 
 
91

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Age 
12-15 months of age at the time of study intervention 
administration 
Notes 
 
 
 
Type of contact 
Visit 1 Safety call 
Visit 2† Visit 23 
Safety 
follow-up 
contact 
 
Time points 
Day 1 Day 2-3 
Day 15 Day 43 
Day 181  
Distribute 
eDiaries/download the 
app 
○ 
 
 
 
 
An eDiary/personal 
electronic device 
application (app) 
will be used to 
capture solicited 
administration site or 
systemic events. The 
participant’s 
parent(s)/LAR(s) 
should be trained on 
the use of the 
eDiary/app. See 
Appendix 4 for 
details 
Laboratory assessment 
Blood sampling for 
antibody determination 
(~3 mL) 
 
 
 
● 
 
See Section 8.1.1 for 
details 
Safety assessments 
Record any concomitant 
medications/vaccinations 
● 
● 
● 
● 
 
See Section 6.8 for 
details 
Record any intercurrent 
medical conditions 
 
  
 
● 
 
See Section 9.3 for 
more information 
Phone contact for safety 
follow-up 
 
● 
 
 
● 
Or any other 
convenient 
procedure 
Recording of solicited 
administration site 
events from Day 1-4 
post study intervention 
administration 
○ 
○ 
 
 
 
Only events 
following the 
administered dose of 
VNS vaccine or VV 
vaccine will be 
solicited 
Safety follow-up with 
clinical staff to review 
post-vaccination safety 
data 
 
 
● 
 
 
 
Recording of solicited 
systemic events from 
Day 1-43 post study 
intervention 
administration 
○ 
○ 
○ 
○ 
 
See Section 8.3 for 
details and 
Appendix 4 for 
definitions 
Recording of non-
serious AEs from Day 1-
43 post study 
intervention 
administration 
● 
● 
● 
● 
 
See Section 8.3 for 
details and 
Appendix 4 for 
definitions 
eDiary/app completion 
reminder 
 
● 
 
 
 
 
Review of eDiaries/app 
data 
 
○ 
● 
● 
 
 
92

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Age 
12-15 months of age at the time of study intervention 
administration 
Notes 
 
 
 
Type of contact 
Visit 1 Safety call 
Visit 2† Visit 23 
Safety 
follow-up 
contact 
 
Time points 
Day 1 Day 2-3 
Day 15 Day 43 
Day 181  
Return of 
eDiaries/uninstall or 
disable the app 
 
 
 
○ 
 
See Section 8.5 for 
details 
Recording of SAEs 
● 
● 
● 
● 
● 
See Section 8.3 for 
details and 
Appendix 4 for the 
definition 
Recording of SAEs 
related to study 
participation, or to a 
concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
The collection and 
reporting periods 
start once the 
participant’s 
parent(s)/LAR(s)’s 
informed consent is 
obtained 
Study Conclusion 
 
 
 
 
● 
See Section 4.3 for 
the definition. 
†Visit 2 (Day 15) may be conducted in-person or virtually. 
Refer to the Study Reference Manual (SRM)/Pharmacy Manual for the volume of the vaccine after reconstitution. 
 
Table 4 
Intervals Between Study Visits 
Interval 
Planned visit interval* 
Allowed interval range 
Visit 1→ Safety call 
1 to 2 days 
1 to 3 days 
Visit 1→Visit 2 
14 days 
14 to 19 days 
Visit 1→Visit 32 
42 days 
35 to 56 days 
Visit 1→ Safety follow-up contact 
180 days 
180 to 201 days 
Note: Whenever possible, the investigator should arrange study visits following the planned visit interval. Deviation 
from allowed interval between Visit 1 and Visit 23 will lead to elimination from the Per Protocol Set. 
2.3.2, Risk Mitigation Strategies: 
The blinded monitoring of study data will be performed by the GSK’s designee/Contract 
Research Organization (IQVIA) (see study administrative structure in Appendix 2 [Table 12]). 
Additional unblinded safety monitoring will be performed by an Independent Data Monitoring 
Committee (IDMC). composed of clinical experts, independent of the study protocol and 
external to GSK and IQVIA, and an independent biostatistician. Frequent Monthly Safety 
Review Team (SRT) review will occur up to the completion of enrollment and vaccination of the 
first 200 participants, to monitor cumulative, blinded safety data (including serious and non-
serious AEs) (see Section 8.2.3). In addition, for the first 200 study participants through their 
93

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Day 43 follow-up, the following criteria would be applied, that would result in a pause in study 
activities, including dosing and enrollment: 
a. Any death at least possibly related to vaccination (refer to Section 8.3.3 for expedited 
reporting) 
b. ≥1 participant with SAE/s at least possibly related to vaccination (refer to Section 8.3.3 
for expedited reporting) 
c. ≥2 participants with the same or similar Grade 3 unsolicited AE at least possibly 
related to vaccination, (refer to Section 8.3.1 for diligent reporting of Grade 3 
unsolicited AEs at each contact/visit) 
Note: “similarity” of the events will be based on medical judgment. 
An enrollment pause is also foreseen for the first IDMC review after 200 participants (50 in each 
group, considering pooled VV groups) are enrolled and vaccinated. The analysis will take place 
once all 200 participants have returned for their Day 43 visit (Visit 23) or have withdrawn from 
the study, within the allowed interval for the visit. A positive outcome of the IDMC review of 
the Day 43 safety follow-up data of the 200 participants will be a pre-requisite for the 
continuation of the study. 
Section 3, Objectives and Endpoints: 
† Includes injection site varicella-like rash. 
Section 4.1, Overall Design: 
There will be 23 in-person study visits: on Day 1, when the participants receive study 
intervention, on Day 15 (either in-person or virtually, for review of post-vaccination safety 
data), and on Day 43, when blood sampling for vaccine antibody testing will be performed. The 
third visit There will also be 12 call safety follow-up call on Day 2-3 and 1 safety follow-up 
contact, on Day 181; will be a safety follow-up contact and it these may be performed over the 
phone or by any other convenient means of communication. The visits should occur within a pre-
defined visit window (see Table 24). 
Section 5.2.1, Medical Conditions: 
• Participant with history of SARS-CoV-2 infection who is still symptomatic. 
Section 5.2.2, Prior and Concomitant Therapy: 
• Planned administration/administration of a vaccine not foreseen by the study protocol in the 
period starting 30 days before the dose and ending at 43 days after the dose of study 
interventions administration* (Visit 23) with the exception of inactivated influenza (flu) 
94

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
vaccine which may be given at any time during the study and administered at a different 
location than the study interventions. 
Any other age-appropriate vaccine may be given starting at Visit 23 and anytime thereafter. 
Section 5.2.4, Other Exclusions: 
• Participants with the following high-risk individuals in their household: 
o Immunocompromised individuals. 
o Pregnant women without documented history of varicella. 
o Newborn infants of mothers without documented history of varicella. 
o Newborn infants born <28 weeks of gestation. 
Section 6.0, Study Intervention, Table 7, Study Interventions Administered: 
*Refer to the SRM/pharmacy manual for the volume after reconstitution 
 
Section 8.1.3, Immunological Correlates of Protection: 
Upon receiving the result, the investigator will assess if any step needs to be taken regarding the 
individual child, while all children are expected to receive a second dose of the varicella vaccine 
as per ACIP recommended schedule at 4 to 6 years of age ([ACIP, 2007]). Study participants 
who do not achieve the pre-specified seroresponse threshold criteria will be re-vaccinated with 
a dose of Varivax. 
Section 8.2.3, Safety Monitoring and Study Holding Rules 
Besides safety monitoring by blinded Study/Center Monitors (see the definition in Appendix 1), 
an IDMC comprising of clinical experts and an independent biostatistician will provide safety 
oversight during the active vaccination period, through unblinded review of the cumulative 
safety data. 
Up to the completion of enrollment and vaccination of the first 200 participants through their 
Day 43 follow-up, enrollment will be paused for an ad hoc IDMC review of the cumulative 
safety data if any of the holding rules are met (See Section 8.2.3.1). 
An enrollment pause is foreseen for the first IDMC review after 200 participants (50 in each 
group, considering pooled VV groups) are enrolled and vaccinated. A positive outcome of the 
IDMC review of the Day 43 safety follow-up data of the 200 participants will be a pre-requisite 
for the continuation of the study. The analysis will take place once all 200 participants have 
returned for their Day 43 visit (Visit 23) or have withdrawn from the study, within the allowed 
interval for the visit. A positive outcome of the IDMC review will be a pre-requisite for the 
continuation of the study. 
95

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
In addition to the planned IDMC meetings, frequent Monthly SRT review will occur up to the 
enrollment and vaccination of the first 200 participants through their Day 43 follow-up, to 
monitor cumulative, blinded, safety data (including serious and non-serious AEs). The blinded 
safety data review by the SRT may trigger an emergency ad hoc IDMC review before 200 
participants are enrolled and vaccinated. During the study, as per the IDMC charter, ad hoc 
IDMC meetings may be convened when a safety concern has been observed. In this case, 
enrollment shall be paused. 
A subsequent IDMC review meeting is planned during the study, after Day 43 safety follow-up 
of 400 participants is completed, no enrollment pause is foreseen for this review. The details of 
the review will be described in an IDMC charter. The analysis will take place once all 400 
participants have returned for their Day 43 visit (Visit 32) or have withdrawn from the study, 
within the allowed interval for the visit. 
Section 8.2.3.1, Study Holding Rules 
The safety holding rules defined in Table 9 only apply to the first 200 study participants 
enrolled. Holding rules 1-3 will be assessed by the investigator on a continuous basis. Holding 
rules 1-3 will be assessed by the IDMC during the safety evaluations on unblinded data. 
Table 9 
Study Holding Rules 
Holding 
Rule 
Event 
Number of participants to 
pause vaccination in all 
groups, pending further 
evaluation by IDMC  
1 
Any death considered at least possibly related to study vaccination 
≥ 1 
2 
Any SAE(s) considered at least possibly related to vaccination 
≥ 1 
3 
Same or similar* Grade 3 unsolicited AE considered to be at least possibly 
related to vaccination 
≥ 2 
AE = adverse event; IDMC = Independent Data Monitoring Committee; SAE = serious adverse event 
*based on medical judgment 
If the investigator becomes aware of a holding rule being met, he/she must suspend 
administration of the study intervention, pause enrollment, and inform IQVIA immediately 
(e.g., holding rules 1-3). Refer to Appendix 4 for contact information. 
GSK via IQVIA will inform all study investigators to suspend the study intervention and 
enrollment if any of the holding rules are met. 
The following communication sequence for the identification of holding rules by the 
investigator must be followed (Figure 2). 
96

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Figure 2  
Communication Flow: Identification of Holding Rules by the Investigator 
 
Section 8.2.3.2 
Outcome of Safety Evaluation 
If a safety signal is observed during the safety evaluations, or if any of the holding rules is met 
for the first 200 participants, the IDMC Chair (or his/her representative) is responsible for the 
urgent communication to GSK, including the rationale for the decision to put the study 
intervention administration on hold or not. 
If no safety signal is observed in the first 200 participants, the favorable outcome of the safety 
evaluations will be documented and provided in writing, authorizing the investigator to start 
enrollment and dosing of the remaining participants in the study. 
GSK via IQVIA will be accountable for notifying all investigators of the decision whether to 
suspend, modify or continue the conduct of the study on all groups or on selected groups. 
Refer to Section 8.2.3.1 for a flow chart for escalation of safety signal. 
97

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Section 9.3, Populations for Analyses, Table 11, Analysis Sets: 
Note: Intercurrent medical conditions that may lead to elimination from the PPS are defined as confirmed 
immunodeficiency condition, or development of varicella or herpes zoster in the interval between study intervention 
administration and the collection of the blood specimen for immunogenicity at Visit 32. 
 
Appendix 1, Abbreviations and the Glossary of Terms: 
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 
 
Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting: 
b) Solicited systemic events 
The following systemic events will be solicited for children 12 to 15 months of age: 
• 
Fever 
• 
Varicella-like rash (including injection site varicella-like rash) 
 
The maximum intensity of administration site redness/swelling/fever/varicella-like rash will be 
scored as follows: 
 
Redness/swelling 
Varicella-like rash* 
Fever† 
0 
None 
None 
< 38.0°C (100.4°F)-Temperature will be 
analyzed 
in 0.5°C ≥ 38.0°C (100.4°F) - ≤ 39.0°C 
(102.2°F) 
 increments from ≥ > 39.0°C (102.2°F) - ≤ 
39.5°C (103.1°F)38°C (≥ 100.4°F). 
Grade 3 fever is defined as > 39.5°C. 
(103.1°F) 
1 
> 0 - ≤ 5 mm 
1-5025 lesions 
2 
> 5 - ≤ 20 mm 
5126-15050 lesions 
3 
> 20 mm 
>≥ 15051 lesions 
* Including injection site varicella-like rash 
† Temperature will be analyzed in 0.5°C increments from ≥ 38.0°C (≥ 100.4°F). 
 
Events Requiring Expedited Reporting to IQVIA: 
SAE(s) throughout the study 
• 
Once an the investigator or designee become aware that study participant(s) have experienced an SAE has 
occurred in a study participant, the investigator or investigator’s designee designated study staff must 
complete information in the electronic Expedited AE Report in the eCRF WITHIN 24 HOURS. The report 
will always be completed as thoroughly as possible with all available details of the event. The report allows 
to specify that the event is serious or non-serious. 
• 
Even if the investigator does not have all information regarding an SAE, the report should still be completed 
within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 
HOURS. The investigator will always provide an assessment of causality at the time of the initial report. 
• 
The investigator will be required to confirm the review of the SAE causality by ticking the “reviewed” box in 
the electronic Expedited AE Report within 72 hours of submission of the SAE. 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of SAEs. 
98

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Grade 3 unsolicited AE(s) for the first 200 study participants through their Day 43 follow-up: 
• 
Once the investigator or designee become aware that study participant(s) have experienced a Grade 3 
unsolicited AE considered to be at least possibly related to vaccination, the investigator or designated 
study staff must complete information in the electronic Expedited AE Report in the eCRF 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 Grade 3 unsolicited AE considered to be 
at least possibly related to vaccination, 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 Grade 3 unsolicited AE(s) causality by 
ticking the “reviewed” box in the electronic Expedited AE Report within 72 hours of submission of the 
Grade 3 unsolicited AE(s). 
• 
Refer to Section 8.3.1 for the details on timeframes for reporting of AE(s). 
 
 
99

CONFIDENTIAL 
217212 (VNS 20-006)  
Protocol Amendment 3.0 
 
Appendix 6 
Signature of Investigator 
PROTOCOL TITLE: A phase II, observer-blind, randomized, controlled study to evaluate 
immunogenicity and safety of a varicella vaccine at various potencies compared with Varivax, as 
a first dose, administered in healthy children in their second year of life. 
PROTOCOL NO: 
217212 (VNS 20-006) 
VERSION:  
 
Protocol Amendment 3.0 
This protocol is a confidential communication of GSK. I confirm that I have read this protocol, I 
understand it, I will work according to this protocol and ensure that all persons assisting me with 
the study are adequately informed about the study interventions and other study-related duties as 
described in the protocol. I will also work consistently with the ethical principles that have their 
origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and the 
applicable laws and regulations. Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior written 
approval from GSK. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to IQVIA. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
Signature of Investigator:  
___________________________ Date: ________________ 
Printed Name:  
 
___________________________ 
Investigator Title:  
 
___________________________ 
 
Name/Address of Center:  
___________________________ 
___________________________ 
___________________________ 
100